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Additional forms of pre-exposure prophylaxis are needed to prevent HIV-1 infection. 3BNC117 and 10-1074 are broadly neutralizing anti-HIV-1 antibodies that target non-overlapping epitopes on the HIV-1 envelope. We investigated the safety, tolerability, pharmacokinetics, and immunogenicity of the intravenous administration of the combination of 3BNC117 and 10-1074 in healthy adults. This randomized, double-blind, placebo-controlled, single center, phase 1 study enrolled healthy adults aged 18-65 years to receive one infusion of 3BNC117 immediately followed by 10-1074 at 10 mg/kg, three infusions of 3BNC117 followed by 10-1074 at 3 mg/kg or 10 mg/kg every 8 weeks, or placebo infusions. The primary outcomes were safety and pharmacokinetics. This trial is registered with ClinicalTrials.gov, number NCT02824536. Twenty-four participants were enrolled in a 3:1 ratio to receive the study products or placebo. The combination of 3BNC117 and 10-1074 was safe and generally well tolerated. There were no serious adverse events considered related to the infusions. The mean elimination half-lives of 3BNC117 and 10-1074 were 16.4 ± 4.6 days and 23.0 ± 5.4 days, respectively, similar to what was observed in previous studies in which each antibody was administered alone. Anti-drug antibody responses were rare and without evidence of related adverse events or impact on elimination kinetics. Single and repeated doses of the combination of 3BNC117 and 10-1074 were well tolerated in healthy adults. These data support the further development of the combination of 3BNC117 and 10-1074 as a long-acting injectable form of pre-exposure prophylaxis for the prevention of HIV-1 infection.

In the RV144 HIV-1 vaccine efficacy trial, IgG antibody (Ab) binding levels to variable regions 1 and 2 (V1V2) of the HIV-1 envelope glycoprotein gp120 were an inverse correlate of risk of HIV-1 infection. To determine if V1V2-specific Abs cross-react with V1V2 from different HIV-1 subtypes, if the nature of the V1V2 antigen used to asses cross-reactivity influenced infection risk, and to identify immune assays for upcoming HIV-1 vaccine efficacy trials, new V1V2-scaffold antigens were designed and tested. Protein scaffold antigens carrying the V1V2 regions from HIV-1 subtypes A, B, C, D or CRF01_AE were assayed in pilot studies, and six were selected to assess cross-reactive Abs in the plasma from the original RV144 case-control cohort (41 infected vaccinees, 205 frequency-matched uninfected vaccinees, and 40 placebo recipients) using ELISA and a binding Ab multiplex assay. IgG levels to these antigens were assessed as correlates of risk in vaccine recipients using weighted logistic regression models. Levels of Abs reactive with subtype A, B, C and CRF01_AE V1V2-scaffold antigens were all significant inverse correlates of risk (p-values of 0.0008-0.05; estimated odds ratios of 0.53-0.68 per 1 standard deviation increase). Thus, levels of vaccine-induced IgG Abs recognizing V1V2 regions from multiple HIV-1 subtypes, and presented on different scaffolds, constitute inverse correlates of risk for HIV-1 infection in the RV144 vaccine trial. The V1V2 antigens provide a link between RV144 and upcoming HIV-1 vaccine trials, and identify reagents and methods for evaluating V1V2 Abs as possible correlates of protection against HIV-1 infection. ClinicalTrials.gov NCT00223080.

