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Background RTS,S/AS01 is the first malaria vaccine to be approved and recommended for widespread implementation by the World Health Organization (WHO). Trials reported lower vaccine efficacies in higher-incidence sites, potentially due to a “rebound” in malaria cases in vaccinated children. When naturally acquired protection in the control group rises and vaccine protection in the vaccinated wanes concurrently, malaria incidence can become greater in the vaccinated than in the control group, resulting in negative vaccine efficacies. Methods Using data from the 2009–2014 phase III trial (NCT00866619) in Lilongwe, Malawi; Kintampo, Ghana; and Lambaréné, Gabon, we evaluate this hypothesis by estimating malaria incidence in each vaccine group over time and in varying transmission settings. After estimating transmission intensities using ecological variables, we fit models with 3-way interactions between vaccination, time, and transmission intensity. Results Over time, incidence decreased in the control group and increased in the vaccine group. Three-dose efficacy in the lowest-transmission-intensity group (0.25 cases per person-year [CPPY]) decreased from 88.2% to 15.0% over 4.5 years, compared with 81.6% to −27.7% in the highest-transmission-intensity group (3 CPPY). Conclusions These findings suggest that interventions, including the fourth RTS,S dose, that protect vaccinated individuals during the potential rebound period should be implemented for high-transmission settings.

Background: RTS,S/AS01 has been recommended by WHO for widespread implementation in medium to high malaria transmission settings. Previous analyses have noted lower vaccine efficacies in higher transmission settings, possibly due to the more rapid development of naturally acquired immunity in the control group. Methods: To investigate a reduced immune response to vaccination as a potential mechanism behind lower efficacy in high transmission areas, we examine initial vaccine antibody (anti-CSP IgG) response and vaccine efficacy against the first case of malaria to exclude the delayed malaria effect using data from three study areas (Kintampo, Ghana; Lilongwe, Malawi; Lambaréné, Gabon) from the 2009-2014 phase III trial (NCT00866619). Our key exposures are parasitemia during the vaccination series and malaria transmission intensity. We calculate vaccine efficacy (one minus hazard ratio) using a cox-proportional hazards model and allowing for the time-varying effect of RTS,S/AS01. Results: We find that antibody responses to the primary three-dose vaccination series were higher in Ghana than in Malawi and Gabon, but that neither antibody levels nor vaccine efficacy against the first case of malaria varied by transmission intensity or parasitemia during the primary vaccination series. Conclusions: We find that vaccine efficacy is unrelated to infections during vaccination. Contributing to a conflicting literature, our results suggest that vaccine efficacy is also unrelated to infections before vaccination, meaning that delayed malaria is likely the main reason for lower efficacy in high transmission settings, not reduced immune responses. This may be reassuring for implementation in high transmission settings, though further studies are needed.

Background RTS,S/AS01 is the first vaccine against malaria to undergo pilot implementation, beginning in 2019 and vaccinating 360,000 children per year in Malawi, Ghana, and Kenya. The four-dose vaccine is given as a primary three-dose series with a fourth dose given approximately 18 months later. The efficacy of RTS,S/AS01 was variable among the 11 sites participating in the 2009–2014 phase III trial (MALARIA-055, NCT00866619), possibly due to differences in transmission intensity. However, a within-site examination of environmental factors related to transmission intensity and their impact on vaccine efficacy has yet to be conducted. Methods We implemented the phase III RTS,S/AS01 trial at the Malawi site, which enrolled 1578 infants (6–12 weeks) and children (5–17 months) living in the Lilongwe District in Central Malawi and followed them for 3 years between 2009 and 2014. A global positioning system survey and an ecological questionnaire were conducted to collect participant household locations and characteristics, while additional data on background malaria prevalence were obtained from a concurrent Malaria Transmission Intensity (MTI) survey. Negative binomial regression models were used to assess whether the efficacy of the vaccine varied by estimated background malaria prevalence, household roof type, or amount of nearby vegetation. Results Vaccine efficacy did not significantly vary by estimated malaria prevalence or by roof type. However, increased vegetation cover was associated with an increase in the efficacy of the three-dose primary RTS,S/AS01 series in the 18 months before the fourth dose and a decrease in the efficacy of the primary vaccine series in the second 18 months following, if the fourth dose was not given. Vegetation cover did not alter the efficacy of the fourth dose in a statistically or practically significant manner. Conclusions Vegetation coverage in this study site might be a proxy for nearness to rivers or branching, shallow wetlands called “dambos” which could serve as breeding sites for mosquitoes. We observed statistically significant modification of the efficacy of RTS,S/AS01 by forest cover, suggesting that initial vaccine efficacy and the importance of the fourth dose varies based on ecological context. Trial registration Efficacy of GSK Biologicals’ Candidate Malaria Vaccine (257049) Against Malaria Disease Caused by P. falciparum Infection in Infants and Children in Africa. NCT00866619 prospectively registered 20 March 2009.

