About

John P. Moore, Ph.D., is a Professor of Microbiology and Immunology at Weill Cornell Medicine. His research focuses on the structure and function of the HIV-1 envelope (Env) glycoprotein trimer, which is critical for the virus's entry into host cells and a key target for host immunity. He and his team utilize their knowledge to design and evaluate recombinant Env proteins as immunogens for vaccine development, aiming to induce broadly active neutralizing antibodies to prevent HIV-1 infection. His work involves designing stable, recombinant trimers called SOSIP glycoproteins that mimic native viral structures, with the goal of eliciting effective immune responses. Dr. Moore collaborates with multidisciplinary teams, including structural biologists and immunologists, to advance this research.

Research topics

• Virology
• Immunology
• Biology
• Chemistry
• Nanotechnology
• Materials science
• Biochemistry
• Cell biology
• Medicine
• Biophysics

Selected publications

• Decoding epitope immunodominance in HIV Env using cryoEM and machine learning

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-11

  articleOpen access

  ABSTRACT Viral surface glycoproteins, such as the HIV envelope protein (Env), present numerous antibody (Ab) epitopes, yet immune responses consistently focus on only a subset, a phenomenon known as immunodominance. Although structural studies have provided insights into Env antigenicity, our understanding of the molecular features that govern efficient Ab engagement remains incomplete, thereby limiting the predictive and rational design of vaccines. Here, we characterized the structural determinants of epitope immunodominance in HIV Env by integrating high-resolution cryoEM-based polyclonal epitope mapping (cryoEMPEM) across different clades with quantitative analyses of epitope topology, accessibility, and physicochemical properties. More than 70 new structures were resolved to assemble a library of >100 Env-antibody complexes. These data informed the development of a surface-centric, machine-learning model to predict relative A ntigen S urface I mmunodominance (ASI model). Comparison of ASI-predicted epitope sites with the specificities of Env-induced antibodies showed that the model accurately identifies immunodominant regions and highlights the structural features driving immune bias. Notably, immunogens redesigned based on model predictions successfully redirected Ab responses toward a normally subdominant epitope, demonstrating the potential of strategies coupling targeted assembly of focused structural libraries with machine learning to uncover complex molecular patterns and enable design of more effective vaccine antigens.

  PublisherOA PDFDOI

• The RV144 Trial Might Still Yield Useful Information

  Current HIV Research · 2025-04-21 · 1 citations

  articleOpen access1st authorCorresponding

  This article discusses how the RV144 Phase 3 HIV-1 vaccine trial conducted over 15 years ago impacted the subsequent direction of research intended to create and evaluate vaccines with potentially greater efficacy. Follow-on Phase 2b and Phase 3 trials directly or indirectly inspired by the modest efficacy reported for the RV144 trial have not shown any significant protection against HIV-1 acquisition. No credibly protective new immunogens have emerged from the Correlates of Protection (CoP) or Risk (CoR) analyses conducted after RV144-inspired studies in either humans or various macaque models. Notably, the RV144 trial did not induce neutralizing antibodies (NAbs), only non-NAbs. However, only NAbs have been shown to be protective in macaque models. One possible but underappreciated explanation for the outcome of the RV144 trial could be trained innate immune responses against the non-HIV-1 canarypox virus vector antigens, considering the placebo group only received saline. In this article, the author outlines how monkey model research based directly or indirectly on the RV144 trial could still yield useful information on the possible role of trained immunity in short-term vaccine protection. However, non-human primate research, in general, should now focus on testing new immunogens that have a reasonable chance of inducing NAbs in humans, rather than expending more resources on CoP/CoR studies inspired by the RV144 trial and its follow-ups.

  PublisherDOI

• Precise targeting of HIV broadly neutralizing antibody precursors in humans

  Science · 2025-05-15 · 35 citations

  articleOpen access

  A protective HIV vaccine will need to induce broadly neutralizing antibodies (bnAbs) in humans, but priming rare bnAb precursor B cells has been challenging. In a double-blinded, placebo-controlled phase 1 human clinical trial, the recombinant, germline-targeting envelope glycoprotein (Env) trimer BG505 SOSIP.v4.1-GT1.1, adjuvanted with AS01 B , induced bnAb precursors of the VRC01-class at a high frequency in the majority of vaccine recipients. These bnAb precursors, which target the CD4 receptor binding site, had undergone somatic hypermutation characteristic of the VRC01-class. A subset of isolated VRC01-class monoclonal antibodies neutralized wild-type pseudoviruses and was structurally extremely similar to bnAb VRC01. These results further support germline-targeting approaches for human HIV vaccine design and demonstrate atomic-level manipulation of B cell responses with rational vaccine design.

  PublisherOA PDFDOI

• Exploit or empower: pros and cons of researching interventions in the Arctic  

  2025-03-15

  preprintOpen access1st authorCorresponding

  Several important climate system tipping points are associated with the thawing Arctic including ice sheet collapse, AMOC shutdown, sea ice loss and permafrost thaw which may be imminent. This prompts examination of interventions to support the vulnerable systems and has raised great debate on potential governance of research into any future deployments. As well as their global impacts these systems also impact the lives of the Arctic Peoples and local ecosystems. The Arctic contains an estimated 25% of global untapped gas reserves and 13% of oil and large amounts of rare earths such as 40% of global palladium. Much of this is beneath hazardous seas, or as with Greenland, largely beneath thick permanent ice. But the Arctic is rapidly losing its ice cover, exposing more land and ice-free ocean, making it an attractive target for resource extraction and a geopolitical pawn.Unfortunately, resource extraction provides limited sustainable benefits, for the locals, with most profits to the big mining companies. However, ice itself is a global resource that, if valued proportionately to the damage its loss causes via flooding and building coastal protection, as well as ice-albedo and carbon-temperature feedbacks would be worth tens of trillions of dollars per meter over the century. Even avoiding raising sea levels by 1 inch would be worth far more than the yearly $500 m Danish “block grant” to Greenland. This would allow Arctic Peoples more self-determination, while disproportionately benefiting the Global South which has limited adaptive capacity compared with the Developed World. The ethical alternative is to value the frozen Arctic as a global good, perhaps with an analogous system to the REDD+ mechanism applied to conserving the Amazon.

  PublisherDOI

• Current HIV Research Thematic Issue on “HIV Vaccine Development”

  Current HIV Research · 2025-11-01

  article1st authorCorresponding
  PublisherDOI

• A modification to heptad repeat 1 of gp41 improves yield and/or quality of soluble pre-fusion HIV-1 envelope glycoprotein trimers

  Journal of Virology · 2025-08-27 · 2 citations

  articleOpen accessSenior author

  Native-like HIV-1 envelope glycoprotein (Env) trimers, exemplified by the SOSIP design, are widely used as immunogens, analytical antigens, and for structural studies. These vaccine research and development programs require trimers that are based on multiple HIV-1 genotypes. While a wide range of protein engineering strategies can produce SOSIP trimers from most Env gene sequences, there are still examples of trimers that are expressed only at impractically low yields or that are unstable. Accordingly, additional protein modifications aimed at overcoming such limitations need to be evaluated. Here, we describe a new heptad repeat 1 modification of gp41, known as dPG, that helps to further stabilize the gp41 component of prototypic and germline-targeting SOSIP trimers in the pre-fusion state and thereby increases post-purification yields substantially. The dPG modification involves a deletion (d) at the highly conserved 566 position that disrupts the heptad repeat and introduces proline (P) and glycine (G) substitutions at positions 567 and 568, respectively. We show that the dPG strategy reinforces previously described stabilization changes in existing SOSIP trimers and can rescue otherwise problematic trimer constructs. The latter includes trimers used to target or analyze human germline antibodies and others derived from the global HIV-1 neutralization panel. In summary, the dPG modification strategy can increase the yield and/or quality of Env trimers that are otherwise difficult to produce. IMPORTANCE: Stabilized, soluble, pre-fusion SOSIP trimers are widely used in HIV-1 Env vaccine research. Protein engineering techniques have identified multiple ways to stabilize SOSIP trimers from a range of genotypes. However, some SOSIP trimers remain difficult to express at adequate yields and/or purity, so there is a need for additional modifications. Here, we identified a sequence change, designated dPG, to the gp41 subunit that increases the yield and/or quality of various otherwise problematic SOSIP trimers without compromising their antigenicity or structure. This new modification may have general value for HIV-1 vaccine research and development.

  PublisherDOI

• Evaluation of the sensitivity of the Health Screening of People in Police Custody (HELP-PC) tool in Northumbria Police, UK

  International Journal of Law and Psychiatry · 2025-06-23 · 2 citations

  articleOpen access

  This paper presents an evaluation of a novel health screening tool implemented in 2016 by Northumbria Police, in the North East of England, United Kingdom. The aim of the study was to determine the sensitivity of the tool in detecting physical and mental health conditions. Secondary aims were to produce useful data on the prevalence of these conditions and onward referrals within custody. The tool was compared to a clinical interview carried out within the custody suite by research psychiatrists. Researchers spent a total of 64 days within the custody suite and interviewed 177 participants. The tool performed variably, with 100 % sensitivity for diabetes, epilepsy and psychosis, however in other areas the sensitivity was lower such as for opioid dependency (18 %). When compared to the pilot study of the tool there is a non-significant trend towards improved sensitivity, with no areas in which sensitivity has reduced. In comparison to a previous evaluation of an alternative tool, this tool has improved sensitivity for asthma (92 vs 49 %, p < 0.001), cardiovascular complaints (38 vs 2 %, p < 0.0001), head injury (72 vs 17 %, p = 0.004) and intellectual disability (82 vs 25 %, p = 0.016). • Detained persons in police custody undergo health screening on arrival. • This aims to identify health risks relevant to their time in custody. • There is a lack of published evidence regarding currently used screening tools. • The HELP-PC tool has been developed and evaluated since 2011. • This tool shows improved sensitivity compared with an alternative tool.

