Abstract
A gold standard of antiviral vaccination has been the safe and effective live-attenuated 17D-based yellow fever virus (YFV) vaccines. Among more than 500 million vaccinees, only a handful of cases have been reported in which vaccinees developed a virulent wild type YFV infection. This efficacy is presumed to be the result of both neutralizing antibodies and a robust T cell response. However, the particular immune components required for protection against YFV have never been evaluated. An understanding of the immune mechanisms that underlie 17D-based vaccine efficacy is critical to the development of next-generation vaccines against flaviviruses and other pathogens. Here we have addressed this question for the first time using a murine model of disease. Similar to humans, vaccination elicited long-term protection against challenge, characterized by high neutralizing antibody titers and a robust T cell response that formed long-lived memory. Both CD4+ and CD8+ T cells were polyfunctional and cytolytic. Adoptive transfer of immune sera or CD4+ T cells provided partial protection against YFV, but complete protection was achieved by transfer of both immune sera and CD4+ T cells. Thus, robust CD4+ T cell activity may be a critical contributor to protective immunity elicited by highly effective live attenuated vaccines.
Highlights
Live-attenuated vaccines (LAV) generally provide the highest level of protection against infectious diseases
We still lack a fundamental understanding of the protective immunity elicited against the virulent yellow fever virus (YFV), a knowledge gap that must be overcome to inform the design of future liveattenuated and subunit vaccines
We found that CD4 + T cells elicited by 17D-204 contributed to protection against virulent YFV, but CD8+ T cells had no effect on the outcomes of survival or disease
Summary
Live-attenuated vaccines (LAV) generally provide the highest level of protection against infectious diseases. The most effective LAVs duplicate the pathogen-specific conditions of natural infection but have their replication curtailed by the innate and adaptive immune responses prior to the onset of clinical disease. The development of LAVs is generally a results-driven empirical process controlling first for attenuation and subsequently for protection. The broad immunological response to these vaccines is often times examined exquisitely, the immunity that directly contributes to protection is more difficult to define. Understanding the immune properties that are required for protection is crucial to the rational design of vaccines against pathogens for which empirical production of a LAV has failed or for which usage of a LAV is prevented by current vaccine standards
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