Homologous Ad26.COV2.S vaccination results in reduced boosting of humoral responses in hybrid immunity, but elicits antibodies of similar magnitude regardless of prior infection.

The impact of previous SARS-CoV-2 infection on the durability of Ad26.COV2.S vaccine-elicited responses, and the effect of homologous boosting has not been well explored. We followed a cohort of healthcare workers for 6 months after receiving the Ad26.COV2.S vaccine and a further one month after they received an Ad26.COV2.S booster dose. We assessed longitudinal spike-specific antibody and T cell responses in individuals who had never had SARS-CoV-2 infection, compared to those who were infected with either the D614G or Beta variants prior to vaccination. Antibody and T cell responses elicited by the primary dose were durable against several variants of concern over the 6 month follow-up period, regardless of infection history. However, at 6 months after first vaccination, antibody binding, neutralization and ADCC were as much as 59-fold higher in individuals with hybrid immunity compared to those with no prior infection. Antibody cross-reactivity profiles of the previously infected groups were similar at 6 months, unlike at earlier time points, suggesting that the effect of immune imprinting diminishes by 6 months. Importantly, an Ad26.COV2.S booster dose increased the magnitude of the antibody response in individuals with no prior infection to similar levels as those with previous infection. The magnitude of spike T cell responses and proportion of T cell responders remained stable after homologous boosting, concomitant with a significant increase in long-lived early differentiated CD4 memory T cells. Thus, these data highlight that multiple antigen exposures, whether through infection and vaccination or vaccination alone, result in similar boosts after Ad26.COV2.S vaccination.

Efficacy of NVX-CoV2373 Covid-19 Vaccine against the B.1.351 Variant.

BACKGROUND: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the coronavirus disease 2019 (Covid-19) pandemic. In a phase 1-2 trial involving healthy adults, the NVX-CoV2373 nanoparticle vaccine had an acceptable safety profile and was associated with strong neutralizing-antibody and antigen-specific polyfunctional CD4+ T-cell responses. Evaluation of vaccine efficacy was needed in a setting of ongoing SARS-CoV-2 transmission. METHODS: In this phase 2a-b trial in South Africa, we randomly assigned human immunodeficiency virus (HIV)-negative adults between the ages of 18 and 84 years or medically stable HIV-positive participants between the ages of 18 and 64 years in a 1:1 ratio to receive two doses of either the NVX-CoV2373 vaccine (5 µg of recombinant spike protein with 50 µg of Matrix-M1 adjuvant) or placebo. The primary end points were safety and vaccine efficacy against laboratory-confirmed symptomatic Covid-19 at 7 days or more after the second dose among participants without previous SARS-CoV-2 infection. RESULTS: Of 6324 participants who underwent screening, 4387 received at least one injection of vaccine or placebo. Approximately 30% of the participants were seropositive for SARS-CoV-2 at baseline. Among 2684 baseline seronegative participants (94% HIV-negative and 6% HIV-positive), predominantly mild-to-moderate Covid-19 developed in 15 participants in the vaccine group and in 29 in the placebo group (vaccine efficacy, 49.4%; 95% confidence interval [CI], 6.1 to 72.8). Vaccine efficacy among HIV-negative participants was 60.1% (95% CI, 19.9 to 80.1). Of 41 sequenced isolates, 38 (92.7%) were the B.1.351 variant. Post hoc vaccine efficacy against B.1.351 was 51.0% (95% CI, -0.6 to 76.2) among the HIV-negative participants. Preliminary local and systemic reactogenicity events were more common in the vaccine group; serious adverse events were rare in both groups. CONCLUSIONS: The NVX-CoV2373 vaccine was efficacious in preventing Covid-19, with higher vaccine efficacy observed among HIV-negative participants. Most infections were caused by the B.1.351 variant. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT04533399.).

Safety and pharmacokinetics of subcutaneous administration of broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs), given to HIV-1 exposed, uninfected neonates and infants: study protocol for a phase I trial.

