About

Raiees Ahmad Andrabi, PhD, is an Associate Professor of Medicine in the Department of Medicine (Infectious Diseases) at the Perelman School of Medicine, University of Pennsylvania. His research focuses on utilizing in vitro directed evolution platforms combined with structure-guided design approaches to develop vaccine immunogens against complex pathogens such as HIV, Influenza virus, Arenaviruses, and Coronaviruses. His laboratory also investigates the immunological basis of B cell affinity maturation pathways to complex antigen surfaces, both in vaccination and infection, with the aim of designing more effective vaccines. His overall goal is to create vaccine immunogens and immunization strategies that induce protective broadly neutralizing antibody responses against complex pathogens through human vaccination.

Research topics

• Biology
• Genetics
• Medicine
• Virology
• Immunology
• Computational biology
• Computer Science
• Internal medicine
• Cell biology
• Neuroscience
• Chemistry
• Molecular biology
• Anatomy

Selected publications

• Rapidly acquired HIV-1 neutralization breadth in a rhesus V2 apex knockin mouse model after a single bolus immunization.

  PubMed · 2026-02-13 · 2 citations

  articleOpen access

  Current immunization strategies to elicit broadly neutralizing antibodies (bnAbs) against HIV-1 generally propose complex, multiboost regimens. In rhesus macaques, simian-human immunodeficiency virus (SHIV) infection rapidly drives the development of some bnAb classes sharing structural similarities with those in humans. Here, we generated a knockin (KI) mouse model with B cells bearing the unmutated common ancestor of a V2 apex-targeted bnAb lineage, V033-a. A single immunization with a germline-targeting native-like trimer, Q23-APEX-GT1, recapitulated the ontogeny of the mature rhesus bnAb in KI mice, including rare, disfavored somatic mutations. Resulting antibodies exhibited potent neutralization against a broad panel of heterologous HIV-1 strains. Boosting with Env escape mutant trimers further improved breadth and potency, and cryo-electron microscopy analysis revealed the structural basis for heterologous neutralization breadth. Nonhuman primate and mouse models combined with structure can serve as a platform for identifying and validating immunogens that streamline HIV vaccination regimens.

  PublisherOA PDFDOI

• Induction of broadly neutralizing HIV antibodies by a two-step mechanism informs vaccine design

  Science · 2026-05-07

  articleOpen access

  A major obstacle confronting HIV-1 vaccine and cure research is the lack of an outbred animal model for rapid and consistent induction of broadly neutralizing antibodies (bNAbs). We designed an epitope-focused simian-human immunodeficiency virus (SHIV.5MUT) that elicited broad and potent V3-glycan-targeted antibodies within a year of infection in 14 of 22 macaques compared with 0 of 14 control animals. SHIV.5MUT elicited bNAbs by a two-step mechanism, inducing an initial wave of V1-directed antibodies that selected for Envs with shortened, hypoglycosylated V1 loops, which in turn primed V3-glycan bNAb precursors. Rhesus bNAbs were immunogenetically and structurally diverse, closely resembling human V3-glycan bNAbs. Env-bNAb coevolution revealed a diverse repertoire of bNAb precursors and the Env variants that matured them, yielding a molecular blueprint for vaccine design.

  PublisherDOI

• Early clonal dominance at priming sets the trajectory for broad HIV serum neutralization

