BACKGROUND:Realizing the potential of HIV prevention options requires understanding product tolerability across diverse groups vulnerable to HIV acquisition. Gender minority (GM) individuals are understudied in clinical trials. SETTING:HVTN 704/HIV Prevention Trials Network 085, a phase 2b randomized HIV prevention trial, enrolled MSM and transgender participants from Brazil, Peru, Switzerland, and the United States to receive an infusion every 8 weeks (10 total) of VRC01 30 mg/kg, VRC01 10 mg/kg, or placebo. Solicited adverse events (AEs) were recorded for 3 days after each infusion. METHODS:Gender was defined by self-report and sex assigned-at-birth. Multivariate mixed logistic models were used to estimate the association between gender (cisgender men [CM] vs. GM participants [transgender women, transgender men, or another gender]) and solicited AE frequency and severity. RESULTS:GM participants reported more solicited AEs than CM among all participants (adjusted OR 1.59, 95% CI: 1.20 to 2.10, P = 0.001) and among placebo recipients (1.72, 1.05 to 2.81, P = 0.031). The severity of solicited AEs (occurrence of grade 2 and higher event) did not significantly differ overall (1.83, 0.79 to 4.20, P = 0.174) or among placebo recipients (3.05, 0.76 to 12.32, P = 0.112). Grade 2 events were reported after 1% and 2% of total infusions among CM and GM participants, respectively. Grade 3-4 events were rare overall (<0.1%). Completion of 10 infusions was high (78.6%) and slightly higher in CM (79.2%) than GM participants (73%). CONCLUSIONS:This is the first report of associations between gender and solicited AEs after monoclonal antibody infusion. GM participants reported more events; severity was low. HIV prevention trials must engage and support GM individuals to best evaluate tolerability of novel agents.

VRC07-523LS is a safe and well-tolerated monoclonal antibody (mAb) targeting the CD4 binding site on the HIV envelope (Env) trimer. Efficacy of VRC07-523LS, in combination with mAbs targeting other HIV epitopes, will be evaluated in upcoming trials to prevent HIV acquisition in adults. However, differences in the pharmacokinetics (PK) of VRC07-523LS when administered alone vs. in combination with other mAbs have not been formally assessed. We performed a cross-protocol analysis of three clinical trials and included data from a total of 146 adults without HIV who received intravenous (n = 95) or subcutaneous (n = 51) VRC07-523LS, either alone (‘single’; n = 100) or in combination with 1 or 2 other mAbs (‘combined’; n = 46). We used an open, two-compartment population PK model to describe serum concentrations of VRC07-523LS over time, accounting for inter-individual variabilities. We compared individual-level PK parameters between the combined vs. single groups using the targeted maximum likelihood estimation method to adjust for participant characteristics. No significant differences were observed in clearance rate, inter-compartmental clearance, distribution half-life, or total VRC07-523LS exposure over time. However, for the combined group, mean central volume of distribution, peripheral volume of distribution, and elimination half-life were slightly greater, corresponding to slightly lower predicted concentrations early post-administration with high levels being maintained in both groups. These results suggest potential PK interactions between VRC07-523LS and other mAbs, but with small clinical impact in the context of HIV prevention. Our findings support coadministration of VRC07-523LS with other mAbs, and the use of the developed PK models to design future trials for HIV prevention.

