Last data update: Jan 27, 2025. (Total: 48650 publications since 2009)
Records 1-29 (of 29 Records) |
Query Trace: Oneko M[original query] |
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Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine
Senkpeil L , Bhardwaj J , Little MR , Holla P , Upadhye A , Fusco EM , Swanson Ii PA , Wiegand RE , Macklin MD , Bi K , Flynn BJ , Yamamoto A , Gaskin EL , Sather DN , Oblak AL , Simpson E , Gao H , Haining WN , Yates KB , Liu X , Murshedkar T , Richie TL , Sim BKL , Otieno K , Kariuki S , Xuei X , Liu Y , Polidoro RB , Hoffman SL , Oneko M , Steinhardt LC , Schmidt NW , Seder RA , Tran TM . JCI Insight 2024 ![]() ![]() ![]() A systems analysis was conducted to determine the potential 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 Pf parasitemia in placebo controls. These same signatures were associated with susceptibility to parasitemia among infants who received the highest and most protective PfSPZ Vaccine dose. Machine learning identified spliceosome, proteosome, and resting dendritic cell signatures as pre-vaccination features predictive of protection after highest-dose PfSPZ vaccination, whereas baseline CSP-specific IgG predicted non-protection. Pre-vaccination innate inflammatory and myeloid signatures were associated with higher sporozoite-specific IgG Ab response but undetectable PfSPZ-specific CD8+ T-cell responses post-vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against infection by sporozoite injection in malaria-naïve mice while diminishing the CD8+ T-cell response to radiation-attenuated sporozoites. These data suggest a dichotomous role of innate stimulation for malaria protection and induction of protective immunity of whole-sporozoite malaria vaccines. The uncoupling of vaccine-induced protective immunity achieved by Abs from more protective CD8+ T cell responses suggest that PfSPZ Vaccine efficacy in malaria-endemic settings may be constrained by opposing antigen presentation pathways. |
Could less be more? Accounting for fractional-dose regimens and different number of vaccine doses when measuring the impact of the RTS, S/AS01E malaria vaccine
Westercamp N , Osei-Tutu L , Schuerman L , Kariuki SK , Bollaerts A , Lee CK , Samuels AM , Ockenhouse C , Bii DK , Adjei S , Oneko M , Lievens M , Attobrah Sarfo MA , Atieno C , Bakari A , Sang T , Kotoh-Mortty MF , Otieno K , Roman F , Buabeng PBY , Ntiamoah Y , Ansong D , Agbenyega T , Ofori-Anyinam O . J Infect Dis 2024 BACKGROUND: The RTS, S/AS01E malaria vaccine (RTS, S) is recommended for children in moderate-to-high Plasmodium falciparum malaria transmission areas. This phase 2b trial (NCT03276962) evaluates RTS, S fractional- and full-dose regimens in Ghana and Kenya. METHODS: 1500 children aged 5-17 months were randomised (1:1:1:1:1) to receive RTS, S or rabies control vaccine. RTS, S groups received two full RTS, S doses at month (M)0/M1 followed by either full (groups R012-20, R012-14-26) or fractional (1/5) doses (groups Fx012-14-26, Fx017-20-32). RESULTS: At M32 post-first dose, vaccine efficacy (VE) against clinical malaria (all episodes) ranged from 38% (R012-20; 95%CI: 24-49) to 53% (R012-14-26; 95%CI: 42-62). Vaccine impact estimates (cumulative number of malaria cases averted/1000 children vaccinated) were 1344 (R012-20), 2450 (R012-14-26), 2273 (Fx012-14-26), 2112 (Fx017-20-32). To account for differences in vaccine volume (fractional- versus full-dose), in a post-hoc analysis, we also estimated cases averted/1000 RTS, S full-dose equivalents: 336 (R012-20), 490 (R012-14-26), 874 (Fx012-14-26), 880 (Fx017-20-32). CONCLUSIONS: VE against clinical malaria was similar in all RTS, S groups. Vaccine impact accounting for full-dose equivalence suggests that using fractional-dose regimens could be a viable dose-sparing strategy. If borne out through trial end (M50), these observations underscore the means to reduce cost per regimen with a goal of maximising impact and optimising supply. |
Sporozoite immunization: Innovative Translational Science to Support the Fight against malaria
