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Background DNA plasmids promise a pragmatic alternative to viral vectors for prime-boost HIV-1 vaccines. We evaluated DNA plasmid versus canarypox virus (ALVAC) primes in 2 randomized, double-blind, placebo-controlled trials in southern Africa with harmonized trial designs. HIV Vaccine Trials Network (HVTN) 111 tested DNA plasmid prime by needle or needleless injection device (Biojector) and DNA plasmid plus gp120 protein plus MF59 adjuvant boost. HVTN 100 tested ALVAC prime and ALVAC plus gp120 protein plus MF59 adjuvant boost (same protein/adjuvant as HVTN 111) by needle. Methods and findings The primary endpoints for this analysis were binding antibody (bAb) responses to HIV antigens (gp120 from strains ZM96, 1086, and TV1; variable 1 and 2 [V1V2] regions of gp120 from strains TV1, 1086, and B.CaseA, as 1086 V1V2 and B.CaseA were correlates of risk in the RV144 efficacy trial), neutralizing antibody (nAb) responses to pseudoviruses TV1c8.2 and MW925.26, and cellular responses to vaccine-matched antigens (envelope [Env] from strains ZM96, 1086, and TV1; and Gag from strains LAI and ZM96) at month 6.5, two weeks after the fourth vaccination. Per-protocol cohorts included vaccine recipients from HVTN 100 (n = 186, 60% male, median age 23 years) enrolled between February 9, 2015, and May 26, 2015 and from HVTN 111 (n = 56, 48% male, median age 24 years) enrolled between June 21, 2016, and July 13, 2017. IgG bAb response rates were 100% to 3 Env gp120 antigens in both trials. Response rates to V1V2 were lower and similar in both trials except to vaccine-matched 1086 V1V2, with rates significantly higher for the DNA-primed regimen than the ALVAC-primed regimen: 96.6% versus 72.7% (difference = 23.9%, 95% CI 15.6%-32.2%, p < 0.001). Among positive responders, bAb net mean fluorescence intensity (MFI) was significantly higher with the DNA-primed regimen than ALVAC-primed for 1086 V1V2 (geometric mean [GM] 2,833.3 versus 1,200.9; ratio = 2.36, 95% CI 1.42-3.92, p 98% in both trials, with significantly higher 50% inhibitory dilution (ID.sub.50) among DNA-primed positive responders (n = 53) versus ALVAC-primed (n = 182) to tier 1A MW965.26 (GM 577.7 versus 265.7, ratio = 2.17, 95% CI 1.67-2.83, p < 0.001) and to TV1c8.2 (GM 187.3 versus 100.4, ratio = 1.87, 95% CI 1.48-2.35, p < 0.001). CD4+ T-cell response rates were significantly higher with DNA plasmid prime via Biojector than ALVAC prime (91.4% versus 52.8%, difference = 38.6%, 95% CI 20.5%-56.6%, p < 0.001 for ZM96.C; 88.0% versus 43.1%, difference = 44.9%, 95% CI 26.7%-63.1%, p < 0.001 for 1086.C; 55.5% versus 2.2%, difference = 53.3%, 95% CI 23.9%-82.7%, p < 0.001 for Gag LAI/ZM96). The study's main limitations include the nonrandomized comparison of vaccines from 2 different trials, the lack of data on immune responses to other non-vaccine-matched antigens, and the uncertain clinical significance of the observed immunological effects. Conclusions In this study, we found that further investigation of DNA/protein regimens is warranted given enhanced immunogenicity to the V1V2 correlates of decreased HIV-1 acquisition risk identified in RV144, the only HIV vaccine trial to date to show any efficacy., Author(s): Zoe Moodie 1,*, Stephen R. Walsh 2,3,4, Fatima Laher 5, Lucas Maganga 6, Michael E. Herce 7, Sarita Naidoo 8, Mina C. Hosseinipour 9, Craig Innes 10, Linda-Gail Bekker [...]