Background:Rising hepatitis C and B virus (HCV and HBV) rates have been reported in men who have sex with men (MSM) and transgender women (TGW). This study characterizes HCV and HBV infections longitudinally among 2,496 MSM/TGW aged 18-50 years and at risk for HIV acquisition enrolled in an HIV-1 vaccine trial in 18 U.S. cities between 2009-2013. Methods:Participants completed behavioral surveys, HIV testing, and blood collection over 24 months. Of the 2,397 participants who consented for future testing, 1,792 (74.8%) had available paired stored blood samples at baseline and a later timepoint (Month 24 [N = 999]; if unavailable, M12 [N = 775] or M15 [N = 18]). Results:Among 1,792 participants, 98.1% were MSM, 0.8% were TGW, and the median age was 30 years (IQR 24, 40). Participants reported a median number of 3 male sex partners (IQR 1,5) within the past 3 months. Condomless insertive anal sex was reported by 55.8% and condomless receptive anal sex by 46.7%.1.3% reported injection drug use. During follow-up, 1.4% reported pre-exposure prophylaxis (PrEP) use. At baseline 11/1792 (0.61%) participants had HCV infection (HCV AB positive, RNA detectable), with all having persistent detectable RNA and chronic HCV infection at follow-up. Phylogenetic analysis showed no clusters of HCV infection. 8 participants had HCV AB positive, RNA undetectable at baseline and follow-up, representing past HCV infection with clearance; only 2 acquired HCV, which cleared over 12-24 months. At baseline, 2 participants (2/1792 = 0.11%) had positive HBsAg, indicating chronic HBV infection. Over 12-24 months, 4 (4/1790, 0.22%) developed HBsAg positivity; these participants had HBcAB positivity at baseline, thereby likely representing reactivation. There were no new HBV infections during follow-up. Conclusion:Among 1,792 men who have sex with men and transgender women aged 18-50 years and at risk for HIV acquisition enrolled in a U.S. HIV-1 vaccine trial, incident hepatitis C infection rates were extremely low, with no cases of incident hepatitis B infection. These rates of incident HCV infection and HBSAg positivity are lower than previously reported among MSM/TGW.

In the Antibody Mediated Prevention (AMP) trials (HVTN 704/HPTN 085 and HVTN 703/HPTN 081), prevention efficacy (PE) of the monoclonal broadly neutralizing antibody (bnAb) VRC01 (vs. placebo) against HIV-1 acquisition diagnosis varied according to the HIV-1 Envelope (Env) neutralization sensitivity to VRC01, as measured by 80% inhibitory concentration (IC80). Here, we performed a genotypic sieve analysis, a complementary approach to gaining insight into correlates of protection that assesses how PE varies with HIV-1 sequence features. We analyzed HIV-1 Env amino acid (AA) sequences from the earliest available HIV-1 RNA-positive plasma samples from AMP participants diagnosed with HIV-1 and identified Env sequence features that associated with PE. The strongest Env AA sequence correlate in both trials was VRC01 epitope distance that quantifies the divergence of the VRC01 epitope in an acquired HIV-1 isolate from the VRC01 epitope of reference HIV-1 strains that were most sensitive to VRC01-mediated neutralization. In HVTN 704/HPTN 085, the Env sequence-based predicted probability that VRC01 IC80 against the acquired isolate exceeded 1 µg/mL also significantly associated with PE. In HVTN 703/HPTN 081, a physicochemical-weighted Hamming distance across 50 VRC01 binding-associated Env AA positions of the acquired isolate from the most VRC01-sensitive HIV-1 strain significantly associated with PE. These results suggest that incorporating mutation scoring by BLOSUM62 and weighting by the strength of interactions at AA positions in the epitope:VRC01 interface can optimize performance of an Env sequence-based biomarker of VRC01 prevention efficacy. Future work could determine whether these results extend to other bnAbs and bnAb combinations.

Background:HIV Vaccine Trials Network (HVTN) 704/085, a placebo-controlled clinical trial assessing the efficacy of VRC01 broadly neutralizing antibody infusion for HIV prevention, offered oral preexposure prophylaxis (PrEP) as the standard of prevention at no cost to participants. Methods:We characterized features of- identified factors associated with- PrEP initiation and discontinuation, and the effects of PrEP initiation on HIV incidence. Results:Of 2221 participants, 31.8% initiated oral PrEP during study follow-up, with the highest proportion of PrEP initiations in Brazil (83.2%) and the United States (US) (54.2%). Prior PrEP use was associated with PrEP initiation (hazard ratio [HR], 2.22 [95% confidence interval {CI}, 1.25-3.95]). Participants from Switzerland (HR, 0.5 [95% CI, .3-1.0]) and Peru (HR, 0.08 [95% CI, .06-.1]) had lower likelihood of PrEP initiation compared to the US, while participants from Brazil had higher likelihood (HR, 2.6 [95% CI, 2.0-3.3]). In the US, PrEP initiation was lower in areas with higher unmet need for PrEP (HR, 0.9 per 5 units [95% CI, 0.8-1.0]). PrEP initiators had 58% less risk of acquiring HIV than PrEP noninitiators. Among PrEP initiators, 34.4% discontinued PrEP during study follow-up. Brazil had 63% less likelihood of PrEP discontinuation than the US (HR, 0.37 [95% CI, .22-.60]). Conclusions:When included as standard of prevention in HVTN 704/085, oral PrEP utilization patterns mirrored those observed in real-life settings. Variable effects of oral PrEP on HIV outcomes in clinical trials may be expected based on regional differences in oral PrEP use.

