Vaccine Efficacy of ALVAC-HIV and Bivalent Subtype C gp120-MF59 in Adults.

BACKGROUND: A safe, effective vaccine is essential to eradicating human immunodeficiency virus (HIV) infection. A canarypox-protein HIV vaccine regimen (ALVAC-HIV plus AIDSVAX B/E) showed modest efficacy in reducing infection in Thailand. An analogous regimen using HIV-1 subtype C virus showed potent humoral and cellular responses in a phase 1-2a trial in South Africa. Efficacy data and additional safety data were needed for this regimen in a larger population in South Africa. METHODS: In this phase 2b-3 trial, we randomly assigned 5404 adults without HIV-1 infection to receive the vaccine (2704 participants) or placebo (2700 participants). The vaccine regimen consisted of injections of ALVAC-HIV at months 0 and 1, followed by four booster injections of ALVAC-HIV plus bivalent subtype C gp120-MF59 adjuvant at months 3, 6, 12, and 18. The primary efficacy outcome was the occurrence of HIV-1 infection from randomization to 24 months. RESULTS: In January 2020, prespecified criteria for nonefficacy were met at an interim analysis; further vaccinations were subsequently halted. The median age of the trial participants was 24 years; 70% of the participants were women. The incidence of adverse events was similar in the vaccine and placebo groups. During the 24-month follow-up, HIV-1 infection was diagnosed in 138 participants in the vaccine group and in 133 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.81 to 1.30; P = 0.84). CONCLUSIONS: The ALVAC-gp120 regimen did not prevent HIV-1 infection among participants in South Africa despite previous evidence of immunogenicity. (HVTN 702 ClinicalTrials.gov number, NCT02968849.).

Risk Factors Associated with HIV Acquisition in Males Participating in HIV Vaccine Efficacy Trials in South Africa.

In South Africa, HIV acquisition risk has been studied less in people assigned male at birth. We studied the associations between risk behaviors, clinical features and HIV incidence amongst males in two South African HIV preventive vaccine efficacy trials. We used Cox proportional hazards models to test for associations between demographics, sexual behaviors, clinical variables and HIV acquisition among males followed in the HVTN 503 (n = 219) and HVTN 702 (n = 1611) trials. Most males reported no male sexual partners (99.09% in HVTN 503) or identified as heterosexual (88.08% in HVTN 702). Annual HIV incidence was 1.39% in HVTN 503 (95% CI 0.76-2.32%) and 1.33% in HVTN 702 (95% CI 0.80-2.07%). Increased HIV acquisition was significantly associated with anal sex (HR 6.32, 95% CI 3.44-11.62), transactional sex (HR 3.42, 95% CI 1.80-6.50), and non-heterosexual identity (HR 16.23, 95%CI 8.13-32.41) in univariate analyses and non-heterosexual identity (HR 14.99, 95% CI 4.99-45.04; p < 0.01) in multivariate analysis. It is appropriate that prevention efforts in South Africa, although focused on the severe epidemic in young women, also encompass key male populations, including men who have sex with men, but also men who engage in anal or transactional sex.

Analysis of the HIV Vaccine Trials Network 702 Phase 2b-3 HIV-1 Vaccine Trial in South Africa Assessing RV144 Antibody and T-Cell Correlates of HIV-1 Acquisition Risk.

