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Purpose The life-saving role of oxygen therapy in African children with severe pneumonia is not yet established. Methods The open-label fractional-factorial COAST trial randomised eligible Ugandan and Kenyan children aged > 28 days with severe pneumonia and severe hypoxaemia stratum (SpO2 3 h receipt of oxygen were excluded. The primary endpoint was 48 h mortality; secondary endpoints included mortality or neurocognitive sequelae at 28 days. Results The trial was stopped early after enrolling 1852/4200 children, including 388 in the severe hypoxaemia stratum (median 7 months; median SpO2 75%) randomised to HFNT (n = 194) or LFO (n = 194) and 1454 in the hypoxaemia stratum (median 9 months; median SpO2 88%) randomised to HFNT (n = 363) vs LFO (n = 364) vs permissive hypoxaemia (n = 727). Per-protocol 15% of patients in the permissive hypoxaemia group received oxygen (when SpO2

Summary Background Triple antimalarial combination therapies combine potent and rapidly cleared artemisinins or related synthetic ozonides, such as arterolane, with two, more slowly eliminated partner drugs to reduce the risk of resistance. We aimed to assess the safety, tolerability, and efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Kenyan children. Methods In this single-centre, open-label, randomised, non-inferiority trial done in Kilifi County Hospital, Kilifi, coastal Kenya, children with uncomplicated Plasmodium falciparum malaria were recruited. Eligible patients were aged 2–12 years and had an asexual parasitaemia of 5000–250 000 parasites per μL. The exclusion criteria included the presence of an acute illness other than malaria, the inability to tolerate oral medications, treatment with an artemisinin derivative in the previous 7 days, a known hypersensitivity or contraindication to any of the study drugs, and a QT interval corrected for heart rate (QTc interval) longer than 450 ms. Patients were randomly assigned (1:1:1), by use of blocks of six, nine, and 12, and opaque, sealed, and sequentially numbered envelopes, to receive either arterolane–piperaquine, arterolane–piperaquine–mefloquine, or artemether–lumefantrine. Laboratory staff, but not the patients, the patients' parents or caregivers, clinical or medical officers, nurses, or trial statistician, were masked to the intervention groups. For 3 days, oral artemether–lumefantrine was administered twice daily (target dose 5–24 mg/kg of bodyweight of artemether and 29–144 mg/kg of bodyweight of lumefantrine), and oral arterolane–piperaquine (arterolane dose 4 mg/kg of bodyweight; piperaquine dose 20 mg/kg of bodyweight) and oral arterolane–piperaquine–mefloquine (mefloquine dose 8 mg/kg of bodyweight) were administered once daily. All patients received 0·25 mg/kg of bodyweight of oral primaquine at hour 24. All patients were admitted to Kilifi County Hospital for at least 3 consecutive days and followed up at day 7 and, thereafter, weekly for up to 42 days. The primary endpoint was 42-day PCR-corrected efficacy, defined as the absence of treatment failure in the first 42 days post-treatment, of arterolane–piperaquine–mefloquine versus artemether–lumefantrine, and, along with safety, was analysed in the intention-to-treat population, which comprised all patients who received at least one dose of a study drug. The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine was an important secondary endpoint and was also analysed in the intention-to-treat population. The non-inferiority margin for the risk difference between treatments was −7%. The study is registered in ClinicalTrials.gov , NCT03452475 , and is completed. Findings Between March 7, 2018, and May 2, 2019, 533 children with P falciparum were screened, of whom 217 were randomly assigned to receive either arterolane–piperaquine (n=73), arterolane–piperaquine–mefloquine (n=72), or artemether–lumefantrine (n=72) and comprised the intention-to-treat population. The 42-day PCR-corrected efficacy after treatment with arterolane–piperaquine–mefloquine (100%, 95% CI 95–100; 72/72) was non-inferior to that after treatment with artemether–lumefantrine (96%, 95% CI 88–99; 69/72; risk difference 4%, 95% CI 0–9; p=0·25). The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine was non-inferior to that of arterolane–piperaquine (100%, 95% CI 95–100; 73/73; risk difference 0%). Vomiting rates in the first hour post-drug administration were significantly higher in patients treated with arterolane–piperaquine (5%, 95% CI 2–9; ten of 203 drug administrations; p=0·0013) or arterolane–piperaquine–mefloquine (5%, 3–9; 11 of 209 drug administrations; p=0·0006) than in patients treated with artemether–lumefantrine (1%, 0–2; three of 415 drug administrations). Upper respiratory tract complaints (n=26 for artemether–lumefantrine; n=19 for arterolane–piperaquine–mefloquine; n=23 for arterolane–piperaquine), headache (n=13; n=4; n=5), and abdominal pain (n=7; n=5; n=5) were the most frequently reported adverse events. There were no deaths. Interpretation This study shows that arterolane–piperaquine–mefloquine is an efficacious and safe treatment for uncomplicated falciparum malaria in children and could potentially be used to prevent or delay the emergence of antimalarial resistance. Funding UK Department for International Development, The Wellcome Trust, The Bill & Melinda Gates Foundation, Sun Pharmaceutical Industries