BACKGROUND: The ambitious goal to eliminate new pediatric HIV infections by 2030 requires accelerated prevention strategies in high-risk settings such as South Africa. One approach could be pre-exposure prophylaxis (PrEP) with broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs). The aim of our study is to define the optimal dose(s), the ideal combination(s) of bNAbs in terms of potency and breadth, and timing of subcutaneous (SC) administration(s) to prevent breast milk transmission of HIV. METHODS: Two bNAbs, CAP256V2LS and VRC07-523LS, will be assessed in a sequential and randomized phase I, single-site, single-blind, dose-finding trial. We aim to investigate the 28-day safety and pharmacokinetics (PK) profile of incrementally higher doses of these bNAbs in breastfeeding HIV-1 exposed born without HIV neonates alongside standard of care antiretroviral (ARV) medication to prevent (infants) or treat (mothers) HIV infection. The trial design includes 3 steps and 7 arms (1, 2, 3, 4, 5, 6 and 6b) with 8 infants in each arm. The first step will evaluate the safety and PK profile of the bNAbs when given alone as a single subcutaneous (SC) administration at increasing mg/kg body weight doses within 96 h of birth: arms 1, 2 and 3 at doses of 5, 10, and 20 mg/kg of CAP256V2LS, respectively; arms 4 and 5 at doses of 20 and 30 mg/kg of VRC07-523LS, respectively. Step two will evaluate the safety and PK profile of a combination of the two bNAbs administered SC at fixed doses within 96 h of birth. Step three will evaluate the safety and PK profile of the two bNAbs administered SC in combination at fixed doses, after 3 months. Arms 1 and 6 will follow sequential recruitment, whereas randomization will occur sequentially between arms (a) 2 & 4 and (b) 3 & 5. Before each randomization, a safety pause will allow review of safety data of the preceding arms. DISCUSSION: The results of this trial will guide further studies on bNAbs to prevent breast milk transmission of HIV. PROTOCOL VERSION: Version 4.0 dated 15 March 2024. TRIAL REGISTRATION: Pan African Clinical Trial Registry (PACTR): PACTR202205715278722, 21 April 2022; South African National Clinical Trial Registry (SANCTR): DOH-27-062022-6058.

Impact of age on antimicrobial prescriptions in hospitalized children at three academic centres in South Africa: a point prevalence survey.

Antimicrobial resistance is a global threat in children, and the emergence of multi-drug-resistant organisms is of concern. This secondary analysis of an antimicrobial point prevalence survey (PPS) in children evaluates the impact of age on antimicrobial use. The mean antimicrobial prescriptions were assessed in neonates, infants, young children (1-5 years), school-going children (6-12 years), and adolescents (13-15 years) from a cross-sectional PPS at three academic hospitals between September 2021 and January 2022. Primary and secondary diagnoses, antibiotic type (World Health Organization AWaRe and Anatomical Therapeutic Chemical classifications), and the incidence of healthcare-associated infections (HAI) were evaluated per age category. Multiple regression models were used to analyse age-related risk factors for HAI. The number of antimicrobials per child (1.7-1.9 per patient) was higher in neonates and infants compared to children 6-12 years old (1.4 per patient). Watch antibiotics, especially carbapenems, were commonly prescribed in neonates (32.5%) and infants (42.2%). Reserve antimicrobial use was notable in neonates (4.7%) and infants (4.1%). The incidence risk ratio (IRR) of HAI was higher in neonates and infants (IRR 2.13; 95% CI 1.23-3.70, IRR 2.20; 95% CI 1.40-3.45, respectively) compared to 6- to 12-year-olds. On multivariate analysis of participants according to age, being HIV infected, length of stay >6 days, high McCabe severity score, having surgery and receipt of blood transfusion were associated with an increased risk of HAI (P < .001 for all) while on univariate analysis only, being premature and/or underweight was associated with an increased risk of HAI in infants (P < .001 for both). Infants with risk factors for HAI significantly influenced antimicrobial prescribing, underscoring the necessity for tailored antimicrobial stewardship and enhanced surveillance. The increased use of Watch antibiotics, particularly carbapenems, in infants warrants closer scrutiny. Further research is required to identify inappropriate antimicrobial use in high-risk hospitalized young children.