Black South Africans accounted for 6.2 out of 6.4 million people living with HIV in South Africa in 2012, highlighting extreme racial disparities in HIV infection. These racial disparities are the result of structural and historical factors, specifically, the racist policies which were facilitated by segregation before, during, and after Apartheid. First, we describe the theoretical context of how racist policies and segregation are linked to HIV prevalence. Next, using data from a 2012 national survey of South Africans (SABSSM IV) and Statistics South Africa (StatsSA), we describe the race-specific geospatial distribution of HIV in South Africa, provide empirical evidence for the impact of Apartheid on important risk factors for HIV infection, and describe the relationship between these risk factors and HIV within racial groups. Using multilevel logistic regression, we find that segregation increases the odds of HIV infection among Black South Africans, even after adjusting for many covariates which are sometimes blamed, in place of structural factors, for a higher HIV prevalence in Black South Africans. We found that the estimated odds of infection in the most segregated municipality was 1.95 (95% CI: 1.15, 3.32) times the odds of infection in the least segregated municipality for Black South Africans. In addition to segregation, we also find other covariates to be differentially associated with HIV infection depending on race, such as gender, age, and sexual behavior. We also find that the HIV infection odds ratio comparing Black and Coloured (i.e., multiple ethnic groups with mixed ancestries from Africa, Asia, and Europe) South Africans varies over space. These results continue to build evidence for the influence of structural and historical factors on the modern geospatial and demographic distribution of HIV.

Purpose of Review Global malaria elimination has little chance of success without an effective vaccine. The first malaria vaccine, RTS,S/AS01e, demonstrated moderate efficacy against clinical malaria in phase III trials and is undergoing large-scale effectiveness trials in Africa. Importantly, the vaccine did not perform equally well between phase III study sites. Though reasons for the moderate efficacy and this variation are unclear, various mechanisms have been suggested. This review summarizes the recent literature on such mechanisms, with a focus on those involving landscape ecology, parasite antigenic variation, and human host genetic differences. Recent Findings Transmission intensity may have a role pre- and post-vaccination in modulating immune responses to the vaccine. Furthermore, malaria incidence may “rebound” in vaccinated populations living in high transmission intensity settings. There is growing evidence that both genetic variation in the parasite circumsporozoite protein and variation of human host genetic factors affect RTS,S vaccine efficacy. These genetic factors may be interacting in complex ways to produce variation in the natural and vaccine-induced immune responses that protect against malaria. Summary Due to the modest efficacy of RTS,S/AS01e, the combinations of factors (ecological, parasite, human host) impacting its effectiveness must be clearly understood, as this information will be critical for implementation policy and future vaccine designs.

SARS-CoV-2 testing data in North Carolina during the first three months of the state's COVID-19 pandemic were analyzed to determine if there were disparities among intersecting axes of identity including race, Latinx ethnicity, age, urban-rural residence, and residence in a medically underserved area. Demographic and residential data were used to reconstruct patterns of testing metrics (including tests per capita, positive tests per capita, and test positivity rate which is an indicator of sufficient testing) across race-ethnicity groups and urban-rural populations separately. Across the entire sample, 13.1% (38,750 of 295,642) of tests were positive. Within racial-ethnic groups, 11.5% of all tests were positive among non-Latinx (NL) Whites, 22.0% for NL Blacks, and 66.5% for people of Latinx ethnicity. The test positivity rate was higher among people living in rural areas across all racial-ethnic groups. These results suggest that in the first three months of the COVID-19 pandemic, access to COVID-19 testing in North Carolina was not evenly distributed across racial-ethnic groups, especially in Latinx, NL Black and other historically marginalized populations, and further disparities existed within these groups by gender, age, urban-rural status, and residence in a medically underserved area.

