Field evaluation of the residual efficacy of new generation insecticides for potential use in indoor residual spray programmes in South Africa.

BACKGROUND: The decreasing residual efficacy of insecticides is an important factor when making decisions on insecticide choice for national malaria control programmes. The major challenge to using chemicals for vector control is the selection for the development of insecticide resistance. Since insecticide resistance has been recorded for most of the existing insecticides used for indoor residual spraying, namely, DDT, pyrethroids, organophosphates and carbamates, and new chemicals are necessary for the continued success of indoor residual spraying. The aim of this study was to assess the residual efficacy of Actellic 300CS, SumiShield™ 50WG and Fludora®Fusion by spraying on different wall surfaces. METHODS: One hundred and sixty-eight houses with different wall surface types (mud, cement, painted cement, and tin) which represented the rural house wall surface types in KwaZulu-Natal, South Africa were used to evaluate the residual efficacy of Actellic 300CS, SumiShield 50WG and Fludora®Fusion with DDT as the positive control. All houses were sprayed by experienced spray operators from the Malaria Control Programme. Efficacy of these insecticides were evaluated by contact bioassays against Anopheles arabiensis, a vector species. The residual efficacy of the insecticide formulations was evaluated against a susceptible insectary-reared population of An. arabiensis using WHO cone bioassays. RESULTS: Effectiveness of the three insecticides was observed up to 12 months post-spray. When assessing the achievement of 100% mortality over time, SumiShield performed significantly better than DDT on mud (OR 2.28, 95% CI 1.72-3.04) and painted cement wall types (OR 3.52, 95% CI 2.36-5.26). On cement wall types, Actellic was found to be less effective than DDT (OR 0.55, 95% CI 0.37-0.82) while Fludora®Fusion was less effective on tin wall types (OR 0.67, 95% CI 0.47-0.95). When compared to the combined efficacy of DDT on mud surfaces, SumiShield applied to each of the mud, cement and painted cement wall types and DDT applied to the cement wall types was found to be significantly more effective. These insecticides usually resulted in 100% mortality for up to 12 months with a delayed mortality period of 96-144 h, depending on the insecticide evaluated and the surface type sprayed. CONCLUSION: Field evaluation of these insecticides have shown that Actellic, SumiShield and Fludora®Fusion are suitable replacements for DDT. Each of these insecticides can be used for malaria vector control, requiring just one spray round. These insecticides can be used in rotation or as mosaic spraying.

Effects of injectable contraception with depot medroxyprogesterone acetate or norethisterone enanthate on estradiol levels and menstrual, psychological and behavioral measures relevant to HIV risk: The WHICH randomized trial.

BACKGROUND: Observational data suggest lower HIV risk with norethisterone enanthate (NET-EN) than with depo-medroxyprogesterone acetate intramuscular (DMPA-IM) injectable contraceptives. If confirmed, a switch between these similar injectable methods would be programmatically feasible and could impact the trajectory of the HIV epidemic. We aimed in this paper to investigate the effects of DMPA-IM and NET-EN on estradiol levels, measures of depression and sexual activity and menstrual effects, relevant to HIV risk; and to ascertain whether these measures are associated with estradiol levels. METHODS: This open-label trial conducted at two sites in South Africa from 5 November 2018 to 30 November 2019, randomized HIV-negative women aged 18-40 to DMPA-IM 150 mg intramuscular 12-weekly (n = 262) or NET-EN 200 mg intramuscular 8-weekly (n = 259). Data were collected on hormonal, behavioral and menstrual effects at baseline and at 25 weeks (25W). RESULTS: At 25W, median 17ß estradiol levels were substantially lower than at baseline (p<0.001) for both methods: 76.5 pmol/L (interquartile range (IQR) 54.1 to 104.2) in the DMPA-IM group (n = 222), and 69.8 pmol/L (IQR: 55.1 to 89.3) in the NET-EN group (n = 225), with no statistical difference between the two methods (p = 0.450). Compared with DMPA-IM, NET-EN users reported significantly less amenorrhoea, fewer sexual acts, fewer users reporting at least one act of unprotected sex, more condom use with steady partner, more days with urge for sexual intercourse, more days feeling partner does not love her, and more days feeling sad for no reason. We did not find a clear association between estradiol levels and sexual behavior, depression and menstrual effects. Behavioral outcomes suggest less sexual exposure with NET-EN than DMPA-IM. The strength of this evidence is high due to the randomized study design and the consistency of results across the outcomes measured. CONCLUSIONS: Estradiol levels were reduced to postmenopausal levels by both methods. Secondary outcomes suggesting less sexual exposure with NET-EN are consistent with reported observational evidence of less HIV risk with NET-EN. A randomized trial powered for HIV acquisition is feasible and needed to answer this important question. TRIAL REGISTRATION: PACTR 202009758229976.

