Safety, tolerability, pharmacokinetics, and neutralisation activities of the anti-HIV-1 monoclonal antibody PGT121.414.LS administered alone and in combination with VRC07-523LS in adults without HIV in the USA (HVTN 136/HPTN 092): a first-in-human, open-label, randomised controlled phase 1 trial.

Background: Multiple broadly neutralising monoclonal antibodies (mAbs) are in development for HIV-1 prevention. The aim of this trial was to test the PGT121.414.

Sex differences in the association between sarcopenia index and sarcopenia: a cross-sectional study from a Chinese community-based population.

Purpose: The sarcopenia index (SI) is a convenient method to screen for sarcopenia, but few studies have analysed whether there are sex differences. The aim of this study was to analyse sex differences in the relationship between SI and sarcopenia in a Chinese community-based population.

Methods: This cross-sectional study included participants from 2011 China Health and Retirement Longitudinal Study.

Putting computational models of immunity to the test - an invited challenge to predict vaccination outcomes.

Systems vaccinology studies have been used to build computational models that predict individual vaccine responses and identify the factors contributing to differences in outcome. Comparing such models is challenging due to variability in study designs. To address this, we established a community resource to compare models predicting booster responses and generate experimental data for the explicit purpose of model evaluation.

Predicting neutralization susceptibility to combination HIV-1 monoclonal broadly neutralizing antibody regimens.

Combination monoclonal broadly neutralizing antibodies (bnAbs) are currently being developed for preventing HIV-1 acquisition. Recent work has focused on predicting in vitro neutralization potency of both individual bnAbs and combination regimens against HIV-1 pseudoviruses using Env sequence features. To predict in vitro combination regimen neutralization potency against a given HIV-1 pseudovirus, previous approaches have applied mathematical models to combine individual-bnAb neutralization and have predicted this combined neutralization value; we call this the combine-then-predict (CP) approach.

Association Between SARS-CoV-2 Viral Load and COVID-19 Vaccination in 4 Phase 3 Trials.

Coronavirus disease 2019 (COVID-19) vaccines reduce severe disease and mortality and may lessen transmission, measured by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load (VL). Evaluating vaccine associations in VL at COVID-19 diagnosis in 4 phase 3 randomized, placebo-controlled vaccine trials, July 2020 to July 2021, VL reductions were 2.78 log10 copies/mL (95% confidence interval [CI], 1.

Safety and Immunogenicity of a DNA Vaccine With Subtype C gp120 Protein Adjuvanted With MF59 or AS01B: A Phase 1/2a HIV-1 Vaccine Trial.

Background: An effective vaccine is required to end the HIV pandemic. We evaluated the safety and immunogenicity of a DNA (DNA-HIV-PT123) vaccine with low- or high-dose bivalent (TV1.C and 1086.

Safety and pharmacokinetics of VRC07-523LS administered via different routes and doses (HVTN 127/HPTN 087): A Phase I randomized clinical trial.

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.

Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV.

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV.

SARS-CoV-2 Viral Load in the Nasopharynx at Time of First Infection Among Unvaccinated Individuals: A Secondary Cross-Protocol Analysis of 4 Randomized Trials.

Importance: SARS-CoV-2 viral load (VL) in the nasopharynx is difficult to quantify and standardize across settings, but it may inform transmission potential and disease severity.

Objective: To characterize VL at COVID-19 diagnosis among previously uninfected and unvaccinated individuals by evaluating the association of demographic and clinical characteristics, viral variant, and trial with VL, as well as the ability of VL to predict severe disease.

Design, Setting, And Participants: This secondary cross-protocol analysis used individual-level data from placebo recipients from 4 harmonized, phase 3 COVID-19 vaccine efficacy trials sponsored by Moderna, AstraZeneca, Janssen, and Novavax.

Factors associated with reactogenicity to an investigational HIV vaccine regimen in HIV vaccine trials network 702.

Background: Reactogenicity informs vaccine safety, and may influence vaccine uptake. We evaluated factors associated with reactogenicity in HVTN 702, a typical HIV vaccine efficacy trial with multiple doses and products.

Methods: HVTN 702, a phase 2b/3 double-blind placebo-controlled trial, randomized 5404 African participants aged 18-35 years without HIV to placebo, or ALVAC-HIV (vCP2438) at months 0, 1 and ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59 at months 3, 6, 12 and 18.

COVID-19 Vaccine Efficacy in Participants With Weakened Immune Systems From 4 Randomized Controlled Trials.

