Global Vaccine Safety

Safety of yellow fever vaccine

Extract from report of GACVS meeting of 18-19 June 2008, published in the WHO Weekly Epidemiological Record on 8 August 2008

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.