Safety of a second homologous Ad26.COV2.S vaccine among healthcare workers in the phase 3b implementation Sisonke study in South Africa.

The Sisonke 2 study provided a homologous boost at least 6 months after administration of the priming dose of Ad26.COV2.S for healthcare workers enrolled on the Sisonke phase 3b implementation study. Safety monitoring was via five reporting sources: (i.) self-report through a web-link; (ii.) paper-based case report forms; (iii.) a toll-free telephonic reporting line; (iv.) healthcare professionals-initiated reports; and (v.) active linkage with National Disease Databases. A total of 2350 adverse events were reported by 2117 of the 240 888 (0.88%) participants enrolled; 1625 of the 2350 reported events are reactogenicity events and 28 adverse events met seriousness criteria. No cases of thrombosis with thrombocytopaenia syndrome were reported; all adverse events including thromboembolic disorders occurred at a rate below the expected population rates apart from one case of Guillain Barre Syndrome and one case of portal vein thrombosis. The Sisonke 2 study demonstrates that two doses of Ad26.COV2.S is safe and well tolerated; and provides a feasible model for national pharmacovigilance strategies for low- and middle-income settings.

Misreporting contraceptive use and the association of peak study progestin levels with weight and BMI among women randomized to the progestin-only injectable contraceptives DMPA-IM and NET-EN.

Progestin-only injectable contraceptives, mainly depo-medroxyprogesterone acetate intramuscular (DMPA-IM), are the most widely used contraceptive methods in sub-Saharan Africa. Insufficient robust data on their relative side-effects and serum concentrations limit understanding of reported outcomes in contraception trials. The WHICH clinical trial randomized HIV-negative women to DMPA-IM (n = 262) or norethisterone enanthate (NET-EN) (n = 259) at two South African sites between 2018-2019. We measured serum concentrations of study and non-study progestins at initiation (D0) and peak serum levels, one week after the 24-week injection [25 weeks (25W)], (n = 435) and investigated associations between study progestin levels, and BMI and weight of participants. Peak median serum concentrations were 6.59 (IQR 4.80; 8.70) nM for medroxyprogesterone (MPA) (n = 161) and 13.6 (IQR 9.01; 19.0) nM for norethisterone (NET) (n = 155). MPA was the most commonly quantifiable non-study progestin at D0 in both arms (54%) and at 25W in the NET-EN arm (27%), followed by NET at D0 in both arms (29%) and at 25W in the DMPA-IM arm (19%). Levonorgestrel was quantifiable in both arms [D0 (6.9%); 25W (3.4%)], while other progestins were quantifiable in ≤ 14 participants. Significant negative time-varying associations were detected between MPA and NET concentrations and weight and BMI in both contraceptive arms and a significant increase was detected for peak serum progestin concentrations for normal weight versus obese women. Contraceptive-related reported outcomes are likely confounded by MPA, more so than NET, with reported DMPA-IM effects likely underestimated, at sites where DMPA-IM is widely used, due to misreporting of contraceptive use before and during trials, and 'tail' effects of DMPA-IM use more than six months before trial enrolment. Peak serum levels of MPA and NET are negatively associated with BMI and weight, suggesting another source of variability between trial outcomes and a potential increase in side-effects for normal weight versus overweight and obese women. Trail registration: The clinical trial was registered with the Pan African Clinical Trials Registry (PACTR 202009758229976).

Vascular thrombosis after single dose Ad26.COV2.S vaccine in healthcare workers in South Africa: open label, single arm, phase 3B study (Sisonke study).

