The development of humoral breadth and protection against influenza

Abstract

Influenza remains a serious global health concern, both as a seasonal pathogen and as a possible pandemic threat arising from novel strains against which the human population has no immunity. Current seasonal influenza vaccines provide a moderate level of protection, but complete protection is not achieved even where vaccination uptake is high. Furthermore, protection induced by both vaccines and infection is limited by lack of recognition of emerging zoonotic strains and seasonal strains that have undergone antigenic shift and/or drift. The current correlate of protection, hemagglutination inhibition, does not fully explain protection, particularly in high-risk groups. Emerging data suggests that antibody extra-neutralizing functions, which activate the innate immune system via interactions with Fc receptors (FcRs), can provide protection against seasonal and emerging pandemic strains. This work used an unbiased, polyclonal humoral profiling approach to explore the effects of an adjuvant, MF59, on the immune response to vaccination and define correlates of protection across multiple high-risk groups. In neonates, vaccine-induced maternal antibodies capable of binding to FcRs and transferring across the placenta provided increased protection. Similarly, in older adults, hemagglutinin- and neuraminidase-specific antibodies capable of activating NK cells provided increased protection. Linked to the importance of these mechanistic correlates of protection, the identification of strategies to broaden immunity is also key for the development of protective vaccines. Thus, to extend the correlates work, analysis of the role of antibody Fc-biology in the evolution of breadth of immunity across both influenza A and B revealed that antibodies capable of binding to FcRs, and especially Fc  receptor 2B, are both a correlate and a predictor of seroconversion to vaccine strains and seroconversion breadth. These antibodies, in addition to marking a matured humoral immune response, also act to promote this maturation upon repeated exposure, highlighting a target for increasing the potency of influenza vaccines. The data presented here implicate vaccine-induced Fc biology in tuning both the direct control and clearance of virus, but also, indirectly, the evolution of the Fab to recognize the breadth of influenza strain diversity, providing strategies for next generation vaccines, particularly in the context of universal influenza vaccine candidates.