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Background: We assessed the safety and immunogenicity of the RTS,S/AS01 malaria vaccine in a subset of children identified as HIV-infected during a large phase III randomized controlled trial conducted in seven sub-Saharan African countries., Methods: Infants 6-12 weeks and children 5-17 months old were randomized to receive 4 RTS,S/AS01 doses (R3R group), 3 RTS,S/AS01 doses plus 1 comparator vaccine dose (R3C group), or 4 comparator vaccine doses (C3C group) at study months 0, 1, 2 and 20. Infants and children with WHO stage III/IV HIV disease were excluded but HIV testing was not routinely performed on all participants; our analyses included children identified as HIV-infected based on medical history or clinical suspicion and confirmed by polymerase chain reaction or antibody testing. Serious adverse events (SAEs) and anti-circumsporozoite (CS) antibodies were assessed., Results: Of 15459 children enrolled in the trial, at least 1953 were tested for HIV and 153 were confirmed as HIV-infected (R3R: 51; R3C: 54; C3C: 48). Among these children, SAEs were reported for 92.2% (95% CI: 81.1-97.8) in the R3R, 85.2% (72.9-93.4) in the R3C and 87.5% (74.8-95.3) in the C3C group over a median follow-up of 39.3, 39.4 and 38.3 months, respectively. Fifteen HIV-infected participants in each group (R3R: 29.4%, R3C: 27.8%, C3C: 31.3%) died during the study. No deaths were considered vaccination-related. In a matched case-control analysis, 1 month post dose 3 anti-CS geometric mean antibody concentrations were 193.3 EU/mL in RTS,S/AS01-vaccinated HIV-infected children and 491.5 EU/mL in RTS,S/AS01-vaccinated immunogenicity controls with unknown or negative HIV status (p = 0.0001)., Conclusions: The safety profile of RTS,S/AS01 in HIV-infected children was comparable to that of the comparator (meningococcal or rabies) vaccines. RTS,S/AS01 was immunogenic in HIV-infected children but antibody concentrations were lower than in children with an unknown or negative HIV status., Clinical Trial Registration: ClinicalTrials.gov: NCT00866619., (Copyright © 2019 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Unprecedented global efforts to prevent malaria morbidity and mortality in sub-Saharan Africa have saved hundreds of thousands of lives across the continent in the last two decades. This study aims to determine how the comparative efficacy and safety of available malaria control interventions intended to improve maternal and child health outcomes have changed over time considering the varied epidemiological contexts on the continent., Methods: We will review all randomised controlled trials that investigated malaria control interventions in pregnant women in sub-Saharan Africa and were published between January 1980 and December 2018. We will subsequently use network meta-regression to estimate temporal trends in the relative and absolute efficacy and safety of Intermittent Preventive Treatments, Intermittent Screening and Treatments, Insecticide-treated bed nets, and their combinations, and predict their ranking according to their relative and absolute efficacy and safety over time. Our outcomes will include 12 maternal and 7 child mortality and morbidity outcomes, known to be associated with either malaria infection or control. We will use intention-to-treat analysis to derive our estimates and meta-regression to estimate temporal trends and the effect modification by HIV infection, malaria endemicity and Plasmodium falciparum resistance to sulfadoxine-pyrimethamine, while adjusting for multiple potential confounders via propensity score calibration., Prospero Registration Number: CRD42018095138., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A phase III, double-blind, randomized, controlled trial (NCT00866619) in sub-Saharan Africa showed RTS,S/AS01 vaccine efficacy against malaria. We now present in-depth safety results from this study. 8922 children (enrolled at 5-17 months) and 6537 infants (enrolled at 6-12 weeks) were 1:1:1-randomized to receive 4 doses of RTS,S/AS01 (R3R) or non-malaria control vaccine (C3C), or 3 RTS,S/AS01 doses plus control (R3C). Aggregate safety data were reviewed by a multi-functional team. Severe malaria with Blantyre Coma Score ≤2 (cerebral malaria [CM]) and gender-specific mortality were assessed post-hoc . Serious adverse event (SAE) and fatal SAE incidences throughout the study were 24.2%-28.4% and 1.5%-2.5%, respectively across groups; 0.0%-0.3% of participants reported vaccination-related SAEs. The incidence of febrile convulsions in children was higher during the first 2-3 days post-vaccination with RTS,S/AS01 than with control vaccine, consistent with the time window of post-vaccination febrile reactions in this study (mostly the day after vaccination). A statistically significant numerical imbalance was observed for meningitis cases in children (R3R: 11, R3C: 10, C3C: 1) but not in infants. CM cases were more frequent in RTS,S/AS01-vaccinated children (R3R: 19, R3C: 24, C3C: 10) but not in infants. All-cause mortality was higher in RTS,S/AS01-vaccinated versus control girls (2.4% vs 1.3%, all ages) in our setting with low overall mortality. The observed meningitis and CM signals are considered likely chance findings, that - given their severity - warrant further evaluation in phase IV studies and WHO-led pilot implementation programs to establish the RTS,S/AS01 benefit-risk profile in real-life settings.

Background: Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design., Methods: In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years., Results: We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses., Conclusions: AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Antibiotic resistance in Africa is increasing but insufficiently recognized as a public health problem. However, there are scarce data for antimicrobial resistance trends among bloodstream isolates in sub-Saharan Africa. Antimicrobial drug resistance trends among bacteria isolated from blood of children < 15 years of age admitted to the Manhiça District Hospital in Mozambique during May 2001-April 2006 were monitored by disk diffusion. We documented a linear trend of increasing resistance throughout the study period to chloramphenicol among isolates of Non-typhi Salmonella (P < 0.001), Escherichia coli (P = 0.002), Staphylococcus aureus (P < 0.001), and Haemophilus influenzae (P < 0.001). Increasing resistance to ampicillin was also observed for H. influenzae isolates (P < 0.001). We report trends of increasing resistance among the most frequent etiologies of bacteremia to the most commonly used antibiotics for empirical therapy in this community. Quinolones and third-generation cephalosporines may be needed in the short term to manage community-acquired infections.

Objective: To provide internationally comparable data on the frequencies of different causes of death., Methods: We analysed verbal autopsies obtained during 1999 -2002 from 12 demographic surveillance sites in sub-Saharan Africa and Bangladesh to find cause-specific and age-specific mortality rates. The cause-of-death codes used by the sites were harmonized to conform to the ICD-10 system, and summarized with the classification system of the Global Burden of Disease 2000 (Version 2)., Findings: Causes of death in the African sites differ strongly from those in Bangladesh, where there is some evidence of a health transition from communicable to noncommunicable diseases, and little malaria. HIV dominates in causes of mortality in the South African sites, which contrast with those in highly malaria endemic sites elsewhere in sub-Saharan Africa (even in neighbouring Mozambique). The contributions of measles and diarrhoeal diseases to mortality in sub-Saharan Africa are lower than has been previously suggested, while malaria is of relatively greater importance., Conclusion: The different patterns of mortality we identified may be a result of recent changes in the availability and effectiveness of health interventions against childhood cluster diseases.