SARS-CoV-2 acquisition induces a spectrum of COVID-19 disease severity and duration among people. Prolonged viral antigen shedding (PVS) is defined as when a person tests positive by direct antigen tests performed a minimum of 21 days apart. It is unclear why some people exhibit delayed SARS-CoV-2 viral antigen clearance. In this cross-sectional observational study enrolling vaccine naive adults from the USA and Peru following recovery from SARS-CoV-2 acquisition, we examined a suite of blood-derived immune measures to understand differences between participants with PVS (n = 36) and without PVS (non-PVS, n = 223). While PVS participants demonstrated lower overall SARS-CoV-2-specific antibody magnitudes, over-representation analysis revealed that immune feature magnitude alone could not fully explain cohort differences. Hierarchical clustering and network analyses identified more highly coordinated antibody responses, T cell activation, and Fc-mediated function among non-PVS compared to PVS participants. These findings link control of viral antigen shedding to a coordinated immune response.

Human Immunodeficiency Virus (HIV)-1 broadly neutralizing antibodies (bNAbs) have demonstrated clinical efficacy, but face manufacturing challenges associated with recombinant protein production and purification. Here, we present a ribonucleic acid (RNA)-encoded bNAb (RibobNAb) platform that enables in vivo antibody production of the clinically validated bNAb PGT121 via lipid nanoparticle (LNP) delivery, supporting rapid evaluation of Fc variants (LS, del294, LS-del294) in vitro and in vivo. We confirmed expression, sub-nanomolar HIV-1 Env binding, and potent neutralization across all RibobNAb variants in vitro. In mice, single RNA-LNP administrations yielded in vivo expression of all RibobNAb variants, with PGT121-LS exhibiting a prolonged half-life compared with PGT121. In non-human primates (NHPs), a single intravenous administration of PGT121-LS RNA-LNP was well tolerated without anti-drug antibody (ADA) formation over 180 days and resulted in PGT121-LS half-lives comparable to the reference protein. Single intramuscular administration showed RibobNAb expression but resulted in ADA development from Day 14 onwards and lower bioavailability. In vivo-expressed PGT121-LS RibobNAb retained identical antiviral functionality to PGT121-LS reference protein. An NHP pharmacokinetics model integrating RNA transfection and translation dynamics enabled allometric scaling and first-in-human dose prediction. We highlight RibobNAbs as an alternative to conventional purified protein antibodies for rapid development of bNAb-based therapeutic strategies.

Sustained serum levels of broadly neutralizing antibodies (bnAbs) are crucial for effective passive immunization against infectious diseases as protection persists only while these bnAbs remain at adequate concentrations within the body. Current obstacles, such as poor pharmacokinetics (PK) and burdensome administration, must be overcome to make bnAbs a viable option for pre- and post-exposure prophylaxis. In this work, we explore how a polymer-nanoparticle (PNP) hydrogel depot technology can be engineered to prolong protein delivery. In-vivo studies in mice and rats demonstrate prolonged protein release, and modeling efforts predict the impact of both the elimination half-life of the active pharmaceutical ingredient and hydrogel depot volume on overall pharmacokinetics. Moreover, flow cytometry characterization reveals that immune cell infiltration into the hydrogel depot can result in faster-than-expected release of antibody cargo on account of active transport via cellular uptake. We then demonstrate that co-formulation of antibodies with an anti-inflammatory agent reduces cellular infiltration and resulting active transport, further extending delivery and pharmacokinetics. Finally, multicompartmental modeling predicts the human PK profiles of clinically relevant HIV bnAbs delivered via subcutaneous hydrogel injection. These findings aid in the development of next generation hydrogel materials that stabilize and slowly release bnAbs for long-term pre-exposure immunoprophylaxis.

A leading HIV vaccine strategy requires a priming immunogen to induce broadly neutralizing antibody (bnAb) precursors, followed by a series of heterologous boosters to elicit somatic hypermutation (SHM) and produce bnAbs. In two randomized, open-label phase 1 human clinical trials, IAVI G002 in the United States and IAVI G003 in Rwanda and South Africa (IAVI, International Aids Vaccine Initiative), we evaluated the safety and immunogenicity of mRNA-encoded nanoparticles as priming immunogens (both trials) and first-boosting immunogens (IAVI G002). The vaccines were generally safe and well tolerated, except that 18% of IAVI G002 participants experienced skin reactions. Priming induced bnAb precursors with substantial frequencies and SHM; heterologous boosting elicited increased SHM, affinity, and neutralization activity toward bnAb development; and elicited antibodies exhibited precise bnAb structural mimicry. The results establish clinical proof of concept that heterologous boosting can advance bnAb precursor maturation and demonstrate bnAb priming in Africa, where the HIV burden is highest.