HVTN 100 evaluated the safety and immunogenicity of an HIV subtype C pox-protein vaccine regimen, investigating a 12-month booster to extend vaccine-induced immune responses. A phase 1-2 randomized double-blind placebo-controlled trial enrolled 252 participants (210 vaccine/42 placebo; median age 23 years; 43% female) between 9 February 2015 and 26 May 2015. Vaccine recipients received ALVAC-HIV (vCP2438) alone at months 0 and 1 and with bivalent subtype C gp120/MF59 at months 3, 6, and 12. Antibody (IgG, IgG3 binding, and neutralizing) and CD4+ T-cell (expressing interferon-gamma, interleukin-2, and CD40 ligand) responses were evaluated at month 6.5 for all participants and at months 12, 12.5, and 18 for a randomly selected subset. The primary analysis compared IgG binding antibody (bAb) responses and CD4+ T-cell responses to 3 vaccine-matched antigens at peak (month 6.5 versus 12.5) and durability (month 12 versus 18) timepoints; IgG responses to CaseA2_gp70_V1V2.B, a primary correlate of risk in RV144, were also compared at these same timepoints. Secondary and exploratory analyses compared IgG3 bAb responses, IgG bAb breadth scores, neutralizing antibody (nAb) responses, antibody-dependent cellular phagocytosis, CD4+ polyfunctionality responses, and CD4+ memory sub-population responses at the same timepoints. Vaccines were generally safe and well tolerated. During the study, there were 2 deaths (both in the vaccine group and both unrelated to study products). Ten participants became HIV-infected during the trial, 7% (3/42) of placebo recipients and 3% (7/210) of vaccine recipients. All 8 serious adverse events were unrelated to study products. Less waning of immune responses was seen after the fifth vaccination than after the fourth, with higher antibody and cellular response rates at month 18 than at month 12: IgG bAb response rates to 1086.C V1V2, 21.0% versus 9.7% (difference = 11.3%, 95% CI = 0.6%-22.0%, P = 0.039), and ZM96.C V1V2, 21.0% versus 6.5% (difference = 14.5%, 95% CI = 4.1%-24.9%, P = 0.004). IgG bAb response rates to all 4 primary V1V2 antigens were higher 2 weeks after the fifth vaccination than 2 weeks after the fourth vaccination: 87.7% versus 75.4% (difference = 12.3%, 95% CI = 1.7%-22.9%, P = 0.022) for 1086.C V1V2, 86.0% versus 63.2% (difference = 22.8%, 95% CI = 9.1%-36.5%, P = 0.001) for TV1c8.2.C V1V2, 67.7% versus 44.6% (difference = 23.1%, 95% CI = 10.4%-35.7%, P < 0.001) for ZM96.C V1V2, and 81.5% versus 60.0% (difference = 21.5%, 95% CI = 7.6%-35.5%, P = 0.002) for CaseA2_gp70_V1V2.B. IgG bAb response rates to the 3 primary vaccine-matched gp120 antigens were all above 90% at both peak timepoints, with no significant differences seen, except a higher response rate to ZM96.C gp120 at month 18 versus month 12: 64.5% versus 1.6% (difference = 62.9%, 95% CI = 49.3%-76.5%, P < 0.001). CD4+ T-cell response rates were higher at month 18 than month 12 for all 3 primary vaccine-matched antigens: 47.3% versus 29.1% (difference = 18.2%, 95% CI = 2.9%-33.4%, P = 0.021) for 1086.C, 61.8% versus 38.2% (difference = 23.6%, 95% CI = 9.5%-37.8%, P = 0.001) for TV1.C, and 63.6% versus 41.8% (difference = 21.8%, 95% CI = 5.1%-38.5%, P = 0.007) for ZM96.C, with no significant differences seen at the peak timepoints. Limitations were that higher doses of gp120 were not evaluated, this study was not designed to investigate HIV prevention efficacy, and the clinical significance of the observed immunological effects is uncertain. In this study, a 12-month booster of subtype C pox-protein vaccines restored immune responses, and slowed response decay compared to the 6-month vaccination. ClinicalTrials.gov NCT02404311. South African National Clinical Trials Registry (SANCTR number: DOH--27-0215-4796).

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 .

HIV vaccine trials routinely measure multiple vaccine-elicited immune responses to compare regimens and study their potential associations with protection. Here we employ unsupervised learning tools facilitated by a bidirectional power transformation to explore the multivariate binding antibody and T-cell response patterns of immune responses elicited by two pox-protein HIV vaccine regimens. Both regimens utilized a recombinant canarypox vector (ALVAC-HIV) prime and a bivalent recombinant HIV-1 Envelope glycoprotein 120 subunit boost. We hypothesized that within each trial, there were participant subgroups sharing similar immune responses and that their frequencies differed across trials. We analyzed data from three trials-RV144 (NCT00223080), HVTN 097 (NCT02109354), and HVTN 100 (NCT02404311), the latter of which was pivotal in advancing the tested pox-protein HIV vaccine regimen to the HVTN 702 Phase 2b/3 efficacy trial. We found that bivariate CD4+ T-cell and anti-V1V2 IgG/IgG3 antibody response patterns were similar by age, sex-at-birth, and body mass index, but differed for the pox-protein clade AE/B alum-adjuvanted regimen studied in RV144 and HVTN 097 (PAE/B/alum) compared to the pox-protein clade C/C MF59-adjuvanted regimen studied in HVTN 100 (PC/MF59). Specifically, more PAE/B/alum recipients had low CD4+ T-cell and high anti-V1V2 IgG/IgG3 responses, and more PC/MF59 recipients had broad responses of both types. Analyses limited to \"vaccine-matched\" antigens suggested that some of the differences in responses between the regimens could have been due to antigens in the assays that did not match the vaccine immunogens. Our approach was also useful in identifying subgroups with unusually absent or high co-responses across assay types, flagging individuals for further characterization by functional assays. We also found that co-responses of anti-V1V2 IgG/IgG3 and CD4+ T cells had broad variability. As additional immune response assays are standardized and validated, we anticipate our framework will be increasingly valuable for multivariate analysis. Our approach can be used to advance vaccine development objectives, including the characterization and comparison of candidate vaccine multivariate immune responses and improved design of studies to identify correlates of protection. For instance, results suggested that HVTN 702 will have adequate power to interrogate immune correlates involving anti-V1V2 IgG/IgG3 and CD4+ T-cell co-readouts, but will have lower power to study anti-gp120/gp140 IgG/IgG3 due to their lower dynamic ranges. The findings also generate hypotheses for future testing in experimental and computational analyses aimed at achieving a mechanistic understanding of vaccine-elicited immune response heterogeneity.

