Youth in southern Africa, particularly adolescent girls and young women, are a key population for HIV prevention interventions. Untreated genital tract infections (GTIs) increase both HIV transmission and acquisition risks. South African GTI treatment guidelines employ syndromic management, which relies on individuals to report GTI signs and symptoms. Syndromic management may, however, underestimate cases, particularly among youth. We compared genital tract infection (GTI) prevalence by symptom-based and laboratory assessment among sexually-experienced youth in South Africa, overall and stratified by sex. Interviewer-administered surveys assessed socio-demographics, behaviors, and GTI symptoms among 352 youth (16-24 yrs., HIV-negative or unknown HIV status at enrollment) enrolled in community-based cohorts in Durban and Soweto (2014–2016). Laboratory tests assessed HIV, Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Mycoplasma genitalium (MG), Trichomonas vaginalis (TV) infections and, among females, bacterial vaginosis (BV) and Candida species. Youth with genital ulcers were tested for HSV-2 and syphilis. We assessed sensitivity (and specificity) of symptom-based reporting in identifying laboratory-confirmed GTIs. At baseline, 16.2% of females (32/198) and < 1% (1/154) of males reported ≥1 GTI symptom. However, laboratory tests identified ≥1 GTI in 70.2% and 10.4%, respectively. Female CT prevalence was 18.2%, NG 7.1%, MG 9.6%, TV 8.1%, and 5.1% were newly diagnosed with HIV. BV prevalence was 53.0% and candidiasis 9.6%. One female case of herpes was identified (0 syphilis). Male CT prevalence was 7.8%, NG 1.3%, MG 3.3%, TV < 1%, and 2.0% were newly diagnosed with HIV. Overall, 77.8% of females and 100% of males with laboratory-diagnosed GTIs reported no symptoms or were asymptomatic. Sensitivity (and specificity) of symptom-based reporting was 14% (97%) among females and 0% (99%) among males. A high prevalence of asymptomatic GTIs and very poor sensitivity of symptom-based reporting undermines the applicability of syndromic GTI management, thus compromising GTI control and HIV prevention efforts among youth. Syndromic GTI management does not meet the sexual health needs of young people. Policy changes incorporating innovations in GTI diagnostic testing are needed to reduce GTIs and HIV-associated risks among youth.

One of the most successful HIV vaccines to date, the RV144 vaccine tested in Thailand, demonstrated correlates of protection including cross-clade V1V2 immunoglobulin G (IgG) breadth, Env-specific CD4⁺ T cell polyfunctionality, and antibody-dependent cellular cytotoxicity (ADCC) in vaccinees with low IgA binding. The HIV Vaccine Trials Network (HVTN) 097 trial evaluated this vaccine regimen in South Africa, where clade C HIV-1 predominates. We compared cellular and humoral responses at peak and durability immunogenicity time points in HVTN 097 and RV144 vaccinee samples, and evaluated vaccine-matched and cross-clade immune responses. At peak immunogenicity, HVTN 097 vaccinees exhibited significantly higher cellular and humoral immune responses than RV144 vaccinees. CD4⁺ T cell responses were more frequent in HVTN 097 irrespective of age and sex, and CD4⁺ T cell Env-specific functionality scores were higher in HVTN 097. Env-specific CD40L⁺ CD4⁺ T cells were more common in HVTN 097, with individuals having this pattern of expression demonstrating higher median antibody responses to HIV-1 Env. IgG and IgG3 binding antibody rates and response magnitude to gp120 vaccine– and V1V2 vaccine–matched antigens were higher or comparable in HVTN 097 than in RV144 ADCC, and ADCP functional antibody responses were elicited in HVTN 097. Env-specific IgG and CD4⁺ Env responses declined significantly over time in both trials. Overall, cross-clade immune responses associated with protection were better than expected in South Africa, suggesting wider applicability of this regimen.

Novel strategies are being researched to discover vaccines to prevent and treat HIV-1. Non-efficacious preventative vaccine approaches include bivalent recombinant gp120 alone, HIV gene insertion into an Adenovirus 5 (Ad5) virus vector and the DNA prime/Ad5 boost vaccine regimen. However, the ALVAC-HIV prime/AIDSVAX® B/E gp120 boost regimen showed 31.2% efficacy at 3.5 years, and is being investigated as clade C constructs with an additional boost. Likewise, although multiple therapeutic vaccines have failed in the past, in a non-placebo controlled trial, a Tat vaccine demonstrated immune cell restoration, reduction of immune activation, and reduced HIV-1 DNA viral load. Monoclonal antibodies for passive immunization or treatment show promise, with VRC01 entering advanced clinical trials.

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).

We explored exposure to and experiences of violence and their risk factors amongst ethnically diverse adolescents from lower socio economic groups in Johannesburg. This cross-sectional study recruited a stratified sample of 16–18 year old adolescents from four low socio-economic suburbs in Johannesburg to reflect ethnic group clustering. We collected socio-demographic, sexual behaviour, alcohol and drug use and trauma events data. Proportions and risk factors were assessed by chi-square and logistic regression. Of 822 adolescents, 57% (n = 469) were female. Approximately 62% (n = 506) were Black, 13% (n = 107) Coloured, 13% (n = 106) Indian and 13% (n = 103) White. Approximately 67% (n = 552) witnessed violence to a non-family member, 28% (n = 228) experienced violence by a non-family member, and 10% (n = 83) reported sexual abuse. Multivariate analysis determined that witnessing violence in the community was associated with being Black (OR: 4.6, 95%CI: 2.7-7.9), Coloured (OR: 3.9, 95%CI: 2.0-7.4) or White (OR: 8.0, 95%CI:4.0-16.2), repeating a grade (OR: 1.5, 95%CI: 1.01-2.1), having more than one sexual partner (OR: 1.7, 95%CI: 1.1-2.5) and ever taking alcohol (OR: 2.1, 95%CI: 1.5-2.9). Witnessing violence in the family was associated with being female (OR: 1.8, 95%CI: 1.3-2.6), being Black (OR: 2.2, 95%CI: 1.1-4.1), or White (OR: 3.0, 95%CI: 1.4-6.4), repeating a grade (OR: 1.6, 95%CI: 1.1-2.2) and ever taking alcohol (OR: 2.9, 95%CI: 2.0-4.3). In low socio-economic areas in Johannesburg, Black, White and Coloured adolescents experience a high burden of violence. Interventions to mitigate the effects of violence are urgently required.