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Biomarkers that predict who among recently Mycobacterium tuberculosis (MTB)-exposed individuals will progress to active tuberculosis are urgently needed. Intracellular microRNAs (miRNAs) regulate the host response to MTB and circulating miRNAs (c-miRNAs) have been developed as biomarkers for other diseases. We performed machine-learning analysis of c-miRNA measurements in the serum of adult household contacts (HHCs) of TB index cases from South Africa and Uganda and developed a c-miRNA-based signature of risk for progression to active TB. This c-miRNA-based signature significantly discriminated HHCs within 6 months of progression to active disease from HHCs that remained healthy in an independent test set [ROC area under the ROC curve (AUC) 0.74, progressors

Resumo: Estudo realizado na Ãfrica do Sul com o objectivo de comparar a incidência de tuberculose durante os 2 primeiros anos de vida em crianças vacinadas à nascença com a administração intradérmica ou percutâ-nea de BCG. A OMS recomenda a vacinação intradérmica, mas a administração preferencial na Ãfrica do Sul até 1999 continuou a ser a percutânea, altura em que o departamento nacional de saúde adoptou a recomendação da OMS. Esta é uma das razões que levou os autores a comparar a eficácia e a segurança das duas formas de administração da vacina. Participaram no estudo 11 680 recém-nascidos, 5775 receberam a vacina por via percutânea e 5905 por via intradérmica. Pretendiase avaliar em primeiro lugar casos de tuber-culose documentados pelo isolamento de M. tuberculosis, ou evidência clínica e radiológica, expressos como incidência cumulativa e, em segundo lugar, a frequência de efeitos adversos, internamentos hospitares por tuberculose ou outras causas e mortalidade. Os autores criaram um algoritmo diagnóstico de tuberculose definindo caso definitivo, caso provável e caso possível, de que se realçam algumas características:Caso definitivo â microbiologia com cultura positiva e sonda de PCR positivo. Caso provável â Radiografa de tórax e clínica compatíveis (excepto baixo peso ou perda e peso recente, se infectacção VIH presente)Caso possível â Radiografia compatível mas sem clínica sugestiva, ou vice-versa. O objectivo primário do estudo demonstrou: ⢠Equivalência das duas vias e administração na incidência cumulativa das três apresentações de casos de tuberculose, conforme definidos. O número acumulado de recém-nascidos com BCG e tuberculose (três formas definidas) nos primeiros 2 anos de vida, diagnosticada em internamento hospital, foi de 362 nos casos com vacinação intradérmica e de 376 com vacinação percutânea. ⢠Ocorrência de alguns casos de tuberculose disseminada, sem diferença estatística entre a via de administração. A meningite tuberculosa ocorreu em três crianças com vacinação intradérmica e em uma com vacinação percutânea. A tuberculose miliar ocorreu apenas em uma criança com vacinação percutânea, assim como um caso de tuberculose abdominal e outro vertebral. Quanto aos resultados secundários: ⢠O total de 2180 crianças foi internado neste intervalo de tempo, com icidência cumulativa semelhante entre os 2 grupos; ⢠A mortalidade teve uma incidência cumulativa de 1,59%, 102 crianças no grupo com vacinação intradérmica e 84 percutâea. Nenhum caso se relacionou com a intervenção, nem a tuberculose foi considerada causa directa de morte; ⢠Reacções adversas significativas foram encontradas em 21 casos, sem diferença significativa entre os 2 grupos. Destas, 16 casos de quelóides (10 no grupo de vacinação intradérmica e 6 na percutânea) e 5 casos de linfadenite axilar supurativa (2 no grupo de vacinação intradérmica e 3 na percutânea). Num caso com imunodeficiência primária vacinado por via percutânea, surgiu BCG disseminada. Os autores concluem que foi encontrada equivalência entre a vacinação BCG intradérmica e percutânea relativamente à incidência de tuberculose num grupo de crianças vacinadas à nascença e seguidas durante 2 anos, sem diferença de segurança entre ambas. Suge-rem que a OMS reveja a política preferencial de vacinação intradérmica, permitindo os programas nacionais de vacinação escolherem a via percutânea se a considerarem mais prática.

Background: Growing evidence suggests that chronic inflammation caused by tuberculosis (TB) may increase the incidence of diabetes. However, the relationship between post-TB pulmonary abnormalities and diabetes has not been well characterized., Methods: We analyzed data from a cross-sectional study in KwaZulu-Natal, South Africa, of people 15 years and older who underwent chest X-ray and diabetes screening with hemoglobin A1c testing. The analytic sample was restricted to persons with prior TB, defined by either (1) a self-reported history of TB treatment, (2) radiologist-confirmed prior TB on chest radiography, and (3) a negative sputum culture and GeneXpert. Chest X-rays of all participants were evaluated by the study radiologist to determine the presence of TB lung abnormalities. To assess the relationships between our outcome of interest, prevalent diabetes (HBA1c ≥6.5%), and our exposure of interest, chest X-ray abnormalities, we fitted logistic regression models adjusted for potential clinical and demographic confounders. In secondary analyses, we used the computer-aided detection system CAD4TB, which scores X-rays from 10 to 100 for detection of TB disease, as our exposure interest, and repeated analyses with a comparator group that had no history of TB disease., Results: In the analytic cohort of people with prior TB (n = 3,276), approximately two-thirds (64.9%) were women, and the average age was 50.8 years (SD 17.4). The prevalence of diabetes was 10.9%, and 53.0% of people were living with HIV. In univariate analyses, there was no association between diabetes prevalence and radiologist chest X-ray abnormalities (OR 1.23, 95%CI 0.95-1.58). In multivariate analyses, the presence of pulmonary abnormalities was associated with an 29% reduction in the odds of prevalent diabetes (aOR 0.71, 95%CI 0.53-0.97, p = 0.030). A similar inverse relationship was observed for diabetes with each 10-unit increase in the CAD4TB chest X-ray scores among people with prior TB (aOR 0.92, 95%CI 0.87-0.97; p = 0.002), but this relationship was less pronounced in the no TB comparator group (aOR 0.96, 95%CI 0.94-0.99)., Conclusions: Among people with prior TB, pulmonary abnormalities on digital chest X-ray are inversely associated with prevalent diabetes. The severity of radiographic post-TB lung disease does not appear to be a determinant of diabetes in this South African population., (© 2024. The Author(s).)

