Symptoms of post-traumatic stress and associations with sexual behaviour and PrEP preferences among young people in South Africa, Uganda and Zimbabwe.

BACKGROUND: It is not known whether post-traumatic stress disorder (PTSD) increases HIV-risk behaviours among young people in sub-Saharan Africa. We assessed associations of PTSD symptoms with sexual behaviour, HIV risk perception, and attitudes towards PrEP among young people taking part in the CHAPS community survey. We hypothesised that PTSD symptoms would increase sexual behaviours associated with HIV risk, hinder PrEP uptake and influence preference for daily versus on-demand PrEP. METHODS: Young people without HIV, aged 13-24 years, were purposively recruited in Johannesburg and Cape Town in South Africa, Wakiso in Uganda, and Chitungwiza in Zimbabwe, and surveyed on socio-demographic characteristics, PrEP knowledge and attitudes, sexual behaviour, HIV perception and salience, and mental health. PTSD symptoms were measured using the Primary Care PTSD Screen for the Diagnostic and Statistical Manual of Mental Disorders 5 (PC-PTSD-5). Logistic and ordinal logistic regression was used to assess associations between PC-PTSD-5 score and socio-demographic characteristics, sexual behaviour, HIV risk perception, PrEP attitudes, and substance use, adjusting for age, sex, setting, depression and anxiety. RESULTS: Of 1330 young people (51% male, median age 19 years), 522 (39%) reported at least one PTSD symptom. There was strong evidence that having a higher PC-PTSD-5 score was associated with reported forced sex (OR 3.18, 95%CI: 2.05-4.93), self-perception as a person who takes risks (OR 1.12, 95%CI: 1.04-1.20), and increased frequency of thinking about risk of HIV acquisition (OR 1.16, 95%CI: 1.08-1.25). PTSD symptoms were not associated with willingness to take PrEP, preference for on-demand versus daily PrEP, or actual HIV risk behaviour such as condomless sex. CONCLUSIONS: Symptoms consistent with probable PTSD were common among young people in South Africa, Uganda and Zimbabwe but did not impact PrEP attitudes or PrEP preferences. Evaluation for PTSD might form part of a general assessment in sexual and reproductive health services in these countries. More work is needed to understand the impact of PTSD on HIV-risk behaviour, forced sex and response to preventive strategies including PrEP

SARS-CoV-2 Beta and Delta variants trigger Fc effector function with increased cross-reactivity

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern (VOCs) exhibit escape from neutralizing antibodies, causing concern about vaccine effectiveness. However, while non-neutralizing cytotoxic functions of antibodies are associated with improved disease outcome and vaccine protection, Fc effector function escape from VOCs is poorly defined. Furthermore, whether VOCs trigger Fc functions with altered specificity, as has been reported for neutralization, is unknown. Here, we demonstrate that the Beta VOC partially evades Fc effector activity in individuals infected with the original (D614G) variant. However, not all functions are equivalently affected, suggesting differential targeting by antibodies mediating distinct Fc functions. Furthermore, Beta and Delta infection trigger responses with significantly improved Fc cross-reactivity against global VOCs compared with D614G-infected or Ad26.COV2.S-vaccinated individuals. This suggests that, as for neutralization, the infecting spike sequence affects Fc effector function. These data have important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader Fc effector responses.The EDCTP2 program of the European Union’s Horizon 2020 program, Wellcome Centre for Infectious Diseases Research in Africa, the SA-MRC, MRC UK, NRF, the Lily and Ernst Hausmann Trust, the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa, the SA Medical Research Council SHIP program, the Center for the AIDS Program of Research (CAPRISA) and an L’Oreal/UNESCO Women in Science South Africa Young Talents award.http://www.cell.com/cell-host-microbe/homeam2023ImmunologyInternal Medicin

Pregnancy Incidence and Correlates during the HVTN 503 Phambili HIV Vaccine Trial Conducted among South African Women

