Lawrence Corey

Extended in vivo activity of VRC01 HIV-1 prophylaxis entails initial protective efficacy and subsequent breakthrough infections

The two parallel antibody-mediated prevention (AMP) efficacy trials evaluated whether intravenous infusion of the anti-CD4 binding site broadly neutralizing antibody VRC01 prevents HIV-1 acquisition. Here, we analyzed HIV-1 acquisition in AMP through the week 104 final study visit. Against viruses considered highly sensitive to VRC01 [80% inhibitory concentration (IC 80 ) < 1 microgram/milliliter], VRC01 prophylaxis maintained cumulative prevention efficacy of 66.3% (95% confidence interval: 32.4, 83.2%), suggesting that the antibody successfully blocked or cleared these infections. In the post–week 80 period (after the final dose at week 72), HIV diagnosis and resistance to VRC01 were more frequent and greater in the VRC01 groups versus placebo. For instance, more HIV diagnoses with viruses considered moderately sensitive or resistant to VRC01 (IC 80 ≥ 5 microgram/milliliter) were made in the VRC01 groups compared with placebo groups (11 versus 1). Plausibly, as in vivo VRC01 concentration waned, suppressed viruses—often evolving greater resistance because of selective pressure—emerged as detectable infections. Our findings suggest that, whereas single antibodies can block sensitive strains, multiple antibodies are likely required to prevent both viral escape and breakthrough infections.

Safety of Autologous Infusion of CER T Cells in Nonhuman Primates

Cellular immunotherapies have shown great promise in the treatment of various diseases. Chimeric engulfment receptor (CER)-engineered T cells were developed to utilize the extracellular T-cell immunoglobulin and mucin domain-containing 4 (TIM-4) domain and intracellular engulfment signaling domains to target and enhance phagocytosis and T-cell cytotoxic function. These processes are activated through TIM-4 binding with phosphatidylserine (PS), a pro-phagocytic “eat me” signal. HIV infection has been shown to induce extracellular PS exposure shortly after infection, and engineered CER T cells have been shown to kill CD4 + T cells infected with simian immunodeficiency virus (SIV) in vitro . In this study, we infused two rhesus macaques (RMs) with CER-1236 T cells (the iteration of CER T cells currently moving forward in human clinical trials for cancer) and evaluated safety, the tissue distribution of the CER-1236 T cells, and antiviral activity against SIV (SIVmac239). Prior to infusions, RMs underwent SIV infection, antiretroviral therapy (ART), and ART cessation. The infusions were well tolerated. Neither of the macaques exhibited clinical evidence of illness nor changes in vital signs, serum chemistry, hematology, or other evaluated physiological parameters beyond what is typically observed with SIV infection. Post-infusion proliferation of CER T cells in PBMC was limited and seen with cells manufactured by the Prodigy system. Histologic and flow cytometry evaluation from post-infusion tissue biopsies and necropsy revealed tissue detection of CER T cells in bronchoalveolar lavage fluid with intermittent detection of infused cells in lymphoid tissue in concert with the limited expansion of T cells in PBMC. No laboratory or clinical evidence of hepatic, splenic, bone marrow, or CNS alterations was noted, and no evidence of in vivo suppression of SIVmac239 was observed as a result of the infusions. The CER-1236 T cell infusions were not associated with any discernable histopathological toxicity. This safety profile of CER-1236 T cells in nonhuman primates portends well for its potential for clinical development, especially for tumors with high expression of the tissue damage receptor PS. Optimization of in vivo functionality will be required for CER T cells to be effective against HIV infection.