Objective: To assess the rates of vascular thrombotic adverse events in the first 35 days after one dose of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in healthcare workers in South Africa and to compare these rates with those observed in the general population. Design: Open label, single arm, phase 3B study. Setting: Sisonke study, South Africa, 17 February to 15 June 2021. Participants: The Sisonke cohort of 477 234 healthcare workers, aged ≥18 years, who received one dose of the Ad26.COV2.S vaccine. Main outcome measures: Observed rates of venous arterial thromboembolism and vaccine induced immune thrombocytopenia and thrombosis in individuals who were vaccinated, compared with expected rates, based on age and sex specific background rates from the Clinical Practice Research Datalink GOLD database (database of longitudinal routinely collected electronic health records from UK primary care practices using Vision general practice patient management software). Results: Most of the study participants were women (74.9%) and median age was 42 years (interquartile range 33-51). Twenty nine (30.6 per 100 000 person years, 95% confidence interval 20.5 to 44.0) vascular thrombotic events occurred at a median of 14 days (7-29) after vaccination. Of these 29 participants, 93.1% were women, median age 46 (37-55) years, and 51.7% had comorbidities. The observed to expected ratios for cerebral venous sinus thrombosis with thrombocytopenia and pulmonary embolism with thrombocytopenia were 10.6 (95% confidence interval 0.3 to 58.8) and 1.2 (0.1 to 6.5), respectively. Because of the small number of adverse events and wide confidence intervals, no conclusions were drawn between these estimates and the expected incidence rates in the population. Conclusions: Vaccine induced immune thrombocytopenia and thrombosis after one dose of the Ad26.COV2.S vaccine was found in only a few patients in this South African population of healthcare workers. These findings are reassuring if considered in terms of the beneficial effects of vaccination against covid-19 disease. These data support the continued use of this vaccine, but surveillance is recommended to identify other incidences of venous and arterial thromboembolism and to improve confidence in the data estimates. Trial registration: ClinicalTrials.gov NCT04838795.

The effect of the COVID-19 lockdown on malaria transmission in South Africa.

BACKGROUND: For a country such as South Africa which is targeting malaria elimination, mobile and migrant populations pose a substantial risk to importation of malaria parasites. It has been hypothesized that halting cross-border movement of mobile and migrant populations will decrease the importation of malaria, however this option is not a politically, operationally, and financially viable prospect. It has social impacts as well, since families live on either side of the border and preventing travel will challenge family ties. Due to the COVID-19 pandemic and closure of ports of entry (land and air) for non-essential travel into South Africa, a unique opportunity arose to test the hypothesis. METHODOLOGY: An interrupted time series analysis was done to assess whether the post-lockdown trends (April-December 2020) in monthly reported imported and local cases differed from the pre-lockdown trends (January 2015-March 2020). The analysis was conducted separately for KwaZulu-Natal, Mpumalanga, and Limpopo provinces. RESULTS: On average, imported cases were lower in the post-intervention period in all three provinces, and local cases were lower in Mpumalanga and Limpopo, though no results were statistically significant. CONCLUSION: Since population movement continued after the travel restrictions were lifted, border screening with testing and treating should be considered for reducing parasite movement. Another option is reducing malaria cases at the source in neighbouring countries by implementing proven, effective vector and parasite control strategies and through a downstream effect reduce malaria entering South Africa.

Pre-race self-reported medical conditions and allergies in 133 641 Comrades ultramarathon (90km) runners - SAFER XXIII.

OBJECTIVES: To determine the prevalence of self-reported pre-race chronic medical conditions and allergies in ultramarathon race entrants and to explore if these are associated with an increased risk of race-day medical encounters (MEs). METHODS: Data from two voluntary open-ended pre-race medical screening questions (Q1 - history of allergies; Q2 - history of chronic medical conditions/prescription medication use) were collected in 133641 Comrades Marathon race entrants (2014-2019). Race-day ME data collected prospectively over 6 years are reported as incidence (per 1000 starters) and incidence ratios (IR: 95%CI's). RESULTS: Pre-race medical screening questions identified race entrants with a history of chronic medical conditions and/or prescription medication use (6.9%) and allergies (7.4%). The % entrants with risk factors for cardiovascular disease (CVD) was 30% and being older (>45 years) or male (27.5%) were the most frequent CVD risk factors. 0.3% of entrants reported existing CVD. The overall incidence of MEs was 20/1000 race starters. MEs were significantly higher in race entrants reporting a 'yes' to Q1 (allergies) (IR = 1.3; 1.1-1.5) (p = 0.014) or Q2 (chronic medical conditions and/or prescription medication use) (IR = 1.3; 1.1-1.5) (p = 0.0006). CONCLUSIONS: Voluntary completion of two open-ended questions identified chronic medical conditions and/or prescription medication use in 6.9% and allergies in 7.4% of ultramarathon race entrants. This is lower than that reported for other races that implemented compulsory completion of a more comprehensive pre-screening questionnaire. Despite potential under-reporting, a pre-race self-reported history of chronic medical conditions and allergies was associated with a higher risk of race-day MEs.

