ObjectiveTo compare the immunogenicity of three yellow fever vaccines from WHO-17D and Brazilian 17DD substrains (different seed-lots). Methods An equivalence trial was carried out involving 1,087 adults in Rio de Janeiro. Vaccines produced by Bio-Manguinhos, Fiocruz (Rio de Janeiro, Brazil) were administered following standardized procedures adapted to allow blocked randomized allocation of participants to coded vaccine types (double-blind). Neutralizing yellow fever antibody titters were compared in pre-and post-immunization serum samples. Equivalence was defined as a difference of no more than five percentage points in seroconversion rates, and ratio between Geometric Mean Titters (GMT) higher than 0.67. Results Seroconversion rates were 98% or higher among subjects previously seronegative, and 90% or more of the total cohort of vaccinees, including those previously seropositive. Differences in seroconversion ranged from -0.05% to -3.02%. The intensity of the immune response was also very similar across vaccines: 14.5 to 18.6 IU/mL. GMT ratios ranged from 0.78 to 0.93. Taking the placebo group into account, the vaccines explained 93% of seroconversion. Viremia was detected in 2.7% of vaccinated subjects from Day 3 to Day 7. ConclusionsThe equivalent immunogenicity of yellow fever vaccines from the 17D and 17DD substrains was demonstrated for the first time in placebo-controlled double-blind randomized trial. The study completed the clinical validation process of a new vaccine seed-lot, provided evidence for use of alternative attenuated virus substrains in vaccine production for a major manufacturer, and for the utilization of the 17DD vaccine in other countries. $ %Rev Saúde Pública 2004;38(5):671-8 www.fsp.usp.br/rsp Immunogenicity of yellow fever vaccines Camacho LAB et al Resumo Objetivo Comparar a imunogenicidade de três vacinas contra febre amarela ) das subcepas WHO-17D e 17DD brasileira (diferentes lotes-semente

Yellow fever (YF), an acute infectious disease, is endemic in the north and central-west of Brazil. This disease can be prevented by the use of a vaccine. In Brazil, four fatal adverse events have been associated with the YF vaccine used in the country (17DD vaccine). We briefly describe the last two fatalities, and estimate the risk of 17DD-associated fatal adverse events under different epidemiological scenarios. Controversies regarding the appropriate denominator that enters the estimation of risk serve as a motivation for each proposed scenario. The statistical procedures used show optimum behaviour when assessing the risk of rare events. Risk estimates vary from 0.043 (95 % CI 0.017-0.110) to 2.131 (95 % CI 0.109-12.071) fatalities per million doses administered. The robust estimates of the risk of fatal adverse events we present constitute an important element in future risk-benefit analysis and point to the need for good quality vaccine coverage and adverse-events surveillance data to assess the risk of vaccination. Although vaccination of YF endemic regions is necessary to maintain low disease prevalence, preventive administration of YF vaccine to the entire population should be cautiously analysed.

OBJECTIVE: To compare the reactogenicity of three yellow fever (YF) vaccines from WHO-17D and Brazilian 17DD substrains (different seed-lots) and placebo. METHODS: The study involved 1,087 adults eligible for YF vaccine in Rio de Janeiro, Brazil. Vaccines produced by Bio-Manguinhos, Fiocruz (Rio de Janeiro, Brazil) were administered ("day 0") following standardized procedures adapted to allow blinding and blocked randomization of participants to coded vaccine types. Adverse events after immunization were ascertained in an interview and in diary forms filled in by each participant. Liver enzymes were measured on days 0, 4-20 and 30 of the study. Viremia levels were measured on days 4 to 20 of follow-up. The immune response was verified through serologic tests. RESULTS: Participants were mostly young males. The seroconversion rate was above 98% among those seronegative before immunization. Compared to placebo, the excess risk of any local adverse events ranged from 0.9% to 2.5%, whereas for any systemic adverse events it ranged from 3.5% to 7.4% across vaccine groups. The excess risk of events leading to search for medical care or to interruption of work activities ranged from 2% to 4.5%. Viremia was detected in 3%-6% of vaccinees up to 10 days after vaccination. Variations in liver enzyme levels after vaccination were similar in placebo and vaccine recipients. CONCLUSIONS: The frequency of adverse events post-immunization against YF, accounting for the background occurrence of nonspecific signs and symptoms, was shown for the first time to be similar for vaccines from 17D and 17DD substrains. The data also provided evidence against viscerotropism of vaccine virus.