Despite expanded antiretroviral therapy (ART) in South Africa, HIV-1 transmission persists. Integrase strand transfer inhibitors (INSTI) and long-acting injectables offer potential for superior viral suppression, but pre-existing drug resistance could threaten their effectiveness. In a community-based study in rural KwaZulu-Natal, prior to widespread INSTI usage, we enroled 18,025 individuals to characterise HIV-1 drug resistance and transmission networks to inform public health strategies. HIV testing and reflex viral load quantification were performed, with deep sequencing (20% variant threshold) used to detect resistance mutations. Phylogenetic and geospatial analyses characterised transmission clusters. One-third of participants were HIV-positive, with 21.7% having detectable viral loads; 62.1% of those with detectable viral loads were ART-naïve. Resistance to older reverse transcriptase (RT)-targeting drugs was found, but INSTI resistance remained low (<1%). Non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, particularly to rilpivirine (RPV) even in ART-naïve individuals, was concerning. Twenty percent of sequenced individuals belonged to transmission clusters, with geographic analysis highlighting higher clustering in peripheral and rural areas. Our findings suggest promise for INSTI-based strategies in this setting but underscore the need for RPV resistance screening before implementing long-acting cabotegravir (CAB) + RPV. The significant clustering emphasises the importance of geographically targeted interventions to effectively curb HIV-1 transmission., (© 2024. The Author(s).)

SARS-CoV-2 clearance requires adaptive immunity but the contribution of neutralizing antibodies and T cells in different immune states is unclear. Here we ask which adaptive immune responses associate with clearance of long-term SARS-CoV-2 infection in HIV-mediated immunosuppression after suppressive antiretroviral therapy (ART) initiation. We assembled a cohort of SARS-CoV-2 infected people in South Africa (n = 994) including participants with advanced HIV disease characterized by immunosuppression due to T cell depletion. Fifty-four percent of participants with advanced HIV disease had prolonged SARS-CoV-2 infection (>1 month). In the five vaccinated participants with advanced HIV disease tested, SARS-CoV-2 clearance associates with emergence of neutralizing antibodies but not SARS-CoV-2 specific CD8 T cells, while CD4 T cell responses were not determined due to low cell numbers. Further, complete HIV suppression is not required for clearance, although it is necessary for an effective vaccine response. Persistent SARS-CoV-2 infection led to SARS-CoV-2 evolution, including virus with extensive neutralization escape in a Delta variant infected participant. The results provide evidence that neutralizing antibodies are required for SARS-CoV-2 clearance in HIV-mediated immunosuppression recovery, and that suppressive ART is necessary to curtail evolution of co-infecting pathogens to reduce individual health consequences as well as public health risk linked with generation of escape mutants., (© 2024. The Author(s).)

Competing Interests: Potential conflicts of interest . The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

Background: Understanding how HIV affects SARS-CoV-2 immunity is crucial for managing COVID-19 in sub-Saharan populations due to frequent coinfections. Our previous research showed that unsuppressed HIV is associated with weaker immune responses to SARS-CoV-2, but the underlying mechanisms are unclear. We investigated how pre-existing T cell immunity against an endemic human coronavirus HCoV-NL63 impacts SARS-CoV-2 T cell responses in people living with HIV (PLWH) compared to uninfected individuals, and how HIV-related T cell dysfunction influences responses to SARS-CoV-2 variants., Methods: We used flow cytometry to measure T cell responses following PBMC stimulation with peptide pools representing beta, delta, wild-type, and HCoV-NL63 spike proteins. Luminex bead assay was used to measure circulating plasma chemokine and cytokine levels. ELISA and MSD V-PLEX COVID-19 Serology and ACE2 Neutralization assays were used to measure humoral responses., Results: Regardless of HIV status, we found a strong positive correlation between responses to HCoV-NL63 and SARS-CoV-2. However, PLWH exhibited weaker CD4 + T cell responses to both HCoV-NL63 and SARS-CoV-2 than HIV-uninfected individuals. PLWH also had higher proportions of functionally exhausted (PD-1high) CD4 + T cells producing fewer proinflammatory cytokines (IFNγ and TNFα) and had elevated plasma IL-2 and IL-12(p70) levels compared to HIV-uninfected individuals. HIV status didn't significantly affect IgG antibody levels against SARS-CoV-2 antigens or ACE2 binding inhibition activity., Conclusion: Our results indicate that the decrease in SARS-CoV-2 specific T cell responses in PLWH may be attributable to reduced frequencies of pre-existing cross-reactive responses. However, HIV infection minimally affected the quality and magnitude of humoral responses, and this could explain why the risk of severe COVID-19 in PLWH is highly heterogeneous., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ng’uni, Musale, Nkosi, Mandolo, Mvula, Michelo, Karim, Moosa, Khan, Jambo, Hanekom, Sigal, Kilembe and Ndhlovu.)