BACKGROUND:SARS-CoV-2 infection results in greater disease severity among immunocompromised individuals compared to healthy individuals. However, there is conflicting information about the impact of chronic HIV infection on immune responses to SARS-CoV-2 infection and vaccination. METHOD:We used a combination of machine learning approaches and network analysis to explore 56 immune markers and comprehensively profile humoral and cellular immunity in a cross-sectional observational cohort of people without HIV (PWOH; n = 216) and people living with HIV (PLWH; n = 43) who recovered from SARS-CoV-2 infection (13-131 days since SARS-COV-2 diagnosis) early in the pandemic. RESULTS:PLWH recovered from symptomatic outpatient COVID-19 exhibit lower humoral and B cell responses to SARS-CoV-2 vs. PWOH but, surprisingly, both symptomatic outpatient and hospitalized PLWH have higher anti-endemic coronavirus antibody responses compared to PWOH counterparts and asymptomatic PLWH. The latter observation suggests that this was not strictly due to broadly elevated levels of anti-endemic coronavirus antibodies in PLWH. Moreover, correlation-based analysis reveals that while different compartments of the immune response to SARS-CoV-2 infection are positively correlated in PWOH recovered from symptomatic outpatient COVID-19, these correlations are weaker in PLWH. CONCLUSION:Our analyses reveal significant differences in the coordinated immune responses elicited by infection in PLWH compared to PWOH.

Sustained serum levels of broadly neutralizing antibodies (bnAbs) are crucial for effective passive immunization against infectious diseases as protection persists only while these bnAbs remain at adequate concentrations within the body. Current obstacles, such as poor pharmacokinetics (PK) and burdensome administration, must be overcome to make bnAbs a viable option for pre- and post-exposure prophylaxis. In this work, we explore how a polymer-nanoparticle (PNP) hydrogel depot technology can be engineered to prolong protein delivery and enable drug exposure on the order of weeks to months. In-vivo studies in mice and rats demonstrate extended protein release compared to bolus administration, and modeling efforts predict the impact of both the elimination half-life of the active pharmaceutical ingredient and hydrogel depot volume on overall pharmacokinetics. Moreover, flow cytometry characterization reveals that immune cell infiltration into the hydrogel depot can result in faster-than-expected release of antibody cargo on account of active transport via cellular uptake. We then demonstrate that co-formulation of antibodies with an anti-inflammatory agent reduces cellular infiltration and resulting active transport, further extending delivery and pharmacokinetics. Finally, multicompartmental modeling predicts the human PK profiles of clinically relevant HIV bnAbs delivered via subcutaneous hydrogel injection. These findings aid in the development of next generation hydrogel materials that stabilize and slowly release bnAbs for long-term pre-exposure immunoprophylaxis.

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. FUNDING:NIAID.

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.