Limited evidence is available to guide treatment of coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A hyperinflammatory state mediated by interleukin-6 (IL-6) has been proposed as a driver of severe disease. Use of the IL-6 receptor inhibitor tocilizumab for severe COVID-19 was first reported in China, where a case series described marked improvements in inflammatory markers, fever, oxygen requirement, and outcomes following its administration. Here, we provide the first description of a tocilizumab-treated cohort of patients with COVID-19 in the United States. We describe 11 patients from a single academic medical center, nine (82%) of whom were critically ill requiring mechanical ventilation in an intensive care unit at the time of tocilizumab administration. C-reactive protein levels decreased in all patients following treatment (median 211.6 pre- vs. 19.7 mg/L 5 days post-tocilizumab [p=0.001]). When IL-6 levels were obtained before and after therapy, wide variation was seen in baseline levels; post-dose IL-6 concentrations were consistently increased. In contrast to prior reports, we did not observe significant clinical improvement in temperature or oxygen requirements in most patients. Two patients were discharged (18%), five remained in critical condition in the intensive care unit (46%), one was weaned off the ventilator to room air (9%), and three died (27%). Our findings suggest that tocilizumab should be used with caution in severe and critically ill patients and highlight the need for data from randomized controlled trials to determine its efficacy in the treatment of COVID-19.

The interleukin-6 receptor antagonist tocilizumab became widely used early in the coronavirus disease 2019 (COVID-19) pandemic based on small observational studies that suggested clinical benefit in COVID-19 patients with a hyperinflammatory state. To inform our local treatment algorithms in the absence of randomized clinical trial results, we performed a rapid analysis of the first 11 hospitalized COVID-19 patients treated with tocilizumab at our academic medical center. We report their early clinical outcomes and describe the process by which we assembled a team of diverse trainees and stakeholders to extract, analyze, and disseminate data during a time of clinical uncertainty.

The objective of this paper is to determine whether deep tubewells installed through arsenic mitigation efforts in rural Bangladesh provide better drinking water microbial quality compared to shallow tubewells. We conducted a stratified random cross-sectional survey of 484 households to assess microbial contamination of deep tubewell water at source and at point of use (POU) compared to shallow tubewell water using the Compartment Bag Test. In addition, we measured storage time, distance, travel time and ownership status among both sets of users to assess deep tubewell efficacy and under what conditions they offer poorer or better water quality. Differences in tubewell characteristics were compared using non-parametric Mann-Whitney U tests and differences in proportions using Z-test. Prevalence ratios of microbial contamination stratified by water quality, storage time and distance to tubewells and ownership were estimated using unadjusted Mantel-Haenszel tests. There was not a significant difference in microbial contamination between shallow and deep tubewells at source. The presence of POU water microbial contamination in storage containers in deep tubewell households was 1.11 times the prevalence in shallow tubewell storage containers (95% CI = 0.97 – 1.27). Deep tubewell users stored water longer and walked significantly farther to obtain water compared to shallow tubewell users. Among deep tubewell households, those residing farther away from the source were 1.24 times as likely to drink contaminated water from storage containers compared to those located nearby (95% CI = 1.04 – 1.48). Our findings suggest that deep tubewells have comparable water quality to shallow tubewells at source, but increasing distance from the household exacerbates risk of microbial contamination at POU.

Deep tubewells are a key component of arsenic mitigation programs in rural Bangladesh. Compared to widely prevalent shallow tubewells, deep tubewells reduce ground-water arsenic exposure and provide better microbial water quality at source. However, the benefits of clean drinking-water at these more distant sources may be abated by higher levels of microbial contamination at point-of-use. One such potential pathway is the use of contaminated surface water for washing drinking-water storage containers. The aim of this study is to compare the prevalence of surface water use for washing drinking-water storage containers among deep and shallow tubewell users in a cohort of 499 rural residents in Matlab, Bangladesh. We employ a multi-level logistic regression model to measure the effect of tubewell type and ownership status on the odds of washing storage containers with surface water. Results show that deep tubewell users who do not own their drinking-water tubewell, have 6.53 times the odds [95% CI: 3.56, 12.00] of using surface water for cleaning storage containers compared to shallow tubewell users, who own their drinking-water source. Even deep tubewell users who own a private well within walking distance have 2.53 [95% CI: 1.36, 4.71] times the odds of using surface water compared to their shallow tubewell counterparts. These results highlight the need for interventions to limit risk substitution, particularly the increased use of contaminated surface water when access to drinking water is reduced. Increasing ownership of and proximity to deep tubewells, although crucial, is insufficient to achieve equity in safe drinking-water access across rural Bangladesh.