Tuberculosis (TB) is a global health emergency. Across the globe, approximately 2 billion people are currently infected with Mycobacterium tuberculosis (Mtb), and of those, 5-10% may progress to become ill and potentially transmit the bacterium. In 2021, nearly 10.6 million people developed TB disease and 1.6 million died. There is an urgent need for accelerated development of new TB-focused interventions, in particular, improved TB vaccines. However, progress in developing highly effective TB vaccines has been slow and is chronically under-resourced. The mRNA vaccine platform may offer an opportunity to accelerate development of new TB vaccines. In April 2023, the World Health Organization convened global experts to discuss the feasibility and potential value of mRNA-based vaccines for TB. Here we report on meeting deliberations related to the current TB vaccine pipeline and potential novel antigens, the status of efforts to identify correlates of protection, potential clinical development strategies and considerations for community acceptance of new TB vaccines based on this relatively new platform. The role of industry collaborations, ethics, social science, and responsibility to the global community regarding transparency and manufacturing capacity building were discussed through expert presentations and panel sessions. The overall conclusion of the meeting is that mRNA-based vaccines constitute a potentially powerful new tool for reducing the global burden of TB., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Monika M. Looney reports financial support was provided by World Health Organization. Munyaradzi Musvosvi & Thomas J. Scriba reports a relationship with mRNA Technology Transfer Programme that includes: funding grants. Munyaradzi Musvosvi & Thomas J. Scriba has patent pending to University Of the Witwatersrand, Johannesburg; University Of Cape Town; The Board of Trustees of the Leland Stanford Junior University. James Southern is employed by the South African Health Products Regulatory Authority as an evaluator of medicines, (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The convergence of infectious diseases and non-communicable diseases in South Africa is challenging to health systems. In this analysis, we assessed the multimorbidity health needs of individuals and communities in rural KwaZulu-Natal and established a framework to quantify met and unmet health needs for individuals living with infectious and non-communicable diseases., Methods: We analysed data collected between May 25, 2018, and March 13, 2020, from participants of a large, community-based, cross-sectional multimorbidity survey (Vukuzazi) that offered community-based HIV, hypertension, and diabetes screening to all residents aged 15 years or older in a surveillance area in the uMkhanyakude district in KwaZulu-Natal, South Africa. Data from the Vukuzazi survey were linked with data from demographic and health surveillance surveys with a unique identifier common to both studies. Questionnaires were used to assess the diagnosed health conditions, treatment history, general health, and sociodemographic characteristics of an individual. For each condition (ie, HIV, hypertension, and diabetes), individuals were defined as having no health needs (absence of condition), met health needs (condition that is well controlled), or one or more unmet health needs (including diagnosis, engagement in care, or treatment optimisation). We analysed met and unmet health needs for individual and combined conditions and investigated their geospatial distribution., Findings: Of 18 041 participants who completed the survey (12 229 [67·8%] were female and 5812 [32·2%] were male), 9898 (54·9%) had at least one of the three chronic diseases measured. 4942 (49·9%) of these 9898 individuals had at least one unmet health need (1802 [18·2%] of 9898 needed treatment optimisation, 1282 [13·0%] needed engagement in care, and 1858 [18·8%] needed a diagnosis). Unmet health needs varied by disease; 1617 (93·1%) of 1737 people who screened positive for diabetes, 2681 (58·2%) of 4603 people who screened positive for hypertension, and 1321 (21·7%) of 6096 people who screened positive for HIV had unmet health needs. Geospatially, met health needs for HIV were widely distributed and unmet health needs for all three conditions had specific sites of concentration; all three conditions had an overlapping geographical pattern for the need for diagnosis., Interpretation: Although people living with HIV predominantly have a well controlled condition, there is a high burden of unmet health needs for people living with hypertension and diabetes. In South Africa, adapting current, widely available HIV care services to integrate non-communicable disease care is of high priority., Funding: Fogarty International Center and the National Institutes of Health, the Bill & Melinda Gates Foundation, the South African Department of Science and Innovation, the South African Medical Research Council, the South African Population Research Infrastructure Network, and the Wellcome Trust., Translation: For the isiZulu translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Antiretroviral therapy (ART) through universal test and treat (UTT) and HIV pre-exposure prophylaxis (PrEP) substantially reduces HIV-related mortality and incidence. Effective ART based prevention has not translated into population-level impact in southern Africa due to sub-optimal coverage among youth. We aim to investigate the effectiveness, implementation and cost effectiveness of peer-led social mobilisation into decentralised integrated HIV and sexual reproductive health (SRH) services amongst adolescents and young adults in KwaZulu-Natal (KZN)., Methods: We are conducting a type 1a hybrid effectiveness/implementation study, with a cluster randomized stepped-wedge trial (SWT) to assess effectiveness and a realist process evaluation to assess implementation outcomes. The SWT will be conducted in 40 clusters in rural KZN over 45 months. Clusters will be randomly allocated to receive the intervention in period 1 (early) or period 2 (delayed). 1) Intervention arm: Resident peer navigators in each cluster will approach young men and women aged 15-30 years living in their cluster to conduct health, social and educational needs assessment and tailor psychosocial support and health promotion, peer mentorship, and facilitate referrals into nurse led mobile clinics that visit each cluster regularly to deliver integrated SRH and differentiated HIV prevention (HIV testing, UTT for those positive, and PrEP for those eligible and negative). Standard of Care is UTT and PrEP delivered to 15-30 year olds from control clusters through primary health clinics. There are 3 co-primary outcomes measured amongst cross sectional surveys of 15-30 year olds: 1) effectiveness of the intervention in reducing the prevalence of sexually transmissible HIV; 2) uptake of universal risk informed HIV prevention intervention; 3) cost of transmissible HIV infection averted. We will use a realist process evaluation to interrogate the extent to which the intervention components support demand, uptake, and retention in risk-differentiated biomedical HIV prevention., Discussion: The findings of this trial will be used by policy makers to optimize delivery of universal differentiated HIV prevention, including HIV pre-exposure prophylaxis through peer-led mobilisation into community-based integrated adolescent and youth friendly HIV and sexual and reproductive health care., Trial Registration: ClinicalTrials.gov Identifier-NCT05405582. Registered: 6th June 2022., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Neutralizing antibodies strongly correlate with protection for COVID-19 vaccines, but the corresponding memory B cells that form to protect against future infection are relatively understudied. Here we examine the effect of prior SARS-CoV-2 infection on the magnitude and phenotype of the memory B cell response to single dose Johnson and Johnson (Ad26.COV2.S) vaccination in South African health care workers. Participants were either naïve to SARS-CoV-2 or had been infected before vaccination. SARS-CoV-2-specific memory B-cells expand in response to Ad26.COV2.S and are maintained for the study duration (84 days) in all individuals. However, prior infection is associated with a greater frequency of these cells, a significant reduction in expression of the germinal center chemokine receptor CXCR5, and increased class switching. These B cell features correlated with neutralization and antibody-dependent cytotoxicity (ADCC) activity, and with the frequency of SARS-CoV-2 specific circulating T follicular helper cells (cTfh). Vaccination-induced effective neutralization of the D614G variant in both infected and naïve participants but boosted neutralizing antibodies against the Beta and Omicron variants only in participants with prior infection. In addition, the SARS-CoV-2 specific CD8+ T cell response correlated with increased memory B cell expression of the lung-homing receptor CXCR3, which was sustained in the previously infected group. Finally, although vaccination achieved equivalent B cell activation regardless of infection history, it was negatively impacted by age. These data show that phenotyping the response to vaccination can provide insight into the impact of prior infection on memory B cell homing, CSM, cTfh, and neutralization activity. These data can provide early signals to inform studies of vaccine boosting, durability, and co-morbidities., (© 2023. Springer Nature Limited.)