Effectiveness of the Ad26.COV2.S vaccine in health-care workers in South Africa (the Sisonke study): results from a single-arm, open-label, phase 3B, implementation study.

BACKGROUND: We aimed to assess the effectiveness of a single dose of the Ad26.COV2.S vaccine (Johnson & Johnson) in health-care workers in South Africa during two waves of the South African COVID-19 epidemic. METHODS: In the single-arm, open-label, phase 3B implementation Sisonke study, health-care workers aged 18 years and older were invited for vaccination at one of 122 vaccination sites nationally. Participants received a single dose of 5 × 1010 viral particles of the Ad26.COV2.S vaccine. Vaccinated participants were linked with their person-level data from one of two national medical insurance schemes (scheme A and scheme B) and matched for COVID-19 risk with an unvaccinated member of the general population. The primary outcome was vaccine effectiveness against severe COVID-19, defined as COVID-19-related admission to hospital, hospitalisation requiring critical or intensive care, or death, in health-care workers compared with the general population, ascertained 28 days or more after vaccination or matching, up to data cutoff. This study is registered with the South African National Clinical Trial Registry, DOH-27-022021-6844, ClinicalTrials.gov, NCT04838795, and the Pan African Clinical Trials Registry, PACTR202102855526180, and is closed to accrual. FINDINGS: Between Feb 17 and May 17, 2021, 477 102 health-care workers were enrolled and vaccinated, of whom 357 401 (74·9%) were female and 119 701 (25·1%) were male, with a median age of 42·0 years (33·0-51·0). 215 813 vaccinated individuals were matched with 215 813 unvaccinated individuals. As of data cutoff (July 17, 2021), vaccine effectiveness derived from the total matched cohort was 83% (95% CI 75-89) to prevent COVID-19-related deaths, 75% (69-82) to prevent COVID-19-related hospital admissions requiring critical or intensive care, and 67% (62-71) to prevent COVID-19-related hospitalisations. The vaccine effectiveness for all three outcomes were consistent across scheme A and scheme B. The vaccine effectiveness was maintained in older health-care workers and those with comorbidities including HIV infection. During the course of the study, the beta (B.1.351) and then the delta (B.1.617.2) SARS-CoV-2 variants of concerns were dominant, and vaccine effectiveness remained consistent (for scheme A plus B vaccine effectiveness against COVID-19-related hospital admission during beta wave was 62% [95% CI 42-76] and during delta wave was 67% [62-71], and vaccine effectiveness against COVID-19-related death during beta wave was 86% [57-100] and during delta wave was 82% [74-89]). INTERPRETATION: The single-dose Ad26.COV2.S vaccine shows effectiveness against severe COVID-19 disease and COVID-19-related death after vaccination, and against both beta and delta variants, providing real-world evidence for its use globally. FUNDING: National Treasury of South Africa, the National Department of Health, Solidarity Response Fund NPC, The Michael & Susan Dell Foundation, The Elma Vaccines and Immunization Foundation, and the Bill & Melinda Gates Foundation.

Mixed-methods cross-sectional study of the prevention of vertical HIV transmission program users unaware of male partner's HIV status, in six South African districts with a high antenatal HIV burden.

