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There is currently no evidence from randomised studies that influenza vaccine given to people with CF is of benefit to them.


BACKGROUND: Viral respiratory tract infections in people with cystic fibrosis (CF) have a deteriorating effect on their lung function and disease progression. Annual influenza vaccination is therefore commonly recommended for people with CF. OBJECTIVES: To assess the effectiveness of influenza vaccination for people with CF. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises of references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. We also contacted the companies which market the influenza vaccines used in the trials to obtain further information about randomised controlled trials.Date of the most recent search of the Cystic Fibrosis Trials Register: 05 March 2009. SELECTION CRITERIA: All randomised and quasi-randomised trials (published or unpublished) comparing any influenza vaccine with a placebo or with another type of influenza vaccine. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Additional information was obtained by contacting the investigators when it was indicated. MAIN RESULTS: Four studies enrolling a total of 179 participants with CF (143 (80%) were children aged 1 to 16 years) were included in this review. There was no study comparing a vaccine to a placebo or a whole virus vaccine to a subunit or split virus vaccine. Two studies compared an intranasal applied live vaccine to an intramuscular inactivated vaccine and the other two studies compared a split virus to a subunit vaccine and a virosome to a subunit vaccine (all intramuscular). The incidence of all reported adverse events was high depending on the type of influenza vaccine. The total adverse event rate ranged from 48 out of 201 participants (24%) for the intranasal live vaccine to 13 out of 30 participants (43%) for the split virus vaccine. With the limitation of a statistical low power there was no significant difference between the study vaccinations. None of the events were severe. All study influenza vaccinations generated a satisfactory serological antibody response. No study reported other clinically important benefits. AUTHORS' CONCLUSIONS: There is currently no evidence from randomised studies that influenza vaccine given to people with CF is of benefit to them. There remains a need for a well-constructed clinical study, that assesses the effectiveness of influenza vaccination on important clinical outcome measures.  

Cochrane Database Syst Rev. 2009 Oct 7;(4):CD001753. PMID: 19821281

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Inactivated flu vaccines have not been proven to be effective or safe in preventing influenza in healthy children under two.


BACKGROUND: The consequences of influenza in children and adults are mainly absenteeism from school and work. However, the risk of complications is greatest in children and people over 65 years old. OBJECTIVES: To appraise all comparative studies evaluating the effects of influenza vaccines in healthy children; assess vaccine efficacy (prevention of confirmed influenza) and effectiveness (prevention of influenza-like illness) and document adverse events associated with influenza vaccines. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, issue 3); OLD MEDLINE (1950 to 1965); MEDLINE (1966 to September 2007); EMBASE (1974 to September 2007); Biological Abstracts (1969 to September 2007); and Science Citation Index (1974 to September 2007). SELECTION CRITERIA: Randomised controlled trials (RCTs), cohort and case-control studies of any influenza vaccine in healthy children under 16 years of age. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: Fifty-one studies with 294,159 observations were included. Sixteen RCTs and 18 cohort studies were included in the analysis of vaccine efficacy and effectiveness. From RCTs, live vaccines showed an efficacy of 82% (95% confidence interval (CI) 71% to 89%) and an effectiveness of 33% (95% CI 28% to 38%) in children older than two compared with placebo or no intervention. Inactivated vaccines had a lower efficacy of 59% (95% CI 41% to 71%) than live vaccines but similar effectiveness: 36% (95% CI 24% to 46%). In children under two, the efficacy of inactivated vaccine was similar to placebo. Variability in study design and presentation of data was such that a meta-analysis of safety outcome data was not feasible. Extensive evidence of reporting bias of safety outcomes from trials of live attenuated vaccines impeded meaningful analysis. AUTHORS' CONCLUSIONS: Influenza vaccines are efficacious in children older than two but little evidence is available for children under two. There was a marked difference between vaccine efficacy and effectiveness. No safety comparisons could be carried out, emphasizing the need for standardisation of methods and presentation of vaccine safety data in future studies. It was surprising to find only one study of inactivated vaccine in children under two years, given current recommendations to vaccinate healthy children from six months old in the USA and Canada. If immunisation in children is to be recommended as a public health policy, large-scale studies assessing important outcomes and directly comparing vaccine types are urgently required.

Altern Ther Health Med. 2009 Sep-Oct;15(5):44-6. PMID: 18425905

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Male newborns vaccinated with hepatitis B prior to 1999 had a 3-fold higher risk for parentally reported autism.


Universal hepatitis B vaccination was recommended for U.S. newborns in 1991; however, safety findings are mixed. The association between hepatitis B vaccination of male neonates and parental report of autism diagnosis was determined. This cross-sectional study used weighted probability samples obtained from National Health Interview Survey 1997-2002 data sets. Vaccination status was determined from the vaccination record. Logistic regression was used to estimate the odds for autism diagnosis associated with neonatal hepatitis B vaccination among boys age 3-17 years, born before 1999, adjusted for race, maternal education, and two-parent household. Boys vaccinated as neonates had threefold greater odds for autism diagnosis compared to boys never vaccinated or vaccinated after the first month of life. Non-Hispanic white boys were 64% less likely to have autism diagnosis relative to nonwhite boys. Findings suggest that U.S. male neonates vaccinated with the hepatitis B vaccine prior to 1999 (from vaccination record) had a threefold higher risk for parental report of autism diagnosis compared to boys not vaccinated as neonates during that same time period. Nonwhite boys bore a greater risk.

J Toxicol Environ Health A. 2010 Jan;73(24):1665-77. PMID: 21058170

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Vaccination is associated with an increased risk for hemolytic anemia.


Several case reports have described immune hemolytic anemia (IHA) following vaccination in children. We examined the risk of IHA in the 42 days following vaccination exposure using a self-controlled case series study design. In our population-based cohort of nearly 4.5 million children in the Vaccine Safety Datalink, we identified 55 confirmed cases of new-onset IHA from 1991 through 2000. We found no association between IHA and diphtheria-pertussis-tetanus vaccination (incidence rate ratio (IRR)=0.65, 95% CI: 0.19-2.24), hepatitis B vaccination (IRR=1.73, 95% CI: 0.59-5.01), or any vaccination (IRR=1.04, 95% CI: 0.46-2.32).

Vaccine. 2009 Dec 9;27(52):7394-7. Epub 2009 Sep 18. PMID: 19766577

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The risk of adverse events from the pertussis vaccine outweighed the risk of pertussis infection.


Since 1975, acceptance of pertussis vaccine has fallen from over 70% to 50% or less in most parts of Britain. This permits evaluation of a continuing natural experiment in which the frequency and severity of whooping cough can be compared those of adverse events following injections of pertussis vaccine. National data show an increase in notifications of whooping cough in most parts of Britain since 1975. Hospital admissions show considerable variation between areas with relatively high rates in some areas of deprivation but very low rates in more affluent areas even where vaccine-acceptance is around 50%. Deaths of infants with whooping cough have decreased steadily since 1900, the rate since 1975 being the lowest ever. Active epidemiological surveillance in Glasgow, with a population of 216,000 children and 13,000 births annually, shows that outbreaks and severe cases requiring admission to hospital were concentrated consistently in a few areas of deprivation. There is a significant correlation between vaccine-acceptance and hospital admission by district of residence but analysis of variance shows this effect to be less than that of overcrowding in households and other deprivation variables. In each of three outbreaks studied prospectively (1974-5, 78-78 and 82) about 30% of cases occurred in children who had received three doses of pertussis vaccine. Such vaccination had a significant protective effect in children aged 1-4 years but not in older children. There was no evidence of a herd immunity sufficient to protect infants below age for vaccination. Admissions to hospital decreased during the period 1970-83. There were no deaths attributable to proven or suspected infections with Bordetella pertussis during the period 1972-1983. No cases of encephalopathy, permanent brain damage or lung damage were detected in a follow up of all cases notified, surveyed or admitted to hospital between 1975 and 1982. Collectively, these national and local data provided estimates of the frequency of infection, complications of infection, admission to hospital and death in children with whooping cough for comparison with local, national and published estimates of the frequency and severity of adverse reactions, encephalopathy, permanent brain damage and death after injections of pertussis vaccine. It is concluded that, in children living in non-deprived circumstances in Britain, the risk of pertussis vaccine during the period 1970-83 exceeded those of whooping cough. In some deprived sectors, the risks from whooping cough might have been marginally higher but there was no evidence that this was associated with any increase in deaths or permanent disabilities.

Dev Biol Stand. 1985;61:395-405. PMID: 3835080

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Over 600 cases of sudden infant death syndrome following vaccination were reported from 1990-1997.


PURPOSE: To examine the fatalities reported to the federally administered Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system, in its first 7 years. METHODS: The working data set included variables such as demographic information, dates of vaccination, adverse event onset and death, vaccines administered, and vaccination facility data. Frequencies for these data and state reporting rates were calculated. RESULTS: A total of 1266 fatalities were reported to VAERS during July 1990 through June 1997. The number of death reports peaked in 1992-1993 and then declined. The overall median age of cases was 0.4 years, with a range of 1 day to 104 years. Nearly half of the deaths were attributed to sudden infant death syndrome (SIDS). CONCLUSIONS: The trend of decreasing numbers of deaths reported to VAERS since 1992-1993 follows that observed for SIDS overall for the US general population following implementation of the 'Back to Sleep' program. These data may support findings of past controlled studies showing that the association between infant vaccination and SIDS is coincidental and not causal. VAERS reports of death after vaccination may be stimulated by the temporal association, rather than by any causal relationship.

Pharmacoepidemiol Drug Saf. 2001 Jun-Jul;10(4):279-85. PMID: 11760487

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Vaccination in infants less than 3 months is associated with an increased risk of sudden infant death syndrome.


Because diphtheria, tetanus, pertussis and poliomyelitis vaccine is routinely given during the period of highest incidence of sudden infant death syndrome (SIDS), we carried out a retrospective case-control study to assess whether such vaccination increased the risk of SIDS. The vaccination status of 118 SIDS and 332 control children, matched for sex, date of birth and age of the victims at death, was compared: the victims of SIDS were not significantly more often vaccinated than control children, the odds ratio was estimated at 1.9 with a 95% confidence interval from 0.9 to 3.9. There was a statistical difference between vaccination status of SIDS cases and controls aged less than three months. Nine percent of SIDS cases under 3 months had been vaccinated whereas the matched controls had not. In our study DTCP vaccination was not a risk factor for SIDS; although more of the SIDS infants less than 3 months of age had been vaccinated. This result however, concerns only one subgroup of the population studied and needs to be confirmed with another study of only SIDS infants less than 3 months of age, because DTCP vaccination was not a risk factor for SIDS when considering the total sample of the study.

Fundam Clin Pharmacol. 1995;9(3):263-70. PMID: 7557822

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Vaccination is associated with a rare autoimmune neurological condition transverse myelitis.


Transverse myelitis is a rare clinical syndrome in which an immune-mediated process causes neural injury to the spinal cord. The pathogenesis of transverse myelitis is mostly of an autoimmune nature, triggered by various environmental factors, including vaccination. Our aim here was to search for and analyze reported cases of transverse myelitis following vaccination. A systematic review of PubMed, EMBASE and DynaMed for all English-language journals published between 1970 and 2009 was preformed, utilizing the key words transverse myelitis, myelitis, vaccines, post-vaccination, vaccination and autoimmunity. We have disclosed 37 reported cases of transverse myelitis associated with different vaccines including those against hepatitis B virus, measles-mumps-rubella, diphtheria-tetanus-pertussis and others, given to infants, children and adults. In most of these reported cases the temporal association was between several days and 3 months, although a longer time frame of up to several years was also suggested. Although vaccines harbor a major contribution to public health in the modern era, in rare cases they may be associated with autoimmune phenomena such as transverse myelitis. The associations of different vaccines with a single autoimmune phenomenon allude to the idea that a common denominator of these vaccines, such as an adjuvant, might trigger this syndrome.

Lupus. 2009 Nov;18(13):1198-204. PMID: 19880568

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Neonate exposure to thimerosal mercury from hepatitis B vaccines may be a significant problem.


Infant exposure to ethylmercury (EtHg) has not only increased but is starting earlier as a result of the current immunization schedule that uses thimerosal-containing vaccines (TCVs). Although vaccination schedule varies considerably between countries, infants in less-developed countries continue to be exposed to EtHg derived from more affordable TCVs. We studied the exposure of newborns to EtHg from hepatitis B vaccines; hospital records (21,685) were summarized for the years 2001 to 2005 regarding date of birth, vaccination date, and birth weight. Most of the vaccinations occurred in the first 24 hours postdelivery; over the 5 years, there was an increase in vaccinations within hours of birth (same day), from 7.4% (2001) to 87.8% (2005). Nearly 94.6% of infants are now being vaccinated within the first 24 hours. Range of mercury exposure spread from 4.2 to 21.1 microg mercury/kg body weight for those receiving TCVs with the highest thimerosal concentration; these exposure levels are conservative for 2% of children receiving vaccines within 2 to 3 postnatal days, when they are still going through physiological postnatal weight loss. Because of the particular timing (transitioning from in utero to ex utero metabolism) and specific aspects of exposure (i.e., parenteral mode, bypassing gastroenteric barriers) and dose (related to vaccine manufacturer and with variation in birth weight), this study reveals critical issues that can modulate toxicokinetics and toxicodynamics of organomercurials in neonates.

Am J Perinatol. 2009 Aug;26(7):523-7. Epub 2009 Mar 12. PMID: 19283656

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Diphtheria immunisation is weakly associated with an increased risk of asthma by age 7 years.


BACKGROUND: There is ongoing conjecture over whether childhood immunisation leads to an increased risk of developing atopic diseases.OBJECTIVE: To examine associations between childhood immunisation and the risk of atopic disease. Method: Immunisation histories of 8443 Tasmanian children born in 1961 obtained from school medical records were linked to the Tasmanian Asthma Study. Associations between immunisation status and atopic diseases were examined while adjusting for possible confounders using multiple logistic regression.RESULTS: Diphtheria immunisation was weakly associated with an increased risk of asthma by age 7 years (odds ratio (OR) 1.3, 95% confidence interval (CI) 1.1 to 1.7), but there was no evidence of any association for four other vaccinations studied. An increased risk of eczema by age 7 years was associated with immunisation against diphtheria (OR 1.5, 95% CI 1.1 to 2.1), tetanus (OR 1.5, 95% CI, 1.1 to 2.0), pertussis (OR 1.5, 95% CI 1.1 to 1.9) and polio (OR 1.4, 95% CI 1.0 to 1.9) but not small pox. Similar but slightly weaker patterns of association were observed between the risk of food allergies and immunisation against diphtheria (OR 1.5, 95% CI 1.0 to 2.1), pertussis (OR 1.4, 95% CI 1.1 to 1.9), polio (OR 1.4, 95% CI 1.00 to 2.1) and tetanus (OR 1.30 95% CI 0.99 to 1.70), but not with small pox. There was no evidence of associations between immunisation history and hay fever, or incidence of later-onset atopic outcomes.CONCLUSIONS: The few effects seen in this study are small and age-dependent, and nearly all our findings support numerous previous studies of no effect of vaccines on asthma. Based on these findings, the fear of their child developing atopic disease should not deter parents from immunising their children, especially when weighed against the benefits.

Thorax. 2007 Mar;62(3):270-5. Epub 2006 Nov 7. PMID: 17090571

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Over 1,000 confirmed cases of vaccine-induced thrombocytopenia were reported between 1990-2008.


We reviewed thrombocytopenia (TP) reports to the US Vaccine Adverse Event Reporting System (VAERS). We examined TP patterns for differences in single versus multiple immunization reports, presence of a live viral vaccine, seriousness, age, and interval to symptom onset. We found 1510 reports of possible TP and after exclusions evaluated 1440 for possible causes. Most (1078; 75%) met the regulatory definition of a serious adverse event. TP was reported after inactivated and live viral vaccines. Platelet counts

Vaccine. 2010 Nov 29. Epub 2010 Nov 29. PMID: 21126606

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38,787 adverse events including infant death (highest in 1-3 month olds) after vaccination were reported between 1991-1994. (The authors speciously claim SIDS and not vaccination caused these deaths).


OBJECTIVE: To provide an overview of the data, function, and performance of the Vaccine Adverse Event Reporting System. DESIGN: Descriptive and correlational analyses. SETTING: United States, 1991 through 1994. SUBJECTS: Reports to the Vaccine Adverse Event Reporting System, a passive national surveillance system, that represents temporal (but not necessarily causal) relationships between vaccinations and adverse events. MAIN OUTCOME MEASURES: Demographic variables, birth weight, vaccine type, severity of adverse event after immunization. RESULTS: A total of 38,787 adverse events was reported during the study period without a clearly increasing or decreasing trend in the annual number of total reports or deaths. Of the deaths with known age, 72.4% were reported in the first year of life, and 63.7% of these were male. The peak age for death reports was 1 to 3 months, with a gradual decline through age 9 months, after which death was relatively rare. Adverse events with onset of symptoms the day of vaccination accounted for 45.5% of total reports; 20.4% had onset of symptoms the following day. Onset within 2 weeks after vaccination was noted for 92.5% of all reports. Simultaneous administration of multiple vaccines was noted in 75.7% of reports for immunizations at ages younger than 20 years. In contrast, among those 20 years or older, only 6.0% of reports named multiple vaccines. Wide geographic variations were noted in adverse event reporting rates for children younger than 2 years, and the states with the lowest reporting rates of less serious events included the most populous states. CONCLUSIONS: The peak age of deaths at ages 1 to 3 months could be expected on the basis of prior studies showing that sudden infant death syndrome deaths peak at that age, that most deaths in the Vaccine Adverse Event Reporting System are attributed to sudden infant death syndrome, and that sudden infant death syndrome has not been associated with vaccination. The large number of reports and national coverage of the Vaccine Adverse Events Reporting System make it useful for monitoring the safety of vaccine lots and for accumulating case series to detect or better understand adverse events that may occur too rarely to be assessed in clinical trials or in the larger studies that are sometimes carried out by manufacturers after vaccine licensure (phase IV studies).

J Pediatr. 1997 Oct;131(4):529-35. PMID: 9386653

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Thimerosol-containing vaccines are associated with autism prevalence and measles-containing vaccines are associated with serious neurological disorders.


BACKGROUND: The purpose of the study was to evaluate the effects of MMR immunization and mercury from thimerosal-containing childhood vaccines on the prevalence of autism.MATERIAL/METHODS: Evaluations of the Biological Surveillance Summaries of the Centers for Disease Control and Prevention (CDC), the U.S. Department of Education datasets, and the CDC's yearly live birth estimates were undertakenRESULTS: It was determined that there was a close correlation between mercury doses from thimerosal--containing childhood vaccines and the prevalence of autism from the late 1980s through the mid-1990s. In contrast, there was a potential correlation between the number of primary pediatric measles-containing vaccines administered and the prevalence of autism during the 1980s. In addition, it was found that there were statistically significant odds ratios for the development of autism following increasing doses of mercury from thimerosal-containing vaccines (birth cohorts: 1985 and 1990-1995) in comparison to a baseline measurement (birth cohort: 1984). The contribution of thimerosal from childhood vaccines (>50% effect) was greater than MMR vaccine on the prevalence of autism observed in this study.CONCLUSIONS: The results of this study agree with a number of previously published studies. These studies have shown that there is biological plausibility and epidemiological evidence showing a direct relationship between increasing doses of mercury from thimerosal-containing vaccines and neurodevelopmental disorders, and measles-containing vaccines and serious neurological disorders. It is recommended that thimerosal be removed from all vaccines, and additional research be undertaken to produce a MMR vaccine with an improved safety profile.

Med Sci Monit. 2004 Mar;10(3):PI33-9. Epub 2004 Mar 1. PMID: 14976450

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Thimerosal exposure is associated with increasing trends of premature puberty in 278,624 subjects from 1990-1996.


BACKGROUND & OBJECTIVES: The US Agency for Toxic Substances and Disease Registry (ATSDR) reports that mercury (Hg) is a known endocrine disruptor and it adversely affects the steroid synthesis pathway in animals and humans, and may interact to enhance the risk for a child developing premature puberty. An association between premature puberty and exposure to Hg from thimerosal-containing vaccines (TCVs) was evaluated in computerized medical records within the Vaccine Safety Datalink (VSD).METHODS: A total of 278,624 subjects were identified in birth cohorts from 1990-1996. The birth cohort prevalence rates of medically diagnosed International Classification of Disease, 9(th) revision (ICD-9) premature puberty and control outcomes were calculated. Exposures to Hg from TCVs were calculated by birth cohort for specific exposure windows from birth-7 months and birth-13 months of age. Poisson regression analysis was used to model the association between the prevalence of outcomes and Hg doses from TCVs.RESULTS: Significantly increased (P

Indian J Med Res. 2010 Apr;131:500-7. PMID: 20424300

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Thimersol exposure in infants significantly increases neurodevelopment disorders in infants, e.g. autism, autism spectrum disorders, tics, attention deficit disorder, and emotional disturbances.