On the economics of broadly neutralizing monoclonal antibodies for HIV prevention in high-income countries

Aim: To quantify the market opportunity and economic impact of broadly neutralizing monoclonal antibodies (bnAbs) as a novel HIV prevention modality in high-income countries. Materials & methods: Using a decision-tree and revenue model applied to an eligible US population of 1299,708 individuals and projecting to 2040, bnAbs are estimated to capture 1 in 8 PrEP users (12.5% of PrEP users, 95% credible interval 7.3% to 21.1%, equivalent to 8.0% of the prevention-eligible population) following assumed US FDA approval in 2030. All estimates are scenario based and conditional on assumed pricing, uptake and behavior; none are observed outcomes. Critically, roughly half of projected bnAb users, nearly 52,000 individuals, would not otherwise use any biomedical HIV prevention, representing a net expansion of PrEP users (95% credible interval: 21,859–95,581). US manufacturer revenue totaled $12.0 billion discounted at 3% per year to 2030 (95% credible interval $6.2 billion to $21.9 billion), equivalent to $14.5 billion undiscounted, over the 11 years from approval to 2040. Total US payer spending rose 3.6% ($463.6 million annually), though the credible interval crosses zero, and the mean cost per prevention user decreased provided bnAbs are priced at the modeled list price of $14,000 per year, below existing injectable PrEP options. Conclusion: Under the assumptions modeled here, bnAbs could reach roughly one in eight PrEP users in high-income countries, about half of them people not otherwise using biomedical prevention. Whether this translates into an attractive commercial opportunity, and whether per-user prevention costs fall or rise, depends principally on how bnAbs are priced relative to long-acting injectable PrEP. These are projections conditional on assumed efficacy, pricing and adoption behavior, not observed outcomes.

Prophylactic treatment with broadly neutralizing antibody VRC01 selects for escape mutants after infection in Antibody-Mediated Prevention trials

Broadly neutralizing antibodies (bnAbs) show promise in HIV prevention, yet viral escape remains a challenge. In the Antibody-Mediated Prevention (AMP) trials, the CD4 binding site (CD4bs) bnAb VRC01 blocked acquisition by VRC01-sensitive strains. However, its influence on viral evolution post acquisition is not fully understood. Here we analysed 11,730 HIV envelope sequences generated during the AMP trials from 47 participants, identifying VRC01-mediated de novo escape mutations in 8 of 26 VRC01-treated participants but none in 21 placebo participants. These mutations were found at very low frequencies (<1%) in globally circulating viruses, suggesting that they may confer fitness costs. Escape mutations, primarily located in the Loop-D and β23/V5 regions of Env, conferred cross-resistance to several CD4bs bnAbs; however, more potent CD4bs bnAbs such as N6 and 1-18 largely retained their activity. Our findings demonstrate that prophylactic VRC01 can select for viral escape after infection, underscoring the need for next-generation bnAbs with improved breadth and potency to enhance durability and efficacy of antibody-based HIV prevention.

VRC01 Exerted Differential Pressure on HIV-1 Envelope From Subtypes B and C That Continued in the First Weeks Postdiagnosis in the Antibody Mediated Prevention Trials

BACKGROUND: The Antibody Mediated Prevention trials (HVTN 703 and HVTN 704) demonstrated that infusions of the bnAb VRC01 prevented HIV-1 acquisition with viruses sensitive to VRC01 neutralization. We evaluated how VRC01 epitope distances differed across groups in the trials. METHODS: We calculated VRC01 epitope distances (a 3D structure informed measure of how the VRC01 epitope in a sequence differs from that epitope in known VRC01 sensitive strains) to compare >35,000 Envelopes sampled from 172 participants with mostly subtype C viruses in HVTN 703 and subtype B in HVTN 704. RESULTS: At the first visit with detectable HIV-1, we found fewer distinct VRC01 epitopes in the sequences from participants in the VRC01 high-dose group in HVTN 704 (p=0.054), suggesting that some epitope variants were blocked in these participants who harbored subtype B viruses. In both trials, VRC01 epitope distances were significantly larger in the VRC01 high-dose groups than in the placebo groups (p≤0.010). Moreover, sequences sampled in the first month after diagnosis showed that the rate of change in VRC01 epitope distances was significantly higher in the VRC01 groups than in the placebo in the HVTN 703 trial (p≤0.036). CONCLUSIONS: These findings show the impact of sieve acquisition (variants blocked among subtype B viruses) and post-acquisition (stronger impact of VRC01-mediated escape in subtype C) effects, highlighting a complex intersection between HIV-1 subtypes, escape pathways and antibody-mediated prevention. The differential pressure exerted by VRC01 on subtype B vs. C viruses emphasizes that escape pathways need to be considered when selecting bnAbs for clinical trials.