Author(s): Lynn Morris 1,2,*, Nonhlanhla N. Mkhize 1 The need for better HIV prevention tools Despite the widespread global rollout of antiretroviral therapy and its ability to reduce onward HIV [...]

An abstract of the article "Knowing Whom We Are trying to Protect: An Assessment of HIV Risk in South African Adolescent Females" by Shaun L. Barnabas, Heather B. Jaspan, Smritee Dabee and colleagues is presented.

Vaginal microbiota varies by geographical location in South African women: Women of African descent are more likely to have bacterial vaginosis than women of other ethnicities. Both diversity and likely specific taxa in these microbial communities are important to sexual and reproductive health, such as HIV risk. However, whether the specific taxa also vary by geographical location and/or ethnicity requires further investigation. Here, we compare the vaginal microbiota of 16-22-year-old black, HIV-negative South African women from two geographically disparate but low-income high population density communities, one in Cape Town (CPT) and one in Johannesburg (JHB). Vaginal microbiota composition was assessed by 16S rRNA gene amplicon sequencing of lateral vaginal wall swabs. Geographical location was significantly associated with vaginal microbiota composition by permutational analysis of variance (PERMANOVA) (p=0.02), as were body mass index BMI (p=0.015) and human papilloma virus (HPV) risk type (p=0.005), while the presence of one or more sexually transmitted infections (STIs) (p=0.053) and hormonal contraceptive (HC) usage (p=0.4) were not. Geographical location remained a significant determinant of microbiota composition independent of BMI, STI status and HPV-risk. Together, geographical location, BMI and HPV-risk explained 10% of the variance in microbiota composition with a large proportion of the variance remaining unexplained. Several taxa differed significantly between geographical location - some by frequency and others by relative abundance. Our results therefore suggest that HIV prophylactic approaches targeting the vaginal microbiota should be geographically tailored. [ABSTRACT FROM AUTHOR]

Young South African women, from resource-poor communities, face several sexual and reproductive health challenges. Here we describe the vaginal microbiota and sexually transmitted infection (STI) prevalence of 102; 16-22-year-old, HIV-negative South African women from a low-income, highpopulation- density community in Cape Town (CPT). Vaginal microbiota were profiled using 16S rRNA amplicon sequencing; bacterial vaginosis (BV) status was established using Nugent scoring and STIs were determined by multiplex polymerase chain reaction. STIs were common, with 55% of women having at least one STI; 41% were infected with high-risk human papilloma virus (HPV) and a further 28% with low-risk HPV; 44% were infected with Chlamydia, 16% of whom had at least one additional STI. Similarly, BV rates were very high, with 55% of women classified as BV-positive (Nugent score -7), 7% as BV-intermediate (Nugent score 3-6) and 38% as BV-negative (Nugent 0-2). Group B Streptococcus (Streptococcus agalactiae), the leading cause of neonatal sepsis, was present in 25% of BV-positive women and 28% of BV-negative women, and was significantly more abundant among BV-negative women. Both Chlamydia infection and BV may adversely affect reproductive health and place these women at additional risk for HIV acquisition. The high abundance of Prevotella amnii, in particular, may increase HIV risk, given its inflammatory capacity. Laboratorybased testing for STIs (Chlamydia and Gonorrhoeae in particular) appear to be warranted in this community, together with further monitoring or treatment of BV. [ABSTRACT FROM AUTHOR]