BACKGROUND: The ALVAC/gp120 + MF59 vaccines in the HIV Vaccine Trials Network (HVTN) 702 efficacy trial did not prevent human immunodeficiency virus-1 (HIV-1) acquisition. Vaccine-matched immunological endpoints that were correlates of HIV-1 acquisition risk in RV144 were measured in HVTN 702 and evaluated as correlates of HIV-1 acquisition. METHODS: Among 1893 HVTN 702 female vaccinees, 60 HIV-1-seropositive cases and 60 matched seronegative noncases were sampled. HIV-specific CD4+ T-cell and binding antibody responses were measured 2 weeks after fourth and fifth immunizations. Cox proportional hazards models assessed prespecified responses as predictors of HIV-1 acquisition. RESULTS: The HVTN 702 Env-specific CD4+ T-cell response rate was significantly higher than in RV144 (63% vs 40%, P = .03) with significantly lower IgG binding antibody response rate and magnitude to 1086.C V1V2 (67% vs 100%, P < .001; Pmag < .001). Although no significant univariate associations were observed between any T-cell or binding antibody response and HIV-1 acquisition, significant interactions were observed (multiplicity-adjusted P ≤.03). Among vaccinees with high IgG A244 V1V2 binding antibody responses, vaccine-matched CD4+ T-cell endpoints associated with decreased HIV-1 acquisition (estimated hazard ratios = 0.40-0.49 per 1-SD increase in CD4+ T-cell endpoint). CONCLUSIONS: HVTN 702 and RV144 had distinct immunogenicity profiles. However, both identified significant correlations (univariate or interaction) for IgG V1V2 and polyfunctional CD4+ T cells with HIV-1 acquisition. Clinical Trials Registration . NCT02968849.

Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine.

BACKGROUND: A safe and effective vaccine for the prevention of human immunodeficiency virus type 1 (HIV-1) infection is a global priority. We tested the efficacy of a DNA prime-recombinant adenovirus type 5 boost (DNA/rAd5) vaccine regimen in persons at increased risk for HIV-1 infection in the United States. METHODS: At 21 sites, we randomly assigned 2504 men or transgender women who have sex with men to receive the DNA/rAd5 vaccine (1253 participants) or placebo (1251 participants). We assessed HIV-1 acquisition from week 28 through month 24 (termed week 28+ infection), viral-load set point (mean plasma HIV-1 RNA level 10 to 20 weeks after diagnosis), and safety. The 6-plasmid DNA vaccine (expressing clade B Gag, Pol, and Nef and Env proteins from clades A, B, and C) was administered at weeks 0, 4, and 8. The rAd5 vector boost (expressing clade B Gag-Pol fusion protein and Env glycoproteins from clades A, B, and C) was administered at week 24. RESULTS: In April 2013, the data and safety monitoring board recommended halting vaccinations for lack of efficacy. The primary analysis showed that week 28+ infection had been diagnosed in 27 participants in the vaccine group and 21 in the placebo group (vaccine efficacy, -25.0%; 95% confidence interval, -121.2 to 29.3; P=0.44), with mean viral-load set points of 4.46 and 4.47 HIV-1 RNA log10 copies per milliliter, respectively. Analysis of all infections during the study period (41 in the vaccine group and 31 in the placebo group) also showed lack of vaccine efficacy (P=0.28). The vaccine regimen had an acceptable side-effect profile. CONCLUSIONS: The DNA/rAd5 vaccine regimen did not reduce either the rate of HIV-1 acquisition or the viral-load set point in the population studied. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00865566.).

Sexually transmitted infections amongst men who have sex with men (MSM) in South Africa.

There is limited data about bacterial STIs in MSM populations in sub-Saharan Africa. Our retrospective analysis used data from the HVTN 702 HIV vaccine clinical trial (October 2016 to July 2021). We evaluated multiple variables. Polymerase chain reaction testing was conducted on urine and rectal samples to detect Neisseria gonorrhoea (NG) and Chlamydia trachomatis (CT) every 6 months. Syphilis serology was conducted at month 0 and thereafter every 12 months. We calculated STI prevalence and the associated 95% confidence intervals until 24 months of follow-up. The trial enrolled 183 participants who identified as male or transgender female, and of homosexual or bisexual orientation. Of these, 173 had STI testing done at month 0, median age was 23 (IQR 20-25) years, with median 20.5 (IQR 17.5-24.8) months follow-up (FU). The clinical trial also enrolled and performed month 0 STI testing on 3389 female participants, median age 23 (IQR 21-27) years, median 24.8 (IQR 18.8-24.8) months FU and 1080 non-MSM males with a median age of 27 (IQR 24-31) years, median 24.8 (IQR 23-24.8) months FU. At month 0, CT prevalence was similar in MSM and females (26.0% vs 23.0%, p = 0.492) but was more prevalent in MSM compared to non-MSM males (26.0% vs 14.3%, p = 0.001). CT was the most prevalent STI among MSM at months 0 and 6 but declined from month 0 to month 6 (26.0% vs 17.1%, p = 0.023). In contrast, NG did not decline in MSM between months 0 and 6 (8.1% vs 7.1%, p = 0.680) nor did syphilis prevalence between months 0 and 12 (5.2% vs 3.8%, p = 0.588). Bacterial STI burden is higher in MSM compared to non-MSM males, and CT is the most prevalent bacterial STI amongst MSM. Preventive STI vaccines, especially against CT, may be helpful to develop.