Symptom Number and Reduced Preinfection Training Predict Prolonged Return to Training after SARS-CoV-2 in Athletes: AWARE IV.

PURPOSE: This study aimed to determine factors predictive of prolonged return to training (RTT) in athletes with recent SARS-CoV-2 infection. METHODS: This is a cross-sectional descriptive study. Athletes not vaccinated against COVID-19 ( n = 207) with confirmed SARS-CoV-2 infection (predominantly ancestral virus and beta-variant) completed an online survey detailing the following factors: demographics (age and sex), level of sport participation, type of sport, comorbidity history and preinfection training (training hours 7 d preinfection), SARS-CoV-2 symptoms (26 in 3 categories; "nose and throat," "chest and neck," and "whole body"), and days to RTT. Main outcomes were hazard ratios (HR, 95% confidence interval) for athletes with versus without a factor, explored in univariate and multiple models. HR < 1 was predictive of prolonged RTT (reduced % chance of RTT after symptom onset). Significance was P < 0.05. RESULTS: Age, level of sport participation, type of sport, and history of comorbidities were not predictors of prolonged RTT. Significant predictors of prolonged RTT (univariate model) were as follows (HR, 95% confidence interval): female (0.6, 0.4-0.9; P = 0.01), reduced training in the 7 d preinfection (1.03, 1.01-1.06; P = 0.003), presence of symptoms by anatomical region (any "chest and neck" [0.6, 0.4-0.8; P = 0.004] and any "whole body" [0.6, 0.4-0.9; P = 0.025]), and several specific symptoms. Multiple models show that the greater number of symptoms in each anatomical region (adjusted for training hours in the 7 d preinfection) was associated with prolonged RTT ( P < 0.05). CONCLUSIONS: Reduced preinfection training hours and the number of acute infection symptoms may predict prolonged RTT in athletes with recent SARS-CoV-2. These data can assist physicians as well as athletes/coaches in planning and guiding RTT. Future studies can explore whether these variables can be used to predict time to return to full performance and classify severity of acute respiratory infection in athletes.

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.

Prevalence of bacteriologically confirmed pulmonary tuberculosis in South Africa, 2017-19: a multistage, cluster-based, cross-sectional survey.

