About

Peter D Kwong, PhD, is the Richard J. Stock Professor of Medical Sciences (Infectious Diseases) at Columbia University and a Professor of Biochemistry and Molecular Biophysics. He received his PhD from Columbia University in 1995 and completed a postdoctoral fellowship with Wayne A. Hendrickson until 2000. He then founded and led the Structural Biology Section at the Vaccine Research Center, National Institutes of Health (NIH), from 2000 to 2023. In December 2023, he returned to Columbia University as the Director of the Aaron Diamond AIDS Research Center. His research is internationally recognized for defining the structural aspects of HIV-1 envelope glycoproteins and their interactions with antibodies, contributing significantly to the understanding of viral evasion mechanisms and vaccine design. His work has focused on applying atomic-level structural biology tools to develop effective vaccines against HIV-1 and other viral pathogens, including the design of stabilized immunogens and the elicitation of broadly neutralizing antibodies. Throughout his career, Kwong has made pivotal contributions to the structural elucidation of HIV-1 envelope components, mechanisms of immune evasion, and vaccine strategies, including the development of immunogens that have informed licensed vaccines such as GSK's AREXVY and Moderna's mRESVIA. He has published over 400 peer-reviewed papers and mentored numerous postdoctoral fellows, many of whom now lead independent research groups.

Research topics

• Biology
• Virology
• Immunology
• Medicine
• Molecular biology
• Computational biology
• Biochemistry
• Chemistry
• Anatomy
• Neuroscience
• Genetics
• Evolutionary biology
• Cell biology
• Pathology

Selected publications

• Structural and genetic basis of HIV-1 envelope V2 apex recognition by rhesus broadly neutralizing antibodies

  The Journal of Experimental Medicine · 2025-07-10 · 10 citations

  articleOpen access

  Broadly neutralizing antibodies targeting the V2 apex of HIV-1 envelope are desired as vaccine design templates, but few have been described. Here, we report 11 lineages of V2 apex-neutralizing antibodies from simian-human immunodeficiency virus (SHIV)-infected rhesus macaques and determine cryo-EM structures for 9. A single V2 apex-neutralizing lineage accounted for cross-clade breadth in most macaques, and somatic hypermutation relative to breadth was generally low, exemplified by antibody V033-a.01 with <5% nucleotide mutation and 37% breadth (208-strain panel). Envelope complex structures revealed eight different antibody classes (one multi-donor) and the complete repertoire of all five possible recognition topologies, recapitulating canonical human modes of apex insertion and C-strand hydrogen bonding. Despite this diversity in recognition, all rhesus-V2 apex antibodies were derived from reading frame two of the DH3-15*01 gene. Collectively, these results define-in rhesus-the structural and genetic basis of HIV-1 V2 apex recognition and demonstrate unprecedented structural plasticity of a highly selected immunogenetic element.

  PublisherOA PDFDOI

• Phenotypic heterogeneity defines B cell responses to repeated SARS-CoV-2 exposures through vaccination and infection

  Cell Reports · 2025-04-01 · 5 citations

  articleOpen access

  Long-lived humoral memory is key to durable immunity against pathogens yet remains challenging to define due to heterogeneity among antigen-reactive B cells. We addressed this gap through longitudinal sampling over the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccinations with or without breakthrough infection. High-dimensional phenotypic profiling performed on ∼72 million B cells showed that receptor-binding domain (RBD) reactivity was associated with five distinct immunoglobulin G (IgG) B cell populations. Two expressed the activation marker CD71, both correlated with neutralizing antibodies, yet the one lacking the memory marker CD27 was induced by vaccination and blunted by infection. Two were resting memory populations; one lacking CD73 arose early and contributed to cross-reactivity; the other, expressing CD73, arose later and correlated with neutralizing antibodies. The fifth, a rare germinal center-like population, contributed to recall responses and was highly cross reactive. Overall, robust and distinct responses to booster vaccination overcame the superiority of hybrid immunity provided by breakthrough infection.

