HIV-1 vaccine development has been stymied by an inability to induce broadly reactive neutralizing antibodies to the envelope (Env) trimer, the sole viral antigen on the virion surface. Antibodies ...isolated from HIV-1-infected donors, however, have been shown to recognize all major exposed regions of the prefusion-closed Env trimer, and an emerging understanding of the immunological and structural characteristics of these antibodies and the epitopes they recognize is enabling new approaches to vaccine design. Antibody lineage-based design creates immunogens that activate the naive ancestor-B cell of a target antibody lineage and that mature intermediate-B cells toward effective neutralization, with proof of principle achieved with select HIV-1-neutralizing antibody lineages in human-gene knock-in mouse models. Epitope-based vaccine design involves the engineering of sites of Env vulnerability as defined by the recognition of broadly neutralizing antibodies, with cross-reactive neutralizing antibodies elicited in animal models. Both epitope-based and antibody lineage-based HIV-1 vaccine approaches are being readied for human clinical trials.
Kwong and Mascola review vaccine approaches to overcome the formidable challenge of eliciting effective antibodies against HIV-1. The structural and immunological information provided by analysis of infection-elicited broadly neutralizing antibodies provides a framework for antibody-to-vaccine approaches of vaccine design.
Antibodies that neutralize diverse strains of HIV-1 develop in ∼20% of HIV-1-infected individuals, and isolation and structural characterization of these antibodies are revealing how they recognize ...the envelope glycoprotein spike. Broadly reactive neutralizing antibodies utilize just a few sites of spike vulnerability and converge on select modes of recognition. These antibodies have unusual features: uncommonly long complementarity-determining loops, extensive somatic mutation, or both. Recent advances in next-generation sequencing of antibody-gene transcripts are providing genetic records of the development of neutralizing antibodies. These records inform an understanding of the naive B cell repertoire, of somatic mutation, and of the resulting antibody features that are critical to effective HIV-1 neutralization; based on these, we propose an ontogeny and structure-based system of antibody classification. The human immune system is capable of developing antibodies that broadly neutralize HIV-1—and an increasingly detailed view is accumulating for how effective immunity against HIV-1 can be generated.
The emergence of SARS-CoV-2 variants has raised concerns about altered sensitivity to antibody-mediated immunity. The relative resistance of SARS-CoV-2 variants B.1.1.7 and B.1.351 to antibody ...neutralization has been recently investigated. We report that another emergent variant from Brazil, P.1, is not only refractory to multiple neutralizing monoclonal antibodies but also more resistant to neutralization by convalescent plasma and vaccinee sera. The magnitude of resistance is greater for monoclonal antibodies than vaccinee sera and evident with both pseudovirus and authentic P.1 virus. The cryoelectron microscopy structure of a soluble prefusion-stabilized spike reveals that the P.1 trimer adopts exclusively a conformation in which one of the receptor-binding domains is in the “up” position, which is known to facilitate binding to entry receptor ACE2. The functional impact of P.1 mutations thus appears to arise from local changes instead of global conformational alterations. The P.1 variant threatens current antibody therapies but less so protective vaccine efficacy.
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•P.1 is refractory to multiple neutralizing mAbs, including three out of the four with EUA•P.1 is relatively resistant to neutralization by convalescent plasma and vaccinee sera•Cryo-EM structure of P.1 spike trimer reveals exclusively one-RBD-up conformation
Wang et al. report that an emergent SARS-CoV-2 variant, P.1, is relatively resistant to neutralization by multiple therapeutic monoclonal antibodies, convalescent plasma, and vaccinee sera. The cryoelectron microscopy structure reveals the P.1 trimer to adopt exclusively a conformation with one of the receptor-binding domains in the “up” position.
Broadly neutralizing antibodies (bNAbs) to HIV-1 can prevent infection and are therefore of great importance for HIV-1 vaccine design. Notably, bNAbs are highly somatically mutated and generated by a ...fraction of HIV-1-infected individuals several years after infection. Antibodies typically accumulate mutations in the complementarity determining region (CDR) loops, which usually contact the antigen. The CDR loops are scaffolded by canonical framework regions (FWRs) that are both resistant to and less tolerant of mutations. Here, we report that in contrast to most antibodies, including those with limited HIV-1 neutralizing activity, most bNAbs require somatic mutations in their FWRs. Structural and functional analyses reveal that somatic mutations in FWR residues enhance breadth and potency by providing increased flexibility and/or direct antigen contact. Thus, in bNAbs, FWRs play an essential role beyond scaffolding the CDR loops and their unusual contribution to potency and breadth should be considered in HIV-1 vaccine design.
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► Framework mutations play a crucial role in broadly neutralizing HIV-1 antibodies ► Mutations in the antibody framework are critical for HIV-1 neutralization ► Increased antibody flexibility can enhance HIV-1 neutralization activity ► FWR mutations can extend direct antigen contact resulting in improved activity
Framework regions play an essential role in the potency of broadly neutralizing antibodies beyond scaffolding and thus should be considered in HIV-1 vaccine design.