Background Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. We conducted a multicenter, randomized, partially blinded Phase I clinical trial to evaluate the safety and serum concentrations of VRC07-523LS, administered in multiple doses and routes to healthy adults without HIV. Methods and findings Participants were recruited between 2 February 2018 and 9 October 2018. A total of 124 participants were randomized to receive 5 VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), subcutaneous (SC) (T4: 2.5 mg/kg, T5: 5 mg/kg), or intramuscular (IM) (T6: 2.5 mg/kg or P6: placebo) routes at 4-month intervals. Participants and site staff were blinded to VRC07-523LS versus placebo for the IM group, while all other doses and routes were open-label. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum PK. Neutralization activity was measured in a TZM-bl assay and antidrug antibodies (ADAs) were assayed using a tiered bridging assay testing strategy. Injections and infusions were well tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusion reactions were reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals [95% CIs]) following the first administration were 29.0 μg/mL (25.2, 33.4), 58.5 μg/mL (49.4, 69.3), and 257.2 μg/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 μg/mL (8.8, 13.3) and 22.8 μg/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 μg/mL (14.7, 18.2) in T6 with IM dosing. Trough GM (95% CIs) concentrations immediately prior to the second administration were 3.4 μg/mL (2.5, 4.6), 6.5 μg/mL (5.6, 7.5), and 27.2 μg/mL (23.9, 31.0) with IV dosing; 0.97 μg/mL (0.65, 1.4) and 3.1 μg/mL (2.2, 4.3) with SC dosing, and 2.6 μg/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titers, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titer ADA at a lone time point. VRC07-523LS has an estimated mean half-life of 42 days across all doses and routes (95% CI: 40.5, 43.5), over twice as long as VRC01 (15 days). Conclusions VRC07-523LS was safe and well tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens. Trial registration ClinicalTrials.gov/ NCT03387150 (posted on 21 December 2017).

Combination monoclonal broadly neutralizing antibody (bnAb) regimens are in clinical development for HIV prevention, necessitating additional knowledge of bnAb neutralization potency/breadth against circulating viruses. Williamson et al. (2021) described a software tool, Super LeArner Prediction of NAb Panels (SLAPNAP), with application to any HIV bnAb regimen with sufficient neutralization data against a set of viruses in the Los Alamos National Laboratory's Compile, Neutralize, and Tally Nab Panels repository. SLAPNAP produces a proteomic antibody resistance (PAR) score for Env sequences based on predicted neutralization resistance and estimates variable importance of Env amino acid features. We apply SLAPNAP to compare HIV bnAb regimens undergoing clinical testing, finding improved power for downstream sieve analyses and increased precision for comparing neutralization potency/breadth of bnAb regimens due to the inclusion of PAR scores of Env sequences with much larger sample sizes available than for neutralization outcomes. SLAPNAP substantially improves bnAb regimen characterization, ranking, and down-selection.

