Antibody Focusing to Conserved Sites of Vulnerability: The Immunological Pathways for ‘Universal’ Influenza Vaccines

Influenza virus remains a serious public health burden due to ongoing viral evolution. Vaccination remains the best measure of prophylaxis, yet current seasonal vaccines elicit strain-specific neutralizing responses that favor the hypervariable epitopes on the virus. This necessitates yearly reformulations of seasonal vaccines, which can be limited in efficacy and also shortchange pandemic preparedness. Universal vaccine development aims to overcome these deficits by redirecting antibody responses to functionally conserved sites of viral vulnerability to enable broad coverage. However, this is challenging as such antibodies are largely immunologically silent, both following vaccination and infection. Defining and then overcoming the immunological basis for such subdominant or ‘immuno-recessive’ antibody targeting has thus become an important aspect of universal vaccine development. This, coupled with structure-guided immunogen design, has led to proof-of-concept that it is possible to rationally refocus humoral immunity upon normally ‘unseen’ broadly neutralizing antibody targets on influenza virus.