Background: The neonatal immune system is uniquely poised to generate broadly neutralizing antibodies (bnAbs) and thus infants are ideal for evaluating HIV vaccine candidates. We present the design and safety of a novel glucopyranosyl lipid A (GLA)-stable emulsion (SE) adjuvant admixed with a first-in-infant CH505 transmitter-founder (CH505TF) gp120 immunogen designed to induce precursors for bnAbs against HIV., Methods: HVTN 135 is a phase I randomized, placebo-controlled trial of CH505TF+GLA-SE or placebo. Healthy infants in South Africa aged ≤5 days, born to mothers living with HIV but HIV nucleic acid negative at birth were randomized to five doses of CH505TF + GLA-SE or placebo at birth and 8, 16, 32, and 54 weeks., Results: 38 infants (median age = 4 days; interquartile range 4, 4.75 days) were enrolled November 2020 to January 2022. Among 28 (10) infants assigned to receive CH505TF + GLA-SE (placebo), most (32/38) completed the 5-dose immunization series and follow-up (35/38). Solicited local and systemic reactions were more frequent in vaccine (8, 28.6% local; 16, 57.1% systemic) vs. placebo recipients (1, 10% local, p = 0.25; 4, 40.0% systemic, p = 0.38). All events were Grade 1 except two Grade 2 events (pain, lethargy). Serious vaccine-related adverse events were not recorded., Conclusions: This study illustrates the feasibility of conducting trials of novel adjuvanted HIV vaccines in HIV-exposed infants receiving standard infant vaccinations. The safety profile of the CH505TF + GLA-SE vaccine was reassuring., Trial Registration: ClinicalTrials.gov NCT04607408., Funding: National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH)., Competing Interests: Declaration of interests OL is a named inventor on patents relating to vaccine adjuvants and to human in vitro systems that model the safety and immunogenicity of adjuvants, vaccines and immunomodulators. He serves as a consultant to GSK and Hillevax and is a co-founder of Ovax, Inc. All other authors declare no conflict of interest.

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)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: The HVTN 100 clinical trial was funded by the National Institute of Allergy and Infectious Diseases (NIAID, https://www.niaid.nih.gov/) U.S. Public Health Service Grants UM1 AI068614 [LOC: HIV Vaccine Trials Network], UM1 AI068618 [LC: HIV Vaccine Trials Network], and UM1 AI068635 [SDMC: HIV Vaccine Trials Network], UM1 AI069453 [Soweto-Bara Clinical Research Site], UM1 AI069519 [Cape Town – Emavundleni Clinical Research Site], UM1 AI069469 [Durban –eThekwini Clinical Research Site], and UM1 AI069422 [Durban – Isipingo Clinical Research Site] and NIH (P30 AI064518). Dr Naicker was supported by a Scientific Leadership Development award from HVTN. The HVTN 100 clinical trial was also funded by the Bill & Melinda Gates Foundation award OPP1110792. The Gates Foundation provided funding to Fred Hutchinson Cancer Center to support the implementation of HVTN 100 at the Soweto-Bara Clinical Research Site, Cape Town-Emavundleni Clinical Research Site, Durban-eThekwini Clinical Research Site, and Durban-Isipingo Clinical Research Site, as well as the Klerksdorp and Soshanguve sites. Funding was provided to Novartis Vaccines and Diagnostics (now part of the GlaxoSmithKline group of companies) by NIAID (HHSN272201300033C//HHSN272201600012C) for the selection and process development of the two gp120 envelope proteins TV1.C and 1086.C, and by the Bill & Melinda Gates Foundation Global Health Grant OPP1017604 and NIAID for the manufacture and release of the gp120 clinical grade material. Role of the funding source: Within the terms of the Grant Award of the Cooperative Agreement with the HIV Vaccine Trials Network (HVTN), the study sponsor, NIAID, contributed to, reviewed, and approved the HVTN 100 study design, contributed to the review and analysis of data, concurred with the decision to publish, and assisted with the preparation of the manuscript. The Gates Foundation contributed to, reviewed, and approved the HVTN 100 study design, and reviewed the data from the study. Neither NIAID or the Gates Foundation were involved in the data collection, and did not perform statistical analyses. GlaxoSmithKline Biologicals SA was provided the opportunity to review a preliminary version of this manuscript, but the authors are solely responsible for final content and interpretation. MK is employed by and holds shares in GSK. All other authors have nothing to declare., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)