Summary We report the primary analysis of the safety and efficacy of the MRKad5 gag/pol/nef HIV-1 sub-type B vaccine in South Africa (SA), where the major circulating clade is sub-type C. Methods This phase IIb double-blind, randomized test-of-concept study was conducted in sexually active HIV-1 sero-negative participants in SA. The co-primary endpoints were a vaccine-induced reduction in HIV-1 acquisition or viral-load setpoint. These were assessed independently in the modified intent-to-treat (MITT) cohort with two-tailed significance tests stratified by gender. Immunogenicity was assessed by interferon-gamma (IFNγ) ELISPOT in peripheral blood mononuclear cells. Following the lack of efficacy of the MRKAd5 HIV-1 vaccine in the Step study, enrollment and vaccination in this study was halted, treatment unblinding occurred and follow-up continued. This study is registered with the SA National Health Research Database (DOH-27-0207-1539) and ClinicalTrials.gov (NCT00413725). Results 801 of a scheduled 3000 participants were enrolled, of whom 360 (44.9%) were women, more than half (55.6%) had Ad5 titres > 200, and almost a third (29.3%) of men were circumcised. 62 MITT participants were diagnosed with HIV-1, 34 in the vaccine arm and 28 in the placebo arm, with infection rates of 4.54 and 3.70 per 100 person-years, respectively. There was no evidence of vaccine efficacy (VE); the hazard ratio adjusted for gender was 1.25 (95% CI: 0.76, 2.05). VE did not differ by Ad5 titre, gender, age, HSV-2 status, or circumcision. The geometric mean viral load setpoint was 20,483 copies/ml (N=33) in vaccinees and 34,032 copies/ml (N=28) in placebo recipients (p=0.39). The vaccine elicited IFNγ-secreting T cells recognizing both clade B (89.2%) and C (77.4%) antigens. Conclusion The MRKAd5 HIV-1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint however early stopping likely compromised our ability to draw conclusions. The high incidence rates seen in SA highlight the critical need for intensified efforts to develop an efficacious vaccine.

BackgroundThis study was undertaken to determine the susceptibility profile and the mechanism of antibiotic resistance in Group B streptococcus (GBS) isolates detected in vaginal and rectal swabs from pregnant women attending Dr George Mukhari Academic Hospital, a University Teaching Hospital in Pretoria, South Africa.MethodsThe samples were collected over an 11-month period, cultured on selective media (colistin and nalidixic acid agar and Todd-Hewitt broth), and GBS positively identified by using different morphological and biochemical tests. The susceptibility testing was done using the Kirby–Bauer and E test methods according to CLSI guidelines 2012. The D test method was used for the detection of inducible clindamycin resistance. Multiplex PCR with specific primers was used to detect different genes coding for resistance.ResultsOut of 413 samples collected, 128 (30.9 %) were positive with GBS. The susceptibility testing revealed that 100 % of isolates were sensitive to penicillin, ampicillin, vancomycin and high level gentamicin. Erythromycin and clindamycin resistance was 21.1 and 17.2 %, respectively, in which 69 % had harboured constitutive macrolide, lincosamide and streptogramin B (MLSB), 17.4 % had inducible MLSB. The M and L phenotypes were present in 6.8 % each. The methylation of target encoded by ermB genes was the commonest mechanism of resistance observed in 55 % of isolates, 38 % of isolates had both ermB and linB genes and efflux pump mediated by mefA genes was also distributed among the isolates.ConclusionsThe study reaffirmed the appropriateness of penicillin as the antibiotic of choice for treating GBS infection. However it identified the challenges of resistance to macrolides and lincosamides used as alternative drugs for individuals allergic to penicillin. More GBS treatment options for penicillin allergic patients need to be researched on.