The study evaluated possible associations between neurodevelopmental disorders (NDs) and exposure to mercury (Hg) from Thimerosal-containing vaccines (TCVs) by examining the automated Vaccine Safety Datalink (VSD). A total of 278,624 subjects were identified in birth cohorts from 1990-1996 that had received their first oral polio vaccination by 3 months of age in the VSD. The birth cohort prevalence rate of medically diagnosed International Classification of Disease, 9th revision (ICD-9) specific NDs and control outcomes were calculated. Exposures to Hg from TCVs were calculated by birth cohort for specific exposure windows from birth-7 months and birth-13 months of age. Poisson regression analysis was used to model the association between the prevalence of outcomes and Hg doses from TCVs. Consistent significantly increased rate ratios were observed for autism, autism spectrum disorders, tics, attention deficit disorder, and emotional disturbances with Hg exposure from TCVs. By contrast, none of the control outcomes had significantly increased rate ratios with Hg exposure from TCVs. Routine childhood vaccination should be continued to help reduce the morbidity and mortality associated with infectious diseases, but efforts should be undertaken to remove Hg from vaccines. Additional studies should be conducted to further evaluate the relationship between Hg exposure and NDs.

J Neurol Sci. 2008 Aug 15;271(1-2):110-8. Epub 2008 May 15. PMID: 18482737

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Thimersol exposure is associated with tics and delayed language acquisition in infants.


OBJECTIVE: To assess the possible toxicity of thimerosal-containing vaccines (TCVs) among infants.METHODS: A 2-phased retrospective cohort study was conducted using computerized health maintenance organization (HMO) databases. Phase I screened for associations between neurodevelopmental disorders and thimerosal exposure among 124 170 infants who were born during 1992 to 1999 at 2 HMOs (A and B). In phase II, the most common disorders associated with exposure in phase I were reevaluated among 16 717 children who were born during 1991 to 1997 in another HMO (C). Relative risks for neurodevelopmental disorders were calculated per increase of 12.5 micro g of estimated cumulative mercury exposure from TCVs in the first, third, and seventh months of life.RESULTS: In phase I at HMO A, cumulative exposure at 3 months resulted in a significant positive association with tics (relative risk [RR]: 1.89; 95% confidence interval [CI]: 1.05-3.38). At HMO B, increased risks of language delay were found for cumulative exposure at 3 months (RR: 1.13; 95% CI: 1.01-1.27) and 7 months (RR: 1.07; 95% CI: 1.01-1.13). In phase II at HMO C, no significant associations were found. In no analyses were significant increased risks found for autism or attention-deficit disorder.CONCLUSIONS: No consistent significant associations were found between TCVs and neurodevelopmental outcomes. Conflicting results were found at different HMOs for certain outcomes. For resolving the conflicting findings, studies with uniform neurodevelopmental assessments of children with a range of cumulative thimerosal exposures are needed.

Pediatrics. 2003 Nov;112(5):1039-48. PMID: 14595043

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Thimersol exposure in infants is associated with an increase risk for tics.


OBJECTIVE: After concerns about the possible toxicity of thimerosal-containing vaccines in the United States, this study was designed to investigate whether there is a relationship between the amount of thimerosal that an infant receives via diphtheria-tetanus-whole-cell pertussis (DTP) or diphtheria-tetanus (DT) vaccination at a young age and subsequent neurodevelopmental disorders.METHODS: A retrospective cohort study was performed using 109 863 children who were born from 1988 to 1997 and were registered in general practices in the United Kingdom that contributed to a research database. The disorders investigated were general developmental disorders, language or speech delay, tics, attention-deficit disorder, autism, unspecified developmental delays, behavior problems, encopresis, and enuresis. Exposure was defined according to the number of DTP/DT doses received by 3 and 4 months of age and also the cumulative age-specific DTP/DT exposure by 6 months. Each DTP/DT dose of vaccine contains 50 microg of thimerosal (25 microg of ethyl mercury). Hazard ratios (HRs) for the disorders were calculated per dose of DTP/DT vaccine or per unit of cumulative DTP/DT exposure.RESULTS: Only in 1 analysis for tics was there some evidence of a higher risk with increasing doses (Cox's HR: 1.50 per dose at 4 months; 95% confidence interval [CI]: 1.02-2.20). Statistically significant negative associations with increasing doses at 4 months were found for general developmental disorders (HR: 0.87; 95% CI: 0.81-0.93), unspecified developmental delay (HR: 0.80; 95% CI: 0.69-0.92), and attention-deficit disorder (HR: 0.79; 95% CI: 0.64-0.98). For the other disorders, there was no evidence of an association with thimerosal exposure.CONCLUSIONS: With the possible exception of tics, there was no evidence that thimerosal exposure via DTP/DT vaccines causes neurodevelopmental disorders.

Pediatrics. 2004 Sep;114(3):584-91. PMID: 15342825

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Rates of autism, speech disorders, mental retardation, infantile spasms, and thinking abnormalities were higher in children exposured to higher thimerosal levels.


Thimerosal is an ethylmercury (49.55% mercury by weight) preservative historically added to some vaccines. Toxicokinetic studies showed children in the United States received doses of mercury from Thimerosal-containing vaccines (TCVs) in excess of safety guidelines. In the United States during the 1990s, diphtheria-tetanus-pertussis (DTP) and Haemophilus influenzae type b (Hib) vaccines (maximally, 50 mug mercury per joint administration) and diphtheria-tetanus-pertussis-Haemophilus influenzae type b (DTPH) vaccines (25 mug mercury per administration) were given to children in the same childhood vaccination schedule at 2, 4, 6, and 15-18 mo, so that children receiving DTP and Hib vaccines may have maximally received an additional 100 mug more mercury exposure from TCVs than children administered DTPH vaccines. A case-control epidemiological study of neurodevelopmental disorders (NDs) reported to the Vaccine Adverse Event Reporting System (VAERS) (online public access version; updated 31 August 2004) following administration of DTP vaccines in comparison DTPH vaccines manufactured by Lederle Laboratories (Pearl River, NY) from 1994 through 1998 was undertaken. Significantly increased odds ratios for autism, speech disorders, mental retardation, infantile spasms, and thinking abnormalities reported to VAERS were found following DTP vaccines in comparison to DTPH vaccines with minimal bias or systematic error. Additional ND research should be undertaken in the context of evaluating mercury-associated exposures, especially since in 2005 the Institute of Medicine issued a report calling into question handling of vaccine safety data by the National Immunization Program of the Centers for Disease Control and Prevention.

J Toxicol Environ Health A. 2006 Aug;69(15):1481-95. PMID: 16766480

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As thimerosal was removed from childhood vaccines, the number of neurodevelopmental disorders decreased in the US.


BACKGROUND: The US is in the midst of an epidemic of neurodevelopmental disorders (NDs). Thimerosal is an ethylmercury-containing compound added to some childhood vaccines. Several previous epidemiological studies conducted in the US have associated Thimerosal-containing vaccine (TCV) administration with NDs. MATERIAL/METHODS: An ecological study was undertaken to evaluate NDs reported to the Vaccine Adverse Event Reporting System (VAERS) from 1991 through 2004 by date of receipt and by date of vaccine administration. The NDs examined included autism, mental retardation, and speech disorders. Statistical trend analysis was employed to evaluate the effects of removal of Thimerosal on the proportion of NDs reported to VAERS. RESULTS: There was a peak in the proportion of ND reports received by VAERS in 2001-2002 and in the proportion of ND reports by date of vaccine administration in 1998. There were significant reductions in the proportion of NDs reported to VAERS as Thimerosal was begun to be removed from childhood vaccines in the US from mid-1999 onwards. CONCLUSIONS: The present study provides the first epidemiological evidence showing that as Thimerosal was removed from childhood vaccines, the number of NDs has decreased in the US. The analysis techniques utilized attempted to minimize chance or bias/confounding. Additional research should be conducted to further evaluate the relationship between TCVs and NDs. This is especially true because the handling of vaccine safety data from the National Immunization Program of the CDC has been called into question by the Institute of Medicine of the National Academy of Sciences in 2005.

Med Sci Monit. 2006 Jun;12(6):CR231-9. Epub 2006 May 29. PMID: 16733480

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Exposure to mercury from thimerosal-containing vaccines was associcated with an increased risk of neurodevelopmental problems in infants from 1992-1997.


BACKGROUND: Thimerosal is an ethylmercury-containing preservative in vaccines. Toxicokinetic studies have shown children received doses of mercury from thimerosal-containing vaccines (TCVs) that were in excess of safety guidelines. Previously, an ecological study showing a significant association between TCVs and neurodevelopmental disorders (NDs) in the US was published in this journal.MATERIAL/METHODS: A two phased population-based epidemiological study was undertaken. Phase one evaluated reported NDs to the Vaccine Adverse Event Reporting System (VAERS) following thimerosal-containing Diphtheria-Tetanus-acellular-Pertussis (DTaP) vaccines in comparison to thimerosal-free DTaP vaccines administered from 1997 through 2001. Phase two evaluated the automated Vaccine Safety Datalink (VSD) for cumulative exposures to mercury from TCVs at 1-, 2-, 3-, and 6-months-of-age for infants born from 1992 through 1997 and the eventual risk of developing NDs.RESULTS: Phase one showed significantly increased risks for autism, speech disorders, mental retardation, personality disorders, and thinking abnormalities reported to VAERS following thimerosal-containing DTaP vaccines in comparison to thimerosal-free DTaP vaccines. Phase two showed significant associations between cumulative exposures to thimerosal and the following types of NDs: unspecified developmental delay, tics, attention deficit disorder (ADD), language delay, speech delay, and neurodevelopmental delays in general.CONCLUSIONS: This study showed that exposure to mercury from TCVs administered in the US was a consistent significant risk factor for the development of NDs. It is clear from these data and other recent publications linking TCVs with NDs that additional ND research should be undertaken in the context of evaluating mercury-associated exposures and thimerosal-free vaccines should be made available.

Med Sci Monit. 2005 Apr;11(4):CR160-70. Epub 2005 Mar 24. PMID: 15795695

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The effectiveness of the 2008-2009 seasonal flu vaccine in England was -6%.


This study reports effectiveness of trivalent influenza vaccine (TIV) against confirmed pandemic influenza infection in England using a retrospective test-negative case-control study. Cases and controls were frequency matched by age, swabbing-week and region. On univariable and multivariable analysis adjusted for underlying clinical risk factors, cases were no more or less likely than controls to be vaccinated with 2008-09 or 2007-08 season TIV. Adjusted vaccine effectiveness for former was -6% (-43% to 22%). Vaccine effectiveness did not differ significantly by age-group or hospitalisation. There was no evidence prior vaccination with TIV significantly altered subsequent risk of pandemic influenza H1N1 2009 infection.

Vaccine. 2011 Jan 31. Epub 2011 Jan 31. PMID: 21292008

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Trial Results: In a sample of 67360 infants, 82% of those mothers whose term infants developed persistent early-onset GBS disease had been screened GBS negative.


BACKGROUND: With the widespread implementation of intrapartum antibiotic prophylaxis (IAP), the rate of early-onset neonatal sepsis and meningitis caused by Streptococcus agalactiae (group B streptococcus [GBS]) has decreased dramatically, especially in term infants. However, cases of GBS disease continue to occur despite IAP and incur significant morbidity and mortality. Inaccurate screening results, improper implementation of IAP, or antibiotic failure all may contribute to persistent disease.OBJECTIVE: To determine if clinical, procedural, or microbiologic factors influenced persistent early-onset GBS disease (EOGBS) cases in a single large maternity service after the institution of a screening-based protocol for IAP.METHODS: Retrospective review of all cases of culture-proven EOGBS at the Brigham and Women's Hospital (Boston, MA) from 1997 to 2003. Serotyping and surface protein analyses were performed on available disease isolates.RESULTS: A total of 67260 infants were live-born during this period. Twenty-five cases of EOGBS (0.37 of 1000 live births) were identified. The overall incidence of EOGBS progressively decreased with different approaches to IAP. Of the 25 cases identified after institution of a screening-based protocol, 17 (68%) occurred in term infants (1 death), and 8 (32%) occurred in preterm infants (3 deaths). Among the mothers of term infants, 14 of 17 (82%) had been screened GBS negative; 1 was GBS unknown. More than half of the mothers of term infants who had screened GBS negative (8 of 14) had intrapartum risk factors for neonatal infection but did not receive antibiotics before delivery. Ten of the 17 term infants were evaluated for infection because of clinical signs of illness, and the remainder were evaluated because of intrapartum sepsis risk factors. Of the mothers of preterm infants, by the time of delivery 3 of 8 had been documented as GBS positive, 2 of 8 had been documented GBS negative, and 3 of 8 remained unknown. Only 1 of 25 women received adequate IAP, but the isolate was resistant to the administered antibiotic (clindamycin). Antibiotic resistance was not a factor in any other case, and no dominant serovariant was identified among tested isolates. Procedural errors (lack of recognition of documented GBS colonization or failure to evaluate infants at risk for sepsis) were identified in 4 cases.CONCLUSIONS: The majority of the remaining cases of EOGBS occurred in infants whose mothers screened negative for GBS colonization. Even in the setting of a maternal GBS-screening program, efforts to evaluate and treat infants with intrapartum clinical risk factors for early-onset sepsis remain important. Until effective vaccines against GBS are available for clinical use, development and implementation of rapid and sensitive techniques for screening for GBS status and antibiotic susceptibility at presentation may help prevent additional cases of invasive GBS disease.

Pediatrics. 2005 May;115(5):1240-6. PMID: 15867030

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Early-onset neonatal group B streptococcal infections in New Zealand 1998-1999 were associated with young maternal age, parity, preterm labour, prolonged membrane rupture, maternal fever and assisted delivery as risk factors. Of the 56 cases, five (9%) w


OBJECTIVE: To determine in New Zealand infants the attack rates, risk factors, preventive policies, strain serotype and antibiotic susceptibilities of early-onset neonatal group B streptococcus (GBS) infection.METHOD: A 2-year prospective active surveillance study was conducted in New Zealand's 19 neonatal units. Cases had to present within 48 h of delivery, be unwell, possess abnormal haematological indices and have GBS isolated from sterile sites.RESULTS: Of the 112 402 infants born in New Zealand during 1998-1999, 56 had early-onset GBS infection, an attack rate of 0.5 per 1000 live births (95% confidence interval [CI] 0.38, 0.65). Seven had meningitis and there was one death (case fatality rate of 1.8%; upper 95% CI 9.5%). Univariate analysis identified young maternal age, parity, preterm labour, prolonged membrane rupture, maternal fever and assisted delivery as risk factors. Preventive policies for GBS were reported by 14 (74%) obstetric centres associated with neonatal units. Of the 56 cases, five (9%) were born to mothers receiving intrapartum antibiotics, 32 (57%) had mothers with risk factors but were not treated with antibiotics, and 19 (34%) were born to mothers without identifiable risk factors for GBS prevention. Serotypes Ia and III predominated, while two isolates were resistant to erythromycin and/or clindamycin.CONCLUSIONS: Rates of early-onset GBS infection are similar to other countries following the introduction of prevention policies. Further reductions are possible with full implementation of these guidelines. Meanwhile, emergence of antibiotic resistance complicates the management of women with penicillin allergy. Vaccine development therefore remains a priority.

J Paediatr Child Health. 2002 Jun;38(3):272-7. PMID: 12047696

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When polled 5% of nonpediatricians would not use Haemophilus influenzae type b vaccine if they had a child born in 2004.


CONTEXT: Immunization has an essential impact on public health worldwide. Numerous studies have shown the efficacy of different vaccines to protect individuals from various diseases. However, some parents choose not to vaccinate their children for reasons such as, among others, doubts regarding their usefulness, concerns over safety or efficacy, etc. Physicians are known to exert a direct influence on immunization rates by answering questions and clarifying misconceptions. Yet, it is unknown how they immunize their own children.OBJECTIVE: We sought to assess how physicians interested in vaccination issues immunized, or would immunize, their own children.DESIGN, SETTING, AND PARTICIPANTS: An 11-question, Web-based survey with a total of 102 discrete answers was sent to 2070 Swiss physicians in October 2004. All physicians were subscribers to a nonprofit, Web-based expert network (InfoVac, www.infovac.ch) that distributes monthly newsletters and answers question within 2 days on immunization issues. The InfoVac network reaches>95% of pediatricians in Switzerland but

Pediatrics. 2005 Nov;116(5):e623-33. PMID: 16263976

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There is a highly statistically significant correlation between increasing number of vaccine doses and increasing infant mortality rates.


The infant mortality rate (IMR) is one of the most important indicators of the socio-economic well-being and public health conditions of a country. The US childhood immunization schedule specifies 26 vaccine doses for infants aged less than 1 year-the most in the world-yet 33 nations have lower IMRs. Using linear regression, the immunization schedules of these 34 nations were examined and a correlation coefficient of r = 0.70 (p

Hum Exp Toxicol. 2011 May 4. Epub 2011 May 4. PMID: 21543527

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There are no randomized controlled trials that assessed the effects of hepatitis B vaccine during pregnancy for preventing infant infection.


BACKGROUND: Infant hepatitis B infection increases risk of chronic infection, cirrhosis or liver cancer (hepatocellular carcinoma) in adult. Perinatal transmission is a common route of infection.OBJECTIVES: To assess the effectiveness and adverse effects of hepatitis B vaccine administered to pregnant women for preventing hepatitis B virus infection in infants.SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 December 2010).SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing hepatitis B vaccination compared with placebo or no treatment during pregnancy for preventing infant infection. We excluded quasi-RCTs and crossover studies.DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility.MAIN RESULTS: We were not able to include any studies.AUTHORS' CONCLUSIONS: We found no RCTs that assessed the effects of hepatitis B vaccine during pregnancy for preventing infant infection. Consequently, this review cannot provide guidance for clinical practice in this area. However, it does identify the need for well-designed randomized clinical trials for the effect of hepatitis B vaccine during pregnancy on the incidence of infant infection and adverse effects.

Cochrane Database Syst Rev. 2011(3):CD007879. Epub 2011 Mar 16. PMID: 21412913

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There is little evidence supporting the belief that vaccines are effective in preventing influenza in healthy adults.


BACKGROUND: Different types of influenza vaccines are currently produced worldwide. Healthy adults are presently targeted mainly in North America.OBJECTIVES: Identify, retrieve and assess all studies evaluating the effects of vaccines against influenza in healthy adults.SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2010, issue 2), MEDLINE (January 1966 to June 2010) and EMBASE (1990 to June 2010).SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing influenza vaccines with placebo or no intervention in naturally-occurring influenza in healthy individuals aged 16 to 65 years. We also included comparative studies assessing serious and rare harms.DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data.MAIN RESULTS: We included 50 reports. Forty (59 sub-studies) were clinical trials of over 70,000 people. Eight were comparative non-RCTs and assessed serious harms. Two were reports of harms which could not be introduced in the data analysis. In the relatively uncommon circumstance of vaccine matching the viral circulating strain and high circulation, 4% of unvaccinated people versus 1% of vaccinated people developed influenza symptoms (risk difference (RD) 3%, 95% confidence interval (CI) 2% to 5%). The corresponding figures for poor vaccine matching were 2% and 1% (RD 1, 95% CI 0% to 3%). These differences were not likely to be due to chance. Vaccination had a modest effect on time off work and had no effect on hospital admissions or complication rates. Inactivated vaccines caused local harms and an estimated 1.6 additional cases of Guillain-Barré Syndrome per million vaccinations. The harms evidence base is limited.AUTHORS' CONCLUSIONS: Influenza vaccines have a modest effect in reducing influenza symptoms and working days lost. There is no evidence that they affect complications, such as pneumonia, or transmission.WARNING: This review includes 15 out of 36 trials funded by industry (four had no funding declaration). An earlier systematic review of 274 influenza vaccine studies published up to 2007 found industry funded studies were published in more prestigious journals and cited more than other studies independently from methodological quality and size. Studies funded from public sources were significantly less likely to report conclusions favorable to the vaccines. The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies. The content and conclusions of this review should be interpreted in light of this finding.

Cochrane Database Syst Rev. 2010(7):CD001269. Epub 2010 Jul 7. PMID: 20614424

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There is no solid evidence available supporting the belief that vaccines are effective in preventing influenza in the elderly.