The VRC01 Antibody Mediated Prevention (AMP) efficacy trials conducted between 2016 and 2020 showed for the first time that passively administered broadly neutralizing antibodies (bnAbs) could prevent HIV-1 acquisition against bnAb-sensitive viruses. HIV-1 viruses isolated from AMP participants who acquired infection during the study in the sub-Saharan African (HVTN 703/HPTN 081) and the Americas/European (HVTN 704/HPTN 085) trials represent a panel of currently circulating strains of HIV-1 and offer a unique opportunity to investigate the sensitivity of the virus to broadly neutralizing antibodies (bnAbs) being considered for clinical development. Pseudoviruses were constructed using envelope sequences from 218 individuals. The majority of viruses identified were clade B and C; with clades A, D, F and G and recombinants AC and BF detected at lower frequencies. We tested eight bnAbs in clinical development (VRC01, VRC07-523LS, 3BNC117, CAP256.25, PGDM1400, PGT121, 10–1074 and 10E8v4) for neutralization against all AMP placebo viruses (n = 76). Compared to older clade C viruses (1998–2010), the HVTN703/HPTN081 clade C viruses showed increased resistance to VRC07-523LS and CAP256.25. At a concentration of 1μg/ml (IC80), predictive modeling identified the triple combination of V3/V2-glycan/CD4bs-targeting bnAbs (10-1074/PGDM1400/VRC07-523LS) as the best against clade C viruses and a combination of MPER/V3/CD4bs-targeting bnAbs (10E8v4/10-1074/VRC07-523LS) as the best against clade B viruses, due to low coverage of V2-glycan directed bnAbs against clade B viruses. Overall, the AMP placebo viruses represent a valuable resource for defining the sensitivity of contemporaneous circulating viral strains to bnAbs and highlight the need to update reference panels regularly. Our data also suggests that combining bnAbs in passive immunization trials would improve coverage of global viruses.

Abstract Background Gender minority individuals are understudied in clinical trials. Realizing the potential of HIV prevention options requires understanding product tolerability across diverse groups vulnerable to HIV acquisition. Within HVTN 704/HPTN 085, a phase 2b trial of the broadly neutralizing antibody (bnAb) VRC01 for HIV prevention, analyses of associations between gender identity and solicited adverse events (solAE) after infusions of VRC01 or saline placebo have not been reported. Methods HVTN 704/HPTN 085 enrolled men who have sex with men and transgender (TG) participants from Brazil, Peru, Switzerland and the US and randomized them 1:1:1 to receive an infusion every 8 weeks (10 total) of VRC01 30 mg/kg, VRC01 10 mg/kg or placebo. solAE were recorded for 3 days after each infusion. Gender was defined by self-report and sex assigned at birth. Odds ratios of the association of gender (cisgender men [CM] vs. gender minority participants [including TG women, TG men or other identity]) and frequency and severity of solAE were adjusted for age, race and ethnicity. Results Of 2,552 participants, 162 identified as TG women (6.3%), 75 as other identity (2.9%) and 15 as TG men (0.6%). Gender minority participants identified as Black/African American (8.7%), other (59.9%) and White (21.8%); 68.3% identified as Hispanic/Latino (Tab. 1). Overall, 867 (37.7%) CM and 107 (42.5%) gender minority participants reported a solAE (Tab. 2). Gender minority participants were more likely to report solAE than CM overall (OR 1.59, 95% CI 1.21-2.10, p=0.001) and among placebo recipients (1.72, 1.05-2.81, 0.032) (Tab. 3). SolAE severity (≥Grade 2) did not significantly differ overall (1.83, 0.79-4.20, 0.174). Grade 2 solAE were reported after 1% and 2% of infusions among CM and gender minority participants, respectively. Grade 3 and 4 events were rare in both groups (< 0.1%). Infusion completion did not differ.Table 1.Demographic and behavioral characteristics by gender identity of participants in HVTN 704/HPTN 085 who did not acquire HIV during the trial.Table 2.Frequency and severity of solicited adverse events by gender identity among VRC01 and placebo recipients.Table 3.Adjusted effect of gender identity on solicited adverse event frequency and severity. Conclusion HVTN 704/HPTN 085 is the first large-scale HIV bnAb preventive trial allowing assessment of associations between gender identity and solAE. Gender minority participants had more frequent solAE, but importantly, infusion completion did not differ and severe solAEs were rare. HIV prevention and bnAb trials must engage and include gender minority individuals to evaluate the tolerability of novel agents. Disclosures Srilatha Edupuganti, MD MPH FIDSA, Sanofi: Grant/Research Support

The Antibody Mediated Prevention (AMP) trials (NCT02716675 and NCT02568215) demonstrated that passive administration of the broadly neutralizing monoclonal antibody VRC01 could prevent some HIV-1 acquisition events. Here, we use mathematical modeling in a post hoc analysis to demonstrate that VRC01 influenced viral loads in AMP participants who acquired HIV. Instantaneous inhibitory potential (IIP), which integrates VRC01 serum concentration and VRC01 sensitivity of acquired viruses in terms of both IC50 and IC80, follows a dose-response relationship with first positive viral load ( p = 0.03), which is particularly strong above a threshold of IIP = 1.6 ( r = -0.6, p = 2e-4). Mathematical modeling reveals that VRC01 activity predicted from in vitro IC80s and serum VRC01 concentrations overestimates in vivo neutralization by 600-fold (95% CI: 300–1200). The trained model projects that even if future therapeutic HIV trials of combination monoclonal antibodies do not always prevent acquisition, reductions in viremia and reservoir size could be expected.