  PublisherDOI

• In silico improvement of affinity for highly protective anti-malarial antibodies

  iScience · 2025-06-14 · 3 citations

  articleOpen access

  approach to improve antibody affinity can thus be used to enhance potency of PfCSP monoclonal antibodies.

  PublisherDOI

• Transient glycan shield reduction induces CD4-binding site broadly neutralizing antibodies in SHIV-infected macaques

  Cell Reports · 2025-06-01 · 5 citations

  articleOpen access

  Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 CD4-binding site (CD4bs) occur infrequently in macaques and humans and have not been reproducibly elicited in any outbred animal model. To address this challenge, we first isolated RHA10, an infection-induced rhesus bNAb with 51% breadth. The cryoelectron microscopy (cryo-EM) structure of RHA10 with the HIV-1 envelope (Env) resembled prototypic human CD4bs bNAbs with CDR-H3-dominated binding. Env-antibody co-evolution revealed transient elimination of two Env CD4bs-proximal glycans near the time of RHA10-lineage initiation, and these glycan-deficient Envs bound preferentially to early RHA10 intermediates, suggesting that glycan deletions in infecting SHIVs could induce CD4bs bNAbs. To test this hypothesis, we constructed SHIV.CH505 variants with CD4bs-proximal glycan deletions. Infection of 11 macaques resulted in accelerated CD4bs bNAb responses in 9 compared with 1 of 115 control macaques. Glycan hole-based immunofocusing coupled to Env-Ab co-evolution can consistently induce broad CD4bs responses in macaques and serve as a model for HIV vaccine design.

  PublisherOA PDFDOI

• Protective immunity against malaria by a nanoparticle CIS43-based junctional vaccine alone or in combination with R21

  npj Vaccines · 2025-09-08

  preprintOpen accessCorresponding

  ABSTRACT Repetitive display of the major repeats of the Plasmodium falciparum circumsporozoite protein (PfCSP) is the basis for two WHO-recommended vaccines: RTS,S/AS01 and R21/Matrix-M. Recently, however, the CIS43 monoclonal antibody that preferentially targets the junctional region of PfCSP has been shown to be highly protective in humans, highlighting its junctional epitope as a key vaccine target. Here, we develop a vaccine based on the tandem repeats of the junctional epitope displayed on a self-assembling nanoparticle, and compare this CIS43-based junctional vaccine alone or in combination with the benchmark R21 vaccine, using both B cell analysis and monoclonal antibody isolation to define targeting of the immune response. Comparable reduction in liver burden was observed following vaccination with junctional and R21 vaccines at a dose of 1 μg. At a dose of 0.25 μg, a modest reduction of malaria-liver burden with the junctional vaccine was observed compared to R21. Further, combining junctional and R21 vaccines induced modestly enhanced protection compared to either vaccine alone. While the R21 vaccine elicited antibodies primarily against the major repeats, the junctional vaccine elicited antibodies against both junctional and major repeat regions. In vivo -B cell analysis and isolation of monoclonal antibodies confirmed differences in vaccine-induced antibody specificities. Altogether, these data suggest the nanoparticle-formatted tandem-repeated CIS43-junctional vaccine to be a promising approach to broaden immunity against malaria, either as a standalone intervention or in combination with R21. HIGHLIGHTS Developed a self-assembling nanoparticle-displayed junctional vaccine of PfCSP based on tandem repeats of the epitope preferentially targeted by the highly protective CIS43 antibody The CIS43-based junctional vaccine at low doses significantly reduced liver burden following malaria challenge in mice Following either low or high doses of the junctional vaccine in naïve mice, adoptively transferred B cells expressing the CIS43 inferred germline sequence yielded a high frequency of germinal center and ASC responses The CIS43-based junctional vaccine elicits antibodies against junctional and major repeat regions whereas the R21 vaccine elicits responses primarily against the major repeat region At low dose, the CIS43-based junctional vaccine given together with the R21 vaccine showed modestly improved control of liver burden compared to either vaccine alone