BACKGROUND: Vaccines have been the main global weapon to minimise the impact of influenza in the elderly for the last four decades and are recommended worldwide for individuals aged 65 years or older. The primary goal of influenza vaccination in the elderly is to reduce the risk of complications among persons who are most vulnerable.OBJECTIVES: To assess the effectiveness of vaccines in preventing influenza, influenza-like illness (ILI), hospital admissions, complications and mortality in the elderly. To identify and appraise comparative studies evaluating the effects of influenza vaccines in the elderly. To document types and frequency of adverse effects associated with influenza vaccines in the elderly.SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register (The Cochrane Library 2009, issue 4); MEDLINE (January 1966 to October Week 1 2009); EMBASE (1974 to October 2009) and Web of Science (1974 to October 2009).SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs, cohort and case-control studies assessing efficacy against influenza (laboratory-confirmed cases) or effectiveness against influenza-like illness (ILI) or safety. Any influenza vaccine given independently, in any dose, preparation or time schedule, compared with placebo or with no intervention was considered.DATA COLLECTION AND ANALYSIS: We grouped reports first according to the setting of the study (community or long-term care facilities) and then by level of viral circulation and vaccine matching. We further stratified by co-administration of pneumococcal polysaccharide vaccine (PPV) and by different types of influenza vaccines. We analysed the following outcomes: influenza, influenza-like illness, hospital admissions, complications and deaths.MAIN RESULTS: We included 75 studies. Overall we identified 100 data sets. We identified one RCT assessing efficacy and effectiveness. Although this seemed to show an effect against influenza symptoms it was underpowered to detect any effect on complications (1348 participants). The remainder of our evidence base included non-RCTs. Due to the general low quality of non-RCTs and the likely presence of biases, which make interpretation of these data difficult and any firm conclusions potentially misleading, we were unable to reach clear conclusions about the effects of the vaccines in the elderly.AUTHORS' CONCLUSIONS: The available evidence is of poor quality and provides no guidance regarding the safety, efficacy or effectiveness of influenza vaccines for people aged 65 years or older. To resolve the uncertainty, an adequately powered publicly-funded randomised, placebo-controlled trial run over several seasons should be undertaken.

Cochrane Database Syst Rev. 2010(2):CD004876. Epub 2010 Feb 17. PMID: 20166072

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Influenza vaccination for healthcare workers who work with the elderly has no effect on laboratory-proven influenza, pneumonia or deaths from pneumonia.


BACKGROUND: Healthcare workers' (HCWs) influenza rates are unknown, but may be similar to the general public and they may transmit influenza to patients.OBJECTIVES: To identify studies of vaccinating HCWs and the incidence of influenza, its complications and influenza-like illness (ILI) in individuals>/= 60 in long-term care facilities (LTCFs).SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2009, issue 3), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to 2009), EMBASE (1974 to 2009) and Biological Abstracts and Science Citation Index-Expanded.SELECTION CRITERIA: Randomised controlled trials (RCTs) and non-RCTs of influenza vaccination of HCWs caring for individuals>/= 60 in LTCFs and the incidence of laboratory-proven influenza, its complications or ILI.DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed risk of bias.MAIN RESULTS: We identified four cluster-RCTs (C-RCTs) (n = 7558) and one cohort (n = 12742) of influenza vaccination for HCWs caring for individuals>/= 60 in LTCFs. Pooled data from three C-RCTs showed no effect on specific outcomes: laboratory-proven influenza, pneumonia or deaths from pneumonia. For non-specific outcomes pooled data from three C-RCTs showed HCW vaccination reduced ILI; data from one C-RCT that HCW vaccination reduced GP consultations for ILI; and pooled data from three C-RCTs showed reduced all-cause mortality in individuals>/= 60.AUTHORS' CONCLUSIONS: No effect was shown for specific outcomes: laboratory-proven influenza, pneumonia and death from pneumonia. An effect was shown for the non-specific outcomes of ILI, GP consultations for ILI and all-cause mortality in individuals>/= 60. These non-specific outcomes are difficult to interpret because ILI includes many pathogens, and winter influenza contributes/= 60. The key interest is preventing laboratory-proven influenza in individuals>/= 60, pneumonia and deaths from pneumonia, and we cannot draw such conclusions.The identified studies are at high risk of bias.Some HCWs remain unvaccinated because they do not perceive risk, doubt vaccine efficacy and are concerned about side effects. This review did not find information on co-interventions with HCW vaccination: hand washing, face masks, early detection of laboratory-proven influenza, quarantine, avoiding admissions, anti-virals, and asking HCWs with ILI not to work. We conclude there is no evidence that vaccinating HCWs prevents influenza in elderly residents in LTCFs. High quality RCTs are required to avoid risks of bias in methodology and conduct, and to test these interventions in combination.

Cochrane Database Syst Rev. 2010(2):CD005187. Epub 2010 Feb 17. PMID: 20166073

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There is a lack of evidence for the effectiveness of influenza vaccines in adults aged 65 years or older.


BACKGROUND: No published meta-analyses have assessed efficacy and effectiveness of licensed influenza vaccines in the USA with sensitive and highly specific diagnostic tests to confirm influenza. METHODS: We searched Medline for randomised controlled trials assessing a relative reduction in influenza risk of all circulating influenza viruses during individual seasons after vaccination (efficacy) and observational studies meeting inclusion criteria (effectiveness). Eligible articles were published between Jan 1, 1967, and Feb 15, 2011, and used RT-PCR or culture for confirmation of influenza. We excluded some studies on the basis of study design and vaccine characteristics. We estimated random-effects pooled efficacy for trivalent inactivated vaccine (TIV) and live attenuated influenza vaccine (LAIV) when data were available for statistical analysis (eg, at least three studies that assessed comparable age groups). FINDINGS: We screened 5707 articles and identified 31 eligible studies (17 randomised controlled trials and 14 observational studies). Efficacy of TIV was shown in eight (67%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 59% [95% CI 51-67] in adults aged 18-65 years). No such trials met inclusion criteria for children aged 2-17 years or adults aged 65 years or older. Efficacy of LAIV was shown in nine (75%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 83% [69-91]) in children aged 6 months to 7 years. No such trials met inclusion criteria for children aged 8-17 years. Vaccine effectiveness was variable for seasonal influenza: six (35%) of 17 analyses in nine studies showed significant protection against medically attended influenza in the outpatient or inpatient setting. Median monovalent pandemic H1N1 vaccine effectiveness in five observational studies was 69% (range 60-93). INTERPRETATION: Influenza vaccines can provide moderate protection against virologically confirmed influenza, but such protection is greatly reduced or absent in some seasons. Evidence for protection in adults aged 65 years or older is lacking. LAIVs consistently show highest efficacy in young children (aged 6 months to 7 years). New vaccines with improved clinical efficacy and effectiveness are needed to further reduce influenza-related morbidity and mortality. FUNDING: Alfred P Sloan Foundation.

Lancet Infect Dis. 2011 Oct 25. Epub 2011 Oct 25. PMID: 22032844

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We concluded that there is no credible evidence that vaccination of healthy people under the age of 60, who are healthcare workers caring for the elderly, affects influenza complications in those cared for.


BACKGROUND: Healthcare workers (HCW) (nurses, doctors, other health professionals, cleaners and porters), have substantial rates of clinical and sub-clinical influenza during influenza seasons and may transmit influenza to those in their care, especially the vulnerable elderly.OBJECTIVES: To identify and summarise comparative studies assessing the effects of vaccinating healthcare workers (HCW) on the incidence of influenza, influenza-like-illness (ILI) and its complications on elderly residents in long-term facilities.SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Database of Systematic Reviews and the NHS Database of Abstracts of Reviews of Effectiveness (DARE) (The Cochrane Library Issue 1, 2006); MEDLINE (January 1966 to Week 1, February 2006); EMBASE (1974 to March 2006); Biological Abstracts (1969 to December 2004); and Science Citation Index-Expanded (1974 to March 2006).SELECTION CRITERIA: Comparative randomised and non-randomised studies reporting the effects of influenza vaccines on the incidence of viral infections in institutions for the elderly of any type, in any schedule of vaccination given to HCW caring for elderly residents of long-term facilities aged 60 years or older.DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the methodological quality using criteria from the Cochrane Reviewers' Handbook and the Newcastle-Ottawa scale (for non-randomised studies).MAIN RESULTS: We included two cluster randomised controlled trials (C-RCT) and one cohort study. Staff vaccination appears to have significant effect against ILI (absolute vaccine efficacy (VE) 86%, 95% confidence interval (CI) 40% to 97%) only when patients are vaccinated too; if patients are not vaccinated, staff immunisation shows no effect (based on one C-RCT). Based on a small number of observations from two C-RCTs, the vaccines have no efficacy against influenza (odds ratio (OR) 0.86, 95% CI 0.44 to 1.68) or lower respiratory tract infections (OR 0.70, 95% CI 0.41 to 1.20) but were effective against deaths from pneumonia (VE 39%, 95% CI 2% to 62%) and deaths from all causes (VE 40%, 95% CI 27% to 50%). All findings must be interpreted with caution given the presence of selection bias.AUTHORS' CONCLUSIONS: We concluded that there is no credible evidence that vaccination of healthy people under the age of 60, who are HCWs caring for the elderly, affects influenza complications in those cared for. However, as vaccinating the elderly in institutions reduces the complications of influenza and vaccinating healthy persons under 60 reduces cases of influenza, those with the responsibility of caring for the elderly in institutions may want to increase vaccine coverage and assess its effects in well-designed studies.

Cochrane Database Syst Rev. 2006 ;3:CD005187. Epub 2006 Jul 19. PMID: 16856082

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"The design and reporting of safety outcomes in MMR vaccine studies, both pre- and post-marketing, are largely inadequate. "


BACKGROUND: Mumps, measles and rubella (MMR) are serious diseases that can lead to potentially fatal illness, disability and death. However, public debate over the safety of the trivalent MMR vaccine and the resultant drop in vaccination coverage in several countries persists, despite its almost universal use and accepted effectiveness.OBJECTIVES: To assess the effectiveness and adverse effects associated with the MMR vaccine in children up to 15 years of age.SEARCH METHODS: For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, PubMed (July 2004 to May week 2, 2011) and Embase.com (July 2004 to May 2011).SELECTION CRITERIA: We used comparative prospective or retrospective trials assessing the effects of the MMR vaccine compared to placebo, do nothing or a combination of measles, mumps and rubella antigens on healthy individuals up to 15 years of age.DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed methodological quality of the included studies. One review author arbitrated in case of disagreement.MAIN RESULTS: We included five randomised controlled trials (RCTs), one controlled clinical trial (CCT), 27 cohort studies, 17 case-control studies, five time-series trials, one case cross-over trial, two ecological studies, six self controlled case series studies involving in all about 14,700,000 children and assessing effectiveness and safety of MMR vaccine. Based on the available evidence, one MMR vaccine dose is at least 95% effective in preventing clinical measles and 92% effective in preventing secondary cases among household contacts.Effectiveness of at least one dose of MMR in preventing clinical mumps in children is estimated to be between 69% and 81% for the vaccine prepared with Jeryl Lynn mumps strain and between 70% and 75% for the vaccine containing the Urabe strain. Vaccination with MMR containing the Urabe strain has demonstrated to be 73% effective in preventing secondary mumps cases. Effectiveness of Jeryl Lynn containing MMR in preventing laboratory-confirmed mumps cases in children and adolescents was estimated to be between 64% to 66% for one dose and 83% to 88% for two vaccine doses. We did not identify any studies assessing the effectiveness of MMR in preventing rubella.The highest risk of association with aseptic meningitis was observed within the third week after immunisation with Urabe-containing MMR (risk ratio (RR) 14.28; 95% confidence interval (CI) from 7.93 to 25.71) and within the third (RR 22.5; 95% CI 11.8 to 42.9) or fifth (RR 15.6; 95% CI 10.3 to 24.2) weeks after immunisation with the vaccine prepared with the Leningrad-Zagreb strain. A significant risk of association with febrile seizures and MMR exposure during the two previous weeks (RR 1.10; 95% CI 1.05 to 1.15) was assessed in one large person-time cohort study involving 537,171 children aged between three months and five year of age. Increased risk of febrile seizure has also been observed in children aged between 12 to 23 months (relative incidence (RI) 4.09; 95% CI 3.1 to 5.33) and children aged 12 to 35 months (RI 5.68; 95% CI 2.31 to 13.97) within six to 11 days after exposure to MMR vaccine. An increased risk of thrombocytopenic purpura within six weeks after MMR immunisation in children aged 12 to 23 months was assessed in one case-control study (RR 6.3; 95% CI 1.3 to 30.1) and in one small self controlled case series (incidence rate ratio (IRR) 5.38; 95% CI 2.72 to 10.62). Increased risk of thrombocytopenic purpura within six weeks after MMR exposure was also assessed in one other case-control study involving 2311 children and adolescents between one month and 18 years (odds ratio (OR) 2.4; 95% CI 1.2 to 4.7). Exposure to the MMR vaccine was unlikely to be associated with autism, asthma, leukaemia, hay fever, type 1 diabetes, gait disturbance, Crohn's disease, demyelinating diseases, bacterial or viral infections.AUTHORS' CONCLUSIONS: The design and reporting of safety outcomes in MMR vaccine studies, both pre- and post-marketing, are largely inadequate. The evidence of adverse events following immunisation with the MMR vaccine cannot be separated from its role in preventing the target diseases.

Cochrane Database Syst Rev. 2012 ;2:CD004407. Epub 2012 Feb 15. PMID: 22336803

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Two of the largest randomized HPV vaccine trials unveiled more severe adverse events in the tested HPV vaccine arm of the study.


This article critically reviews HPV vaccine serious adverse events described in pre-licensure randomized trials and in post-marketing case series. HPV vaccine randomized trials were identified in PubMed. Safety data were extracted. Post-marketing case series describing HPV immunization adverse events were reviewed. Most HPV vaccine randomized trials did not use inert placebo in the control group. Two of the largest randomized trials found significantly more severe adverse events in the tested HPV vaccine arm of the study. Compared to 2871 women receiving aluminum placebo, the group of 2881 women injected with the bivalent HPV vaccine had more deaths on follow-up (14 vs. 3, p = 0.012). Compared to 7078 girls injected with the 4-valent HPV vaccine, 7071 girls receiving the 9-valent dose had more serious systemic adverse events (3.3 vs. 2.6%, p = 0.01). For the 9-valent dose, our calculated number needed to seriously harm is 140 (95% CI, 79-653). The number needed tovaccinate is 1757 (95% CI, 131 to infinity). Practically, none of the serious adverse events occurring in any arm of both studies were judged to be vaccine-related. Pre-clinical trials, post-marketing case series, and the global drug adverse reaction database (VigiBase) describe similar post-HPV immunization symptom clusters. Two of the largest randomized HPV vaccine trials unveiled more severe adverse events in the tested HPV vaccine arm of the study. Nine-valent HPV vaccine has a worrisome number needed to vaccinate/number needed to harm quotient. Pre-clinical trials and post-marketing caseseries describe similar post-HPV immunization symptoms.

Clin Rheumatol. 2017 Jul 20. Epub 2017 Jul 20. PMID: 28730271

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Pertactin-deficient Bordetella pertussis isolates: evidence of increased circulation in Europe, 1998 to 2015.


IntroductionPertussis outbreaks have occurred in several industrialised countries using acellular pertussis vaccines (ACVs) since the 1990s. High prevalence of pertactin (PRN)-deficientisolates has been found in these countries.AimsTo evaluate in Europe: (i) whether proportions of PRN-deficient strains increased in consecutive collections ofclinical isolates; (ii) if the frequency of PRN-deficient strains in countries correlated with the time since ACV introduction; (iii) the presence of pertussis toxin (PT)-, filamentous haemagglutinin (FHA)- or fimbriae (Fim)-deficient isolates.Methodsclinical isolates were obtained from different European countries during four periods (EUpert I-IV studies): 1998 to 2001 (n = 102), 2004 to 2005 (n = 154), 2007 to 2009 (n = 140) and 2012 to 2015 (n = 265). The isolates' selection criteria remained unchanged in all periods. PRN, PT, FHA and Fim2 and Fim3 expression were assessed by ELISA.ResultsIn each period 1.0% (1/102), 1.9% (3/154), 6.4% (9/140) and24.9% (66/265) of isolates were PRN-deficient. In EUpert IV, PRN-deficient isolates occurred in all countries sampled and in six countries their frequency was higher than in EUpert III (for Sweden and the United Kingdom, p 

Euro Surveill. 2019 Feb ;24(7). PMID: 30782265

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This systematic review criticizes the current evidence used to support flu vaccination in infants under 6 months. They outline the evidence of widespread manipulation of conclusions, spurious notoriety of the studies, and evidence of industry conflicts.


BACKGROUND: The consequences of influenza in children and adults are mainly absenteeism from school and work. However, the risk of complications is greatest in children and people over 65 years of age.OBJECTIVES: To appraise all comparative studies evaluating the effects of influenza vaccines in healthy children, assess vaccine efficacy (prevention of confirmed influenza) and effectiveness (prevention of influenza-like illness (ILI)) and document adverse events associated with influenza vaccines.SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3) which includes the Acute Respiratory Infections Group's Specialised Register, OLD MEDLINE (1950 to 1965), MEDLINE (1966 to November 2011), EMBASE (1974 to November 2011), Biological Abstracts (1969 to September 2007), and Science Citation Index (1974 to September 2007).SELECTION CRITERIA: Randomised controlled trials (RCTs), cohort and case-control studies of any influenza vaccine in healthy children under 16 years of age.DATA COLLECTION AND ANALYSIS: Four review authors independently assessed trial quality and extracted data.MAIN RESULTS: We included 75 studies with about 300,000 observations. We included 17 RCTs, 19 cohort studies and 11 case-control studies in the analysis of vaccine efficacy and effectiveness. Evidence from RCTs shows that six children under the age of six need to be vaccinated with live attenuated vaccine to prevent one case of influenza (infection and symptoms). We could find no usable data for those aged two years or younger.Inactivated vaccines in children aged two years or younger are not significantly more efficacious than placebo. Twenty-eight children over the age of six need to be vaccinated to prevent one case of influenza (infection and symptoms). Eight need to be vaccinated to prevent one case of influenza-like-illness (ILI). We could find no evidence of effect on secondary cases, lower respiratory tract disease, drug prescriptions, otitis media and its consequences and socioeconomic impact. We found weak single-study evidence of effect on school absenteeism by children and caring parents from work. Variability in study design and presentation of data was such that a meta-analysis of safety outcome data was not feasible. Extensive evidence of reporting bias of safety outcomes from trials of live attenuated influenza vaccines (LAIVs) impeded meaningful analysis. One specific brand of monovalent pandemic vaccine is associated with cataplexy and narcolepsy in children and there is sparse evidence of serious harms (such as febrile convulsions) in specific situations.AUTHORS' CONCLUSIONS: Influenza vaccines are efficacious in preventing cases of influenza in children older than two years of age, but little evidence is available for children younger than two years of age. There was a difference between vaccine efficacy and effectiveness, partly due to differing datasets, settings and viral circulation patterns. No safety comparisons could be carried out, emphasising the need for standardisation of methods and presentation of vaccine safety data in future studies. In specific cases, influenza vaccines were associated with serious harms such as narcolepsy and febrile convulsions. It was surprising to find only one study of inactivated vaccine in children under two years, given current recommendations to vaccinate healthy children from six months of age in the USA, Canada, parts of Europe and Australia. If immunisation in children is to be recommended as a public health policy, large-scale studies assessing important outcomes, and directly comparing vaccine types are urgently required. The degree of scrutiny needed to identify all global cases of potential harms is beyond the resources of this review. This review includes trials funded by industry. An earlier systematic review of 274 influenza vaccine studies published up to 2007 found industry-funded studies were published in more prestigious journals and cited more than other studies independently from methodological quality and size. Studies funded from public sources were significantly less likely to report conclusions favourable to the vaccines. The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies. The content and conclusions of this review should be interpreted in the light of this finding.

Cochrane Database Syst Rev. 2012 Aug 15(8):CD004879. Epub 2012 Aug 15. PMID: 22895945

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This meta-analysis suggests no link between vaccines and autism but only investigates 10 collective studies (six of which have blatant conflicts of interest, one was authored by a now CDC employee), one vaccine ingredient, and one vaccine (MMR).


There has been enormous debate regarding the possibility of a link between childhood vaccinations and the subsequent development of autism. This has in recent times become a major public health issue with vaccine preventable diseases increasing in the community due to the fear of a 'link' between vaccinations and autism. We performed a meta-analysis to summarise available evidence from case-control and cohort studies on this topic (MEDLINE, PubMed, EMBASE, Google Scholar up to April, 2014). Eligible studies assessed the relationship between vaccine administration and the subsequent development of autism or autism spectrum disorders (ASD). Two reviewers extracted data on study characteristics, methods, and outcomes. Disagreement was resolved by consensus with another author. Five cohort studies involving 1,256,407 children, and five case-control studies involving 9,920 children were included in this analysis. The cohort data revealed no relationship between vaccination and autism (OR: 0.99; 95% CI: 0.92 to 1.06) or ASD (OR: 0.91; 95% CI: 0.68 to 1.20), nor was there a relationship between autism and MMR (OR: 0.84; 95% CI: 0.70 to 1.01), or thimerosal (OR: 1.00; 95% CI: 0.77 to 1.31), or mercury (Hg) (OR: 1.00; 95% CI: 0.93 to 1.07). Similarly the case-control data found no evidence for increased risk of developing autism or ASD following MMR, Hg, or thimerosal exposure when grouped by condition (OR: 0.90, 95% CI: 0.83 to 0.98; p=0.02) or grouped by exposure type (OR: 0.85, 95% CI: 0.76 to 0.95; p=0.01). Findings of this meta-analysis suggest that vaccinations are not associated with the development of autism or autism spectrum disorder. Furthermore, the components of the vaccines (thimerosal or mercury) or multiple vaccines (MMR) are not associated with the development of autism or autism spectrum disorder.