DNA electroporation of HIV Env elicits robust T cell responses and memory B cell responses with muted serum antibody levels that can be boosted with recombinant protein

Phase 1 trial demonstrates T cell and B cell responses in individuals post DNA vaccination, suggesting a new vaccine approach.

VRC01 Selects Rare HIV Escape Mutations After Acquisition in Antibody-Mediated Prevention Trials

Findings reveal cross-resistance in HIV escape mutations post-VRC01 treatment, suggesting implications for enhancing HIV prevention efficacy.

Analysis of antibody markers as immune correlates of risk of severe COVID-19 in the PREVENT-19 efficacy trial of the NVX-CoV2373 recombinant protein vaccine

Analysis identifies geometric mean antibody levels as key predictors of severe COVID-19 in the NVX-CoV2373 cohort, suggesting low responses indicate higher vulnerability.

Limitations of acyclovir and identification of potent HSV antivirals using 3D bioprinted human skin equivalents

Herpes simplex virus (HSV) infection poses global public health concerns with lifelong impacts. Acyclovir, the standard therapy, has limited efficacy in preventing subclinical shedding, and drug resistance occurs in immunocompromised patients, highlighting the need for novel therapeutics. Here we show that acyclovir is significantly less effective in skin-derived keratinocytes than donor-matched fibroblasts. Using 3D bioprinted human skin equivalents (HSEs) in a 96-well plate format, we have screened 738 compounds with broad targets and mechanisms of action, identifying potent antivirals, including 23 known or experimental HSV treatments. Unlike acyclovir, antivirals against HSV helicase/primase or host replication pathways display similar potency across cell types and donor sources in both 2D and 3D models. The reduced potency in keratinocytes may explain acyclovir's limited clinical efficacy. Our 3D bioprinted HSE assay platform enables the integration of patient-derived cells early in drug development and offers a physiologically relevant approach for HSV drug discovery.

Long-Read Deep Sequencing Reveals High Rates of Multilineage Transmission and Rapid Viral Population Changes in Acute HIV Infection

Randomized trial reveals high rates of multilineage HIV transmission during acute infection, suggesting new prevention strategies.

Neutralizing and binding antibodies are a correlate of risk of COVID-19 in the CoVPN 3008 study in people with HIV

People with HIV (PWH) are understudied in COVID-19 vaccine trials, leaving knowledge gaps on whether the identified immune correlates of protection also hold in PWH. CoVPN 3008 (NCT05168813) enrolled predominantly PWH and reported lower COVID-19 incidence for a Hybrid vs. Vaccine Group (baseline SARS-CoV-2-positive and one mRNA-1273 dose vs. negative and two doses). Using case-cohort sampling, antibody markers at enrolment (M0) and four weeks post-final vaccination (Peak) are assessed as immune correlates of COVID-19. For the Hybrid Group [n = 287 (195 PWH)], all M0 markers inversely correlate with COVID-19 through 230 days post-Peak, with 50% inhibitory dilution BA.4/5 neutralizing antibody titer (nAb-ID50 BA.4/5) the strongest and only independent correlate (HR per 10-fold increase=0.46, 95% CI 0.28, 0.75; P = 0.002). For the Vaccine Group [n = 115 (86 PWH)], Peak nAb-ID50 BA.4/5 correlates with reduced COVID-19 risk (1.9%, 1.1%, and 0.3% at titers 10, 100, and 1000 AU/ml) through 92, but not 165, days post-Peak. Using multivariable Cox analysis of binding and nAb, nAb titers predict COVID-19 in PWH. Two doses of a 100-µg Ancestral strain mRNA vaccine in baseline-SARS-CoV-2-negative individuals elicit sufficient cross-reacting Omicron antibodies to reduce COVID-19 incidence for 90 days post-Peak, but viral evolution and waning antibodies abrogate this protection thereafter.