HIV prevention trials are increasingly being conducted in sub-Saharan Africa. Women at risk for HIV are also at risk of pregnancy. To maximize safety, women agree to avoid pregnancy during trials, yet pregnancies occur. Using data from the HVTN 503/"Phambili" vaccine trial, we report pregnancy incidence during and after the vaccination period and identify factors, measured at screening, associated with incident pregnancy.To enrol in the trial, women agreed and were supported to avoid pregnancy until 1 month after their third and final vaccination ("vaccination period"), corresponding to the first 7 months of follow-up. Unsterilized women, pooled across study arms, were analyzed. Poisson regression compared pregnancy rates during and after the vaccination period. Cox proportional hazards regression identified associations with first pregnancy.Among 352 women (median age 23 yrs; median follow-up 1.5 yrs), pregnancy incidence was 9.6/100 women-years overall and 6.8/100 w-yrs and 11.3/100 w-yrs during and after the vaccination period, respectively [Rate Ratio = 0.60 (0.32-1.14), p = 0.10]. In multivariable analysis, pregnancy was reduced among women who: enrolled at sites providing contraception on-site [HR = 0.43, 95% CI (0.22-0.86)]; entered the trial as injectable contraceptive users [HR = 0.37 (0.21-0.67)] or as consistent condom users (trend) [HR = 0.54 (0.28-1.04)]. Compared with women with a single partner of HIV-unknown status, pregnancy rates were increased among women with: a single partner whose status was HIV-negative [HR = 2.34(1.16-4.73)] and; 2 partners both of HIV-unknown status [HR = 4.42(1.59-12.29)]. Women with 2 more of these risk factors: marijuana use, heavy drinking, or use of either during sex, had increased pregnancy incidence [HR = 2.66 (1.24-5.72)].It is possible to screen South African women for pregnancy risk at trial entry. Providing injectable contraception for free on-site and supporting consistent condom use may reduce incident pregnancy. Screening should determine the substance use, partnering, and HIV status of both members of the couple for both pregnancy and HIV prevention.SA National Health Research Database DOH-27-0207-1539; Clinicaltrials.gov NCT00413725

Ad26.COV2.S breakthrough infections induce high titers of neutralizing antibodies against Omicron and other SARS-CoV-2 variants of concern

The Janssen (Johnson & Johnson) Ad26.COV2.S non-replicating viral vector vaccine has been widely deployed for COVID-19 vaccination programs in resource-limited settings. Here we confirm that neutralizing and binding antibody responses to Ad26.COV2.S vaccination are stable for 6 months post-vaccination, when tested against multiple SARS-CoV-2 variants. Secondly, using longitudinal samples from individuals who experienced clinically mild breakthrough infections 4 to 5 months after vaccination, we show dramatically boosted binding antibodies, Fc effector function, and neutralization. These high titer responses are of similar magnitude to humoral immune responses measured in convalescent donors who had been hospitalized with severe illness, and are cross-reactive against diverse SARS-CoV-2 variants, including the neutralizationresistant Omicron (B.1.1.529) variant that currently dominates global infections, as well as SARS-CoV-1. These data have implications for population immunity in areas where the Ad26.COV2.S vaccine has been widely deployed, but where ongoing infections continue to occur at high levels.The South African Medical Research Council, the South African Research Chairs Initiative of the Department of Science and Innovation; the National Research Foundation of South Africa, the EDCTP2 program of the European Union’s Horizon 2020 program, the Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), which is supported by core funding from the Wellcome Trust and the Poliomyelitis Research Foundation, MRC UK, NRF, the Lily and Ernst Hausmann Trust and L’Oreal/Unesco Women in Science South Africa Young Talents awardee.http://www.cell.com/cell-host-microbe/homeImmunologyInternal Medicin

Intra- and Inter-clade Cross-reactivity by HIV-1 Gag Specific T-Cells Reveals Exclusive and Commonly Targeted Regions: Implications for Current Vaccine Trials

The genetic diversity of HIV-1 across the globe is a major challenge for developing an HIV vaccine. To facilitate immunogen design, it is important to characterize clusters of commonly targeted T-cell epitopes across different HIV clades. To address this, we examined 39 HIV-1 clade C infected individuals for IFN-γ Gag-specific T-cell responses using five sets of overlapping peptides, two sets matching clade C vaccine candidates derived from strains from South Africa and China, and three peptide sets corresponding to consensus clades A, B, and D sequences. The magnitude and breadth of T-cell responses against the two clade C peptide sets did not differ, however clade C peptides were preferentially recognized compared to the other peptide sets. A total of 84 peptides were recognized, of which 19 were exclusively from clade C, 8 exclusively from clade B, one peptide each from A and D and 17 were commonly recognized by clade A, B, C and D. The entropy of the exclusively recognized peptides was significantly higher than that of commonly recognized peptides (p = 0.0128) and the median peptide processing scores were significantly higher for the peptide variants recognized versus those not recognized (p = 0.0001). Consistent with these results, the predicted Major Histocompatibility Complex Class I IC50 values were significantly lower for the recognized peptide variants compared to those not recognized in the ELISPOT assay (p<0.0001), suggesting that peptide variation between clades, resulting in lack of cross-clade recognition, has been shaped by host immune selection pressure. Overall, our study shows that clade C infected individuals recognize clade C peptides with greater frequency and higher magnitude than other clades, and that a selection of highly conserved epitope regions within Gag are commonly recognized and give rise to cross-clade reactivities