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-06

  articleOpen accessSenior authorCorresponding

  Summary Inducing broadly neutralizing antibodies (bnAbs) remains a central challenge in HIV vaccine development 1–3 . Germline-targeting immunogens are designed to activate rare bnAb precursor B cell lineages 4–12 , yet the relationships between priming efficiency, clonal dominance, and downstream serum neutralization remain poorly defined. We recently demonstrated that vaccination with an engineered V2-apex germline-targeting trimer Q23-APEX-GT2 successfully recruits and activates rare long-CDRH3 B cell precursors in outbred macaques 13 . Here, we dissect the immunological mechanisms governing bnAb precursor priming and early B cell expansion and define clonal features that drive progression to serum neutralization breadth. Our antigen-specific B cell analyses showed that Q23-APEX-GT2 consistently engaged long-CDRH3 precursors, although priming efficiency varied across animals. Longitudinal deep lineage tracing across lymph node and blood compartments revealed that early recruitment of multiple diverse long-CDRH3 lineages, followed by preferential expansion and dominance of one or two clones, strongly predicted serum neutralization potency. Subsequent CAP256.SU SHIV infection efficiently recalled vaccine-seeded clones, accelerated affinity maturation, and drove broad heterologous neutralization in most animals. Notably, one macaque with diverse and expanded V2-apex lineages rapidly achieved ∼70% serum neutralization breadth. Importantly, longitudinal tracing revealed that bona fide bnAbs can emerge from vaccine-primed precursors, while also uncovering “born-wrong” bnAb-like lineages that expand yet remain non-neutralizing, despite structurally validated recognition of the V2-apex bnAb site. Together, these findings establish priming efficiency coupled with early clonal dominance as key determinants of serum bnAb induction and provide a mechanistic framework to guide rational HIV vaccine design.

  PublisherDOI

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

  PubMed · 2026-02-13 · 3 citations

  articleOpen 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 1 of 16 different simian-human immunodeficiency viruses (SHIVs). We identified the V2 apex region of the envelope (Env) 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 a primary obstacle to V2 apex bNAb elicitation in SHIV-infected macaques and identify specific HIV-1 Envs to advance as vaccine platforms.

  PublisherOA PDFDOI

• Heterologous betacoronavirus spike immunization in nonhuman primates elicits cross-reactive antibodies that neutralize both sarbeco- and merbecoviruses

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-23

  articleSenior author

  Summary In anticipation of future coronavirus (CoV) pandemics, developing vaccines that elicit broadly neutralizing antibodies (bnAbs) against diverse CoVs is critical. Here, we vaccinated rhesus macaques with SARS-CoV-2 spike (S)-protein, then boosted with heterologous β-CoV S-proteins to focus responses to common conserved S2 bnAb epitopes. Initial SARS-CoV-2 priming elicited receptor-binding domain (RBD)-focused responses, while MERS-CoV boosting redirected responses toward the S2 region, including the stem-helix bnAb site. Although S2-directed serum cross-neutralization was undetectable and most isolated cross-reactive monoclonal antibodies (mAbs) targeted non-neutralizing epitopes, two S2 stem-helix mAbs were identified from memory B cells. These bnAbs neutralized diverse sarbeco- and merbecoviruses, including MERS-CoV, and conferred robust in vivo protection against SARS-CoV-2 challenge. Structural studies revealed that these macaque bnAbs closely mimic human S2-stem bnAbs induced by infection. These findings provide proof-of-principle for vaccination strategies that elicit broadly protective β-coronavirus responses and highlight non-human primates as a translational model for evaluating S2-targeted immunogens.

  PublisherDOI

• 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.

  PublisherOA PDFDOI

• Rapid acquisition of HIV-1 neutralization breadth in a rhesus V2 apex germline antibody mouse model after a single bolus immunization

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-17 · 2 citations

  preprintOpen accessCorresponding

  Current vaccine strategies to elicit broadly neutralizing antibodies (bnAbs) against HIV-1 generally propose complex, multi-boost immunization regimens. In rhesus macaques, SHIV infection has been observed to rapidly drive the development of some classes of bnAbs that share structural similarities with those in humans. Here, we generated a knockin mouse model with B cells bearing the unmutated common ancestor (UCA) of the V2 apex-targeted bnAb lineage, V033-a. A single immunization of mice with a germline-targeting native-like trimer was sufficient to recapitulate the ontogeny of the mature rhesus bnAb in knockin mice-including rare, disfavored somatic mutations-leading to the induction of antibodies that exhibited potent neutralization against both autologous and heterologous tier 2 viruses. A boost with Env escape mutant trimers further improved breadth and potency, and cryo-EM structure revealed the structural basis for heterologous neutralization breadth. Non-human primate and mouse models can thus combine with structure to serve as a platform for identifying and confirming immunogens that streamline HIV-vaccination regimens.