BACKGROUND: Elimination of vertical HIV Transmission (VHT) and maternal deaths are global health priorities. Male involvement is one of the most important factors that influences women's decisions, including the uptake of Prevention of vertical HIV transmission (P-VHT). We sought to understand not knowing a male partner's HIV status (MPHIVs) amongst women using services to prevent vertical HIV transmission in six South African districts with high antenatal HIV burden. METHODS: A mixed-methods cross-sectional study was conducted in six South African districts, and data collected through face-to-face interviews with women and focus group discussions (FGDs) with women or male partners. The quantitative data were analyzed using STATA SE-17.0 and an inductive approach was used for qualitative data analysis. RESULTS: Overall, 28.7% of women were unaware of their MPHIVs, while 25.3% and 46.0% knew the MPHIVs was positive or negative, respectively. In multivariable logistic regression, single marital status and unplanned pregnancy increased the odds of not knowing a MPHIVs while a woman's disclosure of her HIV status to the male partner reduced the odds. FDGs highlighted complexities around MPHIVs disclosure, e.g., reluctance to test for HIV and potential interventions including healthcare worker (HCW) assisted HIV disclosure. CONCLUSION: User-informed interventions to address MPHIVs non-disclosure amongst women of child-bearing age, particularly those at risk of unstable sexual partners and unplanned pregnancies, should be strengthened.

"If you work alone on this project, you can't reach your target": unpacking the leader's role in well-performing teams in a maternal and neonatal quality improvement programme in South Africa, before and during COVID-19.

The South African National Department of Health developed a quality improvement (QI) programme to reduce maternal and neonatal mortality and still births. The programme was implemented between 2018 and 2022 in 21 purposively selected public health facilities. We conducted a process evaluation to describe the characteristics and skills of the QI team leaders of well-performing teams. The evaluation was conducted in 15 of the 21 facilities. Facilities were purposively selected and comprised semi-structured interviews with leaders at three time points; reviewing of QI documentation; and 37 intermittently conducted semi-structured interviews with the QI advisors, being QI technical experts who supported the teams. These interviews focused on participants' experiences and perceptions of how the teams performed, and performance barriers and enablers. Thematic data analysis was conducted using Atlas.ti. Variation in team performance was associated with leaders' attributes and skills. However, the COVID-19 pandemic also affected team functioning. Well-performing teams had leaders who effectively navigated COVID-19 and other challenges, who embraced QI and had sound QI skills. These leaders cultivated trust by taking responsibility for failures, correcting members' mistakes in encouraging ways, and setting high standards of care. Moreover, they promoted programme ownership among members by delegating tasks. Given the critical role leaders play in team performance and thus in the outcomes of QI programmes, efforts should focus on leader selection, training, and support.

From purists to pragmatists: a qualitative evaluation of how implementation processes and contexts shaped the uptake and methodological adaptations of a maternal and neonatal quality improvement programme in South Africa prior to, and during COVID-19.

BACKGROUND: Despite progress, maternal and neonatal mortality and still births remain high in South Africa. The South African National Department of Health implemented a quality improvement (QI) programme, called Mphatlalatsane, to reduce maternal and neonatal mortality and still births. It was implemented in 21 public health facilities, seven per participating province, between 2018 and 2022. METHODS: We conducted a qualitative process evaluation of the contextual and implementation process factors' influence on implementation uptake amongst the QI teams in 15 purposively selected facilities. Data collection included three interview rounds with the leaders and members of the QI teams in each facility; intermittent interviews with the QI advisors; programme documentation review; observation of programme management meetings; and keeping a fieldwork journal. All data were thematically analysed in Atlas.ti. Implementation uptake varied across the three provinces and between facilities within provinces. RESULTS: Between March and August 2020, the COVID-19 pandemic disrupted uptake in all provinces but affected QI teams in one province more severely than others, because they received limited pre-pandemic training. Better uptake among other sites was attributed to receiving more QI training pre-COVID-19, having an experienced QI advisor, and good teamwork. Uptake was more challenging amongst hospital teams which had more staff and more complicated MNH services, versus the primary healthcare facilities. We also attributed better uptake to greater district management support. A key factor shaping uptake was leaders' intrinsic motivation to apply QI methodology. We found that, across sites, organic adaptations to the QI methodology were made by teams, started during COVID-19. Teams did away with rapid testing of change ideas and keeping a paper trail of the steps followed. Though still using data to identify service problems, they used self-developed audit tools to record intervention effectiveness, and not the prescribed tools. CONCLUSIONS: Our study underscores the critical role of intrinsic motivation of team leaders, support from experienced technical QI advisors, and context-sensitive adaptations to maximise QI uptake when traditionally recognised QI steps cannot be followed.