The COVID-19 pandemic has had widespread effects across the globe, and its causative agent, SARS-CoV-2, continues to spread. Effective interventions need to be developed to end this pandemic. Single ...and combination therapies with monoclonal antibodies have received emergency use authorization
, and more treatments are under development
. Furthermore, multiple vaccine constructs have shown promise
, including two that have an approximately 95% protective efficacy against COVID-19
. However, these interventions were directed against the initial SARS-CoV-2 virus that emerged in 2019. The recent detection of SARS-CoV-2 variants B.1.1.7 in the UK
and B.1.351 in South Africa
is of concern because of their purported ease of transmission and extensive mutations in the spike protein. Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain. It is not more resistant to plasma from individuals who have recovered from COVID-19 or sera from individuals who have been vaccinated against SARS-CoV-2. The B.1.351 variant is not only refractory to neutralization by most monoclonal antibodies against the N-terminal domain but also by multiple individual monoclonal antibodies against the receptor-binding motif of the receptor-binding domain, which is mostly due to a mutation causing an E484K substitution. Moreover, compared to wild-type SARS-CoV-2, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4-fold) and sera from individuals who have been vaccinated (10.3-12.4-fold). B.1.351 and emergent variants
with similar mutations in the spike protein present new challenges for monoclonal antibody therapies and threaten the protective efficacy of current vaccines.
The field of HIV-1 vaccine research has seen a renaissance with the identification of antibodies that neutralize most circulating HIV-1 strains. An understanding of the structural mode of target ...recognition that these antibodies use and the immune pathways that lead to their development is emerging. This knowledge has provided fundamental insights into the pathways that elicit broadly neutralizing antibodies and provides a foundation for active and passive immunization strategies to prevent HIV-1 infection.
Development of strategies for induction of HIV-1 broadly neutralizing antibodies (bnAbs) by vaccines is a priority. Determining the steps of bnAb induction in HIV-1-infected individuals who make ...bnAbs is a key strategy for immunogen design. Here, we study the B cell response in a bnAb-producing individual and report cooperation between two B cell lineages to drive bnAb development. We isolated a virus-neutralizing antibody lineage that targeted an envelope region (loop D) and selected virus escape mutants that resulted in both enhanced bnAb lineage envelope binding and escape mutant neutralization—traits associated with increased B cell antigen drive. Thus, in this individual, two B cell lineages cooperated to induce the development of bnAbs. Design of vaccine immunogens that simultaneously drive both helper and broadly neutralizing B cell lineages may be important for vaccine-induced recapitulation of events that transpire during the maturation of neutralizing antibodies in HIV-1-infected individuals.
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•The steps in induction of HIV-1 broadly neutralizing antibodies have been mapped•The steps involve cooperation between two distinct B cell antibody lineages•One lineage induced escape mutants with enhanced binding to bnAb precursors
The molecular identification of two B cell lineages that cooperate for the generation of broadly neutralizing antibodies offers new insights into the design of antigens that can be used to elicit protective immunity to HIV infection.
The ability of structure-based design to control the shape and reactivity-the atomic-level chemistry-of an immunogen argues for it being one of the "most powerful" immunogen-design strategies. But ...antigenic reactivity is only one of the properties required to induce a protective immune response. Here, a multidimensional approach is used to exemplify the enabling role atomic-level information can play in the development of immunogens against three viral pathogens, respiratory syncytial virus, influenza A virus, and human immunodeficiency virus (HIV), which have resisted standard approaches to vaccine development. Overall, structure-based strategies incorporating B-cell ontogenies and viral evasion mechanisms appear exceptionally powerful.
The rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (Omicron) variant and its resistance to neutralization by vaccinee and convalescent sera are driving a ...search for monoclonal antibodies with potent neutralization. To provide insight into effective neutralization, we determined cryo-electron microscopy structures and evaluated receptor binding domain (RBD) antibodies for their ability to bind and neutralize B.1.1.529. Mutations altered 16% of the B.1.1.529 RBD surface, clustered on an RBD ridge overlapping the angiotensin-converting enzyme 2 (ACE2)-binding surface and reduced binding of most antibodies. Substantial inhibitory activity was retained by select monoclonal antibodies-including A23-58.1, B1-182.1, COV2-2196, S2E12, A19-46.1, S309, and LY-CoV1404-that accommodated these changes and neutralized B.1.1.529. We identified combinations of antibodies with synergistic neutralization. The analysis revealed structural mechanisms for maintenance of potent neutralization against emerging variants.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) mediates viral entry into cells and is critical for vaccine development against coronavirus disease 2019 (COVID-19). ...Structural studies have revealed distinct conformations of S, but real-time information that connects these structures is lacking. Here we apply single-molecule fluorescence (Förster) resonance energy transfer (smFRET) imaging to observe conformational dynamics of S on virus particles. Virus-associated S dynamically samples at least four distinct conformational states. In response to human receptor angiotensin-converting enzyme 2 (hACE2), S opens sequentially into the hACE2-bound S conformation through at least one on-path intermediate. Conformational preferences observed upon exposure to convalescent plasma or antibodies suggest mechanisms of neutralization involving either competition with hACE2 for binding to the receptor-binding domain (RBD) or allosteric interference with conformational changes required for entry. Our findings inform on mechanisms of S recognition and conformations for immunogen design.
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•SARS-CoV-2 S protein dynamically samples at least 4 distinct conformational states•hACE2 activates S from the ground state to the activated state via an intermediate•Proteolytic processing of S accelerates hACE2-dependent activation•Antibodies can antagonize S by two different mechanisms of neutralization
The SARS-CoV-2 spike protein has been observed to adopt different structural states. Lu et al. directly visualize the conformational dynamics of spike protein on the surface of virus particles and describe how the conformational landscape changes upon activation by the host receptor or antagonism by antibodies.
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