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The radiation-attenuated Plasmodium falciparum sporozoite (PfSPZ) vaccine provides protection against P. falciparum infection in malaria-naive adults. Preclinical studies show that T cell-mediated immunity is required for protection and is readily induced in humans after vaccination. However, previous malaria exposure can limit immune responses and vaccine efficacy (VE) in adults. We hypothesized that infants with less previous exposure to malaria would have improved immunity and protection. We conducted a multi-arm, randomized, double-blind, placebo-controlled trial in 336 infants aged 5–12 months to determine the safety, tolerability, immunogenicity and efficacy of the PfSPZ Vaccine in infants in a high-transmission malaria setting in western Kenya ( NCT02687373 ). Groups of 84 infants each received 4.5 × 105, 9.0 × 105 or 1.8 × 106 PfSPZ Vaccine or saline three times at 8-week intervals. The vaccine was well tolerated; 52 (20.6%) children in the vaccine groups and 20 (23.8%) in the placebo group experienced related solicited adverse events (AEs) within 28 d postvaccination and most were mild. There was 1 grade 3-related solicited AE in the vaccine group (0.4%) and 2 in the placebo group (2.4%). Seizures were more common in the highest-dose group (14.3%) compared to 6.0% of controls, with most being attributed to malaria. There was no significant protection against P. falciparum infection in any dose group at 6 months (VE in the 9.0 × 105 dose group = −6.5%, P = 0.598, the primary statistical end point of the study). VE against clinical malaria 3 months after the last dose in the highest-dose group was 45.8% (P = 0.027), an exploratory end point. There was a dose-dependent increase in antibody responses that correlated with VE at 6 months in the lowest- and highest-dose groups. T cell responses were undetectable across all dose groups. Detection of Vδ2+Vγ9+ T cells, which have been correlated with induction of PfSPZ Vaccine T cell immunity and protection in adults, were infrequent. These data suggest that PfSPZ Vaccine-induced T cell immunity is age-dependent and may be influenced by Vδ2+Vγ9+ T cell frequency. Since there was no significant VE at 6 months in these infants, these vaccine regimens will likely not be pursued further in this age group. The PfSPZ Vaccine does not protect infants from infection with Plasmodium falciparum, the major cause of malaria.

PfSPZ Vaccine, composed of radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum sporozoites, is administered by direct venous inoculation (DVI) for maximal efficacy against malaria. A critical issue for advancing vaccines that are administered intravenously is the ability to efficiently administer them across multiple age groups. As part of a pediatric safety, immunogenicity, and efficacy trial in western Kenya, we evaluated the feasibility and tolerability of DVI, including ease of venous access, injection time, and crying during the procedure across age groups. Part 1 was an age de-escalation, dose escalation trial in children aged 13 months-5 years and infants aged 5-12 months; part 2 was a vaccine efficacy trial including only infants, using the most skilled injectors from part 1. Injectors could use a vein viewer, if needed. A total of 1222 injections (target 0.5 mL) were initiated by DVI in 511 participants (36 were 5-9-year-olds, 65 were 13-59-month-olds, and 410 infants). The complete volume was injected in 1185/1222 (97.0%) vaccinations, 1083/1185 (91.4%) achieved with the first DVI. 474/511 (92.8%) participants received only complete injections, 27/511 (5.3%) received at least one partial injection (

Background Despite available control strategies, malaria morbidity and mortality, especially in infants and young children in sub-Saharan Africa, remain intractable. Malaria vaccination could substantially reduce malaria episodes and deaths. One vaccine candidate is the whole sporozoite PfSPZ Vaccine, consisting of irradiated cryopreserved sporozoites administered by direct venous inoculation (DVI). DVI may be less acceptable than more familiar administration routes, particularly intramuscular. As part of a PfSPZ Vaccine trial among infants in western Kenya, a qualitative study was conducted to explore caregiver and community perceptions of the malaria vaccine trial, including the unique DVI administration procedure. Methods Twelve focus groups and 28 in-depth interviews explored perceptions of the DVI procedure in infants, factors influencing trial acceptability, and barriers to sustained trial participation. Purposively sampled participants included mothers of enrolled children, fathers and mothers who withdrew their children from the trial, village elders, and study clinicians from two trial enrollment sites. An iterative, multi-stage analytic approach, adapted from the Framework Method, was used to synthesize and interpret textual data. Results Desires to prevent malaria and participation incentives (e.g., free consultations and medication) motivated caregivers to enroll their children in the trial. However, numerous factors also demotivated trial participation. Family members’ (i.e., fathers') objections to required blood draws were cited most frequently as drivers of early trial withdrawal, in many cases prior to receiving any vaccine. Among mothers whose children received PfSPZ Vaccine (or placebo), many spoke favourably of DVI administration, describing improved tolerability relative to intramuscularly administered immunizations. Other trial-related challenges cited by caregivers included negative interactions with study clinicians and perceived delays in administering trial procedures. Conclusions Despite high acceptance of DVI among caregivers whose children received PfSPZ Vaccine (or placebo), objections to trial procedures from other non-sensitized household and family members prompted early trial withdrawal and inhibited successful completion of trial procedures for some infants. Implications for future trials include targeting heads of household during sensitization and recruitment activities, as well as equipping trial staff to effectively respond to participant and community concerns regarding trial procedures.

Introduction: In tropical Africa, data about influenza-associated illness burden are needed to assess potential benefits of influenza vaccination among pregnant women. We estimated the incidence of influenza among pregnant women and their infants in Siaya County, Kenya. Methods: We enrolled women at

Background Data on congenital cytomegalovirus (CMV) infection in Africa are limited. Objective To describe the prevalence of congenital CMV infection in a population with high prevalence of maternal HIV and malaria infection in western Kenya. Study design We screened newborns for CMV by polymerase chain reaction assay of saliva swabs and dried blood spots (DBS), and assessed maternal CMV immunoglobulin G (IgG) status by testing serum eluted from newborn’s DBS. We calculated adjusted prevalence ratios (aPRs) using log-binomial regression models. Results Among 1066 mothers, 210 (19·7%) had HIV infection and 207 (19·4%) had malaria infection; 33 (3·1%) mothers had both. Maternal CMV IgG prevalence was 93·1% (95% confidence interval [CI]: 88·3%–96·0%). Among 1078 newborns (12 sets of twins), 39 (3·6%, 95% CI: 2·7–4·9%) were CMV positive. The prevalence of congenital CMV infection by maternal HIV and malaria infection status was 5·0% (95% CI: 2·7–9·2%) for HIV only, 5·1% (95% CI: 2·7–9·4%) for malaria only, 8·8 (95% CI: 3·1–23·0) for HIV and malaria co-infection, and 2·6% (95% CI: 1·7–4·1%) for none. Congenital CMV infection was independently associated with maternal HIV infection (aPR=2·1; 95% CI: 1·0–4·2), adjusting for maternal age, parity, and malaria infection. Conclusions The prevalence of congenital CMV infection was higher than the 0·2–0·7% in developed countries. Maternal HIV infection may increase the risk of congenital CMV infection, but the role of maternal malaria on intrauterine transmission of CMV remains unclear.

Background The whole Plasmodium falciparum sporozoite (PfSPZ) vaccine is being evaluated for malaria prevention. The vaccine is administered intravenously for maximal efficacy. Direct venous inoculation (DVI) with PfSPZ vaccine has been safe, tolerable, and feasible in adults, but safety data for children and infants are limited. Methods We conducted an age de-escalation, dose-escalation randomized controlled trial in Siaya County, western Kenya. Children and infants (aged 5–9 years, 13–59 months, and 5–12 months) were enrolled into 13 age-dose cohorts of 12 participants and randomized 2:1 to vaccine or normal saline placebo in escalating doses: 1.35 × 105, 2.7 × 105, 4.5 × 105, 9.0 × 105, and 1.8 × 106 PfSPZ, with the 2 highest doses given twice, 8 weeks apart. Solicited adverse events (AEs) were monitored for 8 days after vaccination, unsolicited AEs for 29 days, and serious AEs throughout the study. Blood taken prevaccination and 1 week postvaccination was tested for immunoglobulin G antibodies to P. falciparum circumsporozoite protein (PfCSP) using enzyme-linked immunosorbent assay. Results Rates of AEs were similar in vaccinees and controls for solicited (35.7% vs 41.5%) and unsolicited (83.9% vs 92.5%) AEs, respectively. No related grade 3 AEs, serious AEs, or grade 3 laboratory abnormalities occurred. Most (79.0%) vaccinations were administered by a single DVI. Among those in the 9.0 × 105 and 1.8 × 106 PfSPZ groups, 36 of 45 (80.0%) vaccinees and 4 of 21 (19.0%) placebo controls developed antibodies to PfCSP (P < .001). Conclusions PfSPZ vaccine in doses as high as 1.8 × 106 can be administered to infants and children by DVI, and was safe, well tolerated, and immunogenic. Clinical Trials Registration NCT02687373.

Baseline innate immune signatures can influence protective immunity following vaccination. Here, we used systems transcriptional analysis to assess the molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole sporozoite PfSPZ Vaccine in African infants. Innate immune activation and myeloid signatures at pre-vaccination baseline correlated with protection from Plasmodium falciparum infection in placebo controls, while the same signatures predicted susceptibility to infection among infants who received the highest and most protective dose of the PfSPZ Vaccine. Machine learning identified monocytes and an antigen presentation signature as pre-vaccination features predictive of malaria infection after highest-dose PfSPZ vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against malaria infection in mice while diminishing the CD8+ T cell response to radiation-attenuated sporozoites. These data establish a dichotomous role of innate stimulation for malaria protection and induction of protective immunity of whole-sporozoite malaria vaccines.

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.

Multidrug-resistant non-typhoidal Salmonella (NTS) infection has emerged as a prominent cause of invasive infections in Africa. We investigated the prevalence of ceftriaxone-resistant invasive NTS infections, conducted exploratory analysis of risk factors for resistance, and described antimicrobial use in western Kenya. We conducted a secondary analysis of existing laboratory, epidemiology, and clinical data from three independent projects, a malaria vaccine trial, a central nervous system (CNS) study, and the International Emerging Infections Program morbidity surveillance (surveillance program) during 2009-2014. We calculated odds ratios (OR) with 95% confidence intervals (CI) for ceftriaxone-resistant NTS infections compared with ceftriaxone-susceptible infections. We surveyed hospitals, pharmacies, and animal drug retailers about the availability and use of antimicrobials. In total, 286 invasive NTS infections were identified in the three projects; 43 NTS isolates were ceftriaxone- resistant. The absolute prevalence of ceftriaxone resistance varied among these methodologically diverse projects, with 18% (16/90) of isolates resistant to ceftriaxone in the vaccine trial, 89% (16/18) in the CNS study, and 6% (11/178) in the surveillance program. Invasive ceftriaxone-resistant infections increased over time. Most ceftriaxone-resistant isolates were co-resistant to multiple other antimicrobials. Having an HIV-positive mother (OR = 3.7; CI = 1.2-11.4) and taking trimethoprim-sulfamethoxazole for the current illness (OR = 9.6, CI = 1.2-78.9) were significantly associated with acquiring ceftriaxone-resistant invasive NTS infection. Ceftriaxone and other antibiotics were widely prescribed; multiple issues related to prescription practices and misuse were identified. In summary, ceftriaxone-resistant invasive NTS infection is increasing and limiting treatment options for serious infections. Efforts are ongoing to address the urgent need for improved microbiologic diagnostic capacity and an antimicrobial surveillance system in Kenya.

Infections of the central nervous system (CNS) are often acute, with significant morbidity and mortality. Routine diagnosis of such infections is limited in developing countries and requires modern equipment in advanced laboratories that may be unavailable to a number of patients in sub-Saharan Africa. We developed a TaqMan array card (TAC) that detects multiple pathogens simultaneously from cerebrospinal fluid. The 21-pathogen CNS multiple-pathogen TAC (CNS-TAC) assay includes two parasites ( Balamuthia mandrillaris and Acanthamoeba ), six bacterial pathogens ( Streptococcus pneumonia e, Haemophilus influenzae , Neisseria meningitidis , Mycoplasma pneumoniae , Mycobacterium tuberculosis , and Bartonella ), and 13 viruses (parechovirus, dengue virus, Nipah virus, varicella-zoster virus, mumps virus, measles virus, lyssavirus, herpes simplex viruses 1 and 2, Epstein-Barr virus, enterovirus, cytomegalovirus, and chikungunya virus). The card also includes human RNase P as a nucleic acid extraction control and an internal manufacturer control, GAPDH (glyceraldehyde-3-phosphate dehydrogenase). This CNS-TAC assay can test up to eight samples for all 21 agents within 2.5 h following nucleic acid extraction. The assay was validated for linearity, limit of detection, sensitivity, and specificity by using either live viruses (dengue, mumps, and measles viruses) or nucleic acid material (Nipah and chikungunya viruses). Of 120 samples tested by individual real-time PCR, 35 were positive for eight different targets, whereas the CNS-TAC assay detected 37 positive samples across nine different targets. The CNS-TAC assays showed 85.6% sensitivity and 96.7% specificity. Therefore, the CNS-TAC assay may be useful for outbreak investigation and surveillance of suspected neurological disease.

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\xC2\xA0months) and 6537 infants (enrolled at 6-12\xC2\xA0weeks) 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 \xE2\x89\xA42 (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.

Malaria remains a major global public health concern, especially in sub-Saharan Africa. The RTS,S/AS01 malaria candidate vaccine was reviewed by the European Medicines Agency and received a positive scientific opinion; WHO subsequently recommended pilot implementation in sub-Saharan African countries. Because malaria and HIV overlap geographically, HIV-infected children should be considered for RTS,S/AS01 vaccination. We therefore aimed to assess the safety of RTS,S/AS01 in HIV-infected children at two sites in western Kenya.We did a randomised, double-blind, controlled trial at the clinical trial sites of the Kenya Medical Research Institute (KEMRI)-Walter Reed Army Institute of research in Kisumu and the KEMRI/US Centers for Disease Control and Prevention in Siaya. Eligible participants were infants and children aged from 6 weeks to 17 months with WHO stage 1 or 2 HIV disease (documented positive by DNA PCR), whether or not they were receiving antiretroviral therapy (ART). We randomly assigned participants (1:1) to receive three doses of either RTS,S/AS01 or rabies vaccine (both 0·5 mL per dose by intramuscular injection), given once per month at 0, 1, and 2 months. We did the treatment allocation using a web-based central randomisation system stratified by age (6 weeks-4 months, 5-17 months), and by baseline CD4% (10, 10-14, 15-19, and ≥20). Data were obtained in an observer-blind manner, and the vaccine recipient, their parent or carer, the funder, and investigators responsible for the assessment of endpoints were all masked to treatment allocation (only staff responsible for the preparation and administration of the vaccines were aware of the assignment and these individuals played no other role in the study). We provided ART, even if the participants were not receiving ART before the study, and daily co-trimoxazole for prevention of opportunistic infections. The primary outcome was the occurrence of serious adverse events until 14 months after dose 1 of the vaccine, assessed in the intention-to-treat population. This trial was registered at ClinicalTrials.gov, number NCT01148459.Between July 30, 2010, and May 24, 2013, we enrolled 200 children to our study and randomly assigned 99 to receive RTS,S/AS01 and 101 to receive rabies vaccine. 177 (89%) of the 200 children enrolled completed 14 months of follow-up. Serious adverse events were noted in 41 (41·4%, 95% CI 31·6-51·8) of 99 RTS,S/AS01 recipients and 37 (36·6%, 27·3-46·8) of 101 rabies-vaccine recipients (relative risk 1·1, 95% CI 0·8-1·6). 20 (20·2%, 95% CI 12·8-29·5) of 99 RTS,S/AS01 recipients and 12 (11·9%, 6·3-19·8) of 101 rabies-vaccine recipients had at least one serious adverse event within 30 days after vaccination, mainly pneumonia, febrile convulsions, and salmonella sepsis. Five (5·1%, 95% CI 1·7-11·4) of 99 RTS,S/AS01 recipients and four (4·0%, 1·1-9·8) of 101 rabies-vaccine recipients died, but no deaths were deemed related to vaccination. Mortality was associated with five cases of pneumonia (1% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), five cases of gastroenteritis (3% RTS,S/AS01 recipients vs 2% rabies-vaccine recipients), five cases of malnutrition (2% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), one case of sepsis (1% rabies-vaccine recipients), one case of Haemophilus influenza meningitis (1% rabies-vaccine recipients), and one case of tuberculosis (1% RTS,S/AS01 recipients).RTS, S/AS01 was well tolerated when given to children with WHO clinical stage 1 or 2 HIV disease along with high antiretroviral and co-trimoxazole use. Children with HIV disease could be included in future RTS,S/AS01 vaccination programmes.GlaxoSmithKline Biologicals SA and PATH Malaria Vaccine Initiative.

Background Nontyphoidal Salmonella (NTS), mainly serotypes Typhimurium and Enteritidis, cause invasive infections with high mortality in children in sub-Saharan Africa. Multidrug resistance is common, and resistance to third-generation cephalosporins has emerged. Methods We reviewed clinical features, outcomes, and antimicrobial resistance patterns in invasive NTS infections among children aged 6 weeks to 5 years participating in malaria vaccine studies in an area of high malaria and human immunodeficiency virus (HIV) transmission in Siaya, western Kenya. Blood culture was performed in hospitalized children and pediatric outpatients with prolonged fever. Results From July 2009 to December 2013, 1696 children aged 6 weeks to 17 months were enrolled into vaccine trials and followed for up to 53 months. We obtained 1692 blood cultures from 847 children. Of 134 bacterial pathogens isolated, 102 (76.1%) were Salmonella serogroup B or D. Invasive NTS disease occurred in 94 (5.5%) children, with an incidence of 1870, 4134, and 6510 episodes per 100 000 person-years overall, in infants, and in HIV-infected children, respectively. Malaria infection within the past 2 weeks occurred in 18.8% (3/16) of invasive NTS episodes in HIV-infected and 66.2% (53/80) in HIV-uninfected children. Case fatality rate was 3.1%. Salmonella group B resistant to ceftriaxone emerged in 2009 and 2010 (6.2% [2/32 isolates]), rising to 56.5% (13/23 isolates) in 2012 and 2013. Conclusions Incidence of invasive NTS disease was high in this area of high malaria and HIV transmission, especially in HIV-infected children. Rapidly emerging resistance against ceftriaxone requires urgent reevaluation of antibiotic recommendations and primary prevention of exposure to Salmonella.