BACKGROUND: Tuberculosis remains an important clinical and public health issue in South Africa, which has one of the highest tuberculosis burdens in the world. We aimed to estimate the burden of bacteriologically confirmed pulmonary tuberculosis among people aged 15 years or older in South Africa. METHODS: This multistage, cluster-based, cross-sectional survey included eligible residents (age ≥15 years, who had slept in a house for ≥10 nights in the preceding 2 weeks) in 110 clusters nationally (cluster size of 500 people; selected by probability proportional-to-population size sampling). Participants completed face-to-face symptom questionnaires (for cough, weight loss, fever, and night sweats) and manually read digital chest X-ray screening. Screening was recorded as positive if participants had at least one symptom or an abnormal chest X-ray suggestive of tuberculosis, or a combination thereof. Sputum samples from participants who were screen-positive were tested by the Xpert MTB/RIF Ultra assay (first sample) and Mycobacteria Growth Indicator Tube culture (second sample), with optional HIV testing. Participants with a positive Mycobacterium tuberculosis complex culture were considered positive for bacteriologically confirmed pulmonary tuberculosis; when culture was not positive, participants with a positive Xpert MTB/RIF Ultra result with an abnormal chest X-ray suggestive of active tuberculosis and without current or previous tuberculosis were considered positive for bacteriologically confirmed pulmonary tuberculosis. FINDINGS: Between Aug 15, 2017, and July 28, 2019, 68 771 people were enumerated from 110 clusters, with 53 250 eligible to participate in the survey, of whom 35 191 (66·1%) participated. 9066 (25·8%) of 35 191 participants were screen-positive and 234 (0·7%) were identified as having bacteriologically confirmed pulmonary tuberculosis. Overall, the estimated prevalence of bacteriologically confirmed pulmonary tuberculosis was 852 cases (95% CI 679-1026) per 100 000 population; the prevalence was highest in people aged 35-44 years (1107 cases [95% CI 703-1511] per 100 000 population) and those aged 65 years or older (1104 cases [680-1528] per 100 000 population). The estimated prevalence was approximately 1·6 times higher in men than in women (1094 cases [95% CI 835-1352] per 100 000 population vs 675 cases [494-855] per 100 000 population). 135 (57·7%) of 234 participants with tuberculosis screened positive by chest X-ray only, 16 (6·8%) by symptoms only, and 82 (35·9%) by both. 55 (28·8%) of 191 participants with tuberculosis with known HIV status were HIV-positive. INTERPRETATION: Pulmonary tuberculosis prevalence in this survey was high, especially in men. Despite the ongoing burden of HIV, many participants with tuberculosis in this survey did not have HIV. As more than half of the participants with tuberculosis had an abnormal chest X-ray without symptoms, prioritising chest X-ray screening could substantially increase case finding. FUNDING: Global Fund, Bill & Melinda Gates Foundation, USAID.

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.

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.

High Rate of Asymptomatic Carriage Associated with Variant Strain Omicron.

The early widespread dissemination of Omicron indicates the urgent need to better understand the transmission dynamics of this variant, including asymptomatic spread among immunocompetent and immunosuppressed populations. In early December 2021, the Ubuntu clinical trial, designed to evaluate efficacy of the mRNA-1273 vaccine (Moderna) among persons living with HIV (PLWH), began enrolling participants. Nasal swabs are routinely obtained at the initial vaccination visit, which requires participants to be clinically well to receive their initial jab. Of the initial 230 participants enrolled between December 2 and December 17, 2021, 71 (31%) were PCR positive for SARS-CoV-2: all of whom were subsequently confirmed by S gene dropout to be Omicron; 48% of the tested samples had cycle threshold (CT) values <25 and 18% less than 20, indicative of high titers of asymptomatic shedding. Asymptomatic carriage rates were similar in SARS-CoV-2 seropositive and seronegative persons (27% respectively). These data are in stark contrast to COVID-19 vaccine studies conducted pre-Omicron, where the SARS-CoV-2 PCR positivity rate at the first vaccination visit ranged from <1%-2.4%, including a cohort of over 1,200 PLWH largely enrolled in South Africa during the Beta outbreak. We also evaluated asymptomatic carriage in a sub study of the Sisonke vaccine trial conducted in South African health care workers, which indicated 2.6% asymptomatic carriage during the Beta and Delta outbreaks and subsequently rose to 16% in both PLWH and PHLWH during the Omicron period.

Medical Encounters in a 90-km Ultramarathon Running Event: A 6-year Study in 103 131 Race Starters-SAFER XVII.

OBJECTIVE: To determine the incidence and nature of illness-related medical encounters (MEs) at a 90-km, ultramarathon, mass, community-based, endurance running event. DESIGN: Retrospective, descriptive epidemiological study. SETTING: Comrades Marathon (90 km), South Africa. PARTICIPANTS: One lakh three thousand one hundred thirty-one race starters over 6 years (2014-2019). INDEPENDENT VARIABLES: Incidence of moderate and serious/life-threatening MEs. MAIN OUTCOME MEASURES: All MEs were recorded by race medical doctors on race day each year. Medical encounters were recorded by severity, organ system, and final specific diagnosis (2019 consensus statement definition on mass community-based events). Incidences (I: per 1000 starters; 95% confidence intervals) were calculated for MEs. RESULTS: There were 1971 illness-related MEs, with an overall incidence of 19.1 (range, 18.3-20.0). The incidence for serious/life-threatening MEs was 1.8 (range, 1.6-2.1). Incidences of MEs by organ systems affected were as follows: fluid/electrolyte (8.8; 8.3-9.4), central nervous system (4.0; 3.7-4.5), and gastrointestinal system (2.9; 2.6-3.2). Dehydration (I = 7.5: 7.0-8.1) and exercise-associated muscle cramping (I = 3.2: 2.9-3.6) were the 2 most common specific diagnoses. CONCLUSION: The incidence of MEs in the 90-km Comrades Marathon was one of the highest incidences of MEs reported in an endurance running event (1 in 52 starters and 1 in 556 starters for serious/life-threatening MEs). Preventative measures to reduce MEs are needed, and further investigations into the risk factors associated with MEs could assist in managing the risk and better prepare athletes, race organizers, and medical directors.

