Flaviviruses are a group of ~70 small RNA viruses responsible for significant morbidity and mortality across the globe. Efforts to develop effective vaccines for several clinically important flaviviruses are underway. Antibodies are a significant component of the host's protective response against flavivirus infection with the potential to contribute to immunity via several distinct mechanisms, including an ability to directly neutralize virus infection. Conversely, virus-reactive antibodies have been implicated in the increased risk of severe clinical manifestations following secondary dengue virus infection. In this review, we will discuss recent progress toward understanding the molecular basis of antibody-mediated neutralization of flaviviruses. Neutralization requires engagement of the virion with a stoichiometry that exceeds a required threshold. From this perspective, we will discuss viral and host factors that impact the number of antibody molecules bound to the virus particle and significantly modulate the potency of neutralizing antibodies.
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