Association between regular physical activity and the protective effect of vaccination against SARS-CoV-2 in a South African case-control study.

BACKGROUND: Both vaccination and physical activity have been shown to independently decrease the likelihood of severe COVID-19 infection. OBJECTIVE: To assess the association between regular physical activity and vaccination against COVID-19 among healthcare workers. METHODS: A test negative case-control study design was used to estimate the risk of having an associated COVID-19-related hospital admission, among individuals who were unvaccinated compared with those who were fully vaccinated with Ad26.COV2.S (>28 days after a single dose). 196 444 participant tests were stratified into three measured physical activity subgroups with low, moderate and high activity, to test the hypothesis that physical activity is an effect modifier on the relationship between vaccination and hospitalisation. RESULTS: Vaccine effectiveness against a COVID-19-related admission among vaccinated individuals within the low activity group was 60.0% (95% CI 39.0 to 73.8), 72.1% (95% CI 55.2 to 82.6) for the moderate activity group, and 85.8% (95% CI 74.1 to 92.2) for the high activity group. Compared with individuals with low activity levels, vaccinated individuals with moderate and high activity levels had a 1.4 (95% CI 1.36 to 1.51) and 2.8 (95% CI 2.35 to 3.35) times lower risk of COVID-19 admission, respectively (p value <0.001 for both groups). CONCLUSIONS: Regular physical activity was associated with improved vaccine effectiveness against COVID-19 hospitalisation, with higher levels of physical activity associated with greater vaccine effectiveness. Physical activity enhances vaccine effectiveness against severe COVID-19 outcomes and should be encouraged by greater public health messaging.

High Asymptomatic Carriage With the Omicron Variant in South Africa.

We report a 23% asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) Omicron carriage rate in participants being enrolled into a clinical trial in South Africa, 15-fold higher than in trials before Omicron. We also found lower CD4 + T-cell counts in persons with human immunodeficiency virus (HIV) strongly correlated with increased odds of being SARS-CoV-2 polymerase chain reaction (PCR) positive.

Safety evaluation of the single-dose Ad26.COV2.S vaccine among healthcare workers in the Sisonke study in South Africa: A phase 3b implementation trial.

BACKGROUND: Real-world evaluation of the safety profile of vaccines after licensure is crucial to accurately characterise safety beyond clinical trials, support continued use, and thereby improve public confidence. The Sisonke study aimed to assess the safety and effectiveness of the Janssen Ad26.COV2.S vaccine among healthcare workers (HCWs) in South Africa. Here, we present the safety data. METHODS AND FINDINGS: In this open-label phase 3b implementation study among all eligible HCWs in South Africa registered in the national Electronic Vaccination Data System (EVDS), we monitored adverse events (AEs) at vaccination sites through self-reporting triggered by text messages after vaccination, healthcare provider reports, and active case finding. The frequency and incidence rate of non-serious and serious AEs were evaluated from the day of first vaccination (17 February 2021) until 28 days after the final vaccination in the study (15 June 2021). COVID-19 breakthrough infections, hospitalisations, and deaths were ascertained via linkage of the electronic vaccination register with existing national databases. Among 477,234 participants, 10,279 AEs were reported, of which 138 (1.3%) were serious AEs (SAEs) or AEs of special interest. Women reported more AEs than men (2.3% versus 1.6%). AE reports decreased with increasing age (3.2% for age 18-30 years, 2.1% for age 31-45 years, 1.8% for age 46-55 years, and 1.5% for age > 55 years). Participants with previous COVID-19 infection reported slightly more AEs (2.6% versus 2.1%). The most common reactogenicity events were headache (n = 4,923) and body aches (n = 4,483), followed by injection site pain (n = 2,767) and fever (n = 2,731), and most occurred within 48 hours of vaccination. Two cases of thrombosis with thrombocytopenia syndrome and 4 cases of Guillain-Barré Syndrome were reported post-vaccination. Most SAEs and AEs of special interest (n = 138) occurred at lower than the expected population rates. Vascular (n = 37; 39.1/100,000 person-years) and nervous system disorders (n = 31; 31.7/100,000 person-years), immune system disorders (n = 24; 24.3/100,000 person-years), and infections and infestations (n = 19; 20.1/100,000 person-years) were the most common reported SAE categories. A limitation of the study was the single-arm design, with limited routinely collected morbidity comparator data in the study setting. CONCLUSIONS: We observed similar patterns of AEs as in phase 3 trials. AEs were mostly expected reactogenicity signs and symptoms. Furthermore, most SAEs occurred below expected rates. The single-dose Ad26.COV2.S vaccine demonstrated an acceptable safety profile, supporting the continued use of this vaccine in this setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT04838795; Pan African Clinical Trials Registry PACTR202102855526180.