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• Env-antibody coevolution identifies B cell priming as the principal bottleneck to HIV-1 V2 apex broadly neutralizing antibody development

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-06 · 8 citations

  preprintOpen access

  Broadly neutralizing antibodies (bNAbs) are rarely elicited during HIV-1 infection. To identify obstacles to bNAb development, we longitudinally studied 122 rhesus macaques infected by one of 16 different simian-human immunodeficiency viruses (SHIVs). We identified V2 apex as the most common bNAb target and a subset of Envs that preferentially elicited these antibodies. In 10 macaques, we delineated Env-antibody coevolution from B cell priming to bNAb development. Antibody phylogenies revealed permissive developmental pathways guided by evolving Envs that contained few mutations in or near the V2 apex C-strand, which were a sensitive indicator of apex-targeted responses. The absence of such mutations reflected a failure in bNAb priming. These results indicate that efficiency of B cell priming, and not complexities in Env-guided affinity maturation, is the primary obstacle to V2 apex bNAb elicitation in SHIV-infected macaques and identify specific HIV-1 Envs to advance as novel vaccine platforms. One sentence summary: B cell priming is the primary bottleneck to HIV-1 V2 apex bNAb elicitation.

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• Intranasal parainfluenza virus-vectored vaccine expressing SARS-CoV-2 spike protein of Delta or Omicron B.1.1.529 induces mucosal and systemic immunity and protects hamsters against homologous and heterologous challenge

  PLoS Pathogens · 2025-04-21 · 4 citations

  articleOpen access

  The continuous emergence of new SARS-CoV-2 variants requires that COVID vaccines be updated to match circulating strains. We generated B/HPIV3-vectored vaccines expressing 6P-stabilized S protein of the ancestral, B.1.617.2/Delta, or B.1.1.529/Omicron variants as pediatric vaccines for intranasal immunization against HPIV3 and SARS-CoV-2 and characterized these in hamsters. Following intranasal immunization, these B/HPIV3 vectors replicated in the upper and lower respiratory tract and induced mucosal and serum anti-S IgA and IgG. B/HPIV3 expressing ancestral or B.1.617.2/Delta-derived S-6P induced serum antibodies that effectively neutralized SARS-CoV-2 of the ancestral and B.1.617.2/Delta lineages, while the cross-neutralizing potency of B.1.1.529/Omicron S-induced antibodies was lower. Despite the lower cross-neutralizing titers induced by B/HPIV3 expressing S-6P from B.1.1.529/Omicron, a single intranasal dose of all three versions of B/HPIV3 vectors was protective against matched or heterologous WA1/2020, B.1.617.2/Delta or BA.1 (B.1.1.529.1)/Omicron challenge; hamsters were protected from challenge virus replication in the lungs, while low levels of challenge virus were detectable in the upper respiratory tract of a small number of animals. Immunization also protected against lung inflammatory response after challenge, with mild inflammatory cytokine induction associated with the slightly lower level of cross-protection of WA1/2020 and B.1.617.2/Delta variants against the BA.1/Omicron variant. Serum antibodies elicited by all vaccine candidates were broadly reactive against 20 antigenic variants, but the antigenic breadth of antibodies elicited by B/HPIV3-expressed S-6P from the ancestral or B.1.617.2/Delta variant exceeded that of the S-6P B.1.1.529/Omicron expressing vector. These results will guide development of intranasal B/HPIV3 vectors with S antigens matching circulating SARS-CoV-2 variants.

