This efficacy is presumed to be the result of both neutralizing antibodies and a robust T cell response. 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. == Author Summary == The 17D line yellow fever virus (YFV) vaccines are some of the safest and most effective live-attenuated virus vaccines ever produced, protecting recipients for life against deadly yellow fever (YF). As a testament to this safety and efficacy, the 17D line of live-attenuated vaccines has become an important model for the design of future vaccines. However, we still lack a fundamental understanding of the protective immunity elicited against the virulent YFV, a knowledge gap that must be overcome to inform the design of future live-attenuated and subunit vaccines. Humans develop robust antibody and T cell responses following vaccination, leading some to suggest that vaccine-elicited CD8+ T cells are important for protection against virulent YFV. Since this can never be tested in humans, we have used mice to model immunity to the 17D-204 vaccine strain. 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. Our study is the first to demonstrate that vaccine-elicited CD4+ T cells can protect against YFV contamination. These results suggest that vaccine developers should consider the importance of CD4+ T cells when designing vaccines against viruses similar to YFV. == Introduction == 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 contamination but have their replication curtailed by the innate and adaptive immune responses prior to the onset of clinical disease. A well-balanced combination of authentic antigen expression and control can induce a prolific adaptive immune response and the formation of long-lived memory. The development of LAVs is generally a results-driven empirical process controlling first for attenuation and subsequently for protection. Although the broad immunological response to these vaccines is usually often times examined exquisitely, the immunity that directly contributes to protection is usually more difficult to define. Exploring the protective immunity elicited by LAVs would require the use of human subjects, which is usually often not appropriate, or animal model systems which may not accurately represent immunity or disease. However, 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 usually prevented by current vaccine standards. One of the most successful lines of LAVs uses the 17D-based vaccine strains of yellow fever virus (YFV). Since its introduction in the 1930s [1] the 17D-based vaccines (substrains 17D-204 and 17DD) have proven themselves to be amongst Tofogliflozin the most successful and efficacious vaccines created [2]. Centuries prior to the introduction of the 17D line of YFV vaccines, yellow fever (YF) was one of the most feared and widespread epidemic diseases in Africa, Europe, and the Americas. More than 500 million people have been vaccinated with the 17D-based vaccines and only 12 known cases of vaccine failure have resulted in YF [3]. The 17D line of vaccines also has an excellent safety record resulting in extremely rare severe adverse events [4]. Immunization with the 17D line Rabbit Polyclonal to MCM3 (phospho-Thr722) of vaccines remains a mainstay in the YF endemic zones of Central/South America and Sub-Saharan Africa where sylvatic Tofogliflozin YFV reservoirs still seed endemic Tofogliflozin disease and outbreaks, offering the only protection to over 900 million people world-wide [5]. The strong and enduring response from a single vaccination has led to the recommendation that only a single dose is required for life-long immunity [6,7]. As such, the human response to immunization with the 17D line of vaccines has been used to identify gene signatures that correlate with desirable vaccine traits like immunogenicity [8], with the prospect of improving the designs.