Background: An approach to a preventive HIV vaccine is induction of effective broadly neutralizing antibodies (bnAbs) and effector binding antibodies (bAbs). Preclinical studies suggest that trimeric envelope (Env) proteins may elicit nAbs, which led to the development of the recombinant gp145 subtype C Env protein (gp145 C.6980) immunogen. HVTN 122 was a Phase 1 trial that evaluated the safety, tolerability, and immunogenicity of gp145 C.6980 in adults. Methods: Healthy, HIV-1 seronegative adults received three intramuscular injections of gp145 C.6980 with aluminum hydroxide (alum) at months 0, 2, and 6 at either 300 mcg (high dose, n = 25) or 100 mcg (low dose, n = 15), or placebo/saline (placebo, n = 5). Participants were followed for 12 months. Results: Forty-five participants were enrolled. High and low doses of the study protein were well-tolerated, with mild or moderate reactogenicity commonly reported. Only one adverse event (mild injection site pruritis) in one participant (low dose) was considered product-related; there were no dose-limiting toxicities. High and low dose recipients demonstrated robust bAb responses to vaccine-matched consensus gp140 Env and subtype-matched gp120 Env proteins two weeks post-last vaccination (response rates >90 %), while no responses were detected to a heterologous subtype-matched V1V2 antigen. No significant differences were seen between high and low dose groups. Participants in both experimental arms demonstrated nAb response rates of 76.5 % to a tier 1 virus (MW9635.26), but no responses to tier 2 isolates. Env-specific CD4 + T-cell responses were elicited in 36.4 % of vaccine recipients, without significant differences between groups; no participants demonstrated CD8 + T-cell responses. Conclusions: Three doses of novel subtype C gp145 Env protein with alum were safe and well-tolerated. Participants demonstrated bAb, Env-specific CD4 + T-cell, and tier 1 nAb responses, but the regimen failed to induce tier 2 or heterologous nAb responses. Clinical Trials Registration: NCT03382418

BACKGROUND:The phase 2b proof-of-concept Antibody Mediated Prevention (AMP) trials showed that VRC01, an anti-HIV-1 broadly neutralising antibody (bnAb), prevented acquisition of HIV-1 sensitive to VRC01. To inform future study design and dosing regimen selection of candidate bnAbs, we investigated the association of VRC01 serum concentration with HIV-1 acquisition using AMP trial data. METHODS:The case-control sample included 107 VRC01 recipients who acquired HIV-1 and 82 VRC01 recipients who remained without HIV-1 during the study. We measured VRC01 serum concentrations with a qualified pharmacokinetic (PK) Binding Antibody Multiplex Assay. We employed nonlinear mixed effects PK modelling to estimate daily-grid VRC01 concentrations. Cox regression models were used to assess the association of VRC01 concentration at exposure and baseline body weight, with the hazard of HIV-1 acquisition and prevention efficacy as a function of VRC01 concentration. We also compared fixed dosing vs. body weight-based dosing via simulations. FINDINGS:Estimated VRC01 concentrations in VRC01 recipients without HIV-1 were higher than those in VRC01 recipients who acquired HIV-1. Body weight was inversely associated with HIV-1 acquisition among both placebo and VRC01 recipients but did not modify the prevention efficacy of VRC01. VRC01 concentration was inversely correlated with HIV-1 acquisition, and positively correlated with prevention efficacy of VRC01. Simulation studies suggest that fixed dosing may be comparable to weight-based dosing in overall predicted prevention efficacy. INTERPRETATION:These findings suggest that bnAb serum concentration may be a useful marker for dosing regimen selection, and operationally efficient fixed dosing regimens could be considered for future trials of HIV-1 bnAbs. FUNDING:Was provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) (UM1 AI068614, to the HIV Vaccine Trials Network [HVTN]; UM1 AI068635, to the HVTN Statistical Data and Management Center [SDMC], Fred Hutchinson Cancer Center [FHCC]; 2R37 054165 to the FHCC; UM1 AI068618, to HVTN Laboratory Center, FHCC; UM1 AI068619, to the HPTN Leadership and Operations Center; UM1 AI068613, to the HIV Prevention Trials Network [HPTN] Laboratory Center; UM1 AI068617, to the HPTN SDMC; and P30 AI027757, to the Center for AIDS Research, Duke University (AI P30 AI064518) and University of Washington (P30 AI027757) Centers for AIDS Research; R37AI054165 from NIAID to the FHCC; and OPP1032144 CA-VIMC Bill & Melinda Gates Foundation.