This analysis investigates the relationship between drought and antiretroviral treatment (ART) adherence and retention in HIV care in the Hlabisa sub-district, KwaZulu-Natal, South Africa. Data on drought and ART adherence and retention were collated for the study period 2010-2019. Drought was quantified using the 3-month Standard Precipitation Evapotranspiration Index (SPEI) and Standard Precipitation Index (SPI) from station data. Adherence, proxied by the Medication Possession Ratio (MPR), and retention data were obtained from the public ART programme database. MPR and retention were calculated from individuals aged 15-59 years who initiated ART between January 2010 and December 2018 and visited clinic through February 2019. Between 01 January 2010 and 31 December 2018, 40,714 individuals started ART in the sub-district and made 1,022,760 ART visits. The SPI showed that 2014-2016 were dry years, with partial recovery after 2016 in the wet years. In the period from 2010 to 2012, mean 6-month MPR increased from 0.85 in July 2010 to a high of 0.92 in December 2012. MPR then decreased steadily through 2013 and 2014 to 0.78 by December 2014. The mean proportion retained in care 6 months after starting ART showed similar trends to MPR, increasing from 86.9% in July 2010 to 91.4% in December 2012. Retention then decreased through 2013, with evidence of a pronounced drop in January 2014 when the odds of retention decreased by 30% (OR = 0.70, CI = 0.53-0.92, P = 0.01) relative to the end of 2013. Adherence and retention in care decreased during the drought years., (© 2023. The Author(s).)

Approximately 10·6 million people worldwide develop tuberculosis each year, representing a failure in epidemic control that is accentuated by the absence of effective vaccines to prevent infection or disease in adolescents and adults. Without effective vaccines, tuberculosis prevention has relied on testing for Mycobacterium tuberculosis infection and treating with antibiotics to prevent progression to tuberculosis disease, known as tuberculosis preventive treatment (TPT). Novel tuberculosis vaccines are in development and phase 3 efficacy trials are imminent. The development of effective, shorter, and safer TPT regimens has broadened the groups eligible for TPT beyond people with HIV and child contacts of people with tuberculosis; future vaccine trials will be undertaken in an era of increased TPT access. Changes in the prevention standard will have implications for tuberculosis vaccine trials of disease prevention, for which safety and sufficient accrual of cases are crucial. In this paper, we examine the urgent need for trials that allow the evaluation of new vaccines and fulfil the ethical duty of researchers to provide TPT. We observe how HIV vaccine trials have incorporated preventive treatment in the form of pre-exposure prophylaxis, propose trial designs that integrate TPT, and summarise considerations for each design in terms of trial validity, efficiency, participant safety, and ethics., Competing Interests: Declaration of interests GC reports research funding from the US National Institutes of Health (NIH)/Division of AIDS (UM1AI068614, UM1AI068636, 5UM1AI154463). Since March, 2022, MQ has worked full time as an employee of Evidera, a commercial research organisation that receives funding to conduct research on behalf of private pharmaceutical companies; this research is unrelated to the topic of this Personal View. RGW acknowledges project funding from the Wellcome Trust (218261/Z/19/Z), NIH (1R01AI147321-01), European and Developing Countries Clinical Trials Partnership (RIA208D-2505B), UK Medical Research Council (CCF17-7779 via SET Bloomsbury), UK Economic and Social Research Council (ES/P008011/1), Bill & Melinda Gates Foundation (OPP1084276, OPP1135288 & INV-001754), and WHO (2020/985800-0). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may be associated with worse clinical outcomes in people with human immunodeficiency virus (HIV) (PWH). We report anti-SARS-CoV-2 antibody responses in patients hospitalized with coronavirus disease 2019 in Durban, South Africa, during the second SARS-CoV-2 infection wave dominated by the Beta (B.1.351) variant., Methods: Thirty-four participants with confirmed SARS-CoV-2 infection were followed up with weekly blood sampling to examine antibody levels and neutralization potency against SARS-CoV-2 variants. Participants included 18 PWH, of whom 11 were HIV viremic., Results: SARS-CoV-2-specific antibody concentrations were generally lower in viremic PWH than in virologically suppressed PWH and HIV-negative participants, and neutralization of the Beta variant was 4.9-fold lower in viremic PWH. Most HIV-negative participants and antiretroviral therapy-suppressed PWH also neutralized the Delta (B.1.617.2) variant, whereas the majority of viremic PWH did not. CD4 cell counts <500/μL were associated with lower frequencies of immunoglobulin G and A seroconversion. In addition, there was a high correlation between a surrogate virus neutralization test and live virus neutralization against ancestral SARS-CoV-2 virus in both PWH and HIV-negative individuals, but correlation decreased for the Beta variant neutralization in PWH., Conclusions: HIV viremia was associated with reduced Beta variant neutralization. This highlights the importance of HIV suppression in maintaining an effective SARS-CoV-2 neutralization response., Competing Interests: Potential conflicts of interest. C. W. T. and L. F. W. report the following issued patent: US patent 11054429 B1 (SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2-spike protein binding). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