Vaccine. 2014 Jun 17 ;32(29):3623-9. Epub 2014 May 9. PMID: 24814559

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Studies examining the efficacy of the influenza vaccination and safety of these vaccinations are of poor methodological quality and the impact of confounders is high, suggesting a wide gap between vaccination policy and the evidence of its use.


Each year enormous effort goes into producing influenza vaccines for that specific year and delivering them to appropriate sections of the population. Is this effort justified?

BMJ. 2006 Oct 28 ;333(7574):912-5. PMID: 17068038

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This meta-analysis shows that the data available on the safety of aluminum adjuvants is severely lacking. There is also only data available for aluminum hydroxide and does not consider the toxicity of amorphous aluminum hydroxyphosphate.


We have reviewed evidence of adverse events after exposure to aluminium-containing vaccines against diphtheria, tetanus, and pertussis (DTP), alone or in combination, compared with identical vaccines, either without aluminium or containing aluminium in different concentrations. The study is a systematic review with meta-analysis. We searched the Cochrane Vaccines Field Register, the Cochrane Library, Medline, Embase, Biological Abstracts, Science Citation Index, and the Vaccine Adverse Event Reporting System website for relevant studies. Reference lists of retrieved articles were scanned for further studies. We included randomised and semi-randomised trials and comparative cohort studies if the report gave sufficient information for us to extract aluminium concentration, vaccine composition, and safety outcomes. Two reviewers extracted data in a standard way from all included studies and assessed the methodological quality of the studies. We identified 35 reports of studies and included three randomised trials, four semi-randomised trials, and one cohort study. We did a meta-analysis of data from five studies around two main comparisons (vaccines containing aluminium hydroxide vs no adjuvant in children aged up to 18 months and vaccines containing different types of aluminium vs no adjuvants in children aged 10-16 years). In young children, vaccines with aluminium hydroxide caused significantly more erythema and induration than plain vaccines (odds ratio 1.87 [95% CI 1.57-2.24]) and significantly fewer reactions of all types (0.21 [0.15-0.28]). The frequencies of local reactions of all types, collapse or convulsions, and persistent crying or screaming did not differ between the two cohorts of the trials. In older children, there was no association between exposure to aluminium-containing vaccines and onset of (local) induration, swelling, or a raised temperature, but there was an association with local pain lasting up to 14 days (2.05 [1.25-3.38]). We found no evidence that aluminium salts in vaccines cause any serious or long-lasting adverse events. Despite a lack of good-quality evidence we do not recommend that any further research on this topic is undertaken.

Lancet Infect Dis. 2004 Feb ;4(2):84-90. PMID: 14871632

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American Ginseng is safe and effective in reducing relative risk and duration of respiratory symptoms associated with "cold and flu" in adults.


BACKGROUND: COLD-fX (CVT-E002), a proprietary extract of the roots of North American ginseng (Panax quinquefolium), rich in poly-furanosyl-pyranosyl-saccharides, has been found efficacious in the prevention of respiratory infections in institutionalized seniors and healthy adults. OBJECTIVE: We examined the efficacy of COLD-fX in the prevention of acute respiratory illness (ARI) in community dwelling seniors. DESIGN: This was a randomized, double-blind, placebo controlled trial. INTERVENTION: The participants were asked to take 2 capsules/day of either COLD-fX or placebo (200 mg/ capsule) for a period of 4 months. SUBJECTS: A total of 43 community-dwelling adults aged 65 years or older were recruited. Following one month of intervention, subjects were immunized with influenza vaccine. OUTCOME MEASURES: Subjects recorded the incidence and duration of respiratory symptoms during the study. They also recorded the incidence of adverse events during the study. RESULTS: The frequency and duration of ARI during the first two months of the study was found to be similar in the two groups. However, during the last 2 months (November and December) significantly fewer subjects in the COLD-fX group 32% reported ARI compared to the placebo group 62%. The duration of symptoms during the last 2 months was significantly shorter in the COLD-fX group than the placebo group (5.6 days in the COLD-fX group vs 12.6 days in the placebo group). There was no influenza illness circulating in the community during the period of the study. CONCLUSIONS: Ingestion of COLD-fX by immunocompetent seniors during an early "cold and flu" season reduced the relative risk and duration of respiratory symptoms by 48% and 55%, respectively. Daily COLD-fX administration can thus be a safe, natural therapeutic means for the prevention of ARI in healthy seniors.

J Altern Complement Med. 2006 Mar;12(2):153-7. PMID: 16566675

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Chlorella significantly increases the antibody response to influenza vaccination in patients age 50-55 years old.


BACKGROUND: Enhancement of immune function has been claimed as a benefit of some natural health products, although few have been subjected to randomized clinical trials. We evaluated the effect of an oral dietary supplement derived from the edible microalga Chlorella pyrenoidosa on immune response after influenza vaccination. METHODS: We conducted a randomized, double-blind, placebo-controlled community-based clinical trial in a convenience sample of 124 healthy adults at least 50 years of age randomly assigned to receive the study product (200 or 400 mg of a Chlorella-derived dietary supplement) or placebo. Participants took the study product or placebo once daily for 28 days. On day 21, we administered a single dose of a licensed trivalent, inactivated influenza vaccine. We obtained serum specimens to measure hemagglutination inhibition titres before and 7 and 21 days after vaccination. The primary immunological outcomes were the proportion of participants with a 4-fold or greater increase in antibodies and geometric mean antibody titres after vaccination; the proportion of participants reporting adverse events during therapy was the safety outcome. RESULTS: A total of 117 (94%) participants completed all aspects of the study. There were no differences in the proportions of recipients of 200 or 400 mg of the Chlorella-derived dietary supplement or placebo who achieved at least a 4-fold increase in antibodies (proportions for the 3 virus strains ranged from 17.9% to 28.2% for the 200-mg group, from 11.1% to 22.2% for the 400-mg group and from 19.0% to 21.4% for the placebo group; p > 0.05 for all comparisons). Reports of adverse events were similar for recipients of the supplement and placebo, except with regard to fatigue, which was reported more frequently by recipients of 200 mg of the supplement (18/41 or 44%) than by those who received 400 mg of the supplement (8/40 or 20%; p = 0.032) or placebo (8/42 or 19%; p = 0.019). Recipients of 400 mg of the supplement who were 55 years of age or younger had significantly higher geometric mean antibody titres against influenza A/New Caledonia 21 days after vaccination (p = 0.047) and against B/Yamanashi 7 days after vaccination (p = 0.034); the trends were nonsignificant for titres against A/Panama. We also observed similar increases for the proportions of subjects with a 2-fold or greater or a 4-fold or greater increase in antibodies. INTERPRETATION: The Chlorella-derived dietary supplement did not have any effect in increasing the antibody response to influenza vaccine in the overall study population, although there was an increase in antibody response among participants aged 50-55 years. Adverse events were similar among those receiving the supplement and the placebo. Further studies are warranted to explore the range of clinical effects resulting from ingestion of this dietary supplement.

CMAJ. 2003 Jul 22;169(2):111-7. PMID: 12874157

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L-cystine and l-theanine may contribute to enhancing the immune response against the H1N1 virus.


AIM: The immune response to influenza vaccine is attenuated in elderly persons, though they are at greatest risk for morbidity and mortality by influenza virus infection. Experimental studies demonstrate that co-administration of l-cystine and l-theanine enhanced antigen-specific production of immunoglobulin in aged mice infected with influenza virus. We thus investigated the effect of l-cystine and l-theanine on antibody induction by influenza vaccines in elderly persons. METHODS: Residents in a nursing home were randomly allocated to l-cystine and l-theanine (n = 32) or placebo (n = 33). The test substances were administered p.o. for 14 days before immunization. Serum influenza virus antibody titers were measured before and 4 weeks after vaccination. RESULTS: Vaccination significantly elevated hemagglutination inhibition (HI) titers for all the three strains of influenza viruses (A/New Caledonia [H1N1], A/New York [H3N2] and B/Shanghai) in both groups. HI titers after vaccination were not significantly different between the two groups for either strain. Also, the seroconversion rate was not significantly different between the two groups in the aggregate. A stratified analysis showed that the rate of seroconversion was significantly greater in the l-cystine and l-theanine group compared with the placebo group for influenza virus A (H1N1) among subjects with low serum total protein (63% vs 10%, P < 0.05) or low hemoglobin (71% vs 9%, P < 0.05). CONCLUSION: Co-administration of l-cystine and l-theanine before vaccination may enhance the immune response to influenza vaccine in elderly subjects with low serum total protein or hemoglobin.

Geriatr Gerontol Int. 2008 Dec;8(4):243-50. PMID: 19149835

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A green tea extract is efficacious and safe when applied topically in the treatment of external genital and perianal warts.


 BACKGROUND: Benign external genital and perianal warts (condylomata acuminata) are disfiguring, displeasing skin tumours caused by human papillomavirus that may vitally burden affected patients and their partners. Current treatment options are still unsatisfactory due to low efficacy, high recurrence rates or an unfavourable side-effect profile. Although most recently prophylactic vaccines have been recommended for adolescent women, appropriate treatment modalities for anogenital warts are still needed. Green tea catechins exert antiviral, antioxidative, antiproliferative and immunostimulatory activity. Polyphenon E (MediGene AG, Munich, Germany), a proprietary extract of green tea leaves, was therefore investigated for the topical treatment of this frequent viral disease. OBJECTIVES: To investigate Polyphenon E 15% and 10% ointment for efficacy and safety in the treatment of anogenital warts in immunocompetent men and women. METHODS: Five hundred and three patients were randomized to receive either Polyphenon E 15% or 10% ointment or matching vehicle. The topical treatment was self-applied by the patients three times daily to all warts. Assessment of response and of adverse events was performed biweekly until complete clearance of all (baseline and new) anogenital warts or for up to 16 weeks. Recurrence was evaluated during a 12-week treatment-free follow-up period for patients with complete clearance. RESULTS: About 53% of patients treated with Polyphenon E 15% ointment showed complete clearance of all baseline and new anogenital warts, 51% for Polyphenon E 10% ointment, and 37% for vehicle (P = 0.01 and P = 0.03, respectively; two-sided Fisher's exact test; intent-to-treat population, last observation carried forward analysis). Women responded better than men, with about 60% of women and 45% of men in both active groups achieving complete clearance of all warts. Time to complete clearance was comparable for both strengths of Polyphenon E ointment. About 78% of all patients treated with either Polyphenon E 15% or 10% ointment showed wart clearance rates of 50% or better. Less than 6% and 4% of patients in the Polyphenon E 15% and 10% ointment groups experienced wart recurrence during follow-up. Polyphenon E ointments demonstrated a good safety profile with the majority of all adverse events being local application site reactions assessed as mild or moderate. Local reactions declined during continued treatment. CONCLUSIONS: The results indicate that Polyphenon E ointment is an efficacious and safe patient-applied topical treatment for external genital and perianal warts. Its use in intra-anal, intravaginal and cervical condylomas and other intraepithelial lesions warrants further clinical investigation.

Br J Dermatol. 2008 Jun;158(6):1329-38. Epub 2008 Mar 20. PMID: 18363746

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Hepatitis B vaccination may contribute to autoimmune demyelinating complications due to immunological cross-reactivity between Hepatitis B virus surface antigen and myelin basic protein.


On the basis of the reported association between hepatitis B vaccination (HBvacc) and autoimmune demyelinating complications such as multiple sclerosis (MS), we have looked for aminoacid similarities between the small hepatitis B virus surface antigen (SHBsAg), and the MS-autoantigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) that could serve as targets of immunological cross-reactivity. Twenty-mer peptides spanning 4 SHBsAg/MOG and 1 SHBsAg/MBP mimicking pairs, were constructed and tested by ELISA as targets of cross-reactive responses. A total of 147 samples from 58 adults were collected before HBvacc (58/58), and post-HBvacc (48/58 before the second and 41/58 before the third boost). Eighty-seven sera from anti-SHBsAg antibody negative patients with various diseases were tested as pathological controls. Reactivity to at least one of the SHBsAg peptides was found in 8 (14%) pre-HBvacc subjects; amongst the remaining 50, reactivity to at least one of the SHBsAg peptides appeared in 47 (94%) post-HBvacc. Reactivity to at least one of the MOG mimics was present in 4 (8%) pre-HBvacc and in 30 (60%) post-HBvacc (p < 0.001). Overall 30/50 (60%) vaccinees had SHBsAg/MOG double reactivity on at least one occasion compared to none before-vaccination and in 2 (2%) of the pathological controls (p < 0.001 for both). SHBsAg/MOG double reactivity was cross-reactive as confirmed by inhibition studies. At 6 months post-vaccination, 3 of the 4 anti-MOG reactive cases before vaccination and 7 of the 24 (29%) of the anti-MOG reactive cases at 3 months post-vaccination had lost their reactivity to MOG5-24. There was no reactivity to the SHBsAg/MBP mimics. None of the vaccinees reported symptoms of demyelinating disorders. In view of the observed SHBsAg/MOG cross-reactivity, the vaccine's possible role as an immunomodulator of viral/self cross-reactivity must be further investigated.

Clin Dev Immunol. 2005 Sep;12(3):217-24. PMID: 16295528

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Hepatitis B vaccine is associated with an increased risk of multiple sclerosis.


BACKGROUND: A potential link between the recombinant hepatitis B vaccine and an increased risk of multiple sclerosis (MS) has been evaluated in several studies, but some of them have substantial methodologic limitations. METHODS: The authors conducted a nested case-control study within the General Practice Research Database (GPRD) in the United Kingdom. The authors identified patients who had a first MS diagnosis recorded in the GPRD between January 1993 and December 2000. Cases were patients with a diagnosis of MS confirmed through examination of medical records, and with at least 3 years of continuous recording in the GPRD before their date of first symptoms (index date). Up to 10 controls per case were randomly selected, matched on age, sex, practice, and date of joining the practice. Information on receipt of immunizations was obtained from the computer records. RESULTS: The analyses include 163 cases of MS and 1,604 controls. The OR of MS for vaccination within 3 years before the index date compared to no vaccination was 3.1 (95% CI 1.5, 6.3). No increased risk of MS was associated with tetanus and influenza vaccinations. CONCLUSIONS: These findings are consistent with the hypothesis that immunization with the recombinant hepatitis B vaccine is associated with an increased risk of MS, and challenge the idea that the relation between hepatitis B vaccination and risk of MS is well understood.

Neurology. 2004 Sep 14;63(5):838-42. PMID: 15365133

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Human Papilloma Virus (HPV) vaccine is associated with demyelinating events.


Vaccination is generally considered safe in patients with multiple sclerosis (MS). We report five patients who presented with multifocal or atypical demyelinating syndromes within 21 days of immunization with the quadrivalent human papilloma virus (HPV) vaccine, Gardasil. Although the target population for vaccination, young females, has an inherently high risk for MS, the temporal association with demyelinating events in these cases may be explained by the potent immuno-stimulatory properties of HPV virus-like particles which comprise the vaccine. A prospective case-control study of patients with MS or clinically isolated demyelinating syndromes receiving the Gardasil vaccine may provide relevant safety data in this population.

Mult Scler. 2009 Jan;15(1):116-9. Epub 2008 Sep 19. PMID: 18805844

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Chronic fatigue syndrome may be associated with silicone implants and/or vaccinations.


BACKGROUND: Chronic fatigue syndrome (CFS) that defines by prolonged fatigue and other manifestations, was recently integrated into a spectrum of central sensitivity syndromes including several diseases as fibromylagia. CFS etiology is multi-factorial commonly triggered by infectious agents. Vaccines, induce an immune response similarly to infections, and may trigger just like infections autoimmune diseases, CFS and fibromyalgia. Furthermore vaccines contain an adjuvant which enhances their immune stimulation. CASE PRESENTATION: A 56-year-old woman was diagnosed with CFS accompanied by fibromyalgia, demyelination and autoantibodies. Her illness begun following the 2nd dose of hepatitis-B vaccine, and was aggravated by the 3rd vaccination. She underwent silicone breast implantation 6 years before vaccination with no adverse events. However, between the 2nd and 3rd vaccination she suffered a breast injury with local inflammation. Upon explanation of her breast implants silicone leak was observed. DISCUSSION: Vaccines have been reported to precede CFS mainly following exposure to multiple vaccinations (e.g. the Gulf war syndrome), or as an adverse response to the vaccine adjuvant (e.g. the macrophagic myofasciitis syndrome). Silicone is considered an adjuvant to the immune system, and may induce "the adjuvant disease". Silicone implant, especially silicone leak relationship with autoimmunity and CFS has been the focus of considerable debates. CONCLUSION: Our patient illness started following hepatitis-B vaccine, suggesting that it was caused or accelerated by vaccination. In parallel to vaccination our patient suffered from breast injury, which might represent the time of silicone leak. The exposure to the adjuvant, silicone, might have augmented her immune response to the vaccine. To the best of our knowledge this is the first case of combined adverse effect to vaccine and silicone. Vaccine safety in individuals with silicone implants requires further studies.

Autoimmun Rev. 2008 Oct;8(1):52-5. Epub 2008 Aug 24. PMID: 18725327

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Influenza vaccination may increase the risk of Guillain-Barré Syndrome.


CASE REPORT: Miller Fisher Syndrome (MFS) is the most frequent variant of the Guillain-Barré Syndrome. It is characterised by the classic triad of ophthalmoplegia, ataxia and areflexia. We present a case of a patient who developed these clinical findings 5 days after flu vaccination. DISCUSSION: Miller Fisher Syndrome is an unusual condition seen in ophthalmologic clinical practice. Although respiratory and digestive infections have been reported as antecedent infectious agents in MFS, it has not previously been described in relation to the flu vaccine.        

Kidney Int. 2008 Dec;74(11):1461-7. Epub 2008 Sep 24. PMID: 18592444

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Swine and influenza vaccines induce anti-ganglioside antibodies associated with autoimmune neuropathies such as Guillain-Barre syndrome.


BACKGROUND: Receipt of an A/NJ/1976/H1N1 "swine flu" vaccine in 1976, unlike receipt of influenza vaccines used in subsequent years, was strongly associated with the development of the neurologic disorder Guillain-Barré syndrome (GBS). Anti-ganglioside antibodies (e.g., anti-GM(1)) are associated with the development of GBS, and we hypothesized that the swine flu vaccine contained contaminating moieties (such as Campylobacter jejuni antigens that mimic human gangliosides or other vaccine components) that elicited an anti-GM(1) antibody response in susceptible recipients. METHODS: Surviving samples of monovalent and bivalent 1976 vaccine, comprising those from 3 manufacturers and 11 lot numbers, along with several contemporary vaccines were tested for hemagglutinin (HA) activity, the presence of Campylobacter DNA, and the ability to induce anti-Campylobacter and anti-GM(1) antibodies after inoculation into C3H/HeN mice. RESULTS: We found that, although C. jejuni was not detected in 1976 swine flu vaccines, these vaccines induced anti-GM(1) antibodies in mice, as did vaccines from 1991-1992 and 2004-2005. Preliminary studies suggest that the influenza HA induces anti-GM(1) antibodies. CONCLUSIONS: Influenza vaccines contain structures that can induce anti-GM(1) antibodies after inoculation into mice. Further research into influenza vaccine components that elicit anti-ganglioside responses and the role played by these antibodies (if any) in vaccine-associated GBS is warranted.

J Infect Dis. 2008 Jul 15;198(2):226-33. PMID: 18522505

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Increased consumption of genistein is associated with better lung function in patients with asthma.


To determine if micronutrient intake is associated with asthma severity, we administered the Block food frequency questionnaire to participants in a randomized clinical trial of the safety of influenza vaccine for asthmatics. The nutrition substudy included 1033 participants, aged 12-75. Intake of antioxidant vitamins, soy isoflavones, total fruits and vegetables, fats, and fiber was compared with asthma severity at baseline [forced expiratory volume in 1 second (FEV1), peak expiratory flow rate (PEF), asthma symptoms] and the rate of asthma exacerbations during the 2 weeks following influenza vaccination. The only nutrient that had a consistent association with asthma severity was genistein, a soy isoflavone. None of the nutrients evaluated were related to asthma exacerbation rate when adjusted for known confounders. The FEV1 in genistein consumers of at least 250 microg/1000 Kcal/day was 82.1% predicted, 79.9% predicted for those who consumed between 1 and 249 microg/1000 kcal, and 76.2% predicted in genistein nonconsumers (p=0.006); the PEF was 82.7% predicted, 80.8% predicted, and 78.3% predicted, respectively (p=0.009). There were no differences in the Asthma Symptom Utility Index (ASUI). We could not account for these results based on differences in demographics, body mass index, or consumption of other nutrients. Thus, increasing consumption of genistein is associated with better lung function in patients with asthma. Further studies are needed to determine whether dietary supplementation with genistein can reduce asthma severity.