Background:Post-COVID conditions are characterised by persistent symptoms that negatively impact quality of life after SARS-CoV-2 diagnosis. While post-COVID risk factors and symptoms have been extensively described in localised regions, especially in the global north, post-COVID conditions remain poorly understood globally. The global, observational cohort study HVTN 405/HPTN 1901 characterises the convalescent course of SARS-CoV-2 infection among adults in North and South America and Africa.Methods:We categorised the cohort by infection severity (asymptomatic, symptomatic, no oxygen requirement (NOR), non-invasive oxygen requirement (NIOR), invasive oxygen requirement (IOR)). We applied a regression model to assess correlations of demographics, co-morbidities, disease severity, and concomitant medications with COVID-19 symptom persistence and duration across global regions.Results:We enrolled 759 participants from Botswana, Malawi, South Africa, Zambia, Zimbabwe, Peru, and the USA a median of 51 (interquartile range (IQR) = 35-66) days post-diagnosis, from May 2020 to March 2021. 53.8% were female, 69.8% were 18-55 years old (median (md) = 44 years old, IQR = 33-58). Comorbidities included obesity (42.8%), hypertension (24%), diabetes (14%), human immunodeficiency virus (HIV) infection (11.6%) and lung disease (7.5%). 76.2% were symptomatic (NOR = 47.4%; NIOR = 22.9%; IOR = 5.8%). Median COVID-19 duration among symptomatic participants was 20 days (IQR = 11-35); 43.4% reported symptoms after COVID-19 resolution, 33.6% reported symptoms ≥30 days, 9.9% reported symptoms ≥60 days. Symptom duration correlated with disease severity (P < 0.001, NIOR vs NOR; P = 0.003, IOR vs NOR), lung disease (P = 0.001), race (P < 0.05, non-Hispanic Black vs White), and global region (P < 0.001). Prolonged viral shedding correlated with persistent abdominal pain (odds ratio (OR) = 5.51, P < 0.05) and persistent diarrhoea (OR = 6.64, P < 0.01).Conclusions:Post-COVID duration varied with infection severity, race, lung disease, and region. Better understanding post-COVID conditions, including regionally-diverse symptom profiles, may improve clinical assessment and management globally.Registration:Clinicaltrials.gov (#NCT04403880).

Broadly neutralizing monoclonal antibodies (mAbs) are being developed for HIV-1 prevention. Hence, these mAbs and licensed oral pre-exposure prophylaxis (PrEP) (tenofovir-emtricitabine) can be concomitantly administered in clinical trials. In 48 US participants (men and transgender persons who have sex with men) who received the HIV-1 mAb VRC01 and remained HIV-free in an antibody-mediated-prevention trial (ClinicalTrials.gov #NCT02716675), we conduct a post-hoc analysis and find that VRC01 clearance is 0.08 L/day faster (p = 0.005), and dose-normalized area-under-the-curve of VRC01 serum concentration over-time is 0.29 day/mL lower (p < 0.001) in PrEP users (n = 24) vs. non-PrEP users (n = 24). Consequently, PrEP users are predicted to have 14% lower VRC01 neutralization-mediated prevention efficacy against circulating HIV-1 strains. VRC01 clearance is positively associated (r = 0.33, p = 0.03) with levels of serum intestinal Fatty Acid Binding protein (I-FABP), a marker of epithelial intestinal permeability, which is elevated upon starting PrEP (p = 0.04) and after months of self-reported use (p = 0.001). These findings have implications for the evaluation of future HIV-1 mAbs and postulate a potential mechanism for mAb clearance in the context of PrEP.