OCT 2025CoreyProceedings of the National Academy of Sciences

Operation Warp Speed offers a roadmap for improving the efficiency of bench to bedside medical advances

Respiratory Virus Infections and Pulmonary Impairment after Allogeneic Hematopoietic Cell Transplantation

Prospective cohort study reveals links between respiratory virus infections and pulmonary impairment, suggesting targeted interventions. Increased mortality risk highlighted for patients with specific viral infections.

Immune correlates analysis of antibody responses against SARS-CoV-2 variants in the ENSEMBLE vaccine efficacy trial

In Latin American sites of the ENSEMBLE trial of the Ad26.COV2.S vaccine vs. placebo, binding antibodies and neutralizing antibodies measured 4 weeks post-vaccination (∼peak) against circulating lineages (Ancestral, Gamma, Lambda, Mu, Zeta) were assessed as a correlate of risk of, and correlate of protection against, lineage-specific COVID-19. Comparison of lineage-matched controlled vaccine efficacy (VE) curves showed similar relationships across lineages of lineage-specific antibody with VE against lineage-matched COVID-19, supporting a "variant-invariant correlate of protection model" that undergirds immunobridging inferences of efficacy against new variants based on variant-matched neutralizing antibody titers. Lambda departed from this model at undetectable/just-detectable titers: at ∼ peak Reference-specific titers of 2.7 arbitrary units (AU)/mL (just-detectable) and 30 AU/ml, VE against Ancestral COVID-19 was 53.0% (95% CI: 30.7%, 67.9%) and 84.5% (73.6%, 93.0%), respectively; at the same Lambda-specific titers, VE against Lambda COVID-19 was 12.3% (-54.1%, 50.3%) and 91.1% (68.9%, 98.0%). Additional research is needed for Omicron variants.

Neutralizing antibody responses over time in a demographically and clinically diverse cohort of individuals recovered from SARS-CoV-2 acquisition in Africa: A cohort study

Cohort study highlights the relationship between neutralizing antibodies and clinical outcomes in a diverse population recovering from COVID-19, indicating potential impacts of HIV co-infection.

Bayesian estimation of HIV acquisition dates for prevention trials.

Bayesian analysis improves HIV acquisition timing estimates in participants, highlighting better antibody projections.

Validating and leveraging non-SARS-CoV-2 respiratory infection as a negative control outcome in a phase 3 COVID-19 vaccine trial with extended observational follow-up

Phase 3 trial validates non-SARS-CoV-2 infections as a negative control, indicating potential bias in vaccine efficacy estimates.

Influence of the broadly neutralizing antibody VRC01 on HIV breakthrough virus populations in antibody-mediated prevention trials

