Global Vaccine Safety

Meeting of Global Advisory Committee on Vaccine Safety, 18–19 June 2008

Published in the WHO Weekly Epidemiological Record on 8 August 2008

The Global Advisory Committee on Vaccine Safety (GACVS), an expert clinical and scientific advisory body, was established by WHO to deal with vaccine-safety issues of potential global importance independently from WHO and with scientific rigour.1 GACVS held its eighteenth meeting in Geneva, Switzerland, during 18–19 June.2 The committee addressed a range of issues related to the short-term and long-term safety of specific vaccines and also reviewed issues related to vaccine formulations and the use of vaccines in general. The topics addressed in particular are described below.

Vaccine-specific issues

Safety of yellow fever vaccine

The committee was given an update of the evidence regarding the safety of 17D yellow fever vaccines, which focused on serious adverse events including hypersensitivity reactions, vaccine-associated viscerotropic disease (YEL-AVD) and vaccine-associated neurotropic disease (YEL-AND). Globally there are data on 43 well documented cases of YEL-AVD, including cases retrospectively identified since this rare but serious adverse reaction was first recognized in 2001. Based on genomic sequencing of retained samples from 1 patient, the earliest confirmed occurrence of YEL-AVD dates back to 1975.

Among those 43 YEL-AVD cases, 4 fatal cases and 1 case of a survivor occurred among 63 174 people vaccinated in the Ica Region of Peru following a yellow fever vaccination campaign conducted in September–October 2007 after a major earthquake. All 5 YEL-AVD cases in the Ica Region received 1 particular lot of yellow fever vaccine and were among an estimated 42 742 individuals who received vaccine from the same lot during the campaign. No other cases of YEL-AVD occurred among the 20 432 people vaccinated in the Ica Region with a second vaccine lot. The committee noted that this was the first time that multiple cases of YEL-AVD had been detected in a short time frame and associated with a single lot of vaccine. In addition, the incidence of YEL-AVD in this situation (estimated as 11.7/100 000 vaccinated based on the number of people receiving the vaccine lot associated with the 5 cases or 7.9/100 000 based on all those vaccinated in the Ica Region) was noted to be >20 times higher than the risk previously associated with 17D vaccines in general. The committee was presented with the key clinical and virological findings from the case investigation, the overall epidemiological evaluation of adverse events occurring during the campaign, the findings of a review of the vaccine quality and production at the manufacturing facility, as well as the findings and conclusions of an expert panel convened by the Pan American Health Organization and WHO to assist the investigation.

A known risk factor of advanced age was present in 1 case (a 79-year-old male); and a potential risk factor was identified in a 49-year-old female (past history of rheumatoid arthritis and systemic lupus erythematosus as well as treatment with methotrexate and dexamethasone starting 4 days after vaccination). The other cases did not appear to have risk factors or altered immune states that may have contributed to their illness or its outcome. The committee noted that these cases occurred among a population naive for yellow fever infection or vaccination. However, this does not explain the higher incidence when compared with other naive populations in the United States and other non-endemic regions where YEL-AVD has been reported. Further, experience with approximately 3 million vaccine doses (albeit different 17D vaccine products) in vaccination campaigns during 2007–2008 among other naive populations in Latin America (in Argentina and Paraguay) has not resulted in any reported cases of YEL-AVD.

The cause of the cluster of cases in Ica is not clear. Vaccine evaluation showed that the lot administered (as well as its sister lots) met all quality specifications, and the yellow fever virus isolated from 3 confirmed cases was consistent with the vaccine virus and did not appear to have mutated. Approximately 72 000 doses of the vaccine lot common to the YEL-AVD cases was confirmed to have been used elsewhere in Latin America without occurrence of additional cases. Also, approximately 2 million doses from sister lots were distributed for use elsewhere in Latin America, again without any reports of YEL-AVD cases.

In summary, the committee concluded that the high incidence of YEL-AVD observed in Peru remains unexplained. The evidence suggests potential differences in the incidence of adverse events in regions where yellow fever is endemic (ranging from 0–0.21/100 000 doses) and in naive populations (from 0.09–0.4/100 000 doses), which are probably related to population differences (for example, previous vaccination or exposure to wild yellow fever virus). However, with the exception of the cases in Peru, data from other settings show that the estimated incidence of YEL-AVD is up to 0.4 cases/100 000 doses. The GACVS reiterated the need to obtain better estimates of rates of serious adverse events and to be better able to predict which individuals will be at risk for such events and the potential factors contributing to those risks. The committee noted and supported initiatives by WHO and other global partners to obtain better estimates of rates and better prediction of risks, including efforts being undertaken to enhance surveillance and the evaluation of serious adverse events in mass yellow-fever vaccination campaigns in endemic regions in Africa and Latin America. An international laboratory network has been established with a goal of ensuring systematic and coordinated laboratory evaluation of reported cases. This initiative may help elucidate the etiology and pathogenesis of YEL-AVD and YEL-AND and the understanding of the relative contribution of vaccine factors versus host factors.