Abstract Background The HVTN 704/HPTN 085 clinical trial (AMP study) assessed the efficacy of VRC01 broadly neutralizing antibody infusions for HIV prevention. It offered access to oral pre-exposure prophylaxis (PrEP) at no-cost to all participants as standard of HIV prevention care. Understanding PrEP initiation among trial participants and describing its impact on study endpoints can guide future HIV prevention trial design. Methods We characterized sociodemographic and geographic features of PrEP initiation (by self-report) using descriptive statistics. We used Cox models to identify factors associated with PrEP initiation and the association between PrEP initiation (as a time-dependent exposure) and HIV incidence. Results Of 2221 participants off PrEP at enrollment, 31.8% initiated PrEP during the trial. Median time to PrEP initiation was 60 days (range 1-673 days). Brazil had the highest proportion of PrEP initiation among their enrolled participants (83.2%) and Peru had the lowest (5.3%). In US sites, 54.2% initiated PrEP. Southern US sites had the highest proportion of PrEP initiation (68.8%) and the Midwest had the lowest (28.4%). In multivariate analysis, prior PrEP use [HR (95% CI) = 2.2 (1.3-4.0)] was associated with PrEP initiation. Participants from Switzerland [0.5 (0.3-1.0)] and Peru [0.08 (0.06-0.1)] had lower likelihood of PrEP initiation compared to the US, while participants from Brazil had higher likelihood [2.6 (2.0-3.3)]. Age, race, gender, and sexual orientation were not associated with PrEP initiation. HIV incidence rate was 3.6/100 person-years (PY) before PrEP initiation, compared to 1.2/100 PY after PrEP initiation. PrEP initiators had 58% less risk of acquiring HIV after adjusting for behavioral risk score and treatment arm. In the US, higher local PrEP-to-need ratio was also associated with lower PrEP initiation [0.9 per 5 units (0.8-1.0)]. Conclusion Providing PrEP access to AMP participants reduced HIV acquisition among PrEP initiators. Study endpoints were still met due to heterogenous regional PrEP uptake and lower PrEP effectiveness than expected. These data suggest that offering oral PrEP to HIV prevention trial participants as standard of care is a feasible option to consider for future efficacy HIV prevention trial design. Disclosures Valeria D. Cantos, MD, Gilead Sciences: Grant/Research Support Srilatha Edupuganti, MD MPH FIDSA, Sanofi: Grant/Research Support Colleen F. Kelley, MD, MPH, Gilead Sciences: Grant/Research Support|Humanigen: Grant/Research Support|Moderna, Inc.: Grant/Research Support|Novavax, Inc: Grant/Research Support|Viiv Healthcare: Grant/Research Support

People living with HIV-1 (PLWH) exhibit more rapid antibody decline following routine immunization and elevated baseline chronic inflammation than people without HIV-1 (PWOH), indicating potential for diminished humoral immunity during SARS-CoV-2 infection. Conflicting reports have emerged on the ability of PLWH to maintain humoral protection against SARS-CoV-2 coinfection during convalescence. It is unknown whether peak COVID-19 severity, along with HIV-1 infection status, associates with the quality and quantity of humoral immunity following recovery. Using a cross-sectional observational cohort from the United States and Peru, adults were enrolled 1–10 weeks after SARS-CoV-2 infection diagnosis or symptom resolution. Serum antibodies were analyzed for SARS-CoV-2–specific response rates, binding magnitudes, ACE2 receptor blocking, and antibody-dependent cellular phagocytosis. Overall, (a) PLWH exhibited a trend toward decreased magnitude of SARS-CoV-2–specific antibodies, despite modestly increased overall response rates when compared with PWOH; (b) PLWH recovered from symptomatic outpatient COVID-19 had comparatively diminished immune responses; and (c) PLWH lacked a corresponding increase in SARS-CoV-2 antibodies with increased COVID-19 severity when asymptomatic versus symptomatic outpatient disease was compared.