BACKGROUND A safe, effective vaccine is essential to end HIV. A canarypox/protein HIV vaccine regimen showed modest efficacy at reducing infection in Thailand. An analogous regimen using HIV-1 subtype C virus demonstrated potent humoral and cellular responses in a Phase 1/2a trial and triggered a Phase 2b/3 double-blinded trial to assess the safety and efficacy of this regimen in South Africa. METHODS We enrolled and randomized 5,404 healthy, HIV-uninfected 18-35-year olds at 14 sites to vaccine (2,704 participants) or placebo (2,700 participants) between 26 October 2016 and 21 June 2019. The vaccine regimen consisted of two ALVAC-HIV (vCP2438) (expressing HIV-1 subtype C env, clade B gp41 , gag and pro) immunizations at months 0 and 1, with booster immunizations of ALVAC-HIV plus bivalent subtype C gp120 protein/MF59 adjuvant at months 3, 6, 12 and 18. Efficacy was evaluated by HIV testing every 3 months. RESULTS In January 2020, pre-specified non-efficacy criteria were met at an interim analysis; further vaccinations were subsequently halted. The vaccines were safe and well-tolerated in the study population (median age 24, 70% female-sex-at-birth). Over the primary 24-month follow-up, there were 133 infections among placebo recipients and 138 among vaccinees (hazard ratio = 1.02; 95%CI, 0.81-1.30; P=0.84). Pre-specified subgroup analyses demonstrated no difference in efficacy by sex or when restricting to follow-up post-4 th vaccination, and no difference amongst female-sex-at-birth by age, BMI, prevalent STIs, behavioral risk score or region. CONCLUSIONS The ALVAC/gp120 regimen did not prevent HIV infection in South Africans despite prior evidence of immunogenicity. ClinicalTrials.gov (NCT02968849)

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Background The Phambili study, conducted in South Africa amongst a predominantly heterosexual population, evaluated the efficacy of the MRK Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine. Enrollment and vaccinations were stopped, participants unblinded, and follow-up extended when the Step study evaluating the same vaccine in the Americas, Caribbean and Australia was unblinded for non-efficacy with more HIV infections amongst vaccinee than placebo recipients [ZM1]. Extensive analyses over the complete follow-up period, most of which was unblinded, are reported. Methods Phambili participants were HIV-1 uninfected, sexually active men and women aged 18–35 years, followed for 3.5 years. HIV testing and risk reduction counseling occurred at weeks 0, 12, 30 and were switched to a 3 monthly schedule after unblinding. Cox proportional hazards models were used to estimate HIV-1 infection hazard ratios (HR) comparing vaccine to placebo recipients, overall and within subgroups. Long-term vaccine efficacy was evaluated in participants who were unblinded early in follow-up. Results Of the 801 participants enrolled (400 vaccine, 401 placebo), 112 (28%) received 1 vaccination, 259 (65%) 2 vaccinations and 29(7%) 3 vaccinations. More infections occurred in vaccinees (n=63) as compared to placebo (n=37) (adjusted HR (vaccine:placebo) 1.70, 95% CI 1.13–2.55, p = 0.01). We found no increase in infections with the number of vaccinations received and that the HRs did not differ by gender, circumcision, or Ad5 serostatus. Differences in risk behavior at baseline or during the study, or differential drop-out (p=0.40) are unlikely explanations for the increased rate of HIV-1 infections seen in vaccinees. Conclusion The increased HR of HIV-1 acquisition, irrespective of number of doses received, warrants further investigation to understand the biological mechanism. Further use of the Ad5 vector for HIV vaccines is not warranted

Neonatal candidaemia is a common, deadly and costly hospital-associated disease. To determine the genetic diversity of Candida parapsilosis causing fungaemia in South African neonatal intensive care units (NICUs). From February 2009 through to August 2010, cases of candidaemia were reported through laboratory-based surveillance. C. parapsilosis isolates from neonatal cases were submitted for identification by internal transcribed spacer (ITS) region sequencing, antifungal susceptibility testing and microsatellite genotyping. Cluster analysis was performed using Unweighted Pair Group Method with Arithmetic Mean (UPGMA). Of 1671 cases with a viable Candida isolate, 393 (24%) occurred among neonates. Isolates from 143 neonatal cases were confirmed as C. parapsilosis sensu stricto. Many isolates were resistant to fluconazole (77/143; 54%) and voriconazole (20/143; 14%). Of 79 closely-related genotypes, 18 were represented by ≥2 isolates; 61 genotypes had a single isolate each. Seven clusters, comprised of 82 isolates, were identified at five hospitals in three provinces. Isolates belonging to certain clusters were significantly more likely to be fluconazole resistant: all cluster 7 isolates and the majority of cluster 4 (78%), 5 (89%) and 6 (67%) isolates (P<.001). Candida parapsilosis-associated candidaemia in public-sector NICUs was caused by closely related genotypes and there was molecular evidence of undetected outbreaks as well as intra-hospital transmission.

While dedicated adolescent SRHS might best meet the needs of young people in SA, the study suggests that failing this, existing SRHS should be more responsive to adolescent use. Innovations such as mobile outreach services, self-testing and flexible hours will help SRHS respond to adolescents' needs.

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