Eliminating postnatal HIV transmission in high incidence areas: need for complementary biomedical interventions.

The rate of mother-to-child transmission (MTCT) of HIV from breastfeeding is increasing relative to other causes of MTCT. Early effective preconception and antenatal antiretroviral therapy (ART) reduces intrauterine and intrapartum MTCT, whereas maternal post-partum HIV acquisition, untreated maternal HIV, and suboptimal postnatal maternal ART adherence increase the risk of MTCT through breastfeeding. Although the absolute number of cases of MTCT acquired through breastfeeding is decreasing, the rate of decrease is less than the decrease in intrauterine and intrapartum MTCT. Unless current strategies are universally applied, they might not be sufficient to eliminate MTCT due to breastfeeding. Urgent action is needed to evaluate and implement additional preventive biomedical strategies in high HIV prevalence and incidence settings to eliminate MTCT from breastfeeding. Preventive strategies include: pre-exposure prophylaxis in breastfeeding women who have an increased risk of acquiring HIV; postnatal reinforcement strategies, such as maternal retesting for HIV, maternal care reinforcement, and prophylaxis in infants exposed to HIV via breastmilk; and active (vaccine) or passive immunoprophylaxis with long-acting broadly neutralising antibodies.

Impact of antenatal antiretroviral drug exposure on the growth of children who are HIV-exposed uninfected: the national South African Prevention of Mother to Child Evaluation cohort study.

BACKGROUND: The relationship between in-utero antiretroviral (ARV) drug exposure and child growth needs further study as current data provide mixed messages. We compared postnatal growth in the first 18-months of life between children who are HIV-exposed uninfected (CHEU) with fetal exposure to ARV drugs (prophylaxis or triple-drug therapy (ART)) and CHEU not exposed to ARVs. We also examined other independent predictors of postnatal growth. METHODS: We analysed data from a national prospective cohort study of 2526 CHEU enrolled at 6-weeks and followed up 3-monthly till 18-months postpartum, between October 2012 and September 2014. Infant anthropometry was measured, and weight-for-age (WAZ) and length-for-age (LAZ) Z-scores calculated. Generalized estimation equation models were used to compare Z-scores between groups. RESULTS: Among 2526 CHEU, 617 (24.4%) were exposed to ART since -pregnancy (pre-conception ART), 782 (31.0%) to ART commencing post-conception, 879 (34.8%) to maternal ARV prophylaxis (Azidothymidine (AZT)), and 248 (9.8%) had no ARV exposure. In unadjusted analyses, preterm birth rates were higher among CHEU with no ARV exposure than in other groups. Adjusting for infant age, the mean WAZ profile was lower among CHEU exposed to pre-conception ART [-0.13 (95% confidence interval - 0.26; - 0.01)] than the referent AZT prophylaxis group; no differences in mean WAZ profiles were observed for the post-conception ART (- 0.05 (- 0.16; 0.07)), None (- 0.05 (- 0.26; 0.16)) and newly-infected (- 0.18 (- 0.48; 0.13)) groups. Mean LAZ profiles were similar across all groups. In multivariable analyses, mean WAZ and LAZ profiles  for the ARV exposure groups were completely aligned. Several non-ARV factors including child, maternal, and socio-demographic factors independently predicted mean WAZ. These include child male (0.45 (0.35; 0.56)) versus female, higher maternal education grade 7-12 (0.28 (0.14; 0.42) and 12 + (0.36 (0.06; 0.66)) versus ≤ grade7, employment (0.16 (0.04; 0.28) versus unemployment, and household food security (0.17 (0.03; 0.31). Similar predictors were observed for mean LAZ. CONCLUSION: Findings provide evidence for initiating all pregnant women living with HIV on ART as fetal exposure had no demonstrable adverse effects on postnatal growth. Several non-HIV-related maternal, child and socio-demographic factors were independently associated with growth, highlighting the need for multi-sectoral interventions. Longer-term monitoring of CHEU children is recommended.

