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Background. When the decision was made to prepare for a deliberate release of smallpox, the United States had ~15 million doses of Wyeth Dryvax vaccine, which was known to induce significant morbidity when used undiluted; Sanofi Pasteur, Inc., later identified ~85 million additional doses in storage. Methods. Eleven vaccine-dose groups, each with 30 vaccinia-naive subjects, were given diluted Dryvax vaccine or 1 of 2 lots of Sanofi Pasteur smallpox vaccine and were evaluated for vaccination success rates, morbidity, and immune responses. Results. Estimated doses of 106.6-108.2 pfu of virus/mL induced major reactions (or ‘takes’) in 93%-100% of subjects in each dose group. No differences in vaccination take rates, lesion size, erythema, and induration or in serum neutralizing-antibody response were detected between the groups. However, systemic reactogenicity and missed activities were significantly lower for the vaccine groups given doses of 106.6-107.2 pfu/mL than for those given doses of 107.6-108.2 pfu/mL. Conclusions. These findings support the use of a higher dilution of Wyeth Dryvax vaccine and Sanofi Pasteur smallpox vaccine, given that the resulting morbidity should be significantly lower without loss of vaccine effectiveness. A plan for use of higher dilutions would create an enormous stockpile of vaccine. [ABSTRACT FROM AUTHOR]

Background. Postexposure vaccination strategies rely on a rapid induction of poxvirus-specific immune responses. Postvaccination cell-mediated immune (CMI) responses have not been compared by use of controlled trials in previously vaccinated (vaccinia-nonnaive) and nonvaccinated (vaccinia-naive) individuals. Methods. To assess the time course of vaccinia-specific CMI responses, 20 previously vaccinated and 10 vaccinia-naive individuals were vaccinated with Dryvax, and serial blood samples were drawn. Results. Both groups developed peak levels of vaccinia-specific interferon (IFN)-γ-producing T cells by day 14 after vaccination. In vaccinia-nonnaive individuals, vaccinia-specific CMI responses were detected by day 7 after vaccination and preceded the increase in antibody titers. IFN-γ enzyme-linked immunospot responses were significantly different between the 2 groups on days 7 (greater in vaccinia-nonnaive than in vaccinia-naive individuals) and 14 (greater in vaccinia-naive than in vaccinia-nonnaive individuals). Lymphoproliferation responses in vaccinia-nonnaive individuals were significantly higher on days 3 and 7, but cytotoxic T cell lysis activity was not statistically different at any time point. Antibody responses conformed to expected primary and secondary patterns of induction. Conclusions. This study demonstrates that the kinetics of CMI responses are different after primary vaccination versus after revaccination and indicates that memory can exist in individuals vaccinated ⩾30 years ago. These data support the epidemiological observation in smallpox outbreaks that successful revaccination within 4 days of exposure is partially protective. In vaccinia-nonnaive individuals, protection against smallpox during the post- exposure revaccination period may require T cell memory as an essential component for the rapid induction of protective cellular and humoral responses. [ABSTRACT FROM AUTHOR]

Highlights: [•] Reintroduction of Variola major as an agent of bioterrorism remains a concern. [•] A compressed schedule of MVA was evaluated for use in a post event scenario. [•] MVA is well tolerated when given as two standard doses at Days 0 and 28 or 0 and 7. [•] A 2nd dose of MVA at Day 28 compared to Day 7 provided greater antibody responses. [•] INF-γ expression was greatest within 2 weeks after last vaccination. [ABSTRACT FROM AUTHOR]

Immunization with vaccinia virus elicits a protective Ab response that is almost completely CD4+ T cell dependent. A recent study in a rodent model observed a deterministic linkage between Ab and CD4+ T cell responses to particular vaccinia virus proteins suggesting that CD4+ T cell help is preferentially provided to B cells with the same protein specificity (Sette et al. 2008. Immunity 28: 847-858). However, a causal linkage between Ab and CD4+ T cell responses to vaccinia or any other large pathogen in humans has yet to be done. In this study, we measured the Ab and CD4+ T cell responses against four vaccinia viral proteins (A27L, A33R, B5R, and L1R) known to be strongly targeted by humoral and cellular responses induced by vaccinia virus vaccination in 90 recently vaccinated and 7 long-term vaccinia-immunized human donors. Our data indicate that there is no direct linkage between Ab and CD4+ T cell responses against each individual protein in both short-term and long-term immunized donors. Together with the observation that the presence of immune responses to these four proteins is linked together within donors, our data suggest that in vaccinia-immunized humans, individual viral proteins are not the primary recognition unit of CD4+ T cell help for B cells. Therefore, we have for the first time, to our knowledge, shown evidence that CD4+ T cells provide intermolecular (also known as noncognate or heterotypic) help to generate robust Ab responses against four vaccinia viral proteins in humans. [ABSTRACT FROM AUTHOR]