J Asthma. 2004;41(8):833-43. PMID: 15641633

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Evidence exists demonstrating that diptheria-tetanus-pertussis (DTP) vaccines increase mortality in children.


BACKGROUND: Observational studies of diphtheria-tetanus-pertussis (DTP) vaccine from longitudinal study sites have reported divergent effects on child survival, ranging from 10-fold reduction to threefold increased mortality. None of these studies had complete information on DTP vaccinations from both survivors and children who died. We reviewed the data analysis methodology to assess whether methodological differences could explain the divergent results. DESIGN: Studies have used case-control design, survival analysis with interval-fixed vaccination status (landmark approach), and survival analysis with retrospective updating of vaccination status. RESULTS: Seven studies using a case-control design or a landmark approach found a negative effect of DTP on child survival. Eight of nine survival analyses with retrospective updating of vaccination status reported a beneficial effect. This beneficial effect of DTP increased with the length of the interval between data collection visits. Studies with long interval between visits had very high mortality rates among unvaccinated children, low mortality rate ratios for vaccinated compared with unvaccinated children, and strongly beneficial estimates of DTP. CONCLUSION: The divergent results in observational studies of the impact of DTP on child survival are partly because of methodological differences. To assess the impact on mortality of routine vaccinations, observational study designs which minimize the effect of bias are warranted. Randomized trials should be considered.

Trop Med Int Health. 2007 Jan;12(1):15-24. PMID: 17207144

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Diptheria-tetanus-peteruss vaccines increase child mortality in rural Guinea-Bissau.


BACKGROUND: and objective Previous studies from areas with high mortality in West Africa have not found diphtheria-tetanus-pertussis (DTP) vaccine to be associated with the expected reduction in mortality, a few studies suggesting increased mortality. We therefore examined mortality when DTP was first introduced in rural areas of Guinea-Bissau in 1984-1987. Setting Twenty villages in four regions have been followed with bi-annual examinations since 1979. SUBJECTS: In all, 1657 children aged 2-8 months. Design Children were weighed when attending the bi-annual examinations and they were vaccinated whenever vaccines were available. DTP was introduced in the beginning of 1984, oral polio vaccine later that year. We examined mortality for children aged 2-8 months who had received DTP and compared them with children who had not been vaccinated because they were absent, vaccines were not available, or they were sick. MAIN OUTCOME MEASURE: Mortality over the next 6 months from the day of examination for vaccinated and unvaccinated children. RESULTS: Prior to the introduction of vaccines, children who were absent at a village examination had the same mortality as children who were present. During 1984-1987, children receiving DTP at 2-8 months of age had higher mortality over the next 6 months, the mortality rate ratio (MR) being 1.92 (95% CI: 1.04, 3.52) compared with DTP-unvaccinated children, adjusting for age, sex, season, period, BCG, and region. The MR was 1.81 (95% CI: 0.95, 3.45) for the first dose of DTP and 4.36 (95% CI: 1.28, 14.9) for the second and third dose. BCG was associated with slightly lower mortality (MR = 0.63, 95% CI: 0.30, 1.33), the MR for DTP and BCG being significantly inversed. Following subsequent visits and further vaccinations with DTP and measles vaccine, there was no difference in vaccination coverage and subsequent mortality between the DTP-vaccinated group and the initially DTP-unvaccinated group (MR = 1.06, 95% CI: 0.78, 1.44). CONCLUSIONS: In low-income countries with high mortality, DTP as the last vaccine received may be associated with slightly increased mortality. Since the pattern was inversed for BCG, the effect is unlikely to be due to higher-risk children having received vaccination. The role of DTP in high mortality areas needs to be clarified.

Int J Epidemiol. 2004 Apr;33(2):374-80. PMID: 15082643

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Hepatitis C prevalence in Southern Italy may be due to iatrogenic transmission through the Salk Polio vaccine 1956-1965.


Since the first studies on hepatitis C virus (HCV) prevalence were published, it has been evident that southern Italy is an area of hyperendemicity. A recent study conducted in southern Italy suggested that the high prevalence of HCV infection might be the result of past iatrogenic transmission. Polio vaccination with the parenteral Salk vaccine between 1956 and 1965 by multiple use of unsafe glass syringes may have been one of the major causes of the spread of HCV infection among southern Italian adults who are now older than 40 years of age. Persons born between the 1940s and early 1960s have a nearly 3-fold increased risk of HCV seropositivity than the younger age group. The findings are consistent with a cohort effect of exposure to the Salk parenteral vaccination. Copyright 2003 Wiley-Liss, Inc.  

J Med Virol. 2003 May;70(1):49-50. PMID: 12629643

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Chelation therapy may remove damages associated with mercury intoxication.


INTRODUCTION: A great deal of data regarding the toxicology of mercury has been recently reported. Although the most common human exposures to mercury are currently mercury vapour from amalgam tooth fillings, methylmercury from seafood and ethylmercury as a preservative in vaccines, in the past mercury compounds have been used in the treatment of syphilis. CASE PRESENTATION: Mercury intoxication was found in a 67 year-old Italian man affected by neurological symptoms of apparently unknown origin. The patient developed syphilis forty years ago and then underwent therapy with mercurials to treat his chronic bacterial infection. We treated the patient with disodium edetate chelation therapy. Six months after the beginning of the therapy, the patient's neurological symptoms began to decrease, and were completely cured after two years of therapy. CONCLUSION: This case supports the use of chelation therapy with disodium edetate to remove damages caused by mercury intoxication.

Cases J. 2009 Nov 18;2:199. PMID: 19946446

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Propolis, aloe and a Vitamin B complex in combination with interferon is an effective, atraumatic and simple non-surgical treatment of HPV infection.


Cervical dysplasia, a premalignant lesion that can progress to cervical cancer, is caused primarily by a sexually transmitted infection with an oncogenic strain of the human papillomavirus (HPV). The HPV infections are treated through destroying the clinical lesions: laser, cryotherapy, podophyllin... The hope is that by causing local tissue inflammation that the body will be stimulated to mount an antibody response and thereby prevent recurrence. In contrast to other prevention approaches, vaccines can reduce susceptibility in uninfected partners by stimulating the immune system. Aloe vera has also been reported to retard tumour growth and stimulate the immune response to viruses. A list of possible actions of propolis includes: antibacterial, antifungal, antiviral, antioxidant, anticarcinogenic, antithrombotic and immunomodulatory. Research on the possible role of some B vitamins in preventing cancer began in the last few decades, but however this complex have an influence on immune status. The aim of our study is to try to treat the HPV infection as confirmed cause of neoplastic transformation with some herbal therapy and interferon and to try define the guidelines in the management of the HPV positive patients. Goal of this paper is to search for evidence of efficacy of any treatment for HPV infection of the cervix mostly in woman with no concomitant CIN. Fifty five woman affected by HPV genital infection were enrolled in the study from September 2005 to April 2006. Patients were classified according to the results of the HPV testing prior and after the therapy. Patients were randomized into two groups: the first group was HPV positive woman treated with other than recommended therapy (n=20), (control group); the second group was pharmacologically treated with intravaginal administration of an interferon and aloe vera-propolis in recommended scheme (n=35) with treatment of the possible fungal or bacterial genital infection prior to the specific therapy. The almost same therapy was recommended to the male partner. Patients from the second group used B complex during the therapy. Patients were retested for the HPV presence after three or six month from therapy depend of the presence bacterial or fungal genital coinfection. Three months after applied therapy HPV infection was still present in more than 90% of the patients in the first group. In the second group treated according to the recommended therapy scheme HPV infection disappeared in 71.42% of the patients after three months and in 100% of patients after six months. Samples of the cervical smear for the HPV analysis were being taken during routine gynecological examinations, by using sticks with cotton, taken from the Digene Specimen Collection Kit, from the whole surface of a portion, and by mild rotating moves from the outer cervical entrance. Our results suggest that the combination of interferon and herbal therapy with B complex is effective, atraumatic and simple non-surgical treatment of HPV infection. Since prospective efficacy trials will take several years to complete, considering alternative approaches is also worthwhile.

Bosn J Basic Med Sci. 2006 Nov;6(4):79-84. PMID: 17177657

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Autism may be associated with the use of acetaminophen in children.


Schultz et al (2008) raised the question whether regression into autism is triggered, not by the measles-mumps-rubella (MMR) vaccine, but by acetaminophen (Tylenol) given for its fever and pain. Considerable evidence supports this contention, most notably the exponential rise in the incidence of autism since 1980, when acetaminophen began to replace aspirin for infants and young children. The impetus for this shift - a Centers for Disease Control and Prevention warning that aspirin was associated with Reye's syndrome - has since been compellingly debunked. If aspirin is not to be feared as a cause of Reyes syndrome, and acetaminophen is to be feared as a cause of autism, can the autism epidemic be reversed by replacing acetaminophen with aspirin or other remedies?

Altern Med Rev. 2009 Dec;14(4):364-72. PMID: 20030462

56
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Tai Chi augments resting levels of varicella zoster virus-specific cell-mediated immunity - Article 1.


OBJECTIVES: To evaluate the effects of a behavioral intervention, Tai Chi, on resting and vaccine-stimulated levels of cell-mediated immunity (CMI) to varicella zoster virus (VZV) and on health functioning in older adults. DESIGN: A prospective, randomized, controlled trial with allocation to two arms (Tai Chi and health education) for 25 weeks. After 16 weeks of intervention, subjects were vaccinated with VARIVAX, the live attenuated Oka/Merck VZV vaccine licensed to prevent varicella. SETTING: Two urban U.S. communities between 2001 and 2005. PARTICIPANTS: A total of 112 healthy older adults aged 59 to 86. MEASUREMENTS: The primary endpoint was a quantitative measure of VZV-CMI. Secondary outcomes were scores on the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). RESULTS: The Tai Chi group showed higher levels of VZV-CMI than the health education group (P<.05), with a significant rate of increase (P<.001) that was nearly twice that found in the health education group. Tai Chi alone induced an increase in VZV-CMI that was comparable in magnitude with that induced by varicella vaccine, and the two were additive; Tai Chi, together with vaccine, produced a substantially higher level of VZV-CMI than vaccine alone. The Tai Chi group also showed significant improvements in SF-36 scores for physical functioning, bodily pain, vitality, and mental health (P<.05). CONCLUSION: Tai Chi augments resting levels of VZV-specific CMI and boosts VZV-CMI of the varicella vaccine.

J Am Geriatr Soc. 2007 Apr;55(4):511-7. PMID: 17397428

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American ginseng is safe, well tolerated, and potentially effective for preventing acute respiratory illness due to influenza and respiractory syncytial virus infections.


OBJECTIVES: To compare a proprietary extract of American ginseng, CVT-E002, with placebo in preventing acute respiratory illness (ARI) in an institutional setting during the influenza season. DESIGN: Two randomized, double-blind, placebo-controlled trials conducted late in the 2000 (8 week) and 2000-2001 (12 week) influenza seasons. SETTING: Long-term care setting that included nursing home and assisted living at three sites. PARTICIPANTS: Eighty-nine (2000) and 109 (2000-2001) enrolled subjects, average age 81 and 83.5, respectively; 74% women. Approximately 90% had received influenza vaccine in each of the 2 years. INTERVENTION: Oral twice-daily administration of a proprietary ginseng extract, CVT-E002, 200 mg or placebo. MEASUREMENTS: ARI was defined as two new respiratory symptoms or one with a constitutional symptom. Confirmation of viral ARI was by culture (influenza or respiratory syncytial virus (RSV)) or serology for influenza. Laboratory safety monitoring was done at 0, 4, and 8 or 12 weeks. RESULTS: An intent-to-treat analysis of pooled data corrected for drug exposure time showed that the incidence of laboratory-confirmed influenza illness (LCII) was greater in placebo- (7 cases/101 subjects) than CVT-E002-treated (1/97) groups (odds ratio (OR)=7.73, P=.033). Combined data for LCII and RSV illness were also greater in placebo- (9/101) than CVT-E002-treated (1/97) groups (OR=10.50, P=.009), for an overall 89% relative risk reduction of ARI in the CVT-E002 group. CONCLUSION: CVT-E002 was shown to be safe, well tolerated, and potentially effective for preventing ARI due to influenza and RSV.

J Am Geriatr Soc. 2004 Jan;52(1):13-9. PMID: 14687309

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Influenza vaccination does not appear to be effective during pregnancy in preventing hospitalizations and outpatient visits for respiratory illness in pregnant women and their infants.


The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention recommends influenza vaccination for women who will be in the second or third trimester of pregnancy during the influenza season. We analyzed hospital admissions with principal diagnoses of influenza or pneumonia and influenza-like illness (ILI) outpatient visits to study the effectiveness of influenza vaccine during pregnancy in protecting women and infants from influenza-related morbidity. Estimates of influenza vaccine effectiveness across five flu seasons (Fall 1997 to Spring 2002) were calculated using Cox proportional hazards models for women and infant study populations in Kaiser Permanente Northern California. Outpatient utilization outcomes included physician visits with a diagnosis of upper respiratory infection, pharyngitis, otitis media, asthma, bronchial asthma, viral infection, pneumonia, fever, cough, or wheezing associated with respiratory illness. Inpatient outcomes included hospitalizations with principal diagnoses of influenza or pneumonia. Women who received influenza vaccine during pregnancy had the same risk for ILI visits compared with unvaccinated women, adjusting for women's age and week of delivery. When asthma visits were excluded from the outcome measure, we also found no difference in the risk of outpatient visits for vaccinated and unvaccinated women. Hospital admissions for influenza or pneumonia for women in the study population were quite rare and no women died of respiratory illness during pregnancy. Infants born to women who received influenza vaccination had the same risks for influenza or pneumonia admissions compared with infants born to unvaccinated women, adjusting for infant's gender, gestational age, week of birth, and birth facility. Maternal influenza vaccination was also not a significant determinant of risk of ILI (excluding otitis media) outpatient visits for infants, nor did it significantly affect the risk of otitis media visits. Influenza vaccination during pregnancy did not significantly affect the risk of cesarean section, adjusting for the woman's age. It also did not affect the risk of preterm delivery. Although the immunogenicity of influenza vaccination in pregnancy in mother and infant has been well documented, in this study, we were unable to demonstrate the effectiveness of influenza vaccination with data for hospital admissions and physician visits. One possible interpretation of these findings is that typical influenza surveillance measures based on utilization data are not reliable in distinguishing influenza from other respiratory illness. Hospitalizations for respiratory illness were uncommon in both vaccinees and nonvaccinees.

Am J Perinatol. 2004 Aug;21(6):333-9. PMID: 15311370

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MMR vaccination is associated with an increased risk of developing acute immune thrombocytopenia in childhood.


Immune thrombocytopenic purpura (ITP) is an immunomediated disease characterized by a decrease in platelet count and, in its more severe forms, by bleeding symptoms. Many drugs have been implicated in the pathogenesis of drug-induced thrombocytopenia in adults; only limited data on drug-related ITP in children have been published. Our study was set up to evaluate the consistency of the association between drug and vaccine use and ITP in children. This study is part of an Italian multicentre study on adverse drug reactions in children, coordinated by the Italian National Institute of Health, which was started in November 1999 and is ongoing. The study was conducted by enrolling all children aged more than 1 month who were hospitalized through the paediatric emergency department for the following conditions: thrombocytopenia (platelet count

Drug Saf. 2010;33(1):65-72. PMID: 20000868

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Measles-mumps-rubella vaccine that is given in the second year of life is associated with an increased risk of immune thrombocytopenia purpura.


BACKGROUND: The measles-mumps-rubella vaccine has been associated with immune thrombocytopenia purpura in 2 small studies. METHODS: By using the Vaccine Safety Datalink, we identified measles-mumps-rubella-vaccinated children aged 1 to 18. A case of immune thrombocytopenia purpura was defined as a patient with a platelet count of

Pediatrics. 2008 Mar;121(3):e687-92. PMID: 18310189

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Vaccination-associated adverse events occur in approximately 1 of every 6 toddlers receiving measles-mumps-rubella vaccine dose 1, with high fever occurring in 1 of 20


BACKGROUND/OBJECTIVES: In 1989, the American Academy of Pediatrics and the Advisory Committee on Immunization Practices recommended that school children receive 2 doses of measles-mumps-rubella vaccine. With measles and rubella eliminated from the United States, measles-mumps-rubella vaccine adverse events have come under scrutiny, but no study has compared the reactogenicity of the first (measles-mumps-rubella vaccine dose 1) and second (measles-mumps-rubella vaccine dose 2) doses at the most common ages of administration in the United States. METHODS: From a health maintenance organization, 3 groups of children were recruited: (1) toddlers aged 12 to 24 months receiving measles-mumps-rubella vaccine dose 1; (2) kindergartners aged 4 to 6 years receiving measles-mumps-rubella vaccine dose 2; and (3) middle schoolers aged 10 to 12 years receiving measles-mumps-rubella vaccine dose 2. From 2 weeks before measles-mumps-rubella vaccine administration until 4 weeks afterward, families recorded in diaries the occurrence of potentially common symptoms. Postvaccination symptom rates were compared with the prevaccination baseline, with significance assessed by testing incidence rate ratios estimated by Poisson regression. RESULTS: Of 2173 children enrolled, 373 (17%) were lost to attrition, producing a study population of 1800. Compared with the prevaccination baseline, rates of fever, diarrhea, and rash were significantly elevated postvaccination among 535 toddlers receiving measles-mumps-rubella vaccine dose 1. An estimated net 95 (18%) experienced measles-mumps-rubella vaccine-associated events (median onset 5-10 days postvaccination, duration 2-5 days), with high fever (temperature>or = 39.5 degrees C) occurring in 33 (6%). None required medical attention. For 633 kindergartners and 632 middle schoolers, symptom rates were not significantly elevated after measles-mumps-rubella vaccine dose 2 compared with baseline. CONCLUSIONS: Vaccination-associated adverse events occur in approximately 1 of every 6 toddlers receiving measles-mumps-rubella vaccine dose 1, with high fever occurring in 1 of 20. Adverse events are infrequent for measles-mumps-rubella vaccine dose 2 administered to school-aged children.

Pediatrics. 2006 Oct;118(4):1422-30. PMID: 17015532

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Combined MMR and varicella live vaccine is associated with higher rates of febrile convulsion than giving the vaccines separately.


BACKGROUND: A combined measles, mumps, rubella, varicella live vaccine (MMRV, Merck and Co., Inc., US) was recently licensed in the US. Pre-licensure clinical trial data showed a significant increase in fever in days 5-12 following MMRV vaccination as compared to the vaccines given separately (MMR+V). This post-licensure retrospective cohort study was undertaken to assess the incidence of febrile convulsion following MMRV. METHODS: Children ages 12-60 months who received a first dose of MMRV in February 2006-June 2007 in a managed care organization were included in the study. Subjects were optimally matched on age, sex, and calendar date of vaccination to children who received MMR+V concomitantly in November 2003-January 2006, before MMRV licensure. Potential cases of febrile convulsion were identified through administrative data and adjudicated by expert panel, according to pre-specified criteria. RESULTS: During the 30 days post-vaccination, there were 128 and 94 potential convulsion cases among the 31,298 children in the MMRV and MMR+V cohorts, respectively. After review of available medical charts and adjudication, there were 84 cases of confirmed febrile convulsion, 44 (1.41/1000) and 40 (1.28/1000) in the MMRV and MMR+V cohorts, respectively (RR=1.10, 95% CI=0.72, 1.69). In days 5-12 following vaccination, a pre-specified period of interest, the respective numbers were 22 (0.70/1000) and 10 (0.32/1000) (RR=2.20, 95% CI=1.04, 4.65). CONCLUSION: These data suggest that the risk of febrile convulsion is increased in days 5-12 following vaccination with MMRV as compared to MMR+V given separately during the same visit, when post-vaccination fever and rash are also increased in clinical trials. While there was no evidence of an increase in the overall month following vaccination, the elevated risk during this time period should be communicated and needs to be balanced with the potential benefit of a combined vaccine.

Vaccine. 2009 Jul 23;27(34):4656-61. Epub 2009 Jun 9. PMID: 19520201

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Autistic children have elevated levels of measles antibodies indicating that measles vaccination may be causing autoimmunity in these children.


Virus-induced autoimmunity may play a causal role in autism. To examine the etiologic link of viruses in this brain disorder, we conducted a serologic study of measles virus, mumps virus, and rubella virus. Viral antibodies were measured by enzyme-linked immunosorbent assay in the serum of autistic children, normal children, and siblings of autistic children. The level of measles antibody, but not mumps or rubella antibodies, was significantly higher in autistic children as compared with normal children (P = 0.003) or siblings of autistic children (P

Pediatr Neurol. 2003 Apr;28(4):292-4. PMID: 12849883

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Measles virus DNA from the MMR vaccine has been found in peripheral mononuclear cells in patients with ulcerative colitis and children with autism, indicating its possible role in the pathogenesis of these disorders.


It has been reported that measles virus may be present in the intestine of patients with Crohn's disease. Additionally, a new syndrome has been reported in children with autism who exhibited developmental regression and gastrointestinal symptoms (autistic enterocolitis), in some cases soon after MMR vaccine. It is not known whether the virus, if confirmed to be present in these patients, derives from either wild strains or vaccine strains. In order to characterize the strains that may be present, we have carried out the detection of measles genomic RNA in peripheral mononuclear cells (PBMC) in eight patients with Crohn's disease, three patients with ulcerative colitis, and nine children with autistic enterocolitis. As controls, we examined healthy children and patients with SSPE, SLE, HIV-1 (a total of eight cases). RNA was purified from PBMC by Ficoll-paque, followed by reverse transcription using AMV; cDNAs were subjected to nested PCR for detection of specific regions of the hemagglutinin (H) and fusion (F) gene regions. Positive samples were sequenced directly, in nucleotides 8393-8676 (H region) or 5325-5465 (from noncoding F to coding F region). One of eight patients with Crohn disease, one of three patients with ulcerative colitis, and three of nine children with autism, were positive. Controls were all negative. The sequences obtained from the patients with Crohn's disease shared the characteristics with wild-strain virus. The sequences obtained from the patients with ulcerative colitis and children with autism were consistent with being vaccine strains. The results were concordant with the exposure history of the patients. Persistence of measles virus was confirmed in PBMC in some patients with chronic intestinal inflammation.

Dig Dis Sci. 2000 Apr;45(4):723-9. PMID: 10759242

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Rates of intussusception associated with rotavirus vaccines may be significantly underestimated.


BACKGROUND: Because a previous rotavirus vaccine was associated with intussusception, new rotavirus vaccines are monitored postlicensure for any such association. Accurate background intussusception rates are needed to determine whether the number of cases observed after vaccination exceeds that expected by chance. Previously, intussusception rates were obtained from inpatient discharge databases. We sought to determine the rate of intussusception among infants managed only with short-stay or emergency department care. METHODS: Intussusception cases occurring in infants were identified retrospectively at 3 children's hospitals from January 2001 through March 2006, a period without rotavirus vaccine use, by a search of discharge, billing, and radiology databases for International Classification of Diseases, Ninth Revision, Clinical Modification code 560.0 (intussusception) and procedure codes and by review of medical records. RESULTS: Of 156 infants with intussusception fulfilling Brighton level 1 criteria, 81 (52%) were billed as inpatients, 68 (44%) as short-stay patients, and 7 (4%) as emergency department patients only. The use of only inpatients assigned code 560.0 underestimated the total number of level 1 cases at the hospitals by 44%. The mean annual intussusception rate for the hospitals' catchment counties was 49.3 cases per 100,000 live births (inpatient cases: 27.1 cases per 100,000 live births; short-stay or emergency department cases: 22.3 cases per 100,000 live births). CONCLUSIONS: Intussusception rates based solely on inpatient discharge databases could underestimate the true incidence of level 1 intussusception by>40%. Background rates used for assessment of risk after vaccination should account for cases managed only with short-stay or emergency department care.

J Infect Dis. 2009 Nov 1;200 Suppl 1:S264-70. PMID: 19817607

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Rotavirus vaccinations have a history of causing adverse effects such as intussusception.


BACKGROUND: Rotavirus vaccine was licensed on August 31, 1998, and subsequently recommended for routine use among infants. To assess rare adverse events, postlicensure surveillance was conducted. OBJECTIVE: To describe the cases of intussusception among rotavirus vaccine recipients reported to the Vaccine Adverse Event Reporting System from October 1998 through December 1999. SETTING AND PARTICIPANTS: Infants vaccinated with rotavirus vaccine in the United States. OUTCOME MEASURES: Intussusception confirmed by radiology, surgery, or autopsy report with medical record documentation or confirmed by a primary health care provider. RESULTS: There were 98 confirmed cases of intussusception after vaccination with rotavirus vaccine reported to the Vaccine Adverse Event Reporting System; 60 of these developed intussusception within 1 week after vaccination. Based on calculations using vaccine distribution data and intussusception incidence rates from 2 separate databases, an estimated 7 to 16 cases would have been expected to occur in the week after vaccination by chance alone. CONCLUSION: Using a passive surveillance system for vaccine adverse events, we observed at least a fourfold increase over the expected number of intussusception cases occurring within 1 week of receipt of rotavirus vaccine. Other studies were initiated to further define the relationship between rotavirus vaccine and intussusception. In light of these and other data, the rotavirus vaccine manufacturer voluntarily removed its product from the market, and the recommendation for routine use of rotavirus vaccine among US infants has been withdrawn.

Pediatrics. 2001 Jun;107(6):E97. PMID: 11389295

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Rotavirus vaccination has been associated with increased risk for gastroenteritis and intussusception.


BACKGROUND: The rhesus-human rotavirus reassortant-tetravalent vaccine (RRV-TV) was licensed on August, 31, 1998, and subsequently recommended for routine infant immunizations in the United States. After approximately 1 million doses had been administered, an increase in acute risk of intussusception in vaccinees led to the suspension of the use of RRV-TV and its withdrawal from the market. These postmarketing safety studies focused on a single adverse event (intussusception) and, to minimize the risk of a false-positive finding, accepted only cases that met a strict case definition. Safer rotavirus vaccines are needed to prevent the substantial global morbidity and mortality caused by rotavirus infections; their development and future use may benefit from a better understanding of the postmarketing safety profile of RRV-TV beyond intussusception. OBJECTIVE: To characterize more completely the postmarketing surveillance safety profile of RRV-TV more completely by review and analysis of Vaccine Adverse Event Reporting System (VAERS) case reports to better understand 1) whether severe adverse events other than intussusception may have occurred after RRV-TV and 2) the likely scope of gastrointestinal illnesses, of which the previously identified, highly specific intussusception cases may account for just a fraction. SETTING AND PARTICIPANTS: Infants vaccinated with RRV-TV and other vaccines in the United States and for whom a report was submitted to VAERS during September 1, 1998, to December 31, 1999. METHODOLOGY: To detect adverse events of interest other than intussusception, we used proportional morbidity analysis to compare the adverse event profile of VAERS reports among infants who received routine vaccines including RRV-TV (after excluding confirmed and suspected intussusception reports) with infants who received identical vaccine combinations but without RRV-TV. Next, to better capture all described diagnoses, signs, and symptoms associated with the suspected adverse events, a set of new codes was developed and assigned to each VAERS report. All 448 nonfatal RRV-TV-associated reports (including intussusception) were recoded manually from the clinical description on the VAERS report and categorized into clinical groups to better describe a spectrum of reported illnesses after the vaccine. Each report was assigned to one of the following hierarchical and mutually exclusive clinical groups: 1) diagnosed intussusception; 2) suspected intussusception; 3) illness consistent with either gastroenteritis or intussusception; 4) gastroenteritis; 5) other gastrointestinal diagnoses (ie, not consistent with intussusception or rotavirus-like gastroenteritis); and 6) nongastrointestinal diagnoses. RESULTS: Even after excluding intussusception cases, a higher proportion of RRV-TV reports than non-RRV-TV reports included fever and various gastrointestinal symptoms, most notably bloody stool but also vomiting, diarrhea, abdominal pain, gastroenteritis, abnormal stool, and dehydration. Distribution of RRV-TV reports by clinical groups was as follows: diagnosed intussusception (109 [24%], suspected intussusception (36 [8%]), and illness consistent with gastroenteritis or intussusception (33 [7%]), gastroenteritis (101 [22%]), other gastrointestinal diagnoses (10 [2%]), and nongastrointestinal outcomes (159 [35%]). The median time interval between vaccination and illness onset decreased incrementally among the first 4 clinical groups: from 7 days for diagnosed intussusceptions to 3 days for gastroenteritis. CONCLUSIONS: Intussusception and gastroenteritis were the most commonly reported outcomes; however, a substantial number of reports indicate signs and symptoms consistent with either illness, possibly suggestive of a spectrum of gastrointestinal illness(es) related to RRV-TV. Although VAERS data have recognized limitations such as underreporting (that may differ by vaccine) and are nearly always insufficient to prove causality between a vaccine and an adverse event, this safety profile of RRV-TV may aid better understanding of the pathophysiology of intussusception as well as development of future safer rotavirus vaccines.

Pediatrics. 2004 Apr;113(4):e353-9. PMID: 15060267

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Incidence of adverse reactions to vaccines in pediatric populations are under-reported and may be as high as 43.4% for certain vaccine combinations.


OBJECTIVE: To detect the appearance and specify the types of adverse reactions to vaccines registered in a paediatric population. PATIENTS AND METHODS: A 6-month, prospective, observational, multicentre epidemiological vaccine safety study was undertaken in 2002 covering a paediatric population subject to vaccine administration. A two-phase telephone survey of all patients was conducted, comprising an initial call at 1 week and a follow-up call at 30 days after the vaccine administration date. A paediatrician was responsible for diagnosing the specific type of adverse reaction. RESULTS: Of a total sample of 946 children, ranging in age from 0 to 14 years (50.8% girls, 49.1% boys), 191 non-serious suspected adverse reactions were detected, representing 19% of the vaccinated children. Reactions to the diphtheria, tetanus, pertussis acellular and Haemophilus influenzae type b (DTPa + Hib) vaccine appeared in 43.4% of cases, followed by reactions to the measles, mumps, rubella (MMR) [18.4%] and adult tetanus and diphtheria (Td) [17.8%] vaccines. The most frequent types of adverse reactions to vaccines were: injection-site oedema (12.2 per 1000 doses); pain at site of inoculation (10.3 per 1000 doses); temperature not recorded but believed by parents to be very high (4.6 per 1000 doses); and measured temperature indicating fever of 39-40.5 masculineC (4.4 per 1000 doses). Fifty-five percent (n = 21) of cases of injection-site oedema were attributed to DTPa + Hib vaccine (18.8 per 1000 doses), followed by 18.4% (n = 7) attributable to Td vaccine (112 per 1000 doses). Indeed, this latter vaccine was responsible for 43.8% (n = 14; 226 per 1000 doses) of all reported pain at the site of inoculation. MMR vaccine was linked to the occurrence of fever of 39-40.5 masculineC in 52% of cases (n = 10; 29 per 1000 doses). Two children were treated by the emergency services, but there were no deaths or hospitalisations. CONCLUSIONS: An active search for subjects with suspected adverse reactions to vaccines led to the detection of reactions that are usually not reported. Primary-care physicians and nurses must be vigilant for information on adverse reactions to vaccines in paediatric populations.

Clin Drug Investig. 2004;24(8):457-63. PMID: 17523706

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Near complete vaccination coverage for varicella does not prevent outbreaks in those treated.


OBJECTIVES: The implementation of a routine childhood varicella vaccination program in the United States in 1995 has resulted in a dramatic decline in varicella morbidity and mortality. Although disease incidence has decreased, outbreaks of varicella continue to be reported, increasingly in highly vaccinated populations. In 2000, a varicella vaccination requirement was introduced for kindergarten entry in Arkansas. In October 2003, large numbers of varicella cases were reported in a school with high vaccination coverage. We investigated this outbreak to examine transmission patterns of varicella in this highly vaccinated population, to estimate the effectiveness of 1 dose of varicella vaccine, to identify risk factors for vaccine failure, and to implement outbreak control measures. METHODS: A retrospective cohort study involving students attending an elementary school was conducted. A questionnaire was distributed to parents of all of the students in the school to collect varicella disease and vaccination history; parents of varicella case patients were interviewed by telephone. A case of varicella was defined as an acute, generalized, maculopapulovesicular rash without other apparent cause in a student or staff member in the school from September 1 to November 20, 2003. Varicella among vaccinated persons was defined as varicella-like rash that developed>42 days after vaccination. In vaccinated persons, the rash may be atypical, maculopapular with few or no vesicles. Cases were laboratory confirmed by polymerase chain reaction, and genotyping was performed to identify the strain associated with the outbreak. RESULTS: Of the 545 students who attended the school, 88% returned the questionnaire. Overall varicella vaccination coverage was 96%. Forty-nine varicella cases were identified; 43 were vaccinated. Three of 6 specimens tested were positive by polymerase chain reaction. The median age at vaccination of vaccinated students in the school was 18 months, and the median time since vaccination was 59 months. Forty-four cases occurred in the East Wing, where 275 students in grades kindergarten through 2 were located, and vaccination coverage was 99%. In this wing, varicella attack rates among unvaccinated and vaccinated students were 100% and 18%, respectively. Vaccine effectiveness against varicella of any severity was 82% and 97% for moderate/severe varicella. Vaccinated cases were significantly milder compared with unvaccinated cases. Among the case patients in the East Wing, the median age at vaccination was 18.5 and 14 months among non-case patients. Four cases in the West Wing did not result in further transmission in that wing. The Arkansas strains were the same as the common varicella-zoster virus strain circulating in the United States (European varicella-zoster virus strain). CONCLUSIONS: Although disease was mostly mild, the outbreak lasted for approximately 2 months, suggesting that varicella in vaccinated persons was contagious and that 99% varicella vaccination coverage was not sufficient to prevent the outbreak. This investigation highlights several challenges related to the prevention and control of varicella outbreaks with the 1-dose varicella vaccination program and the need for further prevention of varicella through improved vaccine-induced immunity with a routine 2-dose vaccination program. The challenges include: 1-dose varicella vaccination not providing sufficient herd immunity levels to prevent outbreaks in school settings where exposure can be intense, the effective transmission of varicella among vaccinated children, and the difficulty in the diagnosis of mild cases in vaccinated persons and early recognition of outbreaks for implementing control measures. The efficacy of 2 doses of varicella vaccine compared with 1 dose was assessed in a trial conducted among healthy children who were followed for 10 years. The efficacy for 2 doses was significantly higher than for 1 dose of varicella vaccine. This higher efficacy translated into a 3.3-fold lower risk of developing varicella>42 days after vaccination in 2- vs 1-dose recipients. Of the children receiving 2 doses, 99% achieved a glycoprotein-based enzyme-linked immunosorbent assay level of>or =5 units (considered a correlate of protection) 6 weeks after vaccination compared with 86% of children who received 1 dose. The 6-week glycoprotein-based enzyme-linked immunosorbent assay level of>or =5 units has been shown to be a good surrogate for protection from natural disease. Ten years after the implementation of the varicella vaccination program, disease incidence has declined dramatically, and vaccination coverage has increased greatly. However, varicella outbreaks continue to occur among vaccinated persons. Although varicella disease among vaccinated persons is mild, they are contagious and able to sustain transmission. As a step toward better control of varicella outbreaks and to reduce the impact on schools and public health officials, in June 2005, the Advisory Committee on Immunization Practices recommended the use of a second dose of varicella vaccine in outbreak settings. Early recognition of outbreaks is important to effectively implement a 2-dose vaccination response and to prevent more cases. Although the current recommendation of providing a second dose of varicella vaccine during an outbreak offers a tool for controlling outbreaks, a routine 2-dose recommendation would be more effective at preventing cases. Based on published data on immunogenicity and efficacy of 2 doses of varicella vaccine, routine 2-dose vaccination will provide improved protection against disease and further reduce morbidity and mortality from varicella.

Pediatrics. 2006 Jun;117(6):e1070-7. PMID: 16740809

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Varicella outbreaks occur in vaccinated populations, even when receiving 2 doses.


BACKGROUND: In June 2006, the Advisory Committee on Immunization Practices (ACIP) expanded its June 2005 recommendation for a second dose of varicella vaccine during outbreaks to a recommendation for routine school entry second dose varicella vaccination. In October 2006, the Arkansas Department of Health was notified of a varicella outbreak among students where some received a second dose during an outbreak-related vaccination campaign in February 2006. METHODS: The outbreak was investigated using a school-wide parental survey with a follow-up survey of identified case patients. Vaccination status was verified using state and local immunization records. Limited laboratory testing confirmed circulation of wild-type varicella, including varicella in 2-dose vaccine recipients. RESULTS: Vaccination information was available for 871 (99%) of the 880 children. Varicella vaccination coverage was 97% (2-dose, 39%; 1-dose, 58%). A review of the February vaccination clinic found no deficiencies; lot numbers did not differ between cases and noncases. Varicella was confirmed by PCR in 5 (42%) of 12 lesion specimens and by IgM in 1 (6%) of 16 serum specimens. Varicella was reported in 84 children, including 25 (30%) two-dose and 53 (63%) one-dose recipients. Attack rates among 2-dose recipients (10.4%) and 1-dose recipients (14.6%) were not significantly different (RR: 0.72, 95% CI: 0.44-1.15). All 2-dose recipients and 80% of 1-dose recipients reported having 50 or fewer skin lesions. CONCLUSION: This outbreak is the first to document varicella in both 1- and 2-dose vaccine recipients; both groups had mild disease. The vaccine effectiveness of 1 and 2 doses were similar.

Pediatr Infect Dis J. 2009 Aug;28(8):678-81. PMID: 19593254

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HPV vaccination does not have a therapeutic effect in young women with pre-existing human papillomavirus infection.


CONTEXT: Viruslike particle human papillomavirus (HPV) vaccines were designed to prevent HPV infection and development of cervical precancers and cancer. Women with oncogenic HPV infections might consider vaccination as therapy. OBJECTIVE: To determine whether vaccination against HPV types 16 and 18 increases the rate of viral clearance in women already infected with HPV. DESIGN AND SETTING: Phase 3, masked, community-based randomized trial conducted in 2 provinces of Costa Rica. PARTICIPANTS: A total of 2189 women aged 18 to 25 years who were recruited between June 2004 and December 2005. Participants were positive for HPV DNA at enrollment, had at least 6 months of follow-up, and had follow-up HPV DNA results. INTERVENTION: Participants were randomly assigned to receive 3 doses of a bivalent HPV-16/18 L1 protein viruslike particle AS04 candidate vaccine (n = 1088) or a control hepatitis A vaccine (n = 1101) over 6 months. MAIN OUTCOME MEASURES: Presence of HPV DNA was determined in cervical specimins by a molecular hybridization assay using chemiluminescence with HPV RNA probes and by polymerase chain reaction using SPF10 primers and a line probe assay detection system before vaccination and by polymerase chain reaction after vaccination. We compared rates of type-specific viral clearance using generalized estimating equations methods at the 6-month visit (after 2 doses) and 12-month visit (after 3 doses) in the 2 study groups. RESULTS: There was no evidence of increased viral clearance at 6 or 12 months in the group who received HPV vaccine compared with the control group. Clearance rates for HPV-16/18 infections at 6 months were 33.4% (82/248) in the HPV vaccine group and 31.6% (95/298) in the control group (vaccine efficacy for viral clearance, 2.5%; 95% confidence interval, -9.8% to 13.5%). Human papillomavirus 16/18 clearance rates at 12 months were 48.8% (86/177) in the HPV vaccine group and 49.8% (110/220) in the control group (vaccine efficacy for viral clearance, -2.0%; 95% confidence interval, -24.3% to 16.3%). There was no evidence of a therapeutic effect for other oncogenic or nononcogenic HPV categories, among women receiving all vaccine doses, among women with single infections, or among women stratified by the following entry variables: HPV-16/18 serology, cytologic results, HPV DNA viral load, time since sexual debut, Chlamydia trachomatis or Neisseria gonorrhoeae infection, hormonal contraceptive use, or smoking. CONCLUSION: In women positive for HPV DNA, HPV-16/18 vaccination does not accelerate clearance of the virus and should not be used to treat prevalent infections. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00128661.

JAMA. 2007 Aug 15;298(7):743-53. PMID: 17699008

72
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Influenza vaccines were not shown to be effective among children 6 to 59 months of age during 2 influenza seasons.


OBJECTIVE: To measure vaccine effectiveness (VE) in preventing influenza-related health care visits among children aged 6 to 59 months during 2 consecutive influenza seasons. DESIGN: Case-cohort study estimating effectiveness of inactivated influenza vaccine in preventing inpatient/outpatient visits (emergency department [ED] and outpatient clinic). We compared vaccination status of laboratory-confirmed influenza cases with a cluster sample of children from a random sample of practices in 3 counties (subcohort) during the 2003-2004 and 2004-2005 seasons. SETTING: Counties encompassing Rochester, New York, Nashville, Tennessee, and Cincinnati, Ohio. PARTICIPANTS: Children aged 6 to 59 months seen in inpatient/ED or outpatient clinic settings for acute respiratory illnesses and community-based subcohort comparison. Main Exposure Influenza vaccination. MAIN OUTCOME MEASURES: Influenza vaccination status of cases vs subcohort using time-dependent Cox proportional hazards models to estimate VE in preventing inpatient/ED and outpatient visits. RESULTS: During the 2003-2004 and 2004-2005 seasons, 165 and 80 inpatient/ED and 74 and 95 outpatient influenza cases were enrolled, while more than 4500 inpatient/ED and more than 600 outpatient subcohorts were evaluated, respectively. In bivariate analyses, cases had lower vaccination rates than subcohorts. However, significant influenza VE could not be demonstrated for any season, age, or setting after adjusting for county, sex, insurance, chronic conditions recommended for influenza vaccination, and timing of influenza vaccination (VE estimates ranged from 7%-52% across settings and seasons for fully vaccinated 6- to 59-month-olds). CONCLUSION: In 2 seasons with suboptimal antigenic match between vaccines and circulating strains, we could not demonstrate VE in preventing influenza-related inpatient/ED or outpatient visits in children younger than 5 years. Further study is needed during years with good vaccine match.

Anticancer Res. 2009 Nov;29(11):4629-32. PMID: 18838647

73
[+]

Vaccination with measles after DTP and polio vaccine is associated with 2-fold increase in female mortality.


BACKGROUND: The 2-fold increase in female mortality after high-titer measles vaccine may have occurred because many children received diphtheria-tetanus-pertussis (DTP) vaccine or inactivated polio vaccine (IPV) after high-titer measles vaccine. OBJECTIVE: We examined whether DTP vaccine and IPV were associated with increased female mortality when they were the most recent vaccine administered to children who had not received measles vaccine. Setting and Design: IPV was used as a control vaccine in 4 randomized trials of early measles vaccination (MV) with enrollment at 4-6 months of age conducted in Guinea-Bissau. Many children had not received all 3 DTP vaccinations before enrollment, and therefore received DTP after IPV or MV. We examined whether DTP vaccination status at enrollment affected the female-male mortality ratio. Population: 9544 children enrolled in 4 trials. Main outcome measure: The female-male mortality ratio in different vaccine groups. RESULTS: Females had a higher mortality rate than males among children randomized to receive IPV (mortality rate ratio [MR] 1.52, 95% CI 1.02-2.28), but females had a similar mortality rate to males among children randomized to receive MV (MR 1.01, 0.69-1.46) and among children in the IPV group after they had received MV at 9 months of age or later (MR 0.88, 0.68-1.14). Children who had not received a third dose of DTP before enrollment (and were likely to receive DTP after MV or IPV) tended to have a higher mortality than children who had received all 3 doses of DTP (MR 1.30, 0.97-1.73). This effect was seen only among girls (MR 1.61, 1.08-2.40) and not among boys (MR 1.02, 0.67-1.54). Girls had a lower mortality when MV was the most recent vaccine received rather than DTP or IPV (MR 0.49, 0.28-0.87). CONCLUSIONS: Randomization to IPV was associated with higher female than male mortality. However, the increased female mortality might result from additional doses of DTP received after enrollment and before measles vaccination.

Pediatr Infect Dis J. 2007 Mar;26(3):247-52. PMID: 17484223

74
[+]

Vaccination timing and co-administration may be associated with increased mortality, especially in females.


BACKGROUND: According to studies from Guinea-Bissau and Senegal, live vaccines may reduce the female-male mortality ratio (MR) whereas inactivated vaccines increase this ratio. We used data from The Gambia to examine whether similar tendencies could be found in a different setting. SETTING: Forty villages in the Farafenni area in rural Gambia. SUBJECTS: A population of 17,000 was followed with demographic surveillance between 1998 and 2002; 537 children less than 5 years of age died in this period. METHODS: We used two vaccination surveys and community mortality data to examine, first, the female-male mortality ratio (MR) in the age groups in which DTP and MV are recommended and have a high coverage. Second, using vaccination cards seen post-mortem, we examined the distribution of live or inactivated vaccines as last vaccination in different age groups. Third, we examined the effect of DTP and MV administered simultaneously. MAIN OUTCOME MEASURES: The female-male MR in different age groups and for different vaccines. RESULTS: Vaccination coverage was high for BCG, third dose of DTP (DTP3) and MV, reaching a level of 80-90% within a few months of the recommended age of vaccination. First, the female-male MR was 0.93 (0.63-1.38) in the first 2 months of life when children had received no vaccination or the combination of BCG, HBV and OPV. From 2 to 8 months of age, with DTP and HBV being the main vaccinations, the female-male MR was 1.28 (0.86-1.89). Between 9 and 17 months of age, with MV as the main vaccination, this ratio dropped to 0.73 (0.50-1.07), a significant inversion of the female-male MR (p=0.045). Second, using information from vaccination cards of dead children, boys who died at 2-4 months of age were more likely to have received live BCG and girls to have received inactivated DTP and HBV as last vaccination (p

Vaccine. 2006 May 29;24(22):4701-8. Epub 2006 Mar 31. PMID: 16621182

75
[+]

Pneumococcal vaccines are ineffective in children with a history of recurrent acute ear infections.


BACKGROUND: We recently showed that vaccination with a 7-valent pneumococcal conjugate vaccine (PCV7) followed by a 23-valent pneumococcal polysaccharide vaccine (PPSV23) failed to prevent new episodes of acute otitis media (AOM) in previously unvaccinated toddlers and children with a history of recurrent AOM. We describe in detail the impact of pneumococcal vaccinations on nasopharyngeal carriage of S. pneumoniae in this study population. METHODS: The impact of vaccination with PCV7 followed by PPSV23 on pneumococcal nasopharyngeal carriage was studied in a prospective, randomized trial involving 383 children (age range, 1-7 years) with previous AOM. Nasopharyngeal swab specimens were collected at the time of first vaccination and at 6-7-month intervals during the 26-month follow-up period. RESULTS: Overall, pneumococcal carriage rates did not diminish, remaining at approximately 50% in both PCV7/PPSV23 and control vaccinees. A significant shift from conjugate vaccine- to nonconjugate vaccine-type pneumococci was observed in children aged 1-2 years, who received the conjugate vaccine twice before the polysaccharide vaccine was administered. Conjugate vaccine serotype carriage was not influenced in older children, who received the conjugate vaccine once before receiving the polysaccharide booster. CONCLUSIONS: The administration of conjugate vaccines at least twice also after 2 years of age may be mandatory for reducing the carriage of conjugate vaccine serotypes in children with recurrent AOM. Polysaccharide booster vaccination did not affect nasopharyngeal colonization with serotypes not included in the conjugate vaccine.

Clin Infect Dis. 2004 Oct 1;39(7):911-9. Epub 2004 Sep 1. PMID: 15472839

76
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Pneumococcal vaccines are ineffective in children with a history of recurrent acute ear infections - Article 2.


BACKGROUND: Based on two clinical trials in healthy infants the American Academy of Pediatrics (AAP) advices immunization with a 7-valent pneumococcal conjugate vaccine in children with recurrent acute otitis media (AOM). OBJECTIVE: To study the efficacy of a 7-valent pneumococcal conjugate vaccine on acute otitis media recurrences, its immunogenicity and impact on nasopharyngeal Streptococcus pneumoniae carriage in children with a history of frequent acute otitis media. METHODS: In this double-blind, randomized study, 74 Belgian children, aged 1-7 years, with at least 2 clinically diagnosed episodes of acute otitis media in the previous year were enrolled. Children were immunized with either a 7-valent pneumococcal conjugate vaccine followed by a 23-valent pneumococcal polysaccharide booster or a control hepatitis A vaccine. Total follow-up was 26 months. RESULTS: Despite adequate serum IgG responses to all conjugate vaccine pneumococcal serotypes, no reduction of acute otitis media episodes was observed in the pneumococcal vaccine group as compared to the control group (rate ratio: 1.16; 95% CI: 0.69-1.96). Overall nasopharyngeal pneumococcal carriage remained stable. However, a transient shift from conjugate vaccine related S. pneumoniae serogroups to non-vaccine related serogroups was noted following conjugate vaccination. CONCLUSION: Clinically no protective effect of pneumococcal conjugate vaccination on acute otitis media recurrences was found in children with a history of frequent AOM.

Int J Pediatr Otorhinolaryngol. 2006 Feb;70(2):275-85. Epub 2005 Sep 2. PMID: 16140397

77
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Pneumococcal conjugate vaccine is not effective to prevent ear infections in previously unvaccinated toddlers and children with a history of recurrent ear infections.


BACKGROUND: Pneumococcal conjugate vaccine prevents recurrent acute otitis media (AOM) in infants immunised at 2, 4, 6, and 12-15 months of age. We aimed to find out whether this vaccine also prevents AOM in older children who have had previous episodes of AOM. METHODS: In this double-blind, randomised study, we enrolled 383 patients aged 1-7 years who had had two or more episodes of AOM in the year before entry. Randomisation was stratified in four groups according to age (12-24 months vs 25-84 months) and the number of previous AOM episodes (two or three episodes vs four or more episodes). Children received either 7-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine, or hepatitis A or B vaccines. They were followed up for 18 months for recurrence of AOM. We also cultured samples of middle-ear fluid and nasopharyngeal swabs to assess association of pneumococcal serotypes with AOM after vaccination. FINDINGS: We noted no reduction of AOM episodes in the pneumococcal vaccine group compared with controls (intention-to-treat analysis: rate ratio 1.25, 95% CI 0.99-1.57). Although nasopharyngeal carriage of pneumococci of serotypes included in the conjugate-vaccine was greatly reduced after pneumococcal vaccinations, immediate and complete replacement by non-vaccine pneumococcal serotypes took place. INTERPRETATION: These data do not lend support to the use of pneumococcal conjugate vaccine to prevent otitis media in previously unvaccinated toddlers and children with a history of recurrent AOM.

Lancet. 2003 Jun 28;361(9376):2189-95. PMID: 12842372

78
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Pneumococcal vaccines do not appear to reduce the risk of death from pneumonia in adult populations.


BACKGROUND: Diseases caused by Streptococcus pneumoniae (S. pneumoniae) continue to cause substantial morbidity and mortality throughout the world. Polysaccharide pneumococcal vaccines have been developed for over 50 years and may have the potential to prevent disease and death. OBJECTIVES: To assess the effectiveness of polysaccharide pneumococcal vaccination in preventing disease or death in adults. SEARCH STRATEGY: Trials were identified by electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) issue 2, 2003 (which includes the Cochrane ARI Group's specialised register); MEDLINE (January 1966 to June 2003); and EMBASE (1974 to June 2003). We searched existing literature. The bibliographies of all newly revealed studies were read in order to identify further studies. The vaccine manufacturers, the lead authors of newly identified studies not included in existing meta-analyses were contacted. SELECTION CRITERIA: A) Prospective, randomised or quasi-randomised studies comparing pneumococcal vaccines with placebo, control vaccines or no intervention.B) Case-control studies (including indirect cohort studies) assessing pneumococcal vaccine effectiveness against invasive pneumococcal disease. Cohort studies are excluded. DATA COLLECTION AND ANALYSIS: A) Randomised studies. Trial quality assessment was conducted by two reviewers (JH and DT). Data extraction was done by three reviewers (JH, DT, KD). There were many instances of unclear or incomplete data in the trial reports, and the final dataset was arrived at after much deliberation and discussion, including comparison with the data used in two previous reviews of this question. Due to the age of the trials (dating back to 1954 in one case) it was not generally possible to obtain clarification from the authors, though a partial clarification was achieved in one case.B) Non-randomised studies. Study quality was assessed by two reviewers (RA and KD). MAIN RESULTS: The combined results from the randomised studies fail to show that the polysaccharide pneumococcal vaccine is effective in preventing either pneumonia (outcome 6: odds ratio = 0.77, confidence interval 0.58, 1.02, number = 14) or death (outcome 8: odds ratio 0.90, confidence interval 0.76, 1.07, number = 11). Despite encouraging data from some very early trials, pooling trials published from 1977 on suggests there is no effect (outcome 6; odds ratio = 0.96, confidence interval 0.80, 1.15, number = 12; outcome 9: odds ratio = 0.98, confidence interval 0.88, 1.09, number = 10). The available data cannot distinguish whether this heterogeneity in results is due to improvements in trial methodology and reporting, to differences in trial setting or to real loss of efficacy over time. This is because the early, poorly reported trials were conducted in high-risk healthy populations where the expected benefit is greatest. The case-control studies show significant efficacy in preventing invasive pneumococcal disease: OR 0.47 (CI 0.37, 0.59) corresponding to an efficacy of 53%. REVIEWER'S CONCLUSIONS: While polysaccharide pneumococcal vaccines do not appear to reduce the incidence of pneumonia or death in adults with or without chronic illness, or in the elderly (55 years and above), the evidence from non-randomised studies suggests that the vaccines are effective in the reducing the incidence of the more specific outcome, invasive pneumococcal disease, among adults and the immunocompetent elderly (55 years and above). Surveillance data suggest that infection rates vary widely between and also within countries, but a typical figure in developed countries is 0.01%, or 10 per 100,000 per year. Efficacy of 50% then corresponds to a number-needed-to-treat (NNT) of 20,000 vaccinations per infection avoided, and perhaps 50,000 per death avoided.

Cochrane Database Syst Rev. 2003(4):CD000422. PMID: 14583920

79
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The measles-mumps-rubella vaccine causes autoantibodies to be formed against myelin basic protein (the protective coating of the nerves) contributing to the pathogenesis of austim.


Autoimmunity to the central nervous system (CNS), especially to myelin basic protein (MBP), may play a causal role in autism, a neurodevelopmental disorder. Because many autistic children harbor elevated levels of measles antibodies, we conducted a serological study of measles-mumps-rubella (MMR) and MBP autoantibodies. Using serum samples of 125 autistic children and 92 control children, antibodies were assayed by ELISA or immunoblotting methods. ELISA analysis showed a significant increase in the level of MMR antibodies in autistic children. Immunoblotting analysis revealed the presence of an unusual MMR antibody in 75 of 125 (60%) autistic sera but not in control sera. This antibody specifically detected a protein of 73-75 kD of MMR. This protein band, as analyzed with monoclonal antibodies, was immunopositive for measles hemagglutinin (HA) protein but not for measles nucleoprotein and rubella or mumps viral proteins. Thus the MMR antibody in autistic sera detected measles HA protein, which is unique to the measles subunit of the vaccine. Furthermore, over 90% of MMR antibody-positive autistic sera were also positive for MBP autoantibodies, suggesting a strong association between MMR and CNS autoimmunity in autism. Stemming from this evidence, we suggest that an inappropriate antibody response to MMR, specifically the measles component thereof, might be related to pathogenesis of autism.

J Biomed Sci. 2002 Jul-Aug;9(4):359-64. PMID: 12145534

80
[+]

Influenza-related mortality is not prevented with increasing vaccination coverage.


We investigated trends in influenza-related mortality among the elderly population in Italy associated with increased vaccination coverage. Using Italian vital statistics data, we studied monthly death rates for pneumonia and influenza and all-cause for persons>/=65 years of age by 5-year age groups for 1970-2001. Using a classic seasonal regression modelling approach, we estimated the age-specific seasonal excess mortality rates among Italian elderly as a measure of influenza-related deaths. We studied trends in excess mortality after adjusting for population aging and analyzing separately seasons dominated by the severe A/H3N2 subtype and those dominated by other circulating influenza subtypes. After the late 1980s, no decline in age-adjusted excess mortality was associated with increasing influenza vaccination distribution primarily targeted for the elderly. These findings suggest that either the vaccine failed to protect the elderly against mortality (possibly due to immune senescence), and/or the vaccination efforts did not adequately target the frailest elderly. As in the US, our study challenges current strategies to best protect the elderly against mortality, warranting the need for better controlled trials with alternative vaccination strategies.

Vaccine. 2006 Oct 30;24(42-43):6468-75. Epub 2006 Jul 7. PMID: 16876293

81
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Smallpox vaccination has been associated with cardiac complications such as myopericarditis.


In 2002, the US Federal government initiated a campaign to vaccinate military personnel and members of the civilian population against smallpox to counter a possible bioterrorism attack. More than 1,200,000 military personnel and approximately 40,000 civilians have been vaccinated since that time. The incidence of myopericarditis in these vaccinees has clearly exceeded calculated background rates and has prompted discussion about cardiac inflammation and other potential vaccine-associated cardiac complications such as dilated cardiomyopathy (DCM) and myocardial ischemia. Although it seems reasonable to predict that some cases of smallpox-associated myopericarditis will progress to DCM, only small numbers have been documented so far, and a causal relationship is difficult to ascertain. With regard to myocardial ischemia, both historical and current data do not suggest a causal association with the vaccine. We describe a case report of myopericarditis following smallpox immunization and provide a review of all cardiac complications associated with vaccination.

South Med J. 2009 May 7. Epub 2009 May 7. PMID: 19434043

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Among US military personnel vaccinated against smallpox, myopericarditis occurred at a rate of 1 per 12,819 primary vaccinees, and 3.6 fold higher in those without previous vaccinia vaccination.


CONTEXT: In the United States, the annual incidence of myocarditis is estimated at 1 to 10 per 100,000 population. As many as 1% to 5% of patients with acute viral infections involve the myocardium. Although many viruses have been reported to cause myopericarditis, it has been a rare or unrecognized event after vaccination with the currently used strain of vaccinia virus (New York City Board of Health). OBJECTIVE: To describe a series of probable cases of myopericarditis following smallpox vaccination among US military service members reported since the reintroduction of vaccinia vaccine. DESIGN, SETTING, PARTICIPANTS: Surveillance case definitions are presented. The cases were identified either through sentinel reporting to US military headquarters surveillance using the Defense Medical Surveillance System or reports to the Vaccine Adverse Event Reporting System using International Classification of Diseases, Ninth Revision. The cases occurred among individuals vaccinated from mid-December 2002 to March 14, 2003. MAIN OUTCOME MEASURE: Elevated serum levels of creatine kinase (MB isoenzyme), troponin I, and troponin T, usually in the presence of ST-segment elevation on electrocardiogram and wall motion abnormalities on echocardiogram. RESULTS: Among 230,734 primary vaccinees, 18 cases of probable myopericarditis after smallpox vaccination were reported (an incidence of 7.8 per 100,000 over 30 days). No cases of myopericarditis following smallpox vaccination were reported among 95,622 vaccinees who were previously vaccinated. All cases were white men aged 21 years to 33 years (mean age, 26.5 years), who presented with acute myopericarditis 7 to 19 days following vaccination. A causal relationship is supported by the close temporal clustering (7-19 days; mean, 10.5 days following vaccination), wide geographic and temporal distribution, occurrence in only primary vaccinees, and lack of evidence for alternative etiologies or other diseases associated with myopericarditis. Additional supporting evidence is the observation that the observed rate of myopericarditis among primary vaccinees is 3.6-fold (95% confidence interval, 3.33-4.11) higher than the expected rate among personnel who were not vaccinated. The background incidence of myopericarditis did not show statistical significance when stratified by age (20-34 years: 2.18 expected cases per 100,000; 95% confidence interval [CI], 1.90-2.34), race (whites: 1.82 per 100,000; 95% CI, 1.50-2.01), and sex (males: 2.28 per 100,000; 95% CI, 2.04-2.54). CONCLUSION: Among US military personnel vaccinated against smallpox, myopericarditis occurred at a rate of 1 per 12 819 primary vaccinees. Myopericarditis should be considered an expected adverse event associated with smallpox vaccination. Clinicians should consider myopericarditis in the differential diagnosis of patients presenting with chest pain 4 to 30 days following smallpox vaccination and be aware of the implications as well as the need to report this potential adverse advent.

JAMA. 2003 Jun 25;289(24):3283-9. PMID: 12824210

83
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Myocarditis and pericarditis have been reported following smallpox vaccination in Europe, Australia and the United States.


Myocarditis was reported after smallpox vaccination in Europe and Australia, but no association had been reported with the US vaccine. We conducted surveillance to describe and determine the frequency of myocarditis and/or pericarditis (myo/pericarditis) among civilians vaccinated during the US smallpox vaccination program between January and October 2003. We developed surveillance case definitions for myocarditis, pericarditis, and dilated cardiomyopathy after smallpox vaccination. We identified 21 myo/pericarditis cases among 37,901 vaccinees (5.5 per 10,000); 18 (86%) were revacinees, 14 (67%) were women, and the median age was 48 years (range, 25-70 years). The median time from vaccination to onset of symptoms was 11 days (range, 2-42 days). Myo/pericarditis severity was mild, with no fatalities, although 9 patients (43%) were hospitalized. Three additional vaccinees were found to have dilated cardiomyopathy, recognized within 3 months after vaccination. We describe an association between smallpox vaccination, using the US vaccinia strain, and myo/pericarditis among civilians.

Clin Infect Dis. 2008 Mar 15;46 Suppl 3:S242-50. PMID: 18284365

84
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An economic analysis of mass smallpox vaccination reveals that cardiovascular adverse events would be sizeable and costly.