Background Four studies previously indicated that the effect of malaria infection during pregnancy on the risk of low birthweight (LBW, In a meta-analysis using individual participant data, Jordan Cates and colleagues explore potential interactions between malaria and nutrition during pregnancy and their associations with low birthweight., Author summary Why was this study done? More than 125 million pregnant women are at risk of malaria in pregnancy annually, producing detrimental effects on maternal, newborn, and infant health. Maternal undernutrition is estimated to be responsible for 800,000 newborn deaths annually. Prior evidence from 4 small studies indicated that the harmful impact of malaria on fetal growth and birthweight (BW) may depend upon the macronutrient nutritional status of the mother. If malaria and maternal undernutrition have synergistic negative impacts on pregnancy outcomes, interventions targeted to high-risk women might provide substantial public benefit. The present study provides a robust assessment of potential malaria–nutrition interactions in pregnancy and overcomes size and methodological limitations of earlier exploratory studies. What did the researchers do and find? We present a large, pooled analysis of individual participant data from 13 studies conducted in sub-Saharan Africa and the Western Pacific investigating the interaction between maternal malaria infection and malnutrition on the risk of low birthweight (LBW) and reduced mean BW. The findings suggest that women who are both infected with malaria and malnourished are at greater risk of LBW than their uninfected, well-nourished counterparts. However, the study found no conclusive evidence of interaction between the 2, i.e., the impact of malaria on BW was independent of the macronutrient nutritional status of the mother. Subgroup analyses did find that studies conducted just in Africa had slight evidence of interaction, but this was not consistent throughout all analyses. What do these findings mean? Although there was no overall evidence of malaria–nutrition interactions, more than 1 in 3 pregnant women suffered from malaria and/or undernutrition, emphasizing the importance of joint approaches to decrease maternal malaria and improve nutrition to minimize adverse pregnancy outcomes.

BACKGROUND An ongoing phase 3 study of the efficacy, safety, and immunogenicity of candidate malaria vaccine RTS,S/AS01 is being conducted in seven African countries. METHODS From March 2009 through January 2011, we enrolled 15,460 children in two age categories--6 to 12 weeks of age and 5 to 17 months of age--for vaccination with either RTS,S/AS01 or a non-malaria comparator vaccine. The primary end point of the analysis was vaccine efficacy against clinical malaria during the 12 months after vaccination in the first 6000 children 5 to 17 months of age at enrollment who received all three doses of vaccine according to protocol. After 250 children had an episode of severe malaria, we evaluated vaccine efficacy against severe malaria in both age categories. RESULTS In the 14 months after the first dose of vaccine, the incidence of first episodes of clinical malaria in the first 6000 children in the older age category was 0.32 episodes per person-year in the RTS,S/AS01 group and 0.55 episodes per person-year in the control group, for an efficacy of 50.4% (95% confidence interval [CI], 45.8 to 54.6) in the intention-to-treat population and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. Vaccine efficacy against severe malaria was 45.1% (95% CI, 23.8 to 60.5) in the intention-to-treat population and 47.3% (95% CI, 22.4 to 64.2) in the per-protocol population. Vaccine efficacy against severe malaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocol population during an average follow-up of 11 months. Serious adverse events occurred with a similar frequency in the two study groups. Among children in the older age category, the rate of generalized convulsive seizures after RTS,S/AS01 vaccination was 1.04 per 1000 doses (95% CI, 0.62 to 1.64). CONCLUSIONS The RTS,S/AS01 vaccine provided protection against both clinical and severe malaria in African children. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619 .).

BACKGROUND: The RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection. We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014. METHODS: Using data from 8922 African children aged 5-17 months and 6537 African infants aged 6-12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose. We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time. FINDINGS: RTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5-17 months than in those aged 6-12 weeks. Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6-12 weeks and higher immunogenicity in those aged 5-17 months. The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination. Anti-circumsporozoite titres wane according to a biphasic exponential distribution. In participants aged 5-17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42-48) and that of the long-lived component was 591 days (557-632). After primary vaccination 12% (11-13) of the response was estimated to be long-lived, rising to 30% (28-32%) after a booster dose. An anti-circumsporozoite antibody titre of 121 EU/mL (98-153) was estimated to prevent 50% of infections. Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and efficacy wanes more rapidly at higher transmission intensity. INTERPRETATION: Anti-circumsporozoite antibody titres are a surrogate of protection for the magnitude and duration of RTS,S/AS01 efficacy, with or without a booster dose, providing a valuable surrogate of effectiveness for new RTS,S formulations in the age groups considered. FUNDING: UK Medical Research Council.

Objective \ud Information on adverse pregnancy outcomes is important to monitor the impact of public health interventions. Miscarriage is a challenging end point to ascertain and there is scarce information on its rate in low-income countries. The objective was to estimate the background rate and cumulative probability of miscarriage in rural western Kenya.\ud \ud Design \ud This was a population-based prospective cohort.\ud \ud Participants and setting \ud Women of childbearing age were followed prospectively to identify pregnancies and ascertain their outcomes in Siaya County, western Kenya. The cohort study was carried out in 33 adjacent villages under health and demographic surveillance.\ud \ud Outcome measure \ud Miscarriage.\ud \ud Results \ud Between 2011 and 2013, among 5536 women of childbearing age, 1453 pregnancies were detected and 1134 were included in the analysis. The cumulative probability was 18.9%. The weekly miscarriage rate declined steadily with increasing gestation until approximately 20 weeks. Known risk factors for miscarriage such as maternal age, gravidity, occupation, household wealth and HIV infection were confirmed.\ud \ud Conclusions \ud This is the first report of weekly miscarriage rates in a rural African setting in the context of high HIV and malaria prevalence. Future studies should consider the involvement of community health workers to identify the pregnancy cohort of early gestation for better data on the actual number of pregnancies and the assessment of miscarriage.

BACKGROUND: The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. METHODS: We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. RESULTS: The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). CONCLUSIONS: The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).

An outbreak of dysentery in Zimbabwe was associated with a high mortality, especially in children who developed hemolytic uremic syndrome (HUS). To examine the causes of high mortality from HUS and to suggest measures that could reduce the case fatality rate, clinical and laboratory features of 91 children with dysentery were reviewed. Of these, 14 developed HUS; their findings were compared with age-matched controls with dysentery only. Persistent alteration of consciousness after rehydration, pallor, and oliguria were early clinical indicators of HUS. Leukocytosis and leukemoid reaction, microhematuria, and non-resolving hyponatremia distinguished children with HUS from those with dysentery. While Shigella dysenteriae type I was responsible for the dysentery outbreak in the community, most stool cultures of children with HUS were negative. Mortality from HUS was high. Late recognition of HUS and a lack of peritoneal dialysis could have contributed to the fatal outcome in some cases. Early recognition of HUS through close observation of children with dysentery and appropriate laboratory investigations with referral to a hospital, where peritoneal dialysis is available, should improve the outcome.

Background The artemisinin anti-malarials are widely deployed as artemisinin-based combination therapy (ACT). However, they are not recommended for uncomplicated malaria during the first trimester because safety data from humans are scarce. Methods This was a prospective cohort study of women of child-bearing age carried out in 2011–2013, evaluating the relationship between inadvertent ACT exposure during first trimester and miscarriage. Community-based surveillance was used to identify 1134 early pregnancies. Cox proportional hazard models with left truncation were used. Results The risk of miscarriage among pregnancies exposed to ACT (confirmed + unconfirmed) in the first trimester, or during the embryo-sensitive period (≥6 to

Background Animal embryotoxicity data, and the scarcity of safety data in human pregnancies, have prevented artemisinin derivatives from being recommended for malaria treatment in the first trimester except in lifesaving circumstances. We conducted a meta-analysis of prospective observational studies comparing the risk of miscarriage, stillbirth, and major congenital anomaly (primary outcomes) among first-trimester pregnancies treated with artemisinin derivatives versus quinine or no antimalarial treatment. Methods and findings Electronic databases including Medline, Embase, and Malaria in Pregnancy Library were searched, and investigators contacted. Five studies involving 30,618 pregnancies were included; four from sub-Saharan Africa (n = 6,666 pregnancies, six sites) and one from Thailand (n = 23,952). Antimalarial exposures were ascertained by self-report or active detection and confirmed by prescriptions, clinic cards, and outpatient registers. Cox proportional hazards models, accounting for time under observation and gestational age at enrollment, were used to calculate hazard ratios. Individual participant data (IPD) meta-analysis was used to combine the African studies, and the results were then combined with those from Thailand using aggregated data meta-analysis with a random effects model. There was no difference in the risk of miscarriage associated with the use of artemisinins anytime during the first trimester (n = 37/671) compared with quinine (n = 96/945; adjusted hazard ratio [aHR] = 0.73 [95% CI 0.44, 1.21], I2 = 0%, p = 0.228), in the risk of stillbirth (artemisinins, n = 10/654; quinine, n = 11/615; aHR = 0.29 [95% CI 0.08–1.02], p = 0.053), or in the risk of miscarriage and stillbirth combined (pregnancy loss) (aHR = 0.58 [95% CI 0.36–1.02], p = 0.099). The corresponding risks of miscarriage, stillbirth, and pregnancy loss in a sensitivity analysis restricted to artemisinin exposures during the embryo sensitive period (6–12 wk gestation) were as follows: aHR = 1.04 (95% CI 0.54–2.01), I2 = 0%, p = 0.910; aHR = 0.73 (95% CI 0.26–2.06), p = 0.551; and aHR = 0.98 (95% CI 0.52–2.04), p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin (1.5% [95% CI 0.6%–3.5%]) and quinine exposures (1.2% [95% CI 0.6%–2.4%]). Key limitations of the study include the inability to control for confounding by indication in the African studies, the paucity of data on potential confounders, the limited statistical power to detect differences in congenital anomalies, and the lack of assessment of cardiovascular defects in newborns. Conclusions Compared to quinine, artemisinin treatment in the first trimester was not associated with an increased risk of miscarriage or stillbirth. While the data are limited, they indicate no difference in the prevalence of major congenital anomalies between treatment groups. The benefits of 3-d artemisinin combination therapy regimens to treat malaria in early pregnancy are likely to outweigh the adverse outcomes of partially treated malaria, which can occur with oral quinine because of the known poor adherence to 7-d regimens. Review registration PROSPERO CRD42015032371, In a meta-analysis using individual patient data from prospective observational studies, Andy Stergachis and colleagues investigate the risk of of miscarriage, stillbirth, and major congenital anomaly among pregnancies that were treated during the first trimester with artemisinin derivatives versus quinine or no antimalarial treatment., Author summary Why was this study done? Malaria infection is more frequent and severe in pregnant women compared to non-pregnant women, and the adverse consequences of malaria in pregnancy require prompt, safe, and effective treatment. Artemisinin combination therapies (ACTs), the most efficacious antimalarials available, are the recommended first-line treatment for Plasmodium falciparum malaria. Animal embryotoxicity data and the paucity of safety data in human pregnancies have prevented artemisinin derivatives from being recommended for malaria treatment in the first trimester except in life-saving circumstances, yet in malaria endemic countries, many early pregnancies are advertently or inadvertently exposed to ACTs. In this meta-analysis of prospective observational studies, we summarize all available safety data on the effect of artemisinin exposure in the first trimester and compare the risk of miscarriage, stillbirth, and major congenital anomaly for pregnancies treated with artemisinin, quinine, or no antimalarials in the first trimester. What did the researchers do and find? Our team determined the risk of miscarriages, stillbirths, and major congenital anomalies associated with first-trimester artemisinin treatment versus quinine in four independent prospective observational studies across six sites in sub-Saharan Africa using individual participant data meta-analysis. The results were then combined with summary effect estimates from the Shoklo Malaria Research Unit on the Thailand–Myanmar border using aggregated data meta-analysis. We found no difference in the risk of miscarriage, stillbirth, or major congenital anomalies associated with the use of artemisinins anytime during the first trimester compared with the use of quinine during the same gestational period. What do these findings mean? The ACT class of antimalarials should be considered for treatment of malaria in the first trimester of pregnancy. The limited data on the risk of congenital anomalies require further observational studies.