New tuberculosis vaccine candidates that are in the development pipeline need to be studied in people with HIV, who are at high risk of acquiring Mycobacterium tuberculosis infection and tuberculosis disease and tend to develop less robust vaccine-induced immune responses. To address the gaps in developing tuberculosis vaccines for people with HIV, a series of symposia was held that posed six framing questions to a panel of international experts: What is the use case or rationale for developing tuberculosis vaccines? What is the landscape of tuberculosis vaccines? Which vaccine candidates should be prioritised? What are the tuberculosis vaccine trial design considerations? What is the role of immunological correlates of protection? What are the gaps in preclinical models for studying tuberculosis vaccines? The international expert panel formulated consensus statements to each of the framing questions, with the intention of informing tuberculosis vaccine development and the prioritisation of clinical trials for inclusion of people with HIV., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: HIV infection dysregulates the B cell compartment, affecting memory B cell formation and the antibody response to infection and vaccination. Understanding the B cell response to SARS-CoV-2 in people living with HIV (PLWH) may explain the increased morbidity, reduced vaccine efficacy, reduced clearance, and intra-host evolution of SARS-CoV-2 observed in some HIV-1 coinfections., Methods: We compared B cell responses to COVID-19 in PLWH and HIV negative (HIV-ve) patients in a cohort recruited in Durban, South Africa, during the first pandemic wave in July 2020 using detailed flow cytometry phenotyping of longitudinal samples with markers of B cell maturation, homing, and regulatory features., Results: This revealed a coordinated B cell response to COVID-19 that differed significantly between HIV-ve and PLWH. Memory B cells in PLWH displayed evidence of reduced germinal centre (GC) activity, homing capacity, and class-switching responses, with increased PD-L1 expression, and decreased Tfh frequency. This was mirrored by increased extrafollicular (EF) activity, with dynamic changes in activated double negative (DN2) and activated naïve B cells, which correlated with anti-RBD-titres in these individuals. An elevated SARS-CoV-2-specific EF response in PLWH was confirmed using viral spike and RBD bait proteins., Conclusions: Despite similar disease severity, these trends were highest in participants with uncontrolled HIV, implicating HIV in driving these changes. EF B cell responses are rapid but give rise to lower affinity antibodies, less durable long-term memory, and reduced capacity to adapt to new variants. Further work is needed to determine the long-term effects of HIV on SARS-CoV-2 immunity, particularly as new variants emerge., Funding: This work was supported by a grant from the Wellcome Trust to the Africa Health Research Institute (Wellcome Trust Strategic Core Award [grant number 201433/Z/16/Z]). Additional funding was received from the South African Department of Science and Innovation through the National Research Foundation (South African Research Chairs Initiative [grant number 64809]), and the Victor Daitz Foundation., Competing Interests: RK, JS, HS, DM, FK, YG, AN, YZ, IG, MB, KK, MM, NM, DR, OL, JJ, DS, IW, AS, HK, TN, AL No competing interests declared, WH Reviewing editor, eLife, (© 2022, Krause et al.)

Objectives: Population-based universal test and treat (UTT) trials have shown an impact on population-level virological suppression. We followed the ANRS 12249 TasP trial population for 6 years to determine whether the intervention had longer-term survival benefits., Methods: The TasP trial was a cluster-randomized trial in South Africa from 2012 to 2016. All households were offered 6-monthly home-based HIV testing. Immediate antiretroviral therapy (ART) was offered through trial clinics to all people living with HIV (PLHIV) in intervention clusters and according to national guidelines in control clusters. After the trial, individuals attending the trial clinics were transferred to the public ART programme. Deaths were ascertained through annual demographic surveillance. Random-effects Poisson regression was used to estimate the effect of trial arm on mortality among (i) all PLHIV; (ii) PLHIV aware of their status and not on ART at trial entry; and (iii) PHLIV who started ART during the trial., Results: Mortality rates among PLHIV were 9.3/1000 and 10.4/1000 person-years in the control and intervention arms, respectively. There was no evidence that the intervention decreased mortality among all PLHIV [adjusted rate ratio (aRR) = 1.10, 95% confidence interval (CI) = 0.85-1.43, p = 0.46] or among PLHIV who were aware of their status but not on ART. Among individuals who initiated ART, the intervention decreased mortality during the trial (aRR = 0.49, 95% CI = 0.28-0.85, p = 0.01), but not after the trial ended., Conclusions: The 'treat all' strategy reduced mortality among individuals who started ART but not among all PLHIV. To achieve maximum benefit of immediate ART, barriers to ART uptake and retention in care need to be addressed., (© 2022 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: People living with HIV (PLWH) have been reported to have a higher risk of more severe COVID-19 disease and death. We assessed the ability of the Ad26.CoV2.S vaccine to elicit neutralizing activity against the Delta variant in PLWH relative to HIV-negative individuals. We also examined effects of HIV status and suppression on Delta neutralization response in SARS-CoV-2-infected unvaccinated participants., Methods: We enrolled participants who were vaccinated through the SISONKE South African clinical trial of the Ad26.CoV2.S vaccine in healthcare workers (HCWs). PLWH in this group had well-controlled HIV infection. We also enrolled unvaccinated participants previously infected with SARS-CoV-2. Neutralization capacity was assessed by a live virus neutralization assay of the Delta variant., Results: Most Ad26.CoV2.S vaccinated HCWs were previously infected with SARS-CoV-2. In this group, Delta variant neutralization was 9-fold higher compared with the infected-only group and 26-fold higher relative to the vaccinated-only group. No decrease in Delta variant neutralization was observed in PLWH relative to HIV-negative participants. In contrast, SARS-CoV-2-infected, unvaccinated PLWH showed 7-fold lower neutralization and a higher frequency of nonresponders, with the highest frequency of nonresponders in people with HIV viremia. Vaccinated-only participants showed low neutralization capacity., Conclusions: The neutralization response of the Delta variant following Ad26.CoV2.S vaccination in PLWH with well-controlled HIV was not inferior to HIV-negative participants, irrespective of past SARS-CoV-2 infection. In SARS-CoV-2-infected and nonvaccinated participants, HIV infection reduced the neutralization response to SARS-CoV-2, with the strongest reduction in HIV viremic individuals., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