A risk measurement tool for targeted HIV prevention measures amongst young pregnant and lactating women in South Africa.

BACKGROUND: We aimed to develop and validate a tool to identify which pregnant/lactating young South African women (≤ 24 years) are at risk of HIV infection. METHODS: Data from three national South African Prevention of Mother-to-Child Transmission (PMTCT) evaluations were used to internally validate three HIV acquisition risk models for young postpartum women. We used univariate and multivariable logistic regression analysis to determine which risk factors were significant. Model coefficients were rounded and stratified into risk groups and the area under the receiver operating curve (AUROC) was computed. Models were developed to determine which risk factors provided the most predictive accuracy whilst remining clinically meaningful. RESULTS: Data from 9 456 adult and 4 658 young pregnant and lactating women were included in the development and validation data sets, respectively. The optimal model included the following risk factors: age (20-24 years old), informal house structure, two or more pregnancies, mothers who had knowledge of when they received their last HIV test result, no knowledge of the infant's father's HIV status, no knowledge of breastfeeding as a mode of MTCT and knowledge of PMTCT programme. The mean AUROC was 0.71 and 0.72 in the development and validation datasets respectively. The optimum cut off score was ≥ 27, having 84% sensitivity, 44% specificity, and identifying 44% of high-risk women eligible for PrEP. CONCLUSION: The optimal model to be used as a possible risk scoring tool to allow for early identification of those pregnant/lactating women most at-risk of HIV acquisition included both statistically as well as clinically meaningful risk factors. A field-based study is needed to test and validate the effectiveness of this targeted approach.

The Critical Need for Pooled Data on Coronavirus Disease 2019 in African Children: An AFREhealth Call for Action Through Multicountry Research Collaboration.

Globally, there are prevailing knowledge gaps in the epidemiology, clinical manifestations, and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among children and adolescents; and these gaps are especially wide in African countries. The availability of robust age-disaggregated data is a critical first step in improving knowledge on disease burden and manifestations of coronavirus disease 2019 (COVID-19) among children. Furthermore, it is essential to improve understanding of SARS-CoV-2 interactions with comorbidities and coinfections such as human immunodeficiency virus (HIV), tuberculosis, malaria, sickle cell disease, and malnutrition, which are highly prevalent among children in sub-Saharan Africa. The African Forum for Research and Education in Health (AFREhealth) COVID-19 Research Collaboration on Children and Adolescents is conducting studies across Western, Central, Eastern, and Southern Africa to address existing knowledge gaps. This consortium is expected to generate key evidence to inform clinical practice and public health policy-making for COVID-19 while concurrently addressing other major diseases affecting children in African countries.

Revisiting Koch's postulate to determine the plausibility of viral transmission by human milk.

