Influenza Hemagglutinin Structures and Antibody Recognition

Abstract

Hemagglutinin (HA) is most abundant glycoprotein on the influenza virus surface. Influenza HA promotes viral entry by engaging the receptor and mediating virus-host membrane fusion. At the same time, HA is the major antigen of the influenza virus. HA antigenic shift can result in pandemics, whereas antigenic drift allows human circulating strains to escape herd immunity. Most antibody responses against HA are strain-specific. However, antibodies that have neutralizing activities against multiple strains or even subtypes have now been discovered and characterized. These broadly neutralizing antibodies (bnAbs) target conserved regions on HA, such as the receptor-binding site and the stem domain. Structural studies of such bnAbs have provided important insight into universal influenza vaccine and therapeutic design. This review discusses the HA functions as well as HA-antibody interactions from a structural perspective.

Elicitation of broadly protective immunity to influenza by multivalent hemagglutinin nanoparticle vaccines

“…HA is a homotrimeric class I fusion protein, consisting of a head domain that facilitates host cell attachment by binding cell-surface sialosides and a stem domain containing the membrane fusion machinery 18,19 . Both the head and stem contain highly conserved epitopes that are targeted by broadly neutralizing antibodies (bnAbs) capable of protecting against infection by diverse influenza viruses in animal models 18,20,21 . A few such bnAbs are currently being evaluated in human clinical trials for their prophylactic and therapeutic potential 22 .…”

Next-Generation Influenza Vaccines

“…The virology and immunology of influenza has been described in other reviews (Fodor and te Velthuis 2020; tenOever 2020; Topham et al 2020;Wu and Wilson 2020), but some of the features relevant to vaccine development will be briefly reviewed. The goal of influenza immunization is to prevent disease caused by two genera in the Orthomyxoviridae family, influenza A and B. Orthomyxoviruses have a segmented, negative-sense, single-stranded RNA genome, and influenza A and B have eight gene segments that encode at least 11 characterized proteins (Bouvier and Palese 2008).…”

“…Such a vaccine would likely need to induce immune responses to invariant sites of vulnerability of the virus. This could occur by amplifying the response to selected epitopes known to be conserved like the sites on the HA stem or head including the receptor-binding site, the lateral patch, the vesti-gial esterase site, and the trimer interface (Wu and Wilson 2020), the NA catalytic site (Stadlbauer et al 2019), and the M2e (Grandea et al 2010) or by inducing effector T cells, especially if they are tissue resident memory cells localized in the lower airway and lung (Van Braeckel-Budimir and Harty 2017). Another approach would be to prevent induction of antibodies to sites that have narrower specificity.…”

“…These technologies have all contributed to an era of precision vaccinology in which it is possible to conceive influenza immunogens in different ways. In particular, the ability to define and manipulate atomic level details of HA structure and topology including antibody-liganded dynamic conformations has allowed the exact mapping of antigenic supersites and identification of new conserved targets for future vaccines (for review, see Wu and Wilson 2020). The ability to structurally define new sites of vulnerability has been amplified by the ability to rapidly isolate and characterize numerous human mAbs (for review, see Crowe 2018).…”

Experimental Approaches to Identify Host Factors Important for Influenza Virus

“…The current mechanistic mainstay for antiviral therapy is inhibition of viral protein function. In the case of influenza virus, adamantanes target the M2 proton channel to inhibit viral uncoating, neuraminidase inhibitors block virion release, and the new viral polymerase inhibitors prevent transcription or replication of viral RNAs, thereby inhibiting viral replication (see Wilson and Lan 2019;Wu and Wilson 2019;Yewdell 2019). Such therapies place significant selective pressure on these highly adaptable RNA viruses, rapidly selecting for drug resis-tance.…”