Symptom cluster is associated with prolonged return-to-play in symptomatic athletes with acute respiratory illness (including COVID-19): a cross-sectional study-AWARE study I.

BACKGROUND: There are no data relating symptoms of an acute respiratory illness (ARI) in general, and COVID-19 specifically, to return to play (RTP). OBJECTIVE: To determine if ARI symptoms are associated with more prolonged RTP, and if days to RTP and symptoms (number, type, duration and severity) differ in athletes with COVID-19 versus athletes with other ARI. DESIGN: Cross-sectional descriptive study. SETTING: Online survey. PARTICIPANTS: Athletes with confirmed/suspected COVID-19 (ARICOV) (n=45) and athletes with other ARI (ARIOTH) (n=39). METHODS: Participants recorded days to RTP and completed an online survey detailing ARI symptoms (number, type, severity and duration) in three categories: 'nose and throat', 'chest and neck' and 'whole body'. We report the association between symptoms and RTP (% chance over 40 days) and compare the days to RTP and symptoms (number, type, duration and severity) in ARICOV versus ARIOTH subgroups. RESULTS: The symptom cluster associated with more prolonged RTP (lower chance over 40 days; %) (univariate analysis) was 'excessive fatigue' (75%; p<0.0001), 'chills' (65%; p=0.004), 'fever' (64%; p=0.004), 'headache' (56%; p=0.006), 'altered/loss sense of smell' (51%; p=0.009), 'Chest pain/pressure' (48%; p=0.033), 'difficulty in breathing' (48%; p=0.022) and 'loss of appetite' (47%; p=0.022). 'Excessive fatigue' remained associated with prolonged RTP (p=0.0002) in a multiple model. Compared with ARIOTH, the ARICOV subgroup had more severe disease (greater number, more severe symptoms) and more days to RTP (p=0.0043). CONCLUSION: Symptom clusters may be used by sport and exercise physicians to assist decision making for RTP in athletes with ARI (including COVID-19).

Effectiveness and cost-effectiveness of reactive, targeted indoor residual spraying for malaria control in low-transmission settings: a cluster-randomised, non-inferiority trial in South Africa.

BACKGROUND: Increasing insecticide costs and constrained malaria budgets could make universal vector control strategies, such as indoor residual spraying (IRS), unsustainable in low-transmission settings. We investigated the effectiveness and cost-effectiveness of a reactive, targeted IRS strategy. METHODS: This cluster-randomised, open-label, non-inferiority trial compared reactive, targeted IRS with standard IRS practice in northeastern South Africa over two malaria seasons (2015-17). In standard IRS clusters, programme managers conducted annual mass spray campaigns prioritising areas using historical data, expert opinion, and other factors. In targeted IRS clusters, only houses of index cases (identified through passive surveillance) and their immediate neighbours were sprayed. The non-inferiority margin was 1 case per 1000 person-years. Health service costs of real-world implementation were modelled from primary and secondary data. Incremental costs per disability-adjusted life-year (DALY) were estimated and deterministic and probabilistic sensitivity analyses conducted. This study is registered with ClinicalTrials.gov, NCT02556242. FINDINGS: Malaria incidence was 0·95 per 1000 person-years (95% CI 0·58 to 1·32) in the standard IRS group and 1·05 per 1000 person-years (0·72 to 1·38) in the targeted IRS group, corresponding to a rate difference of 0·10 per 1000 person-years (-0·38 to 0·59), demonstrating non-inferiority for targeted IRS (p<0·0001). Per additional DALY incurred, targeted IRS saved US$7845 (2902 to 64 907), giving a 94-98% probability that switching to targeted IRS would be cost-effective relative to plausible cost-effectiveness thresholds for South Africa ($2637 to $3557 per DALY averted). Depending on the threshold used, targeted IRS would remain cost-effective at incidences of less than 2·0-2·7 per 1000 person-years. Findings were robust to plausible variation in other parameters. INTERPRETATION: Targeted IRS was non-inferior, safe, less costly, and cost-effective compared with standard IRS in this very-low-transmission setting. Saved resources could be reallocated to other malaria control and elimination activities. FUNDING: Joint Global Health Trials.