Introduction:Generally, individuals assigned female at birth (AFAB) develop greater immunogenicity to various vaccines than individuals assigned male at birth (AMAB). Little is known about sex-disaggregated immunogenicity to HIV-1 vaccines. We disaggregated immune responses to an experimental HIV vaccine regimen. Methods:We retrospectively analyzed data from HVTN 100, a clinical trial conducted in South Africa during which 143 adults AMAB and 109 AFAB aged 18-40 years without HIV received ALVAC-HIV vCP2438 plus bivalent subtype C gp120/MF59 or placebo at 0, 1, 3, 6, and 12 months. Eligible data were from per-protocol vaccine recipients at month 6.5. We measured IgG binding antibodies, neutralizing antibodies, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and CD4+ IFNγ and/or II-2 responses. We compared sex-based differences in response rates using Barnard's test and response magnitudes using Wilcoxon Rank Sum test. P-values were Holm-adjusted for multiple comparisons. Results:Of 185 vaccine recipients, 73 were AFAB and 112 were AMAB. Vaccine recipients AFAB had greater ADCC response rate (57.5% versus 29.5%; padj = 0.0003) and greater ADCC magnitude (area under the net % granzyme B activity vs log10 curve (AUC), 16.1 versus 11.2; padj = 0.05) to vaccine-matched antigen TV1.C gp120 compared to AMAB. Vaccine recipients AMAB had higher CD4+ T cell response rates to 2/3 vaccine-matched antigens at month 6.5 (ZM96.C gp120, [54.1% versus 36.8%; padj = 0.04]; 1086.C gp120, [44.1% versus 29.4%; padj = 0.05]) than AFAB. CD4+ T cell response magnitudes were similar by sex. IgG binding antibody response rate to B.CaseA V1V2 antigen (associated with reduced HIV acquisition risk in the RV144 trial) was 56.8% among AMAB vaccine recipients versus 38.9% among AFAB (padj = 0.08). There were no sex-based differences in neutralizing antibody or ADCP responses. Discussion:We identified sex-based differences in immune responses to an HIV vaccine regimen, but they varied by immunologic assay. While vaccine recipients AFAB demonstrated higher ADCC responses, AMAB exhibited higher CD4+ T cell response rates. Future analyses should investigate whether vaccine factors such as platform, dosing and adjuvants contribute to sex-based differences in immunogenicity of experimental HIV vaccines.

Background: HIV-1 envelope (Env) variable loops 1 and 2 (V1V2) directed non-neutralizing antibodies were a correlate of decreased transmission risk in the RV144 vaccine trial. Thus, the elicitation and breadth of antibody responses against the V1V2 of HIV-1 Env are important considerations for HIV-1 vaccine candidates. The V1V2 region’s highly variable nature and the extensive diversity of subtype C HIV-1 Envelopes (Envs) make the V1V2 response breadth a high priority for HIV-1 vaccine regimens aiming for V1V2-mediated protection in Southern Africa. Here, we determined whether the breadth of the anti-V1V2 vaccine response can be broadened by including HIV-1 Env strains computationally designed to enhance the coverage of subtype C V1V2 sequence diversity. Methods: Three subtype C Env strains were selected to maximize antibody binding coverage while complementing subtype C vaccine gp120s that were given in human clinical trials in South Africa, as well as to improve epitope accessibility. Humoral immunogenicity of a novel trivalent gp120 vaccine immunogen, a bivalent gp120 boost already in clinical trials (1086C and TV1), and a pentavalent (all five gp120s combined) were evaluated in a preclinical immunization study in guinea pigs. The pentavalent combination was further evaluated with alum versus glucopyranosyl lipid adjuvants formulated in squalene-in-water emulsion (GLA-SE) adjuvants in non-human primates. The breadth of the anti-V1V2 response was assessed using an array of cross-subtype variable loops 1&2 (V1V2) scaffold proteins and linear V2 peptides. Results: The breadth of the IgG response against V1V2 antigens of the trivalent and pentavalent groups was comparable, and both were greater than the breadth of the bivalent group. Linear epitope mapping showed that two linear epitopes in V2 were targeted by the vaccinated animals: the V2 hotspot focused at 169K that potentially correlated with decreased HIV-1 risk in RV144 and the V2.2 site (179LDV/I181) that is part of the integrin α4β7 binding site. The bivalent vaccine elicited a significantly higher magnitude of binding to the V2 hotspot compared to the trivalent vaccine whereas the trivalent vaccine elicited significantly higher binding to the V2.2 epitope compared to the bivalent vaccine, while the pentavalent recognized both regions. Conclusions: These results demonstrate that the three new computationally selected subtype C Envs successfully complemented 1086C and TV1 for broader V1V2 antibody responses, and, in concert with adjuvants that stimulate V1V2 responses, can be considered as part of a rationale immunogen design to improve V1V2 IgG coverage in future vaccine trials in South Africa.

Background: Broadly neutralizing antibodies (bNAbs) against HIV-1 are promising candidates for prevention and treatment. 3BNC117-LS and 10-1074-LS are long-acting bNAbs targeting non-overlapping epitopes on the HIV-1 envelope protein. We evaluated the safety, pharmacokinetics (PK), tolerability, and immunogenicity of intravenous (IV) and subcutaneous (SC) administration of these antibodies, alone or in combination. Methods: Adults without HIV and adults with HIV on suppressive antiretroviral therapy (ART) were enrolled in two first-in-human dose-escalation studies. Participants received 3BNC117-LS, 10-1074-LS, or a combination via IV (3–30 mg/kg) or SC injection (150–600 mg total dose). Primary outcomes were safety and PK. Findings: A total of 116 participants enrolled: 43 in the 3BNC117-LS only study and 73 in the 10-1074-LS and combination bNAb study. All regimens, including the bNAb admixture administered subcutaneously, were safe and generally well tolerated, with no treatment discontinuations or serious adverse events related to antibody treatment. Both bNAbs showed prolonged median elimination half-lives (3BNC117-LS: 65.7 days; 10-1074-LS: 80.3 days), as compared to earlier studies with the parent bNAbs lacking half-life extension modifications, and consistent PK across populations and dose groups. SC bioavailability was 72% for 3BNC117-LS and 65.3% for 10-1074-LS. Anti-drug antibody (ADA) responses were infrequent, of low magnitude and not associated with adverse events or altered PK. Interpretation: 3BNC117-LS and 10-1074-LS demonstrated favorable safety, tolerability, and extended half-lives, supporting quarterly or semi-annual dosing. PK similarity across routes and co-administration groups supports development of fixed-dose combinations. These results inform the design of future studies and optimization of bNAb dosing strategies for HIV-1 prevention and treatment.

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. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.

Induction of broad, durable immune responses is a challenge in HIV vaccine development. HVTN 100 Part A administered subtype C-containing ALVAC-HIV at months 0 and 1, and ALVAC-HIV with bivalent subtype C gp120/MF59 at months 3, 6 and 12. As IgG binding antibody and T-cell responses were similar or greater at month 12.5 vs. month 6.5, but waned by month 18, we investigated vaccine-elicited immune responses after a month 30 boost in this study, HVTN 100 Part B. From 13 September 2017 to 7 August 2018, a subgroup of vaccinees was randomized to receive intramuscular injections of ALVAC+gp120/MF59 (n = 32) or gp120/MF59 alone (n = 31) and a subgroup of placebo recipients was administered placebo (n = 7) at month 30. Primary outcomes were safety, IgG binding antibodies (bAbs) to vaccine-specific and V1V2 Env proteins and vaccine-specific CD4+ T cells at month 30.5. Secondary outcomes included neutralizing and antibody dependent cellular cytotoxicity functions and durability at months 30 and 36. Both vaccine groups had an acceptable safety profile. There were no statistically significant differences in the occurrence or level of IgG bAbs between the vaccine boost groups for any vaccine-specific or V1V2 antigens. IgG responses were higher to vaccine-matched gp120 than to V1V2. The booster vaccination restored the magnitude-breadth IgG bAb response to V1V2 antigens at month 30.5. However, it rapidly waned by month 36. CD4+ T-cell response rates to the 3 vaccine-matched Env antigens for the combined vaccine groups ranged from 37% at month 30, boosted to as high as 91% at month 30.5, and waned by month 36 to as low as 44%, with no significant differences between the vaccine boost groups. Because these responses waned after 6 months, additional strategies may be needed to maintain the durability of prime-boost vaccine regimens and to generate these or other immune responses that confer protection. Trial registration: South African National Clinical Trials Register (SANCTR number: DOH—27-0215-4796) and ClinicalTrials.gov (NCT02404311).

Structure reflects a variety of practices teachers use with the intent to guide students' behavior and increase academic success. A research synthesis was conducted on the role of classroom structure in the academic engagement, disengagement, competence beliefs, and achievement of preschool through high school students. A meta-analysis of 191 samples from 165 correlational studies revealed statistically significant correlations with achievement (.11), engagement (.28), and competence beliefs (.22), and a statistically non-significant relationship with disengagement (-.08). A meta-analysis of 71 samples from 46 structure intervention studies revealed a positive statistically significant average effect (g) on achievement (0.33), engagement (0.46), and disengagement (-0.34), but a statistically non-significant effect for competence beliefs (0.26). Consistent with a dual process model of engagement, associations were stronger for engagement than disengagement. Results related to variation suggested some universality, particularly across grade levels, and underscored the importance of emphasizing anticipatory strategies, minimizing the controlling aspects of structure, and considering the broader context, including the country context, income background of students, or whether structure is paired with other psychological supports. Methodological features also explained variation, highlighting the importance of using methods that center teachers' and students' experiences and align with the nature of the focal outcome.

The modestly efficacious HIV-1 vaccine regimen (RV144) conferred 31% vaccine efficacy at 3 years following the four-shot immunization series, coupled with rapid waning of putative immune correlates of decreased infection risk. New strategies to increase magnitude and durability of protective immunity are critically needed. The RV305 HIV-1 clinical trial evaluated the immunological impact of a follow-up boost of HIV-1-uninfected RV144 recipients after 6-8 years with RV144 immunogens (ALVAC-HIV alone, AIDSVAX B/E gp120 alone, or ALVAC-HIV + AIDSVAX B/E gp120). Previous reports demonstrated that this regimen elicited higher binding, antibody Fc function, and cellular responses than the primary RV144 regimen. However, the impact of the canarypox viral vector in driving antibody specificity, breadth, durability and function is unknown. We performed a follow-up analysis of humoral responses elicited in RV305 to determine the impact of the different booster immunogens on HIV-1 epitope specificity, antibody subclass, isotype, and Fc effector functions. Importantly, we observed that the ALVAC vaccine component directly contributed to improved breadth, function, and durability of vaccine-elicited antibody responses. Extended boosts in RV305 increased circulating antibody concentration and coverage of heterologous HIV-1 strains by V1V2-specific antibodies above estimated protective levels observed in RV144. Antibody Fc effector functions, specifically antibody-dependent cellular cytotoxicity and phagocytosis, were boosted to higher levels than was achieved in RV144. V1V2 Env IgG3, a correlate of lower HIV-1 risk, was not increased; plasma Env IgA (specifically IgA1), a correlate of increased HIV-1 risk, was elevated. The quality of the circulating polyclonal antibody response changed with each booster immunization. Remarkably, the ALVAC-HIV booster immunogen induced antibody responses post-second boost, indicating that the viral vector immunogen can be utilized to selectively enhance immune correlates of decreased HIV-1 risk. These results reveal a complex dynamic of HIV-1 immunity post-vaccination that may require careful balancing to achieve protective immunity in the vaccinated population. Trial registration: RV305 clinical trial (ClinicalTrials.gov number, NCT01435135). ClinicalTrials.gov Identifier: NCT00223080.

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.

Agentic engagement refers to students' proactive and constructive contribution to the flow of instruction. The literature on student agentic engagement is missing the voices and perspectives of teachers. Given that the field knows little about what agentic engagement means to teachers, the goal of this study was to describe agentic engagement from the perspectives of urban high school science teachers. We conducted focus groups with 16 teachers to examine how, why, when, and who questions regarding students' use of agentic engagement in science classes. Results revealed the following themes: (a) Teachers initially struggled with the agentic engagement concept, but also acknowledged that a variety of strategies could be used, though rarely enacted. (b) Teachers emphasized the importance of students' approach for enacting agentic engagement in constructive ways that would increase teacher receptibility. (c) Teachers identified three categories of benefits, including benefits for students, benefits for teachers, and benefits for the class community. (d) Teachers highlighted considerations for effective agentic engagement in their classrooms, including their desire to maintain control. Teachers' deficit-based assumptions of student difficulties in science was identified as a potential barrier to supporting student agentic engagement. Implications for future research and implementation of agentic engagement interventions are discussed.

Broadly neutralizing antibodies (bnAbs) can protect against HIV infection but have not been induced by human vaccination. A key barrier to bnAb induction is vaccine priming of rare bnAb-precursor B cells. In a randomized, double-blind, placebo-controlled phase 1 clinical trial, the HIV vaccine–priming candidate eOD-GT8 60mer adjuvanted with AS01 B had a favorable safety profile and induced VRC01-class bnAb precursors in 97% of vaccine recipients with median frequencies reaching 0.1% among immunoglobulin G B cells in blood. bnAb precursors shared properties with bnAbs and gained somatic hypermutation and affinity with the boost. The results establish clinical proof of concept for germline-targeting vaccine priming, support development of boosting regimens to induce bnAbs, and encourage application of the germline-targeting strategy to other targets in HIV and other pathogens.