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

Abstract

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.

Engineering an Antibody V Gene-Selective Vaccine

“…CDRH3 hypervariability is generated through stochastic N-junctional diversification, where it accounts for the majority of germline BCR diversity and thus forms the principal source of antigen contact affinity ( 4 – 6 ). However, CDRH3 loops do not always explore the antigenic space equally, which is reflected by immunodominance hierarchies in which low frequency BCR target solutions are unable to compete for selection during subsequent antibody affinity maturation within B cell germinal centers ( 7 , 8 ). Such immunological subdominance is a hallmark of broadly neutralizing antibody (bnAb) responses against pathogens that defy conventional vaccine approaches, including HIV and influenza virus ( 8 – 12 ).…”

“…However, CDRH3 loops do not always explore the antigenic space equally, which is reflected by immunodominance hierarchies in which low frequency BCR target solutions are unable to compete for selection during subsequent antibody affinity maturation within B cell germinal centers ( 7 , 8 ). Such immunological subdominance is a hallmark of broadly neutralizing antibody (bnAb) responses against pathogens that defy conventional vaccine approaches, including HIV and influenza virus ( 8 – 12 ). It follows that if bnAb targeting solutions are both rare and reliant on randomly emerging CDRH3 configurations, then vaccine-expansion of the corresponding bnAb response will likely prove difficult.…”

“…Despite this problem, some human bnAbs and nAbs show biased usage of the gene-encoded CDRs that normally surround the hypervariable CDRH3 loops ( 13 – 30 ). This suggests ‘public’ or genetically-reproducible foundation for pathway-amplifying normally immunologically recessive but protective humoral output ( 8 , 10 ). Indeed, we have recently demonstrated that normally subdominant human influenza bnAbs can emerge via germline-encoded affinity for the bnAb target, and that this gene-endowed reproducibility in targeting specificity enables vaccine-amplification of immunodominant serum bnAb responses, triggered and expanded by a single rationally designed influenza immunogen ( 31 , 32 ).…”

Animal Models Utilized for the Development of Influenza Virus Vaccines

“…The main premise for universal influenza virus vaccines is to boost antibody responses that target conserved, yet less accessible, regions of the virus [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. The HA head domain is the primary target of immune responses after infection and vaccination.…”

Fear of Influenza Resurgence amid COVID-19 Pandemic: Need for Effective Flu Vaccine Still Exists

“…The review article by McMillan et al (2021) provides an excellent overview of the next generation influenza vaccines that are aimed to provide universal protection [ 8 ]. Sangesland et al (2021) discussed the strategy of directing antibody responses to functionally conserved sites to confer broad protection against influenza [ 9 ]. However, these conserved regions are often immunologically silent and have reduced capacity to induce robust immune responses.…”