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. 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. Of 185 vaccine recipients, 73 were AFAB and 112 were AMAB. Vaccine recipients AFAB had greater ADCC response rate (57.5% versus 29.5%; = 0.0003) and greater ADCC magnitude (area under the net % granzyme B activity vs log10 curve (AUC), 16.1 versus 11.2; = 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%; = 0.04]; 1086.C gp120, [44.1% versus 29.4%; = 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 ( = 0.08). There were no sex-based differences in neutralizing antibody or ADCP responses. 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.

DNA vectors have been widely used as a priming of poxvirus vaccine in prime/boost regimens. Whether the number of DNA impacts qualitatively or quantitatively the immune response is not fully explored. With the aim to reinforce T-cell responses by optimizing the prime-boost regimen, the multicentric EV03/ANRS VAC20 phase I/II trial, randomized 147 HIV-negative volunteers to either 3xDNA plus 1xNYVAC (weeks 0, 4, 8 plus 24; n = 74) or to 2xDNA plus 2xNYVAC (weeks 0, 4 plus 20, 24; n = 73) groups. T-cell responses (IFN-γ ELISPOT) to at least one peptide pool were higher in the 3xDNA than the 2xDNA groups (91% and 80% of vaccinees) (P = 0.049). In the 3xDNA arm, 26 (37%) recipients developed a broader T-cell response (Env plus at least to one of the Gag, Pol, Nef pools) than in the 2xDNA (15; 22%) arms (primary endpoint; P = 0.047) with a higher magnitude against Env (at week 26) (P<0.001). In both groups, vaccine regimens induced HIV-specific polyfunctional CD4 and CD8 T cells and the production of Th1, Th2 and Th17/IL-21 cytokines. Antibody responses were also elicited in up to 81% of vaccines. A higher percentage of IgG responders was noted in the 2xDNA arm compared to the 3xDNA arm, while the 3xDNA group tended to elicit a higher magnitude of IgG3 response against specific Env antigens. We show here that the modulation of the prime strategy, without modifying the route or the dose of administration, or the combination of vectors, may influence the quality of the responses.

Both neutralization and antibody-dependent cellular cytotoxicity (ADCC) may be required for effective protection against HIV-1 infection. While there is extensive information on the targets of early neutralizing antibody (nAb) responses, much less is known about the targets of ADCC responses, which are more difficult to characterize. In four individuals recruited during acute HIV-infection, ADCC responses were detected 3-7 weeks prior to nAb responses. To determine the relative influence of ADCC and nAb responses on virus evolution, we performed an in-depth investigation of one individual (CAP63) who showed the highest nAb and ADCC responses. Both nAbs and ADCC antibodies targeted the V4 region of the Env, although there were some differences in epitope recognition. We identified accelerated viral evolution in this region concurrent with emergence of nAb activity, but not ADCC activity. Deep sequencing demonstrated that most nAb escape mutations were strongly selected for, however one nAb escape mutation that rendered the virus highly susceptible to autologous ADCC responses, was suppressed despite not affecting viral fitness. This escape mutation also rendered the virus more sensitive to autologous responses, as well as monoclonal antibodies targeting CD4-induced epitopes, compared to the wildtype virus. In conclusion, ADCC responses and nAbs in donor CAP63 recognized overlapping but unique epitopes in the V4 region, and while ADCC activity was present prior to nAbs, it did not drive viral evolution during this time. However, ADCC responses may select against nAb escape pathways that expose other common ADCC epitopes thereby restricting viral replication and expansion.

The outcome of the recent Antibody Mediated Prevention (AMP) trials that tested infusion of the broadly neutralizing antibody (bnAb) VRC01 provides proof of concept for blocking infection from sensitive HIV-1 strains. These results also open up the possibility that triple combinations of bnAbs such as PGT121, PGDM1400, as well as long-lasting LS variants such as VRC07-523 LS, have immunoprophylactic potential. PGT121 and PGDM1400 target the HIV-1 V3 and V2 glycan regions of the gp120 envelope protein, respectively, while VRC07-523LS targets the HIV-1 CD4 binding site. These bnAbs demonstrate neutralization potency and complementary breadth of HIV-1 strain coverage. An important clinical trial outcome is the accurate measurement of in vivo concentrations of passively infused bnAbs to determine effective doses for therapy and/or prevention. Standardization and validation of this testing method is a key element for clinical studies as is the ability to simultaneously detect multiple bnAbs in a specific manner. Here we report the development of a sensitive, specific, accurate, and precise multiplexed microsphere-based assay that simultaneously quantifies the respective physiological concentrations of passively infused bnAbs in human serum to ultimately define the threshold needed for protection from HIV-1 infection.