Background: The antibody-mediated prevention (AMP) studies (HVTN 703/HPTN 081 and HVTN 704/HPTN 085) are harmonized phase 2b trials to assess HIV prevention efficacy and safety of intravenous infusion of anti-gp120 broadly neutralizing antibody VRC01. Antibodies for other indications can elicit infusion-related reactions (IRRs), often requiring premedication and limiting their application. We report on AMP study IRRs. Methods: From 2016 to 2018, 2699 HIV-uninfected, at-risk men and transgender adults in the Americas and Switzerland (704/085) and 1924 at-risk heterosexual women in sub-Saharan Africa (703/081) were randomized 1:1:1 to VRC01 10 mg/kg, 30 mg/kg, or placebo. Participants received infusions every 8 weeks (n = 10/participant) over 72 weeks, with 104 weeks of follow-up. Safety assessments were conducted before and after infusion and at noninfusion visits. A total of 40,674 infusions were administered. Results: Forty-seven participants (1.7%) experienced 49 IRRs in 704/085; 93 (4.8%) experienced 111 IRRs in 703/081 (P < 0.001). IRRs occurred more frequently in VRC01 than placebo recipients in 703/081 (P < 0.001). IRRs were associated with atopic history (P = 0.046) and with younger age (P = 0.023) in 703/081. Four clinical phenotypes of IRRs were observed: urticaria, dyspnea, dyspnea with rash, and “other.” Urticaria was most prevalent, occurring in 25 (0.9%) participants in 704/085 and 41 (2.1%) participants in 703/081. Most IRRs occurred with the initial infusion and incidence diminished through the last infusion. All reactions were managed successfully without sequelae. Conclusions: IRRs in the AMP studies were uncommon, typically mild or moderate, successfully managed at the research clinic, and resolved without sequelae. Analysis is ongoing to explore potential IRR mechanisms.

Since the beginning of the SARS-CoV-2 pandemic, antibody responses and antibody effector functions targeting SARS-CoV-2-infected cells have been understudied. Consequently, the role of these types of antibodies in SARS-CoV-2 disease (COVID-19) and immunity is still undetermined. To provide tools to study these responses, we used plasma from SARS-CoV-2-infected individuals (n = 50) and SARS-CoV-2 naive healthy controls (n = 20) to develop four specific and reproducible flow cytometry-based assays: (i) two assessing antibody binding to, and antibody-mediated NK cell degranulation against, SARS-CoV-2-infected cells and (ii) two assessing antibody binding to, and antibody-mediated NK cell degranulation against, SARS-CoV-2 Spike-transfected cells. All four assays demonstrated the ability to detect the presence of these functional antibody responses in a specific and reproducible manner. Interestingly, we found weak to moderate correlations between the four assays (Spearman rho ranged from 0.50 to 0.74), suggesting limited overlap in the responses captured by the individual assays. Lastly, while we initially developed each assay with multiple dilutions in an effort to capture the full relationship between antibody titers and assay outcome, we explored the relationship between fewer antibody dilutions and the full dilution series for each assay to reduce assay costs and improve assay efficiency. We found high correlations between the full dilution series and fewer or single dilutions of plasma. Use of single or fewer sample dilutions to accurately determine the response rates and magnitudes of the responses allows for high-throughput use of these assays platforms to facilitate assessment of antibody responses elicited by SARS-CoV-2 infection and vaccination in large clinical studies.

The Antibody Mediated Prevention trials showed that the broadly neutralizing antibody (bnAb) VRC01 prevented acquisition of human immunodeficiency virus-1 (HIV-1) sensitive to VRC01. Using AMP trial data, here we show that the predicted serum neutralization 80% inhibitory dilution titer (PT 80 ) biomarker—which quantifies the neutralization potency of antibodies in an individual’s serum against an HIV-1 isolate—can be used to predict HIV-1 prevention efficacy. Similar to the results of nonhuman primate studies, an average PT 80 of 200 (meaning a bnAb concentration 200-fold higher than that required to reduce infection by 80% in vitro) against a population of probable exposing viruses was estimated to be required for 90% prevention efficacy against acquisition of these viruses. Based on this result, we suggest that the goal of sustained PT 80 >200 against 90% of circulating viruses can be achieved by promising bnAb regimens engineered for long half-lives. We propose the PT 80 biomarker as a surrogate endpoint for evaluation of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines.