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: An estimated 3 billion people, largely in low- and middle-income countries, rely on unclean fuels for cooking, heating, and lighting to meet household energy needs. The resulting exposure to household air pollution (HAP) is a leading cause of pneumonia, chronic lung disease, and other adverse health effects. In the last decade, randomized controlled trials of clean cooking interventions to reduce HAP have been conducted. We aim to provide guidance on how to interpret the findings of these trials and how they should inform policy makers and practitioners. Methods: We assembled a multidisciplinary working group of international researchers, public health practitioners, and policymakers with expertise in household air pollution from within academia, the American Thoracic Society, funders, nongovernmental organizations, and global organizations, including the World Bank and the World Health Organization. We performed a literature search, convened four sessions via web conference, and developed consensus conclusions and recommendations via the Delphi method. Results: The committee reached consensus on 14 conclusions and recommendations. Although some trials using cleaner-burning biomass stoves or cleaner-cooking fuels have reduced HAP exposure, the committee was divided (with 55% saying no and 45% saying yes) on whether the studied interventions improved measured health outcomes. Conclusions: HAP is associated with adverse health effects in observational studies. However, it remains unclear which household energy interventions reduce exposure, improve health, can be scaled, and are sustainable. Researchers should engage with policy makers and practitioners working to scale cleaner energy solutions to understand and address their information needs.

Repeated exposure to household air pollution may intermittently raise blood pressure (BP) and affect cardiovascular outcomes. We investigated whether hourly carbon monoxide (CO) exposures were associated with acute increases in ambulatory blood pressure (ABP); and secondarily, if switching to an improved cookstove was associated with BP changes. We also evaluated the feasibility of using 24-h ambulatory blood pressure monitoring (ABPM) in a cohort of pregnant women in Ghana. Participants were 44 women enrolled in the Ghana Randomized Air Pollution and Health Study (GRAPHS). For 27 of the women, BP was measured using 24-h ABPM; home blood pressure monitoring (HBPM) was used to measure BP in the remaining 17 women. Personal CO exposure monitoring was conducted alongside the BP monitoring. ABPM revealed that peak CO exposure (defined as ≥4.1 ppm) in the 2 hours prior to BP measurement was associated with elevations in hourly systolic BP (4.3 mmHg [95% CI: 1.1, 7.4]) and diastolic BP (4.5 mmHg [95% CI: 1.9, 7.2]), as compared to BP following lower CO exposures. Women receiving improved cookstoves had lower post-intervention SBP (within-subject change in SBP of −2.1 mmHg [95% CI: -6.6, 2.4] as compared to control), though this result did not reach statistical significance. 98.1% of expected 24-h ABPM sessions were successfully completed, with 92.5% of them valid according to internationally defined criteria. We demonstrate an association between acute exposure to carbon monoxide and transient increases in BP in a West African setting. ABPM shows promise as an outcome measure for assessing cardiovascular health benefits of cookstove interventions. The GRAPHS trial was registered with clinicaltrials.gov on 13 April 2011 with the identifier NCT01335490 .

Background: Associations between prenatal household air pollution (HAP) exposure or cookstove intervention to reduce HAP and cord blood mononuclear cell (CBMC) mitochondrial deoxyribonucleic acid copy number (mtDNAcn), an oxidative stress biomarker, are unknown. Materials and Methods: Pregnant women were recruited and randomized to one of two cookstove interventions, including a clean-burning liquefied petroleum gas (LPG) stove, or control. Prenatal HAP exposure was determined by serial, personal carbon monoxide (CO) measurements. CBMC mtDNAcn was measured by quantitative polymerase chain reaction. Multivariable linear regression determined associations between prenatal CO and cookstove arm on mtDNAcn. Associations between mtDNAcn and birth outcomes and effect modification by infant sex were explored. Results: LPG users had the lowest CO exposures (p = 0.02 by ANOVA). In boys only, average prenatal CO was inversely associated with mtDNAcn (β = -14.84, SE = 6.41, p = 0.03, per 1ppm increase in CO). When examined by study arm, LPG cookstove had the opposite effect in all children (LPG β = 19.34, SE = 9.72, p = 0.049), but especially boys (β = 30.65, SE = 14.46, p = 0.04), as compared to Control. Increased mtDNAcn was associated with improved birth outcomes. Conclusions: Increased prenatal HAP exposure reduces CBMC mtDNAcn, suggesting cumulative prenatal oxidative stress injury. An LPG stove intervention may reverse this effect. Boys appear most susceptible.

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. 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. 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). 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. ClinicalTrials.gov: NCT00866619.

Associations between prenatal household air pollution exposure (HAP), newborn telomere length and early childhood blood pressure are unknown. Methods: Pregnant women were randomized to liquefied petroleum gas (LPG) stove, improved biomass stove or control (traditional, open fire cook stove). HAP was measured by personal carbon monoxide (CO) (n = 97) and fine particulate matter (PM_2.5) (n = 60). At birth, cord blood mononuclear cells (CBMCs) were collected for telomere length (TL) analyses. At child age four years, we measured resting blood pressure (BP) (n = 97). We employed multivariable linear regression to determine associations between prenatal HAP and cookstove arm and assessed CBMC relative to TL separately. We then examined associations between CBMC TL and resting BP. Results: Higher prenatal PM_2.5 exposure was associated with reduced TL (β = −4.9% (95% CI −8.6, −0.4), p = 0.03, per 10 ug/m³ increase in PM_2.5). Infants born to mothers randomized to the LPG cookstove had longer TL (β = 55.3% (95% CI 16.2, 109.6), p < 0.01)) compared with control. In all children, shorter TL was associated with higher systolic BP (SBP) (β = 0.35 mmHg (95% CI 0.001, 0.71), p = 0.05, per 10% decrease in TL). Increased prenatal HAP exposure is associated with shorter TL at birth. Shorter TL at birth is associated with higher age four BP, suggesting that TL at birth may be a biomarker of HAP-associated disease risk.