  PublisherOA PDFDOI

• 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

• Single-molecule imaging prefusion intermediate conformations of MERS-CoV spike trimers in membrane during entry

  Cell Reports · 2025-06-25 · 2 citations

  articleOpen access

  Middle East respiratory syndrome coronavirus (MERS-CoV) entry into host cells is mediated by the spike (S) glycoprotein trimer. The S2 domain of spike promotes membrane fusion for MERS entry, but its mechanism of action is currently elusive. Here, we applied real-time single-molecule fluorescence resonance energy transfer (smFRET) imaging to MERS-CoV S virions to identify the prefusion intermediate states of the S2 domain on the pathway to membrane fusion and understand their role in S neutralization by S2 stem-helix-targeted neutralizing antibodies. Our observations revealed the S2 domain of unliganded MERS-CoV S to be intrinsically dynamic, with the prefusion conformation transitioning between three distinct prefusion intermediate conformations, whose relative occupancies were remodeled by receptor dipeptidylpeptidase 4 (DPP4), protease TMPRSS2, and antibody binding. Acidic pH dramatically shifts the conformational equilibrium of S2 in favor of the fusion-competent intermediate conformation. Broadly neutralizing antibodies targeting the S2 stem-helix limit the conformational transitions of S2 and inhibit the refolding of spike to the post-fusion state.

  PublisherOA PDFDOI

• Passive infusion of an S2-Stem broadly neutralizing antibody protects against SARS-CoV-2 infection and lower airway inflammation in rhesus macaques

  PLoS Pathogens · 2025-01-23 · 1 citations

  articleOpen accessCorresponding

  The continued evolution of SARS-CoV-2 variants capable of subverting vaccine and infection-induced immunity suggests the advantage of a broadly protective vaccine against betacoronaviruses (β-CoVs). Recent studies have isolated monoclonal antibodies (mAbs) from SARS-CoV-2 recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other β-CoVs. Many of these mAbs target the conserved S2 stem region of the SARS-CoV-2 spike protein, rather than the receptor binding domain contained within S1 primarily targeted by current SARS-CoV-2 vaccines. One of these S2-directed mAbs, CC40.8, has demonstrated protective efficacy in small animal models against SARS-CoV-2 challenge. As the next step in the pre-clinical testing of S2-directed antibodies as a strategy to protect from SARS-CoV-2 infection, we evaluated the in vivo efficacy of CC40.8 in a clinically relevant non-human primate model by conducting passive antibody transfer to rhesus macaques (RM) followed by SARS-CoV-2 challenge. CC40.8 mAb was intravenously infused at 10mg/kg, 1mg/kg, or 0.1 mg/kg into groups (n = 6) of RM, alongside one group that received a control antibody (PGT121). Viral loads in the lower airway were significantly reduced in animals receiving higher doses of CC40.8. We observed a significant reduction in inflammatory cytokines and macrophages within the lower airway of animals infused with 10mg/kg and 1mg/kg doses of CC40.8. Viral genome sequencing demonstrated a lack of escape mutations in the CC40.8 epitope. Collectively, these data demonstrate the protective efficiency of broadly neutralizing S2-targeting antibodies against SARS-CoV-2 infection within the lower airway while providing critical preclinical work necessary for the development of pan-β-CoV vaccines.

  PublisherOA PDFDOI

Frequent coauthors

• Dennis R. Burton

  Scripps Research Institute

  360 shared

• Ge Song

  International AIDS Vaccine Initiative

  148 shared

• Andrew B. Ward

  Scripps Research Institute

  129 shared

• Wanting He

  First Affiliated Hospital of Harbin Medical University

  97 shared

• Ian A. Wilson

  Scripps Research Institute

  96 shared

• Sean Callaghan

  Scripps Research Institute

  85 shared

• Devin Sok

  International AIDS Vaccine Initiative

  72 shared

• Pan-Pan Zhou

  69 shared

Labs

• Raiees Andrabi LabPI

Education

• B.S., Biology

  University of Kashmir, Srinagar, India

  2005

• M.S., Biochemistry

  Hamdard University, New Delhi, India

  2007

• Ph.D., Biochemistry/Philosophy

  All India Institute of Medical Sciences (AIIMS) New Delhi, India

  2012