Background: Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly efficacious at preventing severe disease in the general population, current data are lacking regarding vaccine efficacy (VE) for individuals with mild immunocompromising conditions.

Methods: A post hoc, cross-protocol analysis of participant-level data from the blinded phase of four randomized, placebo-controlled, coronavirus disease 2019 (COVID-19) vaccine phase 3 trials (Moderna, AstraZeneca, Janssen, and Novavax) was performed. We defined a "tempered immune system" (TIS) variable via a consensus panel based on medical history and medications to determine VE against symptomatic and severe COVID-19 cases in TIS participants versus non-TIS individuals starting at 14 days after completion of the primary series through the blinded phase for each of the 4 trials.

Durability of Protection Against COVID-19 Through the Delta Surge for the NVX-CoV2373 Vaccine.

Background: Protein-based vaccines for coronavirus disease 2019 (COVID-19) provide a traditional vaccine platform with long-lasting protection for non-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogens and may complement messenger RNA vaccines as a booster dose. While NVX-CoV2373 showed substantial early efficacy, the durability of protection has not been delineated.

Methods: The PREVENT-19 vaccine trial used a blinded crossover design; the original placebo arm received NVX-CoV2373 after efficacy was established.

Methods for the estimation of direct and indirect vaccination effects by combining data from individual- and cluster-randomized trials.

Both individually and cluster randomized study designs have been used for vaccine trials to assess the effects of vaccine on reducing the risk of disease or infection. The choice between individually and cluster randomized designs is often driven by the target estimand of interest (eg, direct versus total), statistical power, and, importantly, logistic feasibility. To combat emerging infectious disease threats, especially when the number of events from one single trial may not be adequate to obtain vaccine effect estimates with a desired level of precision, it may be necessary to combine information across multiple trials.

Predicting neutralization susceptibility to combination HIV-1 monoclonal broadly neutralizing antibody regimens.

Combination monoclonal broadly neutralizing antibodies (bnAbs) are currently being developed for preventing HIV-1 infection. Recent work has focused on predicting in vitro neutralization potency of both individual bnAbs and combination regimens against HIV-1 pseudoviruses using Env sequence features. To predict in vitro combination regimen neutralization potency against a given HIV-1 pseudovirus, previous approaches have applied mathematical models to combine individual-bnAb neutralization and have predicted this combined neutralization value; we call this the combine-then-predict (CP) approach.

High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials.

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.

Adults on pre-exposure prophylaxis (tenofovir-emtricitabine) have faster clearance of anti-HIV monoclonal antibody VRC01.

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.

Safety, tolerability, pharmacokinetics, and immunological activity of dual-combinations and triple-combinations of anti-HIV monoclonal antibodies PGT121, PGDM1400, 10-1074, and VRC07-523LS administered intravenously to HIV-uninfected adults: a phase 1 randomised trial.

Background: Preclinical and clinical studies suggest that combinations of broadly neutralising antibodies (bnAbs) targeting different HIV envelope epitopes might be required for sufficient prevention of infection. We aimed to evaluate the dual and triple anti-HIV bnAb combinations of PGDM1400 (V2 Apex), PGT121 (V3 glycan), 10-1074 (V3 glycan), and VRC07-523LS (CD4 binding site).

Methods: In this phase 1 trial (HVTN 130/HPTN 089), adults without HIV were randomly assigned (1:1:1) to three dual-bnAb treatment groups simultaneously, or the triple-bnAb group, receiving 20 mg/kg of each antibody administered intravenously at four centres in the USA.

Discovery medicine - the HVTN's iterative approach to developing an HIV-1 broadly neutralizing vaccine.

Purpose Of Review: In the past two decades, there has been an explosion in the discovery of HIV-1 broadly neutralizing antibodies (bnAbs) and associated vaccine strategies to induce them. This abundance of approaches necessitates a system that accurately and expeditiously identifies the most promising regimens. We herein briefly review the background science of bnAbs, provide a description of the first round of phase 1 discovery medicine studies, and suggest an approach to integrate these into a comprehensive HIV-1-neutralizing vaccine.

Safety and immunogenicity of a recombinant oligomeric gp145 subtype C Env protein (gp145 C.6980) HIV vaccine candidate in healthy, HIV-1-uninfected adult participants in the US.

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.

Application of the SLAPNAP statistical learning tool to broadly neutralizing antibody HIV prevention research.

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.