Finally, the committee was presented with data regarding the variation in methods used for measuring the potency of 17D vaccines. Work is under way by WHO and its Expert Committee on Biological Standardization to further standardize the measurement of potency. The GACVS emphasized that being able to assess 17D vaccines against a standardized potency test will be important in assessing vaccine safety.

Based on the data, the committee reiterated that the recommendations for the use of yellow fever vaccine should remain unchanged. There needs to be careful adherence to the indications for vaccine use and assessment of the risks and benefits, including in special groups who have the potential risk of developing serious adverse events. The vaccine should be administered only to those travellers truly at risk of exposure. Further, in communicating safety risks, it should be acknowledged that risk–benefit ratios may differ for vaccination of travellers and vaccination of populations living in at-risk areas.

Further, the committee recommended that in light of the significant number of doses of yellow fever vaccine being delivered (and planned to be delivered) in preventive mass vaccination campaigns in endemic countries, some of which have a high prevalence of HIV infection, consideration should be given to conducting appropriate follow-up studies of vaccine use to improve the data regarding the safety and efficacy of yellow fever vaccination in individuals infected with HIV.

The GACVS recommended that WHO and other global partners identify and prioritize resources to support work in regard to all of the above.

Diphtheria–tetanus–pertussis vaccine and asthma

A recently published article3 suggests there is a reduced risk of asthma when diphtheria–tetanus–pertussis (DTP) vaccination is delayed relative to the recommended Canadian schedule (doses at 2, 4, 6 and 15–18 months of age). This retrospective, longitudinal study looked at children born in Manitoba in 1995 and still living in Manitoba at age 7 years (13 980 children). The committee reviewed the study and considered the approach to be reasonable and the findings a possible signal that require further investigation. Some methodological issues require further review, and the importance of replicating the findings using a different data set was noted. The committee will review the issue at its next meeting in December. In the meantime, all relevant information will be assembled.

Non-specific effects of DTP vaccine on child mortality

Two recent papers4, 5 have discussed methodological issues that might explain inconsistent findings among studies that address non-specific effects of DTP vaccination on mortality in children. The papers discuss potential sources of bias in studies attempting to relate vaccination histories to children’s mortality and how analytic issues could affect the interpretation of observational studies.

The GACVS was presented with a summary of the presentations and discussions from a workshop held in London in April 2008 to consider methodological issues in the design and analysis of studies investigating non-specific effects of vaccination. Three papers from the workshop (on analytical issues, methodological issues related to data collection in observational studies, and potential randomized controlled trials to explore non-specific effects of vaccines) are in preparation.

One of the outcomes of the workshop was a consensus shared by many participants that conclusive evidence for or against non-specific effects of vaccines on mortality, including a potential deleterious effect of DTP vaccination on children’s survival as has been reported in some studies, was unlikely to be obtained from observational studies. The GACVS will keep a watch on the evidence of non-specific effects of vaccination.

Pregnancy outcomes after inadvertent immunization with rubella vaccine

A large amount of data are available on pregnancy outcomes among women inadvertently immunized with rubella vaccine in multiple countries (Germany, the Islamic Republic of Iran, the United Kingdom and the United States). These data arise from both retrospective and prospective cohorts, as well as case–control studies done in the context of routine administration or mass vaccination campaigns. The time of vaccination in relation to the time of conception varied across studies. No neonates were found to have congenital rubella syndrome despite evidence that a few had infection with vaccine virus (defined as immunoglobulin M [IgM] positivity).

The GACVS also considered newly reported data from 5 Latin American countries (Brazil, Costa Rica, Ecuador, El Salvador and Paraguay). A total of 29 663 women who had been inadvertently vaccinated were identified; 3264 of them were susceptible to rubella. Of those who were susceptible, 2236 were followed. By IgM measurement, 68 (3%) potential foetal infections were identified, none of which manifested as congenital rubella syndrome. No increased risk of additional abnormalities was detected when compared with expected background rates of congenital malformation in the population.

The GACVS concluded that these data support WHO’s statement that inadvertent vaccination of women just before conception or during pregnancy poses little, if any, risk to the developing fetus. However, foetal infections have been documented and, although they have not been associated with congenital rubella syndrome, as a precautionary measure rubella vaccination should still be avoided in pregnancy.

General issues

Mitochondrial diseases and vaccination

Considerable media activity in the United States has focused on one case of a child with mitochondrial disease who was diagnosed with encephalopathy some time after receiving 5 vaccines. The United States’ Vaccine Injury Compensation Program had awarded damages on the basis that the vaccinations had aggravated an underlying condition. The GACVS noted that all countries need to have the information and skills to deal with such pressures.

Mitochondrial diseases are inherited disorders of energy metabolism that tend to affect tissues with high energy requirements, such as the brain, heart and liver. These diseases are associated with a variety of symptoms. They are often difficult to diagnose, and there is no effective treatment. Mitochondrial disorders can also lead to cognitive impairment and encephalopathy, resulting in blunted social interaction.

Physiological stress triggered by external factors (for example, fever, cold, heat, starvation, sleep deprivation) may result in a worsening of the metabolic situation which results in deterioration of affected organs. Additionally, inflammatory responses associated with most infectious diseases can precipitate a clinical deterioration in an underlying mitochondrial disease. While vaccines may cause fever, clinicians caring for children with mitochondrial disease recommend vaccinating their patients since the risk of developing an even more devastating clinical deterioration would be associated with natural infection.

The GACVS concluded, on the basis of the limited data available from the United Kingdom and the United States, that there is no convincing evidence to support an association between vaccination and deterioration of mitochondrial disease. The topic will be reviewed further if new findings become available. GACVS supports the current practice standard: children with mitochondrial diseases should receive the immunizations recommended for healthy children.

Thiomersal

The GACVS considered the presentation of a recently published pharmacokinetic study of mercury in premature and low-birth-weight infants who received a birth dose of hepatitis B vaccine containing thiomersal.6 The results suggest that exposure to thiomersal-containing vaccines does not result in accumulation of mercury in blood and that the blood half-life (2.9–4.1 days) of intramuscular ethyl mercury from thiomersal in vaccines in infants is substantially shorter than that of oral methyl mercury in adults. The study concluded that exposure guidelines based on oral methyl mercury may not be appropriate for use in assessing the risk of thiomersal in vaccines at dosages consistent with standard vaccination regimens.

The GACVS also considered the results of a study conducted in Italy that examined the neuropsychological performance 10 years after immunization in infancy with thiomersal-containing vaccines (Tozzi A., unpublished data, 2008). According to the results, higher thiomersal exposure through vaccines administered in the first year of life was significantly associated with lower scores on 2 neuropsychological outcomes (motor function, measured using the finger-tapping test, and language, measured using the Boston naming test). The differences in mean scores were very small, detected only in girls, of doubtful clinical relevance, and not consistent with results from other studies of ethyl mercury. The observed associations may reflect the effect of chance.

On the basis of the presented data, GACVS remains of the view that there is no evidence supporting any change in WHO’s recommendations for thiomersal-containing vaccines and the vaccination of low-birth-weight infants where indicated.

Report from subgroups

The subgroup on adverse events following immunization is revisiting its terms of reference. Two important areas of work include examining vaccine safety signals from WHO’s collaborating centre for international drug monitoring, the Uppsala Monitoring Centre, and supporting the development of a post-marketing surveillance network for prequalified products. The subgroup on vaccine and immune deficiencies presented an agenda of work to develop a series of reviews for specific vaccines and types of immune deficiencies. The subgroup addressing the safety of pandemic influenza vaccine is completing a document entitled “Outline approach to the post-marketing surveillance of seasonal and pandemic influenza vaccines”. No particular concerns have emerged during the past season. The subgroup on vaccine formulation plans to develop a database of vaccine components that could be used to track adverse events following immunization.

    • See No. 41, 1999, pp. 337-338.
    • GACVS invited additional experts to present evidence with respect to the safety of yellow fever vaccination and clusters of reported cases of viscerotropic disease in Peru, mitochondrial disease, the safety of thimerosal and the use of rubella vaccine during pregnancy. Depending on the session, these experts were affiliated with Peru’s Ministry of Health; the United States’ Centers for Disease Control and Prevention, Atlanta, Georgia; the Institute of Neuroscience, Newcastle University, England; the Epidemiology Unit of Bambino Gesu Hospital, Rome, Italy; the Department of Microbiology/Immunology, Pediatrics and Medicine, University of Rochester, New York; the Pan American Health Organization; the United Kingdom’s National Institute for Biological Standards and Control; and the University of Texas Medical Branch, Galveston, Texas.
    • McDonald K et al. Delay in diphtheria, pertussis, tetanus vaccination is associated with a reduced risk of childhood asthma. Journal of Allergy and Clinical Immunology, 2008, 121:626–631.
    • Jensen H et al. Survival bias in observational studies of the impact of routine immunizations on childhood survival. Tropical Medicine and International Health, 2007, 12:5–14.
    • Aaby P et al. DTP vaccination and child survival in observational studies with incomplete vaccination data. Tropical Medicine and International Health, 2007, 12:15–24.
    • Pichichero ME et al. Mercury levels in newborns and infants after receipt of thimerosal-containing vaccines. Pediatrics 2008, 121:e208–e214 (http://pediatrics.aappublications.org/cgi/reprint/121/2/e208.pdf).
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