  PublisherDOI

• Anti-Malaria Antibody Engineering Broadens Recognition Motifs and Reveals New Homotypic Interactions that Enhance Protective Breadth

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-01 · 2 citations

  preprintOpen access

  ABSTRACT The monoclonal antibody L9 mediates high-level protection against malaria in children for up to 6 months in Africa. L9 preferentially binds with high affinity to the NVDP minor repeat on the P. falciparum circumsporozoite protein (PfCSP). Here, we sought to improve the affinity of L9 to enhance protection against rare strains with two spatially separated minor repeats or a single minor repeat. Site saturation mutagenesis and yeast display-screening identified a panel of affinity-improved variants. In vivo challenge showed one variant, L9_yd19, to be modestly more potent against a chimeric transgenic Plasmodium encoding PfCSP with two widely spaced minor repeats from a Kenyan parasite strain, with no loss in potency against the benchmark 3D7 strain with its standard complement of minor repeats. L9_yd19 also had high affinity against NANP major repeats and was protective against transgenic Plasmodium with PfCSP containing only NANP major repeats (NANP 12 ). Cryo-EM studies revealed L9_yd19 to recognize PfCSP with two distinct homotypic interfaces, which combined to yield two trimeric layers of antibodies comprising asymmetric trimers that dimerized in a head-to-head fashion. These data reveal a new antibody mechanism that utilizes interfaces involving dual homotypic symmetry elements, a 2-fold and an asymmetric 3-fold, for potentially improved malaria prevention. HIGHLIGHTS L9 is a highly protective antimalarial antibody that preferentially binds the NVDP minor repeat on Plasmodium falciparum circumsporozoite protein (PfCSP) and also binds with low affinity to the NANP major repeat; due to these targeting preferences, it has shown reduced protection against designed transgenic malaria strains with only a single NVDP motif (Fig. 1). Using yeast display, a panel of L9 variants were generated based on higher affinity against the minor NVDP and major NANP motifs to determine if they could improve protection against strains with fewer minor repeat regions or only containing major repeats (Figs 1-4). One L9 variant, L9_yd19 showed enhanced protection against chimeric transgenic CSP variants with a single minor repeat or two minor repeats in which the spacing was separated; L9_yd19 also showed protection against chimeric transgenic CSP variants containing only the NANP major repeat (Figs. 4-5). Cryo-EM analyses revealed L9_yd19 recognition of CSP to comprise two distinct homotypic interfaces: a side-to-side interface within asymmetric antibody trimer and a head-to-head interface between antibody trimers related by 2-fold symmetry that combined to yield a higher-order complex comprising two trimeric layers of antibodies (Figs. 6-7) Structure-function studies reveal a new antibody-based structural mechanism with dual homotypic interfaces mediating protection against varying numbers and spacing of minor repeats and major repeats.

  PublisherOA PDFDOI

• Fostemsavir analog BMS-818251 has enhanced viral neutralization potency and similar escape mutation profile

  Antimicrobial Agents and Chemotherapy · 2025-08-27

  articleOpen accessSenior author

  ABSTRACT BMS-818251, a fostemsavir analog, is a next-generation HIV-1 attachment inhibitor with enhanced potency and a similar resistance profile. By using ex vivo viral outgrowth assays with HIV+ donor samples, we demonstrate here that BMS-818251 exhibits superior viral suppression compared to temsavir, the active form of fostemsavir. To map potential resistance pathways, we employed deep mutational scanning and pseudotyped virus neutralization assays to identify escape mutations within the HIV-1 envelope glycoprotein (Env). These mutations were largely clustered around the BMS-818251 binding site, with key resistance mutations reducing drug-binding affinity. Several of the enriched mutations, such as S375I/N, M426L, and M475I, have been previously observed in fostemsavir-treated patients, highlighting their clinical relevance. Isothermal titration calorimetry revealed reduced binding affinity as the primary mechanism of resistance, though with notable exceptions, such as R429G, suggesting additional factors to influence viral escape. Ex vivo Env sequencing confirmed selection of resistance mutations under BMS-818251 pressure, reinforcing the predictive value of deep mutational scanning for in vivo resistance monitoring. Compared to fostemsavir, BMS-818251 achieved more effective viral suppression at lower concentrations, even in donor samples harboring preexisting resistance mutations. These findings support the continued development of BMS-818251 as a promising alternative to fostemsavir, with potential benefits for patients with multidrug-resistant HIV-1.

