Influenza immunization elicits antibodies specific for an egg-adapted vaccine strain

Abstract

For broad protection against infection by viruses such as influenza or HIV, vaccines should elicit antibodies that bind conserved viral epitopes, such as the receptor-binding site (RBS). RBS-directed antibodies have been described for both HIV1–3 and influenza virus4–8, and the design of immunogens to elicit them is a goal of vaccine research in both fields. Residues in the RBS of influenza virus hemagglutinin (HA) determine a preference for the avian or human receptor, α -2,3-linked sialic acid and α -2,6-linked sialic acid, respectively9,10. Transmission of an avian-origin virus between humans generally requires one or more mutations in the sequences encoding the influenza virus RBS to change the preferred receptor from avian to human9,11,12, but passage of a human-derived vaccine candidate in chicken eggs can select for reversion to avian receptor preference13–15. For example, the X-181 strain of the 2009 new pandemic H1N1 influenza virus, derived from the A/California/07/2009 isolate and used in essentially all vaccines since 2009, has arginine at position 226, a residue known to confer preference for an α -2,3 linkage in H1 subtype viruses13,14; the wild-type A/California/07/2009 isolate, like most circulating human H1N1 viruses, has glutamine at position 226. We describe, from three different individuals, RBS-directed antibodies that recognize the avian-adapted H1 strain in current influenza vaccines but not the circulating new pandemic 2009 virus; Arg226 in the vaccine-strain RBS accounts for the restriction. The polyclonal sera of the three donors also reflect this preference. Therefore, when vaccines produced from strains that are never passaged in avian cells become widely available, they may prove more capable of eliciting RBS-directed, broadly neutralizing antibodies than those produced from egg-adapted viruses, extending the established benefits of current seasonal influenza immunizations.

CryoEM Structure of an Influenza Virus Receptor-Binding Site Antibody–Antigen Interface

“…Receptor mimicry by CDRH3 is similar to examples we have described previously [14–16], although the loop itself is substantially longer. Fig.…”

“…Residue 226 is Gln in most human H1 isolates, but passage of vaccine strains in chicken eggs can select for a mutation to Arg, because of its preference for the avian receptor [16]. In the vaccine-strain Solomon Islands HA we used for crystallization, residue 226 is indeed Arg, which bridges between HA S136 and T105 at the flexible tip of the antibody CDRH3; Gln could do the same (Fig.…”

Monomeric Intermediates Formed by Vesiculovirus Glycoprotein during Its Low-pH-induced Structural Transition

“…To obtain a stable trimeric pre-fusion structure, the C-terminal part of the ectodomain is fused to a trimerization motif, based either on the transcription factor GCN4, as in the case of coronavirus S [70], parainfluenza virus 5 F glycoproteins [71] and Hendra virus F glycoprotein [72], or the T4 fibritin motif, as in the case of respiratory syncytial virus fusion glycoprotein [73]. Even for influenza HA, the dogma of the stability of the trimeric state all along the structural transition could be called into question in view of the growing number of crystalline structures that do not display any threefold symmetry (PDB entry codes: 4EDA, 5A3I 5K9K, 5K9O and 5IBL) [74][75][76][77] (Fig. 4).…”

“…Indeed, as mentioned above, some progresses have already been made for both class I [81][82][83][84]92] and class II fusion glycoproteins [67][68][69]; however, a higher resolution will be required to get a reliable quasi-atomic model of those intermediates. [74] and in two monomeric HA structures [74,77]. Second row: ribbon diagrams of HA2 structure (H3 subtype) [79] as in the prefusion protomer, in two monomeric HA0 structures [76] and as in its trimeric post-fusion conformation [80].…”

Antibodies against egg- and cell-grown influenza A(H3N2) viruses in adults hospitalized during the 2017-2018 season

“…Immunologic studies have proposed mechanisms for the lack of antibody cross-reactivity between egg-257 grown and circulating viruses. A study of plasmablasts in individuals receiving influenza 258 A(H1N1)pdm2009 vaccine found that individuals with a highly-specific antibody response to a reversion 259 present in the vaccine strain had no binding to the A(H1N1) circulating strain [22]. With regards to more 260 recent H3N2 strains, similar immunologic patterns of antibody misdirection have been reported for 261 residue 160 in antigenic site B of HA [7].…”