  PublisherDOI

• HIV-1 envelope trimer vaccine induces sex-associated differences in antibody responses: a phase 1 clinical trial

  Nature Communications · 2025-11-21 · 3 citations

  articleOpen access

  A protective vaccine will be the most powerful instrument to reduce HIV-1 infections worldwide and help bring about a lasting end to the AIDS epidemic. The single centre, randomised, open-label, uncontrolled, phase 1 ACTHIVE-001 clinical trial (NCT03961438) aims to assess the safety and immunogenicity of the ConM SOSIP.v7 native-like trimer protein vaccine, based on an HIV-1 group M consensus sequence, in HIV-negative adults. Twenty-four individuals were enrolled to receive three dosages of ConM SOSIP.v7 protein vaccine in a liposome formulation containing a high dose of the TLR4-agonist MPLA. The primary outcome is vaccine reactogenicity, whereas the main secondary outcome is binding and neutralising antibody responses. Overall, the vaccine is safe and well-tolerated. Furthermore, the vaccine elicits robust strain-specific binding and neutralising antibody responses in nearly all vaccinees. Post-hoc exploratory analyses demonstrate that female-born participants have 22- and 6-fold higher neutralisation titres after the second and third vaccination, respectively. The vaccine adjuvant induces higher levels of IL-6 secretion from in vitro cultured monocytes from female compared to male participants, providing a possible mechanistic explanation for the sex-based differences. Our study highlights the need to take sex-based differences into consideration when assessing HIV-1 vaccine candidates and adjuvants.

  PublisherOA PDFDOI

• Germline-targeting HIV Envelope SOSIP immunization more frequently elicits broadly-neutralizing antibody precursor responses in infant compared to juvenile rhesus macaques

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-30 · 1 citations

  preprintOpen access

  A vaccine capable of inducing broadly neutralizing antibodies (bnAbs) is essential for effective prevention against HIV in children and adolescents. Germline-targeting vaccine strategies aim to stimulate bnAb precursor B cells through carefully designed immunogens, such as the stabilized SOSIP trimers, which mimic native HIV envelope (Env) proteins while presenting key neutralizing epitopes to germline B cell receptors. Given the ability of children living with HIV to develop bnAbs earlier and at a higher frequency than adults, we compared the immunogenicity of a CD4 binding site (CD4bs) bnAb germline-targeting SOSIP trimer immunization strategy in infant (n = 5) and juvenile (n = 4) rhesus macaques (RMs). Animals received 3 doses of the germline-targeting BG505 GT1.1 immunogen, followed by 3 boosts of wild-type BG505 SOSIP, each adjuvanted with the TLR7/8 agonist, 3M-052-SE. After 1.5 years, the RMs were further boosted with a mixed clade B Env trimer nanoparticle to enhance heterologous virus neutralization responses. This germline-targeting strategy induced equivalent titers of neutralizing antibodies in both groups of RMs, yet the infants exhibited a higher magnitude of vaccine-specific IgG binding. Notably, after 3 doses of BG505 GT1.1 SOSIP, infants had higher BG505 GT1.1-specific IgD- B cells. Upon completion of the vaccine regimen, 4 of 5 infants developed a CD4bs bnAb precursor response detectable in serum compared to only 1 of 4 juveniles. Finally, administration of the mixed clade B nanoparticle was able to increase the breadth of antibody responses in 3 of 5 infants and 2 of 4 juveniles. These results suggest that immunization in early-life may enhance bnAb induction and highlight the potential for future pediatric HIV-1 vaccine strategies.

  PublisherOA PDFDOI

• Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site

  Science Immunology · 2024-08-30 · 36 citations

  articleOpen access

  Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)-specific VRC01-class B cells in knock-in mice and drives VRC01-class maturation. In nonhuman primates (NHPs), GT1.1 primes CD4bs-specific neutralizing serum responses. Selected monoclonal antibodies (mAbs) isolated from GT1.1-immunized NHPs neutralize fully glycosylated BG505 virus. Two mAbs, 12C11 and 21N13, neutralize subsets of diverse heterologous neutralization-resistant viruses. High-resolution structures revealed that 21N13 targets the same conserved residues in the CD4bs as VRC01-class and CH235-class bnAbs despite its low sequence similarity (~40%), whereas mAb 12C11 binds predominantly through its heavy chain complementarity-determining region 3. These preclinical data underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers.

  PublisherOA PDFDOI

Recent grants

• NIH Grant U19AI076982

  NIH · $9.2M · 2013

• NIH Grant R21AI042721

  NIH · $495k · 1999

• NIH Grant R01AI045463

  NIH · $4.8M · 2011

• NIH Grant P01AI052048

  NIH · $5.2M · 2005

• Neutralization of primary HIV-1 viruses

  NIH · $5.2M · 1994–2028

Frequent coauthors

• Rogier W. Sanders

  Cornell University

  355 shared

• Per Johan Klasse

  Cornell University

  178 shared

• Andrew B. Ward

  Scripps Research Institute

  151 shared

• Thomas J. Ketas

  Cornell University

  147 shared

• Ian A. Wilson

  Scripps Research Institute

  130 shared

• David D. Ho

  Columbia University

  129 shared

• James Μ. Binley

  San Diego Biomedical Research Institute

  113 shared

• Dennis R. Burton

  Scripps Research Institute

  109 shared