  PublisherDOI

• Demonstration of <i>in vivo</i> efficacy, cryo-EM-epitope identification, and breadth of two anti-alphavirus bispecific single domain antibodies

  Journal of Virology · 2025-12-16 · 2 citations

  articleOpen access

  Venezuelan equine encephalitis virus (VEEV) is an arbovirus that causes a disease in which 4%-14% of individuals can develop neurological symptoms. Prior to 1970, VEEV was developed as a biological threat agent due to its stability and high morbidity when administered by aerosol. Currently, no FDA-licensed vaccines nor therapeutics for VEEV exist. Single-domain antibodies (sdAbs) may provide a therapeutic option due to their small size and ability to bind recessed epitopes not recognized by conventional antibodies. This study identified two bivalent sdAbs that were able to protect mice from a lethal challenge against both epizootic and enzootic subtypes of VEEV. Cryo-EM structures of sdAb-VEEV complexes revealed the sdAbs that comprised the bivalent sdAbs to recognize a mixture of conserved and non-conserved regions of the VEEV envelope proteins. While all three of the cryo-EM-characterized epitopes were unique in terms of their recognized VEEV residues, two sdAbs, V2B3 and V2C3, overlapped sterically, explaining why only their combinations with the non-sterically overlapping sdAb V3A8f, which composed the bivalent sdAbs described here, were so particularly effective. Binding and neutralization studies found that the bivalent sdAbs have the potential to be broad-spectrum anti-alphavirus therapeutics as they cross-neutralize multiple alphaviruses.IMPORTANCEAlphaviruses are no longer geographically constrained to one region of the world but are expanding to be of global concern. In many regions of the world, multiple alphaviruses co-circulate; therefore, having a therapeutic that is pan-alphavirus is important. A cocktail of multiple pan-alphavirus binding/neutralizing antibodies (Abs) may provide optimal coverage against alphaviruses while decreasing the prevalence of viral escape mutants, which could cause the therapeutic to no longer be efficacious. Structures of these Abs, defining their recognition, could assist in identifying optimal combinations. A bivalent pan-alphavirus single-domain antibody could be used in a cocktail with already identified alphavirus IgG antibodies.

  PublisherDOI

Recent grants

• NIH Grant Z01AI005022

  NIH · $733k

• NIH Grant Z01AI005068

  NIH · $194k

• NIH Grant Z01AI005069

  NIH · $309k

• Design Of Immunogens

  NIH · $21.5M

• CAPRISA HIV-1 neutralizing antibodies: Harnessing ontogeny for immunogen design

  NIH · $874k · 2015–2019

Frequent coauthors

• John R. Mascola

  806 shared

• Tongqing Zhou

  National Institute of Allergy and Infectious Diseases

  633 shared

• Lawrence Shapiro

  Columbia University

  561 shared

• Baoshan Zhang

  National Institutes of Health

  557 shared

• Nicole A. Doria‐Rose

  National Institutes of Health

  362 shared

• Jason Gorman

  361 shared

• Mark K. Louder

  National Institute of Allergy and Infectious Diseases

  319 shared

• Gwo‐Yu Chuang

  Moderna Therapeutics (United States)

  316 shared

Labs

• Columbia University Irving Medical Center Biochemistry and Molecular BiophysicsPI

Education

• Ph.D.

  Columbia University

  1995

Awards & honors

• Presidential Early Career Award for Scientists and Engineers…
• Norman P. Salzman Award in Virology (2012)
• Fellow of the American Society of Microbiology (2004)
• Director’s Award, National Institutes of Health (2007)
• NIAID Merit Award (2010)