Background Naturally acquired immunity to malaria is incompletely understood. We used controlled human malaria infection (CHMI) to study the impact of past exposure to malaria in Kenyan adults in relation to infection with a non-Kenyan parasite strain. Methods We administered 3.2x103 aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (SPZ) [Sanaria® PfSPZ Challenge, NF54 West African strain] by direct venous inoculation and undertook clinical monitoring and serial quantitative PCR (qPCR) of the 18S ribosomal RNA gene. The study endpoint was met when either: parasitaemia reached ≥500 parasites/μl blood; clinically significant symptoms were seen; or at 21 days after inoculation. All volunteers received antimalarial drug treatment on meeting the endpoint. Results One hundred and sixty-one (161) volunteers underwent CHMI between Aug 4, 2016, and Feb 14, 2018. CHMI was well tolerated with no severe or serious adverse events. Nineteen volunteers (11.8%) were excluded from the analysis based on detection of antimalarial drugs above the minimal inhibitory concentration or parasites genotyped as non-NF54. Of the 142 volunteers who were eligible for analysis: 26 (18.3%) had febrile symptoms and were treated; 30 (21.1%) reached ≥500 parasites/μl and were treated; 53 (37.3%) had parasitaemia without meeting thresholds for treatment and; 33 (23.2%) remained qPCR negative. Conclusion We find that past exposure to malaria, as evidenced by location of residence, in some Kenyan adults can completely suppress in vivo growth of a parasite strain originating from outside Kenya.TRAIL REGISTRATION. The study was registered on ClinicalTrials.gov (NCT02739763). Funding Wellcome Trust.

Background Snakebite is a priority neglected tropical disease and causes a range of complications that vary depending on the snake species. Randomised clinical trials have used varied outcome measures that do not allow results to be compared or combined. In accordance with the Core Outcomes Measurements in Effectiveness Trials (COMET) initiative, this systematic review aims to support the development of a globally relevant core outcome set for snakebite. Methods All randomised controlled trials, secondary analyses of randomised controlled trials and study protocols investigating the efficacy of therapeutics for human snakebite envenoming were eligible for inclusion. Study screening and data extraction were conducted in duplicate by two independent reviewers. All primary and secondary outcome measures were extracted and compiled, as were adverse event outcome measures. Similar outcome measures were grouped into domains. The study was prospectively registered with PROSPERO: CRD42020196160. Results This systematic review included 43 randomised controlled trials, two secondary analyses and 13 study protocols. A total of 382 outcome measures were extracted and, after duplicates were merged, there were 153 unique outcomes. The most frequently used outcome domain (‘venom antigenaemia’) was included in less than one third of the studies. The unique outcomes were classified into 60 outcome domains. Patient-centred outcomes were used in only three of the studies. Discussion Significant heterogeneity in outcome measures exists in snakebite clinical trials. Consensus is needed to select outcome measures that are valid, reliable, patient-centred and feasible. The results of this systematic review strongly support the development of a core outcome set for use in snakebite clinical trials., Author summary Standardised outcome measures for snakebite randomised controlled trials are needed to enable results to be compared and combined between studies. This systematic review was conducted to understand the variations in outcome measure use in snakebite randomised controlled trials, and to create a comprehensive list of outcome measures from which to develop a core outcome set (COS). A total of 153 unique outcome measures were extracted from the 58 studies identified in this systematic review. Of these 153 unique outcome measures, 91 were used in only in a single study. Although a form of bedside whole blood clotting test was used in 30 of the 58 studies, 18 unique methods of measurement were identified. Only three studies, all conducted in the USA, included patient-centred outcomes. This systematic review demonstrates the strong need for a snakebite core outcome set, which will support the adoption of valid, reproducible, and patient-centred outcome measures, and enable downstream meta-analyses.