SARS-CoV-2 Omicron (B.1.1.529) BA.4 and BA.5 sub-lineages, first detected in South Africa, have changes relative to Omicron BA.1 including substitutions in the spike receptor binding domain. Here we isolated live BA.4 and BA.5 viruses and measured BA.4/BA.5 neutralization elicited by BA.1 infection either in the absence or presence of previous vaccination as well as from vaccination without BA.1 infection. In BA.1-infected unvaccinated individuals, neutralization relative to BA.1 declines 7.6-fold for BA.4 and 7.5-fold for BA.5. In vaccinated individuals with subsequent BA.1 infection, neutralization relative to BA.1 decreases 3.2-fold for BA.4 and 2.6-fold for BA.5. The fold-drop versus ancestral virus neutralization in this group is 4.0-fold for BA.1, 12.9-fold for BA.4, and 10.3-fold for BA.5. In contrast, BA.4/BA.5 escape is similar to BA.1 in the absence of BA.1 elicited immunity: fold-drop relative to ancestral virus neutralization is 19.8-fold for BA.1, 19.6-fold for BA.4, and 20.9-fold for BA.5. These results show considerable escape of BA.4/BA.5 from BA.1 elicited immunity which is moderated with vaccination and may indicate that BA.4/BA.5 may have the strongest selective advantage in evading neutralization relative to BA.1 in unvaccinated, BA.1 infected individuals., (© 2022. The Author(s).)

In some instances, unsuppressed HIV has been associated with severe COVID-19 disease, but the mechanisms underpinning this susceptibility are still unclear. Here, we assessed the impact of HIV infection on the quality and epitope specificity of SARS-CoV-2 T cell responses in the first wave and second wave of the COVID-19 epidemic in South Africa. Flow cytometry was used to measure T cell responses following peripheral blood mononuclear cell stimulation with SARS-CoV-2 peptide pools. Culture expansion was used to determine T cell immunodominance hierarchies and to assess potential SARS-CoV-2 escape from T cell recognition. HIV-seronegative individuals had significantly greater CD4 + T cell responses against the Spike protein compared to the viremic people living with HIV (PLWH). Absolute CD4 count correlated positively with SARS-CoV-2-specific CD4 + and CD8 + T cell responses (CD4 r=0.5, p=0.03; CD8 r=0.5, p=0.001), whereas T cell activation was negatively correlated with CD4 + T cell responses (CD4 r=-0.7, p=0.04). There was diminished T cell cross-recognition between the two waves, which was more pronounced in individuals with unsuppressed HIV infection. Importantly, we identify four mutations in the Beta variant that resulted in abrogation of T cell recognition. Taken together, we show that unsuppressed HIV infection markedly impairs T cell responses to SARS-Cov-2 infection and diminishes T cell cross-recognition. These findings may partly explain the increased susceptibility of PLWH to severe COVID-19 and also highlights their vulnerability to emerging SARS-CoV-2 variants of concern., Competing Interests: TN, CC, AP, TN, FK, MM, IG, KJ, WH, AS, ZN No competing interests declared, (© 2022, Nkosi, Chasara et al.)

The extent to which Omicron infection 1-9 , with or without previous vaccination, elicits protection against the previously dominant Delta (B.1.617.2) variant is unclear. Here we measured the neutralization capacity against variants of severe acute respiratory syndrome coronavirus 2 in 39 individuals in South Africa infected with the Omicron sublineage BA.1 starting at a median of 6 (interquartile range 3-9) days post symptom onset and continuing until last follow-up sample available, a median of 23 (interquartile range 19-27) days post symptoms to allow BA.1-elicited neutralizing immunity time to develop. Fifteen participants were vaccinated with Pfizer's BNT162b2 or Johnson & Johnson's Ad26.CoV2.S and had BA.1 breakthrough infections, and 24 were unvaccinated. BA.1 neutralization increased from a geometric mean 50% focus reduction neutralization test titre of 42 at enrolment to 575 at the last follow-up time point (13.6-fold) in vaccinated participants and from 46 to 272 (6.0-fold) in unvaccinated participants. Delta virus neutralization also increased, from 192 to 1,091 (5.7-fold) in vaccinated participants and from 28 to 91 (3.0-fold) in unvaccinated participants. At the last time point, unvaccinated individuals infected with BA.1 had low absolute levels of neutralization for the non-BA.1 viruses and 2.2-fold lower BA.1 neutralization, 12.0-fold lower Delta neutralization, 9.6-fold lower Beta variant neutralization, 17.9-fold lower ancestral virus neutralization and 4.8-fold lower Omicron sublineage BA.2 neutralization relative to vaccinated individuals infected with BA.1. These results indicate that hybrid immunity formed by vaccination and Omicron BA.1 infection should be protective against Delta and other variants. By contrast, infection with Omicron BA.1 alone offers limited cross-protection despite moderate enhancement., (© 2022. The Author(s).)

