Canonical features of human antibodies recognizing the influenza hemagglutinin trimer interface

Abstract

SUMMARYBroadly reactive antibodies targeting the influenza A hemagglutinin (HA) head domain are thought to be rare and to require extensive somatic mutations or unusual structural features to achieve breadth against divergent HA subtypes. Here we describe common genetic and structural features of diverse human antibodies from several individuals recognizing the trimer interface (TI) of the influenza HA head, a recently identified site of vulnerability1–3. We examined the sequence of TI-reactive antibodies, determined crystal structures for TI antibody-antigen complexes, and analyzed the contact residues of the antibodies on HA to discover common genetic and structural features of TI antibodies. Our data reveal that many TI antibodies are encoded by a light chain variable gene segment incorporating a shared somatic mutation. In addition, these antibodies have a shared acidic residue in the heavy chain despite originating from diverse heavy chain variable gene segments. These studies show that the TI region of influenza HA is a major antigenic site with conserved structural features that are recognized by a common human B cell public clonotype. The canonical nature of this antibody-antigen interaction suggests that the TI epitope might serve as an important new target for structure-based vaccine design.

Universal stabilization of the influenza hemagglutinin by structure-based redesign of the pH switch regions

“…Uncleaved HA ectodomain (HA0) is monomeric and does not induce significant amounts of neutralizing antibodies. Although several antibodies that recognize the trimer interface have been described, suggesting some degree of reversible "breathing" of the HA trimer apex (3)(4)(5)(6), the cleaved HA at the viral surface is predominantly in a closed trimeric conformation (7)(8)(9). For all current vaccines and emerging recombinant vaccine vectors or nucleic acid vaccines (10), the delivery of a conformationally correct prefusion HA trimer with improved expression, quality, and stability is crucial (11).…”

An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer

“…The continued investigation into identifying protective epitopes using mAbs as we have done here may inform future structurebased rational design of next-generation SARS-CoV-2 vaccines by revealing protective sites whose structure should be preserved in engineered vaccine antigens. Most potently neutralizing SARS-CoV-2 mAbs discovered to date recognize the RBD region, while some moderately neutralizing NTD-directed mAbs also were identified Baum et al, 2020;Cerutti et al, 2021b;Chen et al, 2021b;Chi et al, 2020;Dong et al, 2021;Hansen et al, 2020;McCallum et al, 2021;Pinto et al, 2020;Rogers et al, 2020;Shi et al, 2020;Suryadevara et al, 2021;Turner et al, 2021c;Zost et al, 2020a). All of the NTD-reactive mAbs reported to date have lost their neutralizing capacity against certain emerging VOC.…”

“…Recently several reports about mAbs targeting the trimer interface of multiple viral antigens have been published. For instance, the non-neutralizing influenza mAbs FluA20 and 5J6 that recognize the hemagglutinin trimer interface (Bangaru et al, 2019;Zost et al, 2021) were identified from influenza-vaccinated individuals. Also, epitope mapping using polyclonal serum from vaccinated rabbits identified antibodies recognizing the HIV envelope glycoprotein trimer interface (Turner et al, 2021a).…”

“…Efficacy studies are complicated by the emergence of SARS-CoV-2 variants of concern (VOC) that can escape some neutralizing antibodies. Antibodies that neutralize SARS-COV-2 VOC have been studied broadly by many groups, both in terms of their potency and structure Baum et al, 2020;Cerutti et al, 2021b;Chen et al, 2021b;Chi et al, 2020;Dong et al, 2021;Hansen et al, 2020;McCallum et al, 2021;Pinto et al, 2020;Rogers et al, 2020;Shi et al, 2020;Suryadevara et al, 2021;Turner et al, 2021b;Zost et al, 2020a). Similarly, it has been reported that unrelated individuals can produce genetically and functionally similar clones of antibodies ("public clonotypes") following infection or vaccination ((Chen et al, 2021a;Robbiani et al, 2020;Soto et al, 2019;Yuan et al, 2020)18-22).…”

Convergent antibody responses to the SARS-CoV-2 spike protein in convalescent and vaccinated individuals

“…In recent years, public B cell clonotypes have been identified in the human antibody repertoires formed in response to diverse viruses including Ebola [18][19][20] , influenza [21][22][23][24][25] , human immunodeficiency virus 1 (HIV-1) [26][27][28][29] , hepatitis C 30,31 , SARS-CoV-2 [32][33][34] , and in healthy individuals 35,36 . These studies reveal a convergence of B cell selection resulting in circulating B cells clones with genetically similar antigen receptor genes in multiple individuals.…”