A descriptive analysis of transgender participants in phase 1-2a trials of the HIV Vaccine Trials Network (HVTN) in the United States and Peru.

BACKGROUND: HIV disproportionately impacts transgender populations globally, creating challenges to inclusion in trials requiring low HIV risk profiles (LHRP) for acquisition. Our knowledge of transgender individuals with LHRP is limited. We conducted an analysis of transgender and cisgender individuals in HVTN trials enrolling individuals with LHRP. METHODS: We analyzed data from 694 participants enrolled in the phase 1-2a HVTN trials in the US and Peru from 2009 to 2014 that included individuals who reported gender identity (GI) differing from assigned birth sex (transgender [TG]), and compared them with those who reported a congruent GI (cisgender [CG]). RESULTS: 681 participants (98%) were CG and 13 (2%) were TG. Mean age was 25 years. 16% were Hispanic and most (69%) were White. Reasons for enrolling included to help find an effective vaccine (TG 100%; CG 98%) and help their community (TG 100%; CG 96%). Significant differences by GI were observed in reported pre-existing conditions (p = 0.004); however, approximately 10% of pre-existing conditions reported by TG were GI-related (e.g., gender dysphoria). Significant differences were observed in hormone therapy use (p < 0.001) and mental health medications (p = 0.007). Retention was excellent with 2.1% missed visits and no discontinuations of vaccination for TG and 3% missed visits and 7.1% discontinuations among CG. There was no statistically significant difference in HIV incidence. CONCLUSIONS: Primary reasons for participation were altruistic for all participants. Comparable to CG counterparts, TG participants maintained LHRP, followed trial procedures, and had high retention, facilitating meaningful early phase HIV preventive vaccine trial contributions.

Daily Vaginal Swabs and Mobile Phone Sex Report for Assessing HIV Virion Exposure Prospectively Among a Cohort of Young Sexually Active Women in South Africa (HVTN 915).

BACKGROUND: Measurements of HIV exposure could help identify subpopulations at highest risk of acquisition and improve the design of HIV prevention efficacy trials and public health interventions. The HVTN 915 study evaluated the feasibility of self-administered vaginal swabs for detection of HIV virions to assess exposure. METHODS: Fifty 18- to 25-year-old sexually active HIV-seronegative women using contraception were enrolled in Soweto, South Africa. Participants self-administered daily vaginal swabs and answered sexual behavior questions through mobile phone for 90 days. Clinician-administered vaginal swabs, behavioral questionnaires, HIV diagnostic testing, and counseling were performed at 8 clinic visits. Glycogen concentrations assessed adherence to swabbing. Y-chromosome DNA (Yc-DNA) assessed the accuracy of reported condom use. HIV exposure was measured by virion polymerase chain reaction in swabs from 41 women who reported unprotected vaginal sex during follow-up. RESULTS: Glycogen was detected in 315/336 (93.8%) participant-collected and in all clinician-collected swabs. Approximately 20/39 daily swabs (51.3%) linked to mobile reports of unprotected sex tested positive for Yc-DNA, whereas 10/187 swabs collected after 3 days of abstinence or protected sex (5.3%) had detectable Yc-DNA. No participant became HIV infected during the study; yet, exposure to HIV was detected by nucleic acids in 2 vaginal swabs from 1 participant, collected less than 1 hour after coitus. CONCLUSION: There was high adherence to daily vaginal swabbing. Daily mobile surveys had accurate reporting of unprotected sex. Detection of HIV in self-collected vaginal swabs from an uninfected participant demonstrated it was possible to measure HIV exposure, but the detection rate was lower than expected.