Background: In the Investigation of the Management of Pericarditis (IMPI) randomized control, 2x2 factorial trial, Mycobacterium indicus pranii ( MIP ) immunotherapy, adjunctive corticosteroids or MIP combined with corticosteroids was compared to standard tuberculosis (TB) therapy for tuberculous pericarditis (TBP). While MIP and/or the combination of MIP and corticosteroids had no impact on all-cause mortality or pericarditis related outcomes, corticosteroids reduced the incidence of constrictive pericarditis at 12 months. Data suggests that both adjunctive therapies modulate the immune and inflammatory responses to pulmonary TB. Whether they affect systemic antigen-specific T cell responses, key immune mediators of Mycobacterium tuberculosis control , in patients with TBP is unknown., Methods: Participants with definite or probable TBP were randomly assigned to receive five injections of MIP or placebo at 2-week intervals and either 6 weeks of oral prednisolone or placebo. Frequencies of CD4 and CD8 T cells expressing IFN-γ, IL-2 or TNF in response to MIP or purified protein derivative stimulation were measured by intracellular cytokine staining and flow cytometry up to 24 weeks post treatment., Results: Immunotherapy with MIP did not significantly modulate frequencies of Th1 CD4 and CD8 T cells compared to placebo. Adjunctive prednisolone also did not change mycobacteria-specific CD4 or CD8 T cell responses. By contrast, combinatorial therapy with MIP and prednisolone was associated with a modest increase in frequencies of multifunctional and single cytokine-expressing CD4 T cell responses at 6 and 24 weeks post treatment., Conclusions: Consistent with the lack of a significant clinical effect in the IMPI trial, MIP immunotherapy did not significantly modulate mycobacteria-specific T cell responses. Despite the positive effect of prednisolone on hospitalizations and constrictive pericarditis in the IMPI trial, prednisolone did not significantly reduce pro-inflammatory T cell responses in this sub-study. The modest improvement of mycobacteria-specific T cell upon combinatorial therapy with MIP and prednisolone requires further investigation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Climate change is directly and indirectly linked to human health, including through access to treatment and care. Our systematic review presents a systems understanding of the nexus between drought and antiretroviral therapy (ART) adherence in HIV-positive individuals in the African setting. Narrative synthesis of 111 studies retrieved from Web of Science, PubMed/MEDLINE, and PsycINFO suggests that livelihoods and economic conditions, comorbidities and ART regimens, human mobility, and psychobehavioural dispositions and support systems interact in complex ways in the drought-ART adherence nexus in Africa. Economic and livelihood-related challenges appear to impose the strongest impact on human interactions, actions, and systems that culminate in non-adherence. Indeed, the complex pathways identified by our systems approach emphasise the need for more integrated research approaches to understanding this phenomenon and developing interventions., Competing Interests: Declaration of interests CCI and DK received grant funding paid to their institution for this work from the Sussex Sustainability Research Programme (SSRP), University of Sussex. The SSRP grant provided salary support for KSO and SN and travel support for SA-K to visit the project sites. CCI received conference attendance support from Gilead Sciences unrelated to the submitted work. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Characterizing SARS-CoV-2 evolution in specific geographies may help predict properties of the variants that come from these regions. We mapped neutralization of a SARS-CoV-2 strain that evolved over 6 months from ancestral virus in a person with advanced HIV disease in South Africa; this person was infected prior to emergence of the Beta and Delta variants. We longitudinally tracked the evolved virus and tested it against self-plasma and convalescent plasma from ancestral, Beta, and Delta infections. Early virus was similar to ancestral, but it evolved a multitude of mutations found in Omicron and other variants. It showed substantial but incomplete Pfizer BNT162b2 escape, weak neutralization by self-plasma, and despite pre-dating Delta, it also showed extensive escape of Delta infection-elicited neutralization. This example is consistent with the notion that SARS-CoV-2 evolving in individual immune-compromised hosts, including those with advanced HIV disease, may gain immune escape of vaccines and enhanced escape of Delta immunity, and this has implications for vaccine breakthrough and reinfections., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The emergence of the SARS-CoV-2 variant of concern Omicron (Pango lineage B.1.1.529), first identified in Botswana and South Africa, may compromise vaccine effectiveness and lead to re-infections 1 . Here we investigated Omicron escape from neutralization by antibodies from South African individuals vaccinated with Pfizer BNT162b2. We used blood samples taken soon after vaccination from individuals who were vaccinated and previously infected with SARS-CoV-2 or vaccinated with no evidence of previous infection. We isolated and sequence-confirmed live Omicron virus from an infected person and observed that Omicron requires the angiotensin-converting enzyme 2 (ACE2) receptor to infect cells. We compared plasma neutralization of Omicron relative to an ancestral SARS-CoV-2 strain and found that neutralization of ancestral virus was much higher in infected and vaccinated individuals compared with the vaccinated-only participants. However, both groups showed a 22-fold reduction in vaccine-elicited neutralization by the Omicron variant. Participants who were vaccinated and had previously been infected exhibited residual neutralization of Omicron similar to the level of neutralization of the ancestral virus observed in the vaccination-only group. These data support the notion that reasonable protection against Omicron may be maintained using vaccination approaches., (© 2021. The Author(s).)