In the HIV antibody mediated prevention (AMP) trials, the broadly neutralizing antibody VRC01 demonstrated protective efficacy against new diagnoses with susceptible HIV strains. To understand how VRC01 shaped breakthrough infections, we performed deep sequencing on 172 participants in the placebo and treatment arms, generating 63,444 gag-Δpol (2.5 kb) and 53,088 rev-env-Δnef (3 kb) sequences. Sequences were classified into transmitted founder lineages (TFLs), and infections with multiple distinct lineages were determined. Multilineage infections were detected in ∼38% of participants in both the African (HVTN 703/HPTN 081) and Americas/Europe (HVTN 704/HPTN 085) cohorts, regardless of placebo or treatment group, or cohort. The high levels of multilineage infections could be attributed to minor lineages (<5% abundance) identified in 20% of participants. Infection with VRC01 discordant viruses (IC80s >3-fold different) was observed in 40% of multilineage infections, with a trend toward greater intra-host neutralization differences with increasing VRC01 dose (Jonckheere-Terpstra test, p=0.072). In six VRC01 treated participants who acquired both sensitive (IC80<1µg/ml) and resistant viruses (IC80>3µg/ml), the sensitive lineages declined over time. Recombination was pervasive, observed in 63% of multilineage infections at the time of HIV diagnosis. In one treated participant infected with VRC01 discordant lineages, recombinant viruses preferentially inherited the resistance mutation (binomial p=0.004). In conclusion, our in-depth analysis of breakthrough viruses in the AMP trials revealed a high frequency of multilineage infections, including infections with viruses with different VRC01 sensitivities. This analysis also highlights the role of recombination in shaping intra-host viral evolution and facilitating escape from VRC01. Significance This work advances our understanding of the diversity of initial viral infection and evolution and in vivo activity of broadly neutralizing antibodies (bNAbs). Deep sequencing revealed ∼38% of HIV acquisitions with multiple transmitted founder lineages, higher than previous studies. These occurrences were similar in the placebo and VRC01 groups. Viral recombination among post-acquisition variants was common under antibody selection and appeared to favor resistant sequences in the treatment group. These data suggest as with single antiviral therapy, passive and active immunization of bNAbs should be directed at multiple antigen targets of HIV-1.

Fixed dosing versus weight-based dosing of HIV-1 prophylactic monoclonal antibodies in adults: a post-hoc, cross-protocol pharmacokinetics modelling study

BACKGROUND: Pharmacokinetic (PK) modelling and simulations have been used to support label changes of dosing levels or strategies for multiple marketed therapeutic monoclonal antibodies (mAbs). Using data from early-phase clinical trials in adults without HIV-1, we compared fixed and weight-based dosing strategies for three HIV-1 broadly neutralising mAbs planned for prevention efficacy evaluation: PGDM1400LS, PGT121.414.LS, and VRC07-523LS. METHODS: We used a two-compartment population PK model to describe overall trends and inter-individual variability in post-administration serum concentrations over time from individuals administered PGDM1400LS (n = 95), PGT121.414.LS (n = 113), or VRC07-523LS (n = 251) subcutaneously or intravenously. We evaluated the effect of body weight on various PK parameters, including clearance rate, and simulated mAb concentrations after fixed and weight-based dosing administrations using sex-specific weights observed in participants from two recent HIV-1 mAb efficacy trials. We compared magnitudes and inter-individual variabilities of concentrations at specific post-administration timepoints, areas under the time-concentration curves (AUC), and predicted neutralisation titres against representative HIV-1 virus strains. FINDINGS: For all three mAbs, we observed a modest effect of body weight on clearance rate and volumes of the central and peripheral compartments. The population-level magnitude and variability in time-specific concentrations, AUC, and predicted neutralisation titres were comparable between the two dosing strategies for both sexes. The relationship between body weight and concentrations differed between the two dosing strategies with a positive correlation for weight-based dosing and a negative correlation for fixed dosing. For individuals with body weight below the 15th or above the 85th percentiles, fixed dosing resulted in <3% difference in median AUC compared to the overall population. For lower weight individuals, fixed dosing improved AUC, potentially correcting the underdosing seen in the previous weight-based mAb efficacy trials. For higher weight individuals (e.g., >100 kg), body weight-based dosing or a higher fixed dose may be preferred. INTERPRETATION: For HIV-1 prophylactic mAbs, a fixed-dose approach, possibly banded by weight categories may be advantageous over weight-based dosing, as it offers increased operational efficiency while maintaining comparable pharmacokinetics and inter-individual consistency.

Analytical treatment interruption among women with HIV in southern Africa who received VRC01 or placebo in the Antibody Mediated Prevention Study: ATI stakeholder engagement, implementation and early clinical data

Randomized trial evaluates ART-free control in women post-HIV acquisition, suggesting implications for future interventions.