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis

Background Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in “real-life” settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. Methods and findings Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5–5.2) years for the total cohort and 6.4 (3.6–8.0) years in Europe, 3.7 (2.0–5.4) years in North America, 2.5 (1.2–4.4) years in South and Southeast Asia, 5.0 (2.7–7.5) years in South America and the Caribbean, and 2.1 (0.9–3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3–2.1) years in North America to 7.1 (5.3–8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4–2.6) years in North America to 7.9 (6.0–9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%–2.8%), 15.6% (15.1%–16.0%), and 11.3% (10.9%–11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%–1.1%]) and highest in South America and the Caribbean (4.4% [3.1%–6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%–6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%–13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. Conclusion To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses

Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages

Generalist and specialist species differ in the breadth of their ecological niches. Little is known about the niche width of obligate human pathogens. Here we analyzed a global collection of Mycobacterium tuberculosis lineage 4 clinical isolates, the most geographically widespread cause of human tuberculosis. We show that lineage 4 comprises globally distributed and geographically restricted sublineages, suggesting a distinction between generalists and specialists. Population genomic analyses showed that, whereas the majority of human T cell epitopes were conserved in all sublineages, the proportion of variable epitopes was higher in generalists. Our data further support a European origin for the most common generalist sublineage. Hence, the global success of lineage 4 reflects distinct strategies adopted by different sublineages and the influence of human migration.We thank S. Lecher, S. Li and J. Zallet for technical support. Calculations were performed at the sciCORE scientific computing core facility at the University of Basel. This work was supported by the Swiss National Science Foundation (grants 310030_166687 (S.G.) and 320030_153442 (M.E.) and Swiss HIV Cohort Study grant 740 to L.F.), the European Research Council (309540-EVODRTB to S.G.), TB-PAN-NET (FP7-223681 to S.N.), PathoNgenTrace projects (FP7-278864-2 to S.N.), SystemsX.ch (S.G.), the German Center for Infection Research (DZIF; S.N.), the Novartis Foundation (S.G.), the Natural Science Foundation of China (91631301 to Q.G.), and the National Institute of Allergy and Infectious Diseases (5U01-AI069924-05) of the US National Institutes of Health (M.E.)

Trust in the provider and accurate self-reported PrEP adherence among adolescent girls and young women in South Africa and Zimbabwe: HPTN 082 study

Abstract Background Trust is an important cornerstone of patient-provider communication. Accurate reporting of pre-exposure prophylaxis (PrEP) adherence is vital for providers to determine who needs adherence support, especially adolescent girls and young women (AGYW) disproportionately affected by newly diagnosed HIV. Methods This is a secondary analysis of the HPTN 082 open-label PrEP demonstration trial. From 2016–2018, 451 AGYW aged 16–25 years were enrolled in South Africa (Cape Town and Johannesburg) and Zimbabwe (Harare). PrEP was initiated by 427, and 354 (83%) had month three patient-reported adherence responses and intracellular tenofovir diphosphate (TFV-DP) measurements. The patient-reported adherence response to ‘In the past month, how often did you take the tablet?’ was dichotomized as ‘high’ if the response was every day or most days, and ‘low’ if some days or not many days or never. The biomarker marker evidence of adherence in dried blood spots was defined as ‘high’ if TFV-DP ≥ 700, and ‘low’ if < 350 fmol/punch. We used multinomial logistic regression to examine if trust in the PrEP provider was associated with concordance between patient-reported adherence and intracellular tenofovir-diphosphate (TFV-DP). Results AGYW who reported trust in their providers were almost four-fold (aOR 3.72, 95% CI 1.20–11.51) more likely to have concordant adherence (high self-reported adherence and high TFV-DP concentrations) compared to discordant non-adherence (high self-reported adherence and low TFV-DP concentrations). Conclusion Education and training of providers to build trusting relationships with AGYW may lead to more accurate reporting of PrEP adherence. With accurate reporting, adequate support can be provided to bolster adherence. Trial registration ClinicalTrials.gov Identifier: NCT02732730