The 2015 El Niño-triggered drought in Southern Africa caused widespread economic and livelihood disruption in South Africa, imposing multiple physical and health challenges for rural populations including people living with HIV (PLHIV). We examined the economic, social and demographic impacts of drought drawing on 27 in-depth interviews in two cohorts of PLHIV in Hlabisa, uMkhanyakude district, KwaZulu-Natal. Thematic analysis revealed how drought-enforced soil water depletion, dried-up rivers, and dams culminated in a continuum of events such as loss of livestock, reduced agricultural production, and insufficient access to water and food which was understood to indirectly have a negative impact on HIV treatment adherence. This was mediated through disruptions in incomes, livelihoods and food systems, increased risk to general health, forced mobility and exacerbation of contextual vulnerabilities linked to poverty and unemployment. The systems approach, drawn from interview themes, hypothesises the complex pathways of plausible networks of impacts from drought through varying socioeconomic factors, exacerbating longstanding contextual precarity, and ultimately challenging HIV care utilisation. Understanding the multidimensional relationships between climate change, especially drought, and poor HIV care outcomes through the prism of contextual vulnerabilities is vital for shaping policy interventions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Cross-sectional screening programs are used to detect and refer individuals with non-communicable diseases to healthcare services. We evaluated the positive predictive value of cross-sectional measurements for Diabetes Mellitus (DM) and hypertension (HTN) as part of a community-based disease screening study, 'Vukuzazi' in rural South Africa., Methods: We conducted community-based screening for HTN and DM using the World Health Organization STEPS protocol and glycated haemoglobin A1c (HbA1c) testing, respectively. Nurses conducted follow-up home visits for confirmatory diagnostic testing among individuals with a screening BP above 140/90 mmHg and/or HbA1c above 6.5% at the initial screen, and without a prior diagnosis. We assessed the positive predictive value of the initial screening, compared to the follow up measure. We also sought to identify a screening threshold for HTN and DM with greater than 90% positive predictive value., Results: Of 18,027 participants enrolled, 10.2% (1,831) had a screening BP over 140/90 mmHg. Of those without a prior diagnosis, 871 (47.6%) received follow-up measurements. Only 51.2% (451) of those with completed follow-up measurements had a repeat BP>140/90 mmHg at the home visit and were referred to care. To achieve a 90% correct referral rate, a systolic BP threshold of 192 was needed at first screening. For DM screening, 1,615 (9.0%) individuals had an HbA1c > 6.5%, and of those without a prior diagnosis, 1,151 (71.2%) received a follow-up blood glucose. Of these, only 34.1% (395) met criteria for referral for DM. To ensure a 90% positive predictive value i.e. a screening HbA1c of >16.6% was needed., Conclusions: A second home-based screening visit to confirm a diagnosis of DM and HTN reduced health system referrals by 48% and 66%, respectively. Two-day screening programmes for DM and HTN screening might save individual and healthcare resources and should be evaluated carefully in future cost effectiveness evaluations., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2021 The Author(s).)

There are conflicting reports on the effects of HIV on COVID-19. Here, we analyzed disease severity and immune cell changes during and after SARS-CoV-2 infection in 236 participants from South Africa, of which 39% were people living with HIV (PLWH), during the first and second (Beta dominated) infection waves. The second wave had more PLWH requiring supplemental oxygen relative to HIV-negative participants. Higher disease severity was associated with low CD4 T cell counts and higher neutrophil to lymphocyte ratios (NLR). Yet, CD4 counts recovered and NLR stabilized after SARS-CoV-2 clearance in wave 2 infected PLWH, arguing for an interaction between SARS-CoV-2 and HIV infection leading to low CD4 and high NLR. The first infection wave, where severity in HIV negative and PLWH was similar, still showed some HIV modulation of SARS-CoV-2 immune responses. Therefore, HIV infection can synergize with the SARS-CoV-2 variant to change COVID-19 outcomes., Competing Interests: FK, IG, SC, YZ, RK, MB, KK, YG, HR, NM, MM, DM, DR, TN, WH, BG, RL, EW, Td, MM, GL, AL, HK, AS No competing interests declared, (© 2021, Karim et al.)

Computer-aided digital chest radiograph interpretation (CAD) can facilitate high-throughput screening for tuberculosis (TB), but its use in population-based active case-finding programs has been limited. In an HIV-endemic area in rural South Africa, we used a CAD algorithm (CAD4TBv5) to interpret digital chest x-rays (CXR) as part of a mobile health screening effort. Participants with TB symptoms or CAD4TBv5 score above the triaging threshold were referred for microbiological sputum assessment. During an initial pilot phase, a low CAD4TBv5 triaging threshold of 25 was selected to maximize TB case finding. We report the performance of CAD4TBv5 in screening 9,914 participants, 99 (1.0%) of whom were found to have microbiologically proven TB. CAD4TBv5 was able to identify TB cases at the same sensitivity but lower specificity as a blinded radiologist, whereas the next generation of the algorithm (CAD4TBv6) achieved comparable sensitivity and specificity to the radiologist. The CXRs of people with microbiologically confirmed TB spanned a range of lung field abnormality, including 19 (19.2%) cases deemed normal by the radiologist. HIV serostatus did not impact CAD4TB's performance. Notably, 78.8% of the TB cases identified during this population-based survey were asymptomatic and therefore triaged for sputum collection on the basis of CAD4TBv5 score alone. While CAD4TBv6 has the potential to replace radiologists for triaging CXRs in TB prevalence surveys, population-specific piloting is necessary to set the appropriate triaging thresholds. Further work on image analysis strategies is needed to identify radiologically subtle active TB.