Background: Children hospitalised with severe acute malnutrition (SAM) are frequently complicated (>50%) by diarrhoea (≥3 watery stools/day) which is accompanied by poor outcomes. Rehydration guidelines for SAM are exceptionally conservative and controversial, based upon expert opinion. The guidelines only permit use of intravenous fluids for cases with advanced shock and exclusive use of low sodium intravenous and oral rehydration solutions (ORS) for fear of fluid and/or sodium overload. Children managed in accordance to these guidelines have a very high mortality. The proposed GASTROSAM trial is the first step in reappraising current recommendations. We hypothesize that liberal rehydration strategies for both intravenous and oral rehydration in SAM children with diarrhoea may reduce adverse outcomes. Methods An open Phase II trial, with a partial factorial design, enrolling Ugandan and Kenyan children aged 6 months to 12 years with SAM hospitalised with gastroenteritis (>3 loose stools/day) and signs of moderate and severe dehydration. In Stratum A (severe dehydration) children will be randomised (1:1:2) to WHO plan C (100mls/kg Ringers Lactate (RL) with intravenous rehydration given over 3-6 hours according to age including boluses for shock), slow rehydration (100 mls/kg RL over 8 hours (no boluses)) or WHO SAM rehydration regime (ORS only (boluses for shock (standard of care)). Stratum B incorporates all children with moderate dehydration and severe dehydration post-intravenous rehydration and compares (1:1 ratio) standard WHO ORS given for non-SAM (experimental) versus WHO SAM-recommended low-sodium ReSoMal. The primary outcome for intravenous rehydration is urine output (mls/kg/hour at 8 hours post-randomisation), and for oral rehydration a change in sodium levels at 24 hours post-randomisation. This trial will also generate feasibility, safety and preliminary data on survival to 28 days. Discussion. If current rehydration strategies for non-malnourished children are safe in SAM this could prompt future evaluation in Phase III trials.

The government of Kenya has launched a phased rollout of COVID-19 vaccination. A major barrier is vaccine hesitancy; the refusal or delay of accepting vaccination. This study evaluated the level and determinants of vaccine hesitancy in Kenya. We conducted a cross-sectional study administered through a phone-based survey in February 2021 in four counties of Kenya. Multivariate logistic regression was used to identify individual perceived risks and influences, context-specific factors, and vaccine-specific issues associated with COVID-19 vaccine hesitancy. COVID-19 vaccine hesitancy in Kenya was high: 60.1%. Factors associated with vaccine hesitancy included: older age, lower education level, perceived difficulty in adhering to government regulations on COVID-19 prevention, less adherence to wearing of face masks, not having ever been tested for COVID-19, no reported socio-economic loss as a result of COVID public-health restriction measures, and concerns regarding vaccine safety and effectiveness. There is a need for the prioritization of interventions to address vaccine hesitancy and improve vaccine confidence as part of the vaccine roll-out plan. These messaging and/or interventions should be holistic to include the value of other public health measures, be focused and targeted to specific groups, raise awareness on the risks of COVID-19 and effectively communicate the benefits and risks of vaccines.

BackgroundNeurological complications due to chikungunya virus (CHIKV) infection have been described in different parts of the world, with children being disproportionately affected. However, the burden of CHIKV-associated neurological disease in Africa is currently unknown.MethodsWe estimated the incidence of CHIKV infection among children hospitalised with neurological disease in coastal Kenya. We used reverse-transcriptase polymerase chain reaction (RT-PCR) to systematically test for CHIKV in cerebrospinal fluid (CSF) samples from children aged FindingsThere were 18,341 paediatric admissions during the 5-year study period, of which 4,332 (24%) had CSF collected. The most common clinical reasons for CSF collection were impaired consciousness, seizures and coma (47%, 22% and 21% of all collections, respectively). After acute investigations done for immediate clinical care, CSF samples were available for 3,980 admissions, of which 367 (9.2%) were CHIKV RT-PCR positive. The annual incidence of CHIKV-associated neurological disease varied between 13 to 58 episodes per 100,000 person-years among all children InterpretationAlthough not previously recognized, CHIKV-associated neurological disease is common in coastal Kenya and a significant public health burden.

Background Human infection studies (HIS) that involve deliberately infecting healthy volunteers with a pathogen raise important ethical issues, including the need to ensure that benefits and burdens are understood and appropriately accounted for. Building on earlier work, we embedded social science research within an ongoing malaria human infection study in coastal Kenya to understand the study benefits and burdens experienced by study stakeholders in this low-resource setting and assess the wider implications for future research planning and policy. Methods Data were collected using qualitative research methods, including in-depth interviews (44), focus group discussions (10) and non-participation observation. Study participants were purposively selected (key informant or maximal diversity sampling), including volunteers in the human infection study, study staff, community representatives and local administrative authorities. Data were collected during and up to 18 months following study residency, from sites in Coastal and Western Kenya. Voice recordings of interviews and discussions were transcribed, translated, and analysed using framework analysis, combining data- and theory-driven perspectives. Findings Physical, psychological, economic and social forms of benefits and burdens were experienced across study stages. Important benefits for volunteers included the study compensation, access to health checks, good residential living conditions, new learning opportunities, developing friendships and satisfaction at contributing towards a new malaria vaccine. Burdens primarily affected study volunteers, including experiences of discomfort and ill health; fear and anxiety around aspects of the trial process, particularly deliberate infection and the implications of prolonged residency; anxieties about early residency exit; and interpersonal conflict. These issues had important implications for volunteers’ families, study staff and the research institution’s reputation more widely. Conclusion Developing ethically and scientifically strong HIS relies on grounded accounts of volunteers, study staff and the wider community, understood in the socioeconomic, political and cultural context where studies are implemented. Recognition of the diverse, and sometimes perverse, nature of potential benefits and burdens in a given context, and who this might implicate, is critical to this process. Prior and ongoing stakeholder engagement is core to developing these insights.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. \ud \ud \ud METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. \ud \ud \ud FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. \ud \ud \ud INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. \ud \ud \ud FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

BackgroundYellow fever vaccine stocks have been insufficient to cover exceptional demands for outbreak response. Fractional dosing evidence is limited to the 17DD substrain vaccine. We assessed the immunogenicity and safety of one-fifth fractional dose compared to standard dose of each of the four WHO-prequalified yellow fever vaccines produced from three substrains.MethodsWe conducted a randomized, double-blind, non-inferiority trial in Mbarara, Uganda and Kilifi, Kenya. 960 participants aged 18-59 years without previous yellow fever vaccination or infection were recruited from communities and randomized to receive one of four vaccines and to standard or fractional dosage. Vaccine was administered subcutaneously by unblinded nurse. Other study personnel and participants were blinded to vaccine allocation. Primary immunogenicity outcome, seroconversion, was measured in the per-protocol population; safety outcomes included all vaccinated participants. We defined non-inferiority as no more than 10% decrease in seroconversion in fractional compared to standard dose arms 28 days post-vaccination. Seroconversion was defined as ≥4-fold rise in neutralizing antibody titers measured by 50% plaque reduction neutralization test (PRNT50).ClinicalTrials.gov Identifier: NCT02991495, following participants.FindingsBetween 6th November 2017 and 21st February 2018, 960 participants, total sample goal, were randomized. The primary per-protocol analysis includes 899 participants, with 110 to 117 participants per arm. The absolute difference in seroconversion between fractional and standard doses by vaccine was 1.71% (95%CI: −2.60, 5.28), −0.90% (95%CI: −4.24, 3.13), 1.82% (95%CI: −2.75, 5.39), 0.0% (95%CI: −3.32, 3.29). Fractional doses from all four vaccines met the non-inferiority criterion. There were no safety concerns.InterpretationThese results support fractional dosing of all WHO-prequalified yellow fever vaccines for the general adult population for outbreak response in situations of vaccine shortage.FundingThe study was funded by Médecins Sans Frontières Foundation, Wellcome Trust (grant no. 092654) and the UK Department for International Development. Vaccines were donated in kind.Research in contextEvidence before this studyIn July 2016, following major yellow fever (YF) outbreaks in two countries, WHO published a secretariat information paper including a review of studies assessing the immunogenicity of fractional doses of YF vaccines and recommended consideration of fractional doses to manage a vaccine shortage. Following this, fractional doses of YF vaccine produced by Bio-Manguinhos/Fiocruz (17DD substrain) were given to approximately 7.5 million non-pregnant adults and children ≥ 2 years of age in Kinshasa, Democratic Republic of Congo. The evidence base to support this action was limited to a single vaccine substrain and to a specific context. To broaden and simplify recommendations, WHO called for additional research to be conducted. We designed a trial to assess non-inferiority in seroconversion of fractional (one-fifth dose) versus standard dose for each of the four WHO-prequalified YF vaccines at 28 days post-vaccination in an adult population in Kenya and Uganda. We selected vaccine batches as close as possible to each manufacturer’s minimum release specification.Added value of this studyThis is the first randomized controlled trial assessing all four WHO-prequalified YF vaccines, providing information on the immunogenicity and safety of fractional doses of the different vaccine substrains at 10 days, 28 days and one year post-vaccination. The results show that, at 28 days post-vaccination, most participants had high levels of neutralizing antibodies and that seroconversion rates in the fractional dose arms were non-inferior to standard dose for each of the four vaccines. Seroconversion rates and neutralizing antibodies remained high up to one year post-vaccination for both fractional and standard doses for all vaccines. These results are aligned with previous studies using the 17DD substrain vaccine but extend the evidence to randomized comparisons of all four vaccines and to a sub-Saharan Africa context. To our knowledge, this is the first trial assessing immunogenicity of fractional doses at 10 days post-vaccination.Implications of all the available evidenceOur study supports the use of one-fifth fractional doses of all four WHO-prequalified yellow fever vaccines for the general adult population and fills a critical knowledge gap to support WHO policy on the use of fractional dosing of yellow fever vaccine for outbreak response. The immunogenicity and safety of fractional dosing in children and specific populations, such as those living with HIV, is yet to be determined. Long-term studies are warranted to confirm the duration of protection.

Background: The life-saving role of oxygen therapy in children with clinically-defined severe pneumonia is not yet established. We hypothesised liberal oxygenation strategies and/or respiratory support may improve the high in-hospital mortality. Methods: The open-label fractional-factorial COAST trial in Ugandan and Kenyan children aged >28 days with feature of severe pneumonia. In stratum A (severe hypoxaemia: SpO2 3hours receipt of oxygen were excluded. The primary endpoint was 48-hour mortality; secondary endpoints included mortality or neurocognitive sequelae at 28 days. Findings: The Trial Steering Committee recommended halting recruitment for feasibility after 1842/4200 (44%) children enrolled. Of 1852 recruited, 388 in stratum A (median 7 months; median age SpO2 75%) were randomised to HFNT (n=194) or LFO (n=194) and 1454 in stratum B (median 9 months; median SpO2 88%) were randomised to HFNT (n=363) vs LFO (n=364) vs control (n=727). Per-protocol 109/726(15%) of controls received oxygen (when SpO2

Malaria remains a major public health burden despite approval for implementation of a partially effective pre-erythrocytic malaria vaccine. There is an urgent need to accelerate development of a more effective multi-stage vaccine. Adults in malaria endemic areas may have substantial immunity provided by responses to the blood stages of malaria parasites, but field trials conducted on several blood-stage vaccines have not shown high levels of efficacy. We will use the controlled human malaria infection (CHMI) models with malaria-exposed volunteers to identify correlations between immune responses and parasite growth rates in vivo. Immune responses more strongly associated with control of parasite growth should be prioritized to accelerate malaria vaccine development. We aim to recruit up to 200 healthy adult volunteers from areas of differing malaria transmission in Kenya, and after confirming their health status through clinical examination and routine haematology and biochemistry, we will comprehensively characterize immunity to malaria using >100 blood-stage antigens. We will administer 3,200 aseptic, purified, cryopreserved Plasmodium falciparum sporozoites (PfSPZ Challenge) by direct venous inoculation. Serial quantitative polymerase chain reaction to measure parasite growth rate in vivo will be undertaken. Clinical and laboratory monitoring will be undertaken to ensure volunteer safety. In addition, we will also explore the perceptions and experiences of volunteers and other stakeholders in participating in a malaria volunteer infection study. Serum, plasma, peripheral blood mononuclear cells and whole blood will be stored to allow a comprehensive assessment of adaptive and innate host immunity. We will use CHMI in semi-immune adult volunteers to relate parasite growth outcomes with antibody responses and other markers of host immunity. Registration: ClinicalTrials.gov identifier NCT02739763.