Decadal epidemiology of malaria in KwaZulu-Natal, a province in South Africa targeting elimination.

BACKGROUND: Although malaria remains a noteworthy disease in South Africa, the provinces are at differing stages of the malaria elimination continuum. KwaZulu-Natal has consistently reported the lowest number of cases over the past 5 years and it is expected that the goal of elimination will be achieved in this province over the next few years. The study reports on few key indicators that realistically represents the provinces progress over the past decade. Local and imported morbidity and mortality is seen as the key indicator as is malaria in children under the age of five and pregnant women. The only vector control intervention in the province is indoor residual spraying (IRS) and this gives an estimate of the population protected by this intervention. METHODS: Trend analysis was used to examine the changing epidemiology in KwaZulu-Natal over the past decade from 2008 to 2018. The data used in this decadal analysis was obtained from the provincial Department of Health. Since malaria is a medically notifiable disease, all malaria cases diagnosed in the province are reported from health facilities and are captured in the malaria information system in the province. RESULTS: The results have shown that imported cases are on the increase whilst local cases are decreasing, in keeping with an elimination objective. Preventing secondary cases is the key to reaching elimination. Only 10% of the cases reported occur in children under 5 years whereas the cases in pregnant women account for about 1% of the reported cases. Over 85% of the houses receive IRS and this is also the same proportion of the population protected by the intervention. CONCLUSION: Several challenges to elimination have been identified but these are not insurmountable. Although there are major impediments to achieving elimination, the changing epidemiology suggests that major strides have been made in the past 10 years and KwaZulu-Natal is on track to achieving this milestone in the next few years.

The feasibility of malaria elimination in South Africa.

BACKGROUND: Following the last major malaria epidemic in 2000, malaria incidence in South Africa has declined markedly. The decrease has been so emphatic that South Africa now meets the World Health Organization (WHO) threshold for malaria elimination. Given the Millennium Development Goal of reversing the spread of malaria by 2015, South Africa is being urged to adopt an elimination agenda. This study aimed to determine the appropriateness of implementing a malaria elimination programme in present day South Africa. METHODS: An assessment of the progress made by South Africa in terms of implementing an integrated malaria control programme across the three malaria-endemic provinces was undertaken. Vector control and case management data were analysed from the period of 2000 until 2011. RESULTS: Both malaria-related morbidity and mortality have decreased significantly across all three malaria-endemic provinces since 2000. The greatest decline was seen in KwaZulu-Natal where cases decreased from 42,276 in 2000 to 380 in 2010 and deaths dropped from 122 in 2000 to six in 2010. Although there has been a 49.2 % (8,553 vs 4,214) decrease in the malaria cases reported in Limpopo Province, currently it is the largest contributor to the malaria incidence in South Africa. Despite all three provinces reporting average insecticide spray coverage of over 80%, malaria incidence in both Mpumalanga and Limpopo remains above the elimination threshold. Locally transmitted case numbers have declined in all three malaria provinces but imported case numbers have been increasing. Knowledge gaps in vector distribution, insecticide resistance status and drug usage were also identified. CONCLUSIONS: Malaria elimination in South Africa is a realistic possibility if certain criteria are met. Firstly, there must be continued support for the existing malaria control programmes to ensure the gains made are sustained. Secondly, cross border malaria control initiatives with neighbouring countries must be strongly encouraged and supported to reduce malaria in the region and the importation of malaria into South Africa. Thirdly, operational research, particularly on vector distribution and insecticide resistance status must be conducted as a matter of urgency, and finally, the surveillance systems must be refined to ensure the information required to inform an elimination agenda are routinely collected.