HIV-1 VACCINES. Diversion of HIV-1 vaccine-induced immunity by gp41-microbiota cross-reactive antibodies.

An HIV-1 DNA prime vaccine, with a recombinant adenovirus type 5 (rAd5) boost, failed to protect from HIV-1 acquisition. We studied the nature of the vaccine-induced antibody (Ab) response to HIV-1 envelope (Env). HIV-1-reactive plasma Ab titers were higher to Env gp41 than to gp120, and repertoire analysis demonstrated that 93% of HIV-1-reactive Abs from memory B cells responded to Env gp41. Vaccine-induced gp41-reactive monoclonal antibodies were non-neutralizing and frequently polyreactive with host and environmental antigens, including intestinal microbiota (IM). Next-generation sequencing of an immunoglobulin heavy chain variable region repertoire before vaccination revealed an Env-IM cross-reactive Ab that was clonally related to a subsequent vaccine-induced gp41-reactive Ab. Thus, HIV-1 Env DNA-rAd5 vaccine induced a dominant IM-polyreactive, non-neutralizing gp41-reactive Ab repertoire response that was associated with no vaccine efficacy.

Intentions to use preexposure prophylaxis among current phase 2B preventive HIV-1 vaccine efficacy trial participants.

In November 2010, the iPrEx study reported that preexposure prophylaxis (PrEP) with daily tenofovir disoproxil fumarate/emtricitabine reduced HIV infections by 44% among men who have sex with men and subsequent trials corroborated efficacy among heterosexual men and women. During regularly scheduled follow-up visits from January to March 2011, participants in an ongoing phase 2b vaccine efficacy trial completed an anonymous Web survey about PrEP. Among 376 respondents, 17% reported they were very likely to use PrEP in the next year. Nonwhite participants were more likely to use PrEP. Among those with some level of interest, intent to use PrEP was greatest if the drug were available through the clinical trial or health insurance. Most (91%) believed taking PrEP would not change their willingness to stay in the vaccine trial and few thought it would affect recruitment. As key stakeholders, currently enrolled trial participants can offer vital input about emerging prevention technologies that may affect the design of future HIV vaccine and nonvaccine prevention trials.

A phase IIA randomized clinical trial of a multiclade HIV-1 DNA prime followed by a multiclade rAd5 HIV-1 vaccine boost in healthy adults (HVTN204).

BACKGROUND: The safety and immunogenicity of a vaccine regimen consisting of a 6-plasmid HIV-1 DNA prime (envA, envB, envC, gagB, polB, nefB) boosted by a recombinant adenovirus serotype-5 (rAd5) HIV-1 with matching inserts was evaluated in HIV-seronegative participants from South Africa, United States, Latin America and the Caribbean. METHODS: 480 participants were evenly randomized to receive either: DNA (4 mg i.m. by Biojector) at 0, 1 and 2 months, followed by rAd5 (10(10) PU i.m. by needle/syringe) at 6 months; or placebo. Participants were monitored for reactogenicity and adverse events throughout the 12-month study. Peak and duration of HIV-specific humoral and cellular immune responses were evaluated after the prime and boost. RESULTS: The vaccine was well tolerated and safe. T-cell responses, detected by interferon-γ (IFN-γ) ELISpot to global potential T-cell epitopes (PTEs) were observed in 70.8% (136/192) of vaccine recipients overall, most frequently to Gag (54.7%) and to Env (54.2%). In U.S. vaccine recipients T-cell responses were less frequent in Ad5 sero-positive versus sero-negative vaccine recipients (62.5% versus 85.7% respectively, p = 0.035). The frequency of HIV-specific CD4+ and CD8+ T-cell responses detected by intracellular cytokine staining were similar (41.8% and 47.2% respectively) and most secreted ≥2 cytokines. The vaccine induced a high frequency (83.7%-94.6%) of binding antibody responses to consensus Group M, and Clades A, B and C gp140 Env oligomers. Antibody responses to Gag were elicited in 46% of vaccine recipients. CONCLUSION: The vaccine regimen was well-tolerated and induced polyfunctional CD4+ and CD8+ T-cells and multi-clade anti-Env binding antibodies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00125970.