Background: Zika virus (ZIKV) was first discovered in East Africa in 1947. ZIKV has caused microcephaly in the Americas, but it is not known whether ZIKV is a cause of microcephaly in East Africa. Methods: We used surveillance data from 11,061 live births at Kilifi County Hospital in coastal Kenya between January 2012 and October 2016 to identify microcephaly cases and conducted a nested case-control study to determine risk factors for microcephaly. Gestational age at birth was estimated based on antenatal ultrasound scanning (‘Scanned cohort’) or last menstrual period (‘LMP cohort’, including births ≥37 weeks’ gestation only). Controls were newborns with head circumference Z scores between >-2 and ≤2 SD that were compared to microcephaly cases in relation to ZIKV exposure and other maternal and newborn factors. Results: Of the 11,061 newborns, 214 (1.9%, 95%CI 1.69, 2.21) had microcephaly. Microcephaly prevalence was 1.0% (95%CI 0.64, 1.70, n=1529) and 2.1% (95%CI 1.81, 2.38, n=9532) in the scanned and LMP cohorts, respectively. After excluding babies Conclusions: Microcephaly was prevalent in coastal Kenya, but does not appear to be related to ZIKV exposure; the ZIKV response observed in our study population was largely due to cross-reactive responses to DENV or other related flaviviruses. Further research into potential causes and the clinical consequences of microcephaly in this population is urgently needed.

Background Many parts of Africa have witnessed reductions in Plasmodium falciparum transmission over the last 15 years. Since immunity to malaria is acquired more rapidly at higher transmission, the slower acquisition of immunity at lower transmission may partially offset the benefits of reductions in transmission. We examined the clinical spectrum of disease and predictors of mortality after sustained changes in transmission intensity, using data collected from 1989 to 2016. Methods We conducted a temporal observational analysis of 18,000 children, aged 14 days to 14 years old, who were admitted to Kilifi County Hospital, Kenya, from 1989 to 2016 with malaria. We describe the trends over time of the clinical and laboratory criteria for severe malaria and associated risk of mortality. Results During the time periods 1989–2003, 2004–2008, and 2009–2016, Kilifi County Hospital admitted averages of 657, 310, and 174 cases of severe malaria per year including averages of 48, 14, and 12 malaria-associated deaths per year, respectively. The median ages in years of children admitted with cerebral malaria, severe anaemia, and malaria-associated mortality were 3.0 (95% confidence interval (CI) 2.2–3.9), 1.1 (95% CI 0.9–1.4), and 1.1 (95% CI 0.3–2.2) in the year 1989, rising to 4.9 (95% CI 3.9–5.9), 3.8 (95% CI 2.5–7.1), and 5 (95% CI 3.3–6.3) in the year 2016. The ratio of children with cerebral malaria to severe anaemia rose from 1:2 before 2004 to 3:2 after 2009. Hyperparasitaemia was a risk factor for death after 2009 but not in earlier time periods. Conclusion Despite the evidence of slower acquisition of immunity, continued reductions in the numbers of cases of severe malaria resulted in lower overall mortality. Our temporal data are limited to a single site, albeit potentially applicable to a secular trend present in many parts of Africa. Electronic supplementary material The online version of this article (10.1186/s12916-019-1359-9) contains supplementary material, which is available to authorized users.

Glycoconjugate vaccines have dramatically reduced the incidence of encapsulated bacterial diseases in toddlers under 2 years of age, but vaccine-induced antibody levels in this age group wane rapidly. We immunized adults and 12-month-old toddlers with heptavalent pneumococcal conjugate vaccine to determine differences in B-cell and antibody responses. The adults and 12-month-old toddlers received a pneumococcal conjugate vaccine. The toddlers received a second dose at 14 months of age. The frequencies of diphtheria toxoid and serotype 4, 14, and 23F polysaccharide-specific plasma cells and memory B cells were determined by enzyme-linked immunospot assay. The toddlers had no preexisting polysaccharide-specific memory B cells or serum immunoglobulin G (IgG) antibody but had good diphtheria toxoid-specific memory responses. The frequencies of plasma cells and memory B cells increased by day 7 (P< 0.0001) in the adults and the toddlers following a single dose of conjugate, but the polysaccharide responses were significantly lower in the toddlers than in the adults (P= 0.009 to