As breastfeeding is of utmost importance for child development and survival, identifying whether breast milk is a route of transmission for human viruses is critical. Based on the principle of Koch's postulate, we propose an analytical framework to determine the plausibility of viral transmission by breast milk. This framework is based on five criteria: viral infection in children receiving breast milk from infected mothers; the presence of virus, viral antigen, or viral genome in the breast milk of infected mothers; the evidence for the virus in breast milk being infectious; the attempts to rule out other transmission modalities; and the reproduction of viral transmission by oral inoculation in an animal model. We searched for evidence in published reports to determine whether the 5 criteria are fulfilled for 16 human viruses that are suspected to be transmissible by breast milk. We considered breast milk transmission is proven if all 5 criteria are fulfilled, as probable if 4 of the 5 criteria are met, as possible if 3 of the 5 criteria are fulfilled, and as unlikely if less than 3 criteria are met. Only five viruses have proven transmission through breast milk: human T-cell lymphotropic virus 1, human immunodeficiency virus, human cytomegalovirus, dengue virus, and Zika virus. The other 11 viruses fulfilled some but not all criteria and were categorized accordingly. Our framework analysis is useful for guiding public health recommendations and for identifying knowledge gaps amenable to original experiments.

Breastfeeding advice for reality: Women's perspectives on primary care support in South Africa.

Breastfeeding education and support are critical health worker skills. Confusion surrounding infant feeding advice linked to the HIV epidemic has reduced the confidence of health workers to support breastfeeding. High antiretroviral therapy coverage of breastfeeding women living with HIV, and an Infant Feeding policy supportive of breastfeeding, now provides an opportunity to improve breastfeeding practices. Challenges remain in restoring health worker confidence to support breastfeeding. This qualitative study presents findings from focus group discussions with mothers of young infants, exploring their experiences of health worker breastfeeding counselling and support. Analysis followed the thematic framework approach. Six researchers reviewed the transcripts, coded them independently, then jointly reviewed the codes, and agreed on a working analytical framework. Although mothers received antenatal breastfeeding messages, these appeared to focus rigidly on the importance of exclusivity. Mothers described receiving some practical support with initiation of breastfeeding after delivery, but support and advice for post-natal breastfeeding challenges were often incorrect or absent. The support also ignored the context in which women make infant feeding decisions, including returning to work and pressures from family members. Despite improved breastfeeding policies, restoring confidence in health workers to support breastfeeding remains a challenge. The post-natal period, when mothers experience breastfeeding difficulties, is particularly critical, and our findings reinforce the importance of continuity of care between communities and health facilities. This research has implications for how health workers are trained to support breastfeeding. Greater attention is needed on developing skills and confidence in identifying, assessing, and supporting women experiencing breastfeeding challenges.

An educational intervention to update health workers about HIV and infant feeding.

Clinical guidelines are used to translate research findings into evidence-based clinical practice but are frequently not comprehensively adopted by health workers (HWs). HIV and infant feeding guidelines were revised by the World Health Organization to align feeding advice for HIV-exposed and unexposed infants, and these were adopted in South Africa in 2017. We describe an innovative, team-based, mentoring programme developed to update HWs on these guidelines. The intervention was underpinned by strong theoretical frameworks and aimed to improve HWs' attitudes, knowledge, confidence, and skills about breastfeeding in the context of HIV. On-site workshops and clinical mentoring used interactive participatory methods and a simple low-tech approach, guided by participants' self-reported knowledge gaps. Workshops were conducted at 24 participating clinics over three sessions, each lasting 1-2 hr. Evaluation data were collected using a self-administered questionnaire. Of 303 participating HWs, 249/303 (82.2%) attended all workshops. Achieving high workshop attendance was challenging and "catch-up" sessions were required to achieve good coverage. Common knowledge gaps identified included antiretroviral therapy adherence monitoring during breastfeeding and management of viral load results (173 participants), management of breast conditions (79), and advice about expressing and storing breastmilk (64). Most participants reported all their knowledge gaps were addressed and anticipated that their practice would change. We describe a feasible, sustainable approach to updating HWs on HIV and infant feeding guidelines and improving skills in breastfeeding counselling in resource-constrained settings. This approach could be adapted to other topics and, with further evaluation, implemented at scale using existing resources.