Of>39,000 civilian public health responders vaccinated against smallpox in 2003, 203 reported cardiovascular adverse events (CAEs). An association exists between the US vaccinia strain and myocarditis and/or pericarditis ("myo/pericarditis" [MP]). Other associations are inconclusive. We used surveillance and follow-up survey data of CAE case patients to estimate the resources used during the 2003 smallpox vaccination program and used a probabilistic model to estimate the potential costs of CAEs in a mass vaccination campaign. For every million adult vaccinees, 3001 CAEs (including 351 MP cases) would occur, with>92% in revaccinees. CAEs would require a median of 5934 outpatient visits, 1786 emergency department visits, 533 days in general wards, 132 days in intensive care units, 5484 cardiac enzymes tests, 3504 electrocardiograms, 3049 chemistry tests, 2828 complete blood counts, and 1444 transthoracic echocardiograms, among other procedures. CAEs would reduce productivity (15,969 work days lost) and cost $11 per vaccinee. In a mass vaccination campaign, the care of a sizable number of CAEs would be resource intensive.

J Rheumatol. 1994 Jul;21(7):1305-9. PMID: 18284356

85
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Erythema multiforme has been reported as a possible side effect of vaccination for human papillomavirus.


Erythema multiforme (EM) is an acute self-limited immune-mediated reaction manifested by target skin lesions with mucous membrane involvement. The most common causes are infections and drugs. Vaccinations have been reported as a triggering factor, and they may be a frequent cause of EM in childhood. A 19-year-old female developed several target lesions of the hands and feet 10 days after the second dose of human papillomavirus (HPV) vaccine. Clinico-histologically, a diagnosis of EM minor was made. Treatment with topical corticosteroids and oral antihistamines resulted in complete clearance of the rash. Four months later, she received the last booster dose of the vaccine. A few subtle lesions appeared and disappeared spontaneously after a few days. Gardasil is a non-infectious vaccine, developed for the prevention of cervical cancer, precancerous genital lesions and genital warts. It delivers the major capsid (L1) protein of HPV types 6, 11, 16 and 18. Mild local reactions are the main adverse events. The only serious events are very rare cases of anaphylaxis. In our patient, the temporal relationship between the development of EM and the vaccination suggests that the HPV vaccine probably was the causal agent. This is the first published case of EM following HPV vaccination.

Dermatology. 2010;220(1):60-2. Epub 2009 Nov 3. PMID: 19887766

86
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Postlicensure safety survelliance has revealed a disproportionate reporting of syncope and venous thromboembolic events following quadrivalent HPV vaccination.


CONTEXT: In June 2006, the Food and Drug Administration licensed the quadrivalent human papillomavirus (types 6, 11, 16, and 18) recombinant vaccine (qHPV) in the United States for use in females aged 9 to 26 years; the Advisory Committee on Immunization Practices then recommended qHPV for routine vaccination of girls aged 11 to 12 years. OBJECTIVE: To summarize reports to the Vaccine Adverse Event Reporting System (VAERS) following receipt of qHPV. DESIGN, SETTING, AND PARTICIPANTS: Review and describe adverse events following immunization (AEFIs) reported to VAERS, a national, voluntary, passive surveillance system, from June 1, 2006, through December 31, 2008. Additional analyses were performed for some AEFIs in prelicensure trials, those of unusual severity, or those that had received public attention. Statistical data mining, including proportional reporting ratios (PRRs) and empirical Bayesian geometric mean methods, were used to detect disproportionality in reporting. MAIN OUTCOME MEASURES: Numbers of reported AEFIs, reporting rates (reports per 100,000 doses of distributed vaccine or per person-years at risk), and comparisons with expected background rates. RESULTS: VAERS received 12 424 reports of AEFIs following qHPV distribution, a rate of 53.9 reports per 100,000 doses distributed. A total of 772 reports (6.2% of all reports) described serious AEFIs, including 32 reports of death. The reporting rates per 100,000 qHPV doses distributed were 8.2 for syncope; 7.5 for local site reactions; 6.8 for dizziness; 5.0 for nausea; 4.1 for headache; 3.1 for hypersensitivity reactions; 2.6 for urticaria; 0.2 for venous thromboembolic events, autoimmune disorders, and Guillain-Barré syndrome; 0.1 for anaphylaxis and death; 0.04 for transverse myelitis and pancreatitis; and 0.009 for motor neuron disease. Disproportional reporting of syncope and venous thromboembolic events was noted with data mining methods. CONCLUSIONS: Most of the AEFI rates were not greater than the background rates compared with other vaccines, but there was disproportional reporting of syncope and venous thromboembolic events. The significance of these findings must be tempered with the limitations (possible underreporting) of a passive reporting system.

JAMA. 2009 Aug 19;302(7):750-7. PMID: 19690307

87
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Varicella-zoster vaccine has been linked to herpes zoster opthalmicus and encephalitis as possible, though rare side effects.


Varicella-zoster virus vaccine has diminished the consequences of chicken pox in terms of health and economical burden. The increasing number of doses administered worldwide has revealed rare but important adverse effects that had not occurred during clinical trials. We report here the case of an immunocompetent 3(1/2)-year-old girl who developed encephalitis and herpes zoster opthalmicus 20 months after her immunization with varicella-zoster virus vaccine. Molecular analysis confirmed the vaccine strain as the causative agent. After an intravenous course with acyclovir, the child made a full recovery with no neurologic sequelae.

Pediatrics. 2010 Apr;125(4):e969-72. Epub 2010 Mar 1. PMID: 20194287

88
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At the present time, the only poliovirus-caused poliomyelitis cases reported in Brazil and other countries of the Americas are of vaccine etiology.


At the present time, the only poliovirus-caused poliomyelitis cases reported in Brazil and other countries of the Americas are of vaccine etiology. It is important for epidemiological surveillance and immunization programs to evaluate the epidemiological profile of cases of vaccine-associated paralytic poliomyelitis (VAPP) in order to establish criteria for case definition and vaccination strategies. To research VAPP in Brazil, 30 cases diagnosed and classified as such by the Ministry of Health between 1989 and 1995 were submitted to a descriptive study of clinical, laboratory, and epidemiological data. In addition, the risk of occurrence of VAPP was estimated in relation to determinants based on a cohort of 3,656 persons with acute flaccid paralysis. Among individuals who had received oral polio vaccine (OPV) from 4 to 40 days before the onset of paralysis, we found a relative risk of 8.88 (95% CI: 4.37-18.03) for VAPP as compared with persons who had not been vaccinated during the same time interval. For individuals who developed VAPP in the period following national vaccination days, the estimated relative risk was 2.94 (95% CI: 1.44-6.00). For the first dose of OPV administered to the general population the estimated risk was 1 case of VAPP for every 2.39 million doses; for total doses of OPV the risk was 1 case in 13.03 million doses. A major share of VAPP cases were related to children affected by prodromes (fever and gastrointestinal signs and/or symptoms), isolation of vaccine poliovirus type 2, paralysis of the lower limbs, and a mean age of 1 year.

Rev Panam Salud Publica. 2000 Apr;7(4):219-24. PMID: 10846924

89
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Vaccine-associated paralytic poliomyelitis (VAPP) has emerged as the predominant form of the disease in the United States since 1980.


Poliomyelitis caused by wild poliovirus has been virtually nonexistent in the United States since 1980, and vaccine-associated paralytic poliomyelitis (VAPP) has emerged as the predominant form of the disease. We reviewed national surveillance data on poliomyelitis for 1960-1989 to assess the changing risks of wild-virus, vaccine-associated, and imported paralytic disease; we also sought to characterize the epidemiology of poliomyelitis for the period 1980-1989. The risk of VAPP has remained exceedingly low but stable since the mid-1960s, with approximately 1 case occurring per 2.5 million doses of oral poliovirus vaccine (OPV) distributed during 1980-1989. Since 1980 no indigenous cases of wild-virus disease, 80 cases of VAPP, and five cases of imported disease have been reported in the United States. Three distinct groups are at risk of vaccine-associated disease: recipients of OPV (usually infants receiving their first dose), persons in contact with OPV recipients (mostly unvaccinated or inadequately vaccinated adults), and immunologically abnormal individuals. Overall, 93% of cases in OPV recipients and 76% of vaccine-associated cases have been related to administration of the first or second dose of OPV. Our findings suggest that adoption of a sequential vaccination schedule (inactivated poliovirus vaccine followed by OPV) would be effective in decreasing the risk of VAPP while retaining the proven public health benefits of OPV.

Clin Infect Dis. 1992 Feb;14(2):568-79. PMID: 1554844

90
[+]

Varicella vaccine virus can be contagious and infect others.


A 12-month-old healthy boy had approximately 30 vesicular skin lesions 24 days after receiving varicella vaccine. Sixteen days later his pregnant mother had 100 lesions. Varicella-vaccine virus was identified by polymerase chain reaction in the vesicular lesions of the mother. After an elective abortion, no virus was detected in the fetal tissue. This case documents transmission of varicella-vaccine virus from a healthy 12-month-old infant to his pregnant mother.

Homeopathy. 2009 Apr;98(2):77-82. PMID: 9255208

91
[+]

Varicella vaccine virus can be contagious and infect others - Article 2.


Twelve days after receiving an investigational Oka strain live attenuated varicella vaccine, a 38-year-old healthy white woman developed a rash consisting of 30 scattered lesions. Sixteen days later, her 2 children also developed rash. Swabs obtained from the skin lesions of the vaccinee and her children demonstrated the presence of varicella-zoster virus (VZV) DNA by a polymerase chain reaction (PCR) assay. Restriction endonuclease polymorphisms present in wild and vaccine type VZV were examined, and the amplified VZV DNA was determined to be vaccine type. This case documents transmission of varicella vaccine type virus from a healthy vaccinee to susceptible household contacts. Since vaccine-associated rashes are uncommon and mild, it is likely that transmission of vaccine virus will also be uncommon. With widespread immunization beginning in the United States, ongoing studies will define the frequency of this transmission.

J Infect Dis. 1997 Oct;176(4):1072-5. PMID: 9333170

92
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Varicella vaccine has been associated with viremia and streptococcal toxic shock syndrome.


A 49-year-old health care worker received varicella vaccine in accordance with current Australian guidelines. She developed streptococcal toxic shock syndrome, complicated by acute atraumatic dislocation of the right wrist secondary to poststreptococcal reactive arthritis - to our knowledge, the first report of spontaneous wrist dislocation as a complication in this condition. Vaccination was accompanied by prolonged viraemia with the varicella vaccine strain - also, we believe, the first report of this in an immunocompetent patient.

Med J Aust. 2009 Apr 20;190(8):451-3. PMID: 19374621

93
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Varicella vaccine may be associated with aplastic anemia in children.


Varicella zoster vaccine is a safe vaccine that is rarely associated with life-threatening complications. We describe an immunocompetent child who developed transient severe aplastic anemia concomitant with a typical clinical and laboratory-proven chickenpox syndrome 3 weeks after immunization. A causative association between the vaccine and the hematologic disease is possible, and pediatricians should be aware of this severe although rare adverse event.

Pediatr Infect Dis J. 2009 Aug;28(8):746-8. PMID: 19633522

94
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Between 1995 and 2005 25,306 adverse events were reported from varicella vaccine.


Widespread use of varicella vaccine in the United States could enable detection of rare adverse events not identified previously. We reviewed data from 1995 to 2005 from the Vaccine Adverse Event Reporting System, including data from laboratory analyses, to distinguish adverse events associated with wild-type varicella-zoster virus (VZV) versus those associated with vaccine strain. Almost 48 million doses of varicella vaccine were distributed between 1995 and 2005. There were 25,306 adverse events reported (52.7/100,000 doses distributed); 5.0% were classified as serious (2.6/100,000 doses distributed). Adverse events associated with evidence of vaccine-strain VZV included meningitis in patients with concurrent herpes zoster. Patients with genetic predispositions may rarely have disease triggered by receipt of varicella vaccine. Overall, serious adverse events reported after varicella vaccination continue to be rare and must be considered relative to the substantial benefits of varicella vaccination. Ongoing safety surveillance and further studies may shed light on some of the hypothesized associations.

J Infect Dis. 2008 Mar 1;197 Suppl 2:S170-7. PMID: 18419393

95
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Administration of varicella vaccine before the age of 15 months, and the prescription of oral steroids, may be associated with a slightly increased risk of breakthrough disease.


OBJECTIVE: Varicella breakthrough, the occurrence of varicella disease>42 days after vaccination, is indicative of vaccination failure. A sevenfold increased risk of breakthrough among vaccinated children with asthma was observed in a 1996 varicella outbreak in a child care center. More recent outbreak investigations have also identified age at vaccination as a potential risk factor for breakthrough. We assessed the association of varicella breakthrough with asthma, steroids, age at varicella vaccination, and timing of measles-mumps-rubella (MMR) vaccination. METHODS: We performed a retrospective cohort study among children born after 1993 and followed up through 1999 at 2 health maintenance organizations ([HMOs] A and B) in the United States. Information was obtained from automated vaccination, clinic, hospital discharge, and pharmacy records. RESULTS: We identified 268 and 97 breakthrough cases among 80 584 and 8181 children vaccinated against varicella at HMOs A and B, respectively. Varicella breakthrough was not associated with asthma, inhaled steroids prescribed at any time, and oral steroids prescribed before vaccination. An increased risk of varicella breakthrough was found in the 3 months immediately after prescription for oral steroids at HMO A (adjusted relative risk [aRR]: 2.4; 95% confidence interval [CI]: 1.3-4.4) and HMO B (aRR: 2.8; 95% CI: 1.0-7.8), when varicella vaccine was given before 15 months of age at HMO A (aRR: 1.4; 95% CI: 1.1-1.9), and when varicella vaccination followed MMR vaccine within 28 days at HMO A (aRR: 3.1; 95% CI: 1.5-6.4). CONCLUSIONS: Varicella vaccine failure in children was not associated with asthma or the use of inhaled steroids, but with the use of oral steroids. Administration of varicella vaccine before the age of 15 months may be associated with a slightly increased risk of breakthrough disease. As currently recommended, varicella vaccination should not be administered for 28 days after MMR vaccination.

Pediatrics. 2003 Aug;112(2):e98-103. PMID: 12897314

96
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Varicella vaccine has been reported to viral meningitis in an immunocompetent child.


Herpes zoster complicated by meningitis has been mainly reported in immunocompromised patients after reactivation of wild-type varicella-zoster virus. We present one of the first cases of aseptic meningitis after herpes zoster caused by reactivation of vaccine-type varicella-zoster virus in an immunocompetent child. We also highlight the increasing role of both wild-type and vaccine strains of varicella-zoster virus as a cause of viral meningoencephalitis and the use of appropriate laboratory tools to rapidly and accurately identify the virus in order to provide prompt patient care and management.

Ann Emerg Med. 2009 Jun;53(6):792-5. Epub 2008 Nov 22. PMID: 19028409

97
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Varicella vaccine has been reported to cause chronic, acyclovir-resistant herpes zoster infection in an immunosuppressed child.


A 1-year-old boy was vaccinated with the Oka strain of varicella just prior to the discovery of a tumor that required intensive antitumor therapy. Three months later he developed herpes zoster, which developed into chronic verrucous lesions that were refractory to treatment with acyclovir and which subsequently disseminated. DNA from a biopsy specimen of a chronic herpes-zoster lesion indicated that the Oka vaccine strain of the the virus caused this severe complication. Analysis of this viral DNA demonstrated a mutation in the viral thymidine kinase gene. Plasmids containing this altered gene were unable to produce functional thymidine kinase in an in vitro translation system. The presence of this mutation would explain the clinical resistance to acyclovir. This is the first report of Oka-strain varicella virus causing severe disease after reactivation and of resistance to acyclovir during an infection caused by this virus.

J Infect Dis. 2003 Oct 1;188(7):954-9. Epub 2003 Sep 26. PMID: 14513413

98
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Varciella vaccine has been reported to cause herpes zoster skin lesions and meningitis in a previously healthy boy.


A previously healthy boy who had received varicella vaccine developed herpes zoster with meningitis. The vaccine strain recovered from scabs of 3 skin lesions had the wild-type allele at position 108111, a vaccine marker never previously associated with vaccine-associated adverse events. The vaccine strain from cerebrospinal fluid also contained mutations never previously observed at vaccine-associated single nucleotide polymorphisms that would alter amino acid sequences in ORF54 and ORF59. The presence of distinct strains in skin lesions and cerebrospinal fluid indicate that>1 variant strain may reactivate to cause herpes zoster.

J Infect Dis. 2008 Nov 15;198(10):1444-7. PMID: 18826373

99
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Combination chemotherapy and chemoradiation does not improve overall survival in inoperabe advanced pancreatic cancer over single chemotherapy alone.


BACKGROUND: Pancreatic cancer has a poor prognosis. The benefit of chemotherapy, radiotherapy or both as a palliative treatment of advanced or relapsed disease is uncertain. OBJECTIVES: To assess the effects of chemotherapy and/or radiotherapy in the management of pancreatic adenocarcinoma in people with inoperable advanced disease. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which includes the Cochrane Upper Gastrointestinal and Pancreatic Diseases (UGPD) Group Trials Register (The Cochrane Library 2005, Issue 1); CANCERLIT (1975-2002); MEDLINE (1966 to January 2005); and EMBASE (1980 to January 2005). We handsearched reference lists from trials revealed by electronic searches to identify further relevant trials. We searched published abstracts from relevant conference proceedings. We contacted colleagues and experts in the field, and asked them to provide details of outstanding clinical trials and any relevant unpublished materials. SELECTION CRITERIA: Randomised controlled trials (single- or double-blind) in patients with advanced inoperable pancreatic cancer, in which one of the intervention types (chemotherapy or radiotherapy) was contrasted with either placebo or another type of intervention. Studies comparing non-chemotherapy agents such as biological agents, hormones, immunostimulants, vaccines and cytokines were excluded. DATA COLLECTION AND ANALYSIS: Studies were assessed for eligibility and quality. Data were extracted by groups of two independent reviewers, with conflicts resolved by a third reviewer. Study authors were contacted for more information. MAIN RESULTS: Fifty trials (7043 participants) were included. Chemotherapy significantly reduced the one-year mortality (odds ratio (OR) 0.37, 95% confidence interval (CI) 0.25 to 0.57, P value<0.00001) when compared to best supportive care. Also, chemoradiation improved one year survival (0% versus 58%, P value 0.001) when compared to best supportive care. There was no significant difference in one-year mortality for 5FU alone versus 5FU combinations (OR 0.90, 95% CI 0.62 to 1.30); single-agent chemotherapy versus gemcitabine (OR 1.34, 95% CI 0.88 to 2.02, P value 0.17); or gemcitabine alone versus gemcitabine combinations (OR 0.88, 95% CI 0.74 to 1.05). However, subgroup analysis showed that platinum-gemcitabine combinations reduced six-month mortality compared to gemcitabine alone (OR 0.59, 95% CI 0.43 to 0.81, P value 0.001). A qualitative overview suggested that chemoradiation produced better survivals than either best supportive care or radiotherapy. Chemoradiation treatment was associated with more toxicity. AUTHORS' CONCLUSIONS: Chemotherapy appears to prolong survival in people with advanced pancreatic cancer and can confer clinical benefits and improve quality of life. Combination chemotherapy did not improve overall survival compared to single-agent chemotherapy. Gemcitabine is an acceptable control arm for future trials investigating scheduling and combinations with novel agents. There is insufficient evidence to recommend chemoradiation in patients with locally advanced inoperable pancreatic cancer as a superior alternative to chemotherapy alone.

Cochrane Database Syst Rev. 2009(4):CD002093. Epub 2009 Oct 7. PMID: 19821291

100
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The vaccine adjuvant squalene in anthrax vaccines given to soldiers in the Gulf War resulted in the formation of antibodies to squalene which are associated with Gulf War Syndrome.


We previously reported that antibodies to squalene, an experimental vaccine adjuvant, are present in persons with symptoms consistent with Gulf War Syndrome (GWS) (P. B. Asa et al., Exp. Mol. Pathol 68, 196-197, 2000). The United States Department of Defense initiated the Anthrax Vaccine Immunization Program (AVIP) in 1997 to immunize 2.4 million military personnel. Because adverse reactions in vaccinated personnel were similar to symptoms of GWS, we tested AVIP participants for anti-squalene antibodies (ASA). In a pilot study, 6 of 6 vaccine recipients with GWS-like symptoms were positive for ASA. In a larger blinded study, only 32% (8/25) of AVIP personnel compared to 15.7% (3/19) of controls were positive (P>0.05). Further analysis revealed that ASA were associated with specific lots of vaccine. The incidence of ASA in personnel in the blinded study receiving these lots was 47% (8/17) compared to an incidence of 0% (0/8; P<0.025) of the AVIP participants receiving other lots of vaccine. Analysis of additional personnel revealed that in all but one case (19/20; 95%), ASA were restricted to personnel immunized with lots of vaccine known to contain squalene. Except for one symptomatic individual, positive clinical findings in 17 ASA-negative personnel were restricted to 4 individuals receiving vaccine from lots containing squalene. ASA were not present prior to vaccination in preimmunization sera available from 4 AVIP personnel. Three of these individuals became ASA positive after vaccination. These results suggest that the production of ASA in GWS patients is linked to the presence of squalene in certain lots of anthrax vaccine.

Neuropharmacology. 2011 Feb-Mar;60(2-3):252-8. Epub 2010 Sep 22. PMID: 12127050

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