BACKGROUND: Protein-polysaccharide vaccines have made a significant impact on the burden of disease caused by encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and have the potential to do so for Salmonella Typhi. Nepal is one of many resource-poor nations with limited information on the epidemiology of childhood infections caused by these pathogens. METHODS: Over a 21-month period, we studied children aged ≤12 years admitted to an urban hospital in Nepal with suspected bacteremia, meningitis, or pneumonia. Patan Hospital is a non-profit hospital with the second largest pediatric unit in the Kathmandu Valley. RESULTS: Of 2039 children enrolled in the study, 142 (7.5%) included in the analysis had positive blood cultures. The agents of enteric fever, Salmonella Typhi and Salmonella Paratyphi, accounted for 59/142 (42%) of all bacteremias and were the most frequently cultured pathogens in children ≥1 year of age. S. pneumoniae was isolated in 16% of positive blood cultures and was the most common cause of bacteremia in children

Aim: To compare diagnostic accuracy of procalcitonin for early diagnosis of serious bacterial infection (SBI) in children presenting with fever and no focus of infection. Methods: Prospective, observational study involving 72 children (1-36 mo) presenting to the paediatric units of two university hospitals. All children had blood cultures, urine cultures, white blood cell counts (WBC), chest X-ray, C-reactive protein (CRP) and procalcitonin (PCT) done at presentation. Results: Eight (11.1%) children had SBI (I pneumonia, 2 meningitis, 4 septicaemia/occult bacteraemia, 2 pyelonephritis), 19 (26.4%) had possible bacterial infection (received antibiotic treatment, but no organism grown) and 45 (62.5%) had viral or possible viral infection (virus isolated and/or uneventful recovery without antibiotics). PCT (>2 ng/l), CRP (>50 mg/l) and McCarthy's score ( 50 mg/l), PCT (>2 ng/l), white blood cells (>15x10(5)/l) and McCarthy's score (

We conducted a phase 3 randomized controlled trial looking at the immunogenicity and safety of a novel combined Haemophilus influenzae type b and Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine, Hib-MenC-TT in a 2-, 3-, and 4-month primary infant immunization schedule. SBA MenC titers > or =1:8 and anti-PRP concentrations > or =0.15 microg/mL were measured in 99.2% and 100%, respectively, of the infants receiving Hib-MenC-TT.

Supplemental Digital Content is available in the text, Using nasopharyngeal carriage as a marker of vaccine impact, pneumococcal colonization and its relation to invasive disease were examined in children, their parents, and older adults in the United Kingdom following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) and prior to 13-valent pneumococcal conjugate vaccine (PCV13). A cross-sectional observational study was conducted, collecting nasopharyngeal swabs from children aged 25 to 55 months who had previously received 3 doses of PCV7, their parents, and adults aged ≥65 years. Pneumococcal serotyping was conducted according to World Health Organization guidelines with nontypeable isolates further analyzed by molecular serotyping. A national invasive disease surveillance program was conducted throughout the corresponding period. Pneumococcus was isolated from 47% of children, 9% of parents, and 2.2% of older adults. For these groups, the percentage of serotypes covered by PCV7 were 1.5%, 0.0%, and 15.4%, with a further 20.1%, 44.4%, and 7.7% coverage added by those in PCV13. In each group, the percentage of disease due to serotypes covered by PCV7 were 1.0%, 7.4% and 5.1% with a further 65.3%, 42.1%, and 61.4% attributed to those in PCV13. The prevalence of carriage is the highest in children, with direct vaccine impact exemplified by low carriage and disease prevalence of PCV7 serotypes in vaccinated children, whereas the indirect effects of herd protection are implied by similar observations in unvaccinated parents and older adults.

Background and aims In the UK, a seven valent pneumococcal conjugate vaccine (PCV7) was introduced in 2006 for children under 2 years of age in a 3 dose schedule; 2, 4, 12 months of age and was found to be highly effective against vaccine-types, but serotype replacement reduced the overall impact against pneumococcal disease. In April 2010 PCV13 replaced PCV7 in the routine infant schedule without a catch-up campaign. We assessed the prevalence and serotype distribution of pneumococcal nasopharyngeal carriage in 3 generations prior to widespread use of PCV13. Methods Children who received 3 doses of PCV7 (age range 21– 55 months), their parents and a cohort of community-dwelling adults aged 65 and over were recruited. A swab was taken, placed in STGG media and cultured within 8 hours. Pneumococci were cultured, serotyped using the Quellung reaction and genotyped using multilocus sequence typing. Results S.pneumoniae was recovered from 46% (270/592) of children, 12% (12/100) of parents and 6.2% (37/600) of older adults. PCV13 vaccine-types were found in 20% of children (56/270).The 10 most common serotypes among children, in descending order, were: 19A, 11A, 23B, 6C, nontypeables, 3, 22F, 23A, 35F and 21. 4/12 serotypes in parents and 3/37 in older adults were vaccine-types. Conclusions 18 months after the launch of PCV13 in the UK, vaccine-type pneumococci were still circulating among preschool children although most isolates were non-vaccine types. Carriage rates in parents and older adults were lower. Further studies will allow monitoring of the impact of the vaccine once PCV13 immunity is fully established in early childhood.

Background: Pneumococcal disease is a significant cause of morbidity and mortality in young children in Nepal, and currently available pneumococcal conjugate vaccines offer moderate coverage of invasive disease isolates. Methods: A prevalence study of children aged 1.5 to 24 months in urban and rural Nepal was conducted. In the urban group, nasopharyngeal swabs (NPS) were transported using silica desiccant packages (SDP) with delayed processing (2 weeks), or skim-milk-tryptone-glucose-glycerin (STGG) with immediate processing (within 8 hours). Pneumococcal nasopharyngeal carriage prevalence, serogroup/type distribution and isolate genotypes (as defined by multilocus sequence typing) were determined. Results: 1101 children were enrolled into the study: 574 in the urban group and 527 in the rural group. Overall carriage prevalence based on culture from specimens transported and stored in STGG was 58.7% (337/574), compared to 40.9% (235/574) in SDP. There was concordance of detection of pneumococcus in 67% of samples. Using the SDP method, pneumococcal carriage prevalence was higher in the rural population (69.2%; 364/526) compared to the urban population (40.9%; 235/574). Serogroup/type distribution varied with geographical location. Over half of the genotypes identified in both the urban and rural pneumococcal populations were novel. Conclusion: The combination of delayed culture and transport using SDP underestimates the prevalence of pneumococcal carriage; however, in remote areas, this method could still provide a useful estimate of carriage prevalence and serogroup/type distribution. Vaccine impact is unpredictable in a setting with novel genotypes and limited serotype coverage as described here. Consequently, continued surveillance of pneumococcal isolates from carriage and disease in Nepali children following the planned introduction of pneumococcal conjugate vaccines introduction will be essential. © 2014 Hanieh et al.

BACKGROUND: Streptococcus pneumoniae is a leading cause of pneumonia and meningitis in young children. Before implementation of the pneumococcal conjugate vaccine in developing countries, there is an urgent need to provide regional epidemiological data on pneumococcal disease. The aims of this study were to determine the prevalence and serotype distribution of invasive pneumococcal disease among young children hospitalized in urban Nepal. METHODS: Children aged 2 months to 5 years who were admitted to Patan Hospital, Kathmandu, with fever and/or suspected pneumonia, meningitis, or bacteremia were recruited. Blood culture specimens were collected from all participants. In cases of suspected meningitis, cerebrospinal fluid specimens were cultured and were tested for S. pneumoniae antigen. RESULTS: A total of 885 children were recruited during the 21-month study period. Of these, 76 (9%) had meningitis and 498 (56%) had pneumonia, on the basis of clinical criteria. Radiographically confirmed pneumonia occurred in 354 (40%), and probable or definite meningitis occurred in 47 (5%). S. pneumoniae was isolated in specimens from 17 (2%) of the children. Serotypes 1 and 12A were isolated most frequently, and only 1 of 17 isolates had a serotype contained in the currently available 7-valent pneumococcal conjugate vaccine. CONCLUSIONS: More than 60% of children aged