Richie TL , Church LWP , Murshedkar T , Billingsley PF , James ER , Chen MC , Abebe Y , Natasha Kc , Chakravarty S , Dolberg D , Healy SA , Diawara H , Sissoko MS , Sagara I , Cook DM , Epstein JE , Mordmüller B , Kapulu M , Kreidenweiss A , Franke-Fayard B , Agnandji ST , López Mikue MA , McCall MBB , Steinhardt L , Oneko M , Olotu A , Vaughan AM , Kublin JG , Murphy SC , Jongo S , Tanner M , Sirima SB , Laurens MB , Daubenberger C , Silva JC , Lyke KE , Janse CJ , Roestenberg M , Sauerwein RW , Abdulla S , Dicko A , Kappe SHI , Sim BKL , Duffy PE , Kremsner PG , Hoffman SL . Expert Rev Vaccines 2023 22 (1) 964-1007 INTRODUCTION: Malaria, a devastating febrile illness caused by protozoan parasites, sickened 247,000,000 people in 2021 and killed 619,000, mostly children and pregnant women in sub-Saharan Africa. A highly effective vaccine is urgently needed, especially for Plasmodium falciparum (Pf), the deadliest human malaria parasite. AREAS COVERED: Sporozoites (SPZ), the parasite stage transmitted by Anopheles mosquitoes to humans, are the only vaccine immunogen achieving > 90% efficacy against Pf infection. This review describes > 30 clinical trials of PfSPZ vaccines in the U.S.A., Europe, Africa, and Asia, based on first-hand knowledge of the trials and PubMed searches of 'sporozoites,' 'malaria,' and 'vaccines.' EXPERT OPINION: First generation (radiation-attenuated) PfSPZ vaccines are safe, well tolerated, 80-100% efficacious against homologous controlled human malaria infection (CHMI) and provide 18-19 months protection without boosting in Africa. Second generation chemo-attenuated PfSPZ are more potent, 100% efficacious against stringent heterologous (variant strain) CHMI, but require a co-administered drug, raising safety concerns. Third generation, late liver stage-arresting, replication competent (LARC), genetically-attenuated PfSPZ are expected to be both safe and highly efficacious. Overall, PfSPZ vaccines meet safety, tolerability, and efficacy requirements for protecting pregnant women and travelers, with licensure for these populations possible within five years. Protecting children and mass vaccination programs to block transmission and eliminate malaria are long-term objectives. |
Post-discharge risk of mortality in children under 5 years of age in western Kenya: A retrospective cohort study
Kwambai TK , Kariuki S , Smit MR , Nevitt S , Onyango E , Oneko M , Khagayi S , Samuels AM , Hamel MJ , Laserson K , Desai M , Ter Kuile FO . Am J Trop Med Hyg 2023 109 (3) 704-712 Limited evidence suggests that children in sub-Saharan Africa hospitalized with all-cause severe anemia or severe acute malnutrition (SAM) are at high risk of dying in the first few months after discharge. We aimed to compare the risks of post-discharge mortality by health condition among hospitalized children in an area with high malaria transmission in western Kenya. We conducted a retrospective cohort study among recently discharged children aged < 5 years using mortality data from a health and demographic surveillance system that included household and pediatric in-hospital surveillance. Cox regression was used to compare post-discharge mortality. Between 2008 and 2013, overall in-hospital mortality was 2.8% (101/3,639). The mortality by 6 months after discharge (primary outcome) was 6.2% (159/2,556) and was highest in children with SAM (21.6%), followed by severe anemia (15.5%), severe pneumonia (5.6%), "other conditions" (5.6%), and severe malaria (0.7%). Overall, the 6-month post-discharge mortality in children hospitalized with SAM (hazard ratio [HR] = 3.95, 2.60-6.00, P < 0.001) or severe anemia (HR = 2.55, 1.74-3.71, P < 0.001) was significantly higher than that in children without these conditions. Severe malaria was associated with lower 6-month post-discharge mortality than children without severe malaria (HR = 0.33, 0.21-0.53, P < 0.001). The odds of dying by 6 months after discharge tended to be higher than during the in-hospital period for all children, except for those admitted with severe malaria. The first 6 months after discharge is a high-risk period for mortality among children admitted with severe anemia and SAM in western Kenya. Strategies to address this risk period are urgently needed. |
Fetal sex and risk of pregnancy-associated malaria in Plasmodium falciparum-endemic regions: a meta-analysis
Unger HW , Hadiprodjo AJ , Gutman JR , Briand V , Fievet N , Valea I , Tinto H , D'Alessandro U , Landis SH , Ter Kuile F , Ouma P , Oneko M , Mwapasa V , Slutsker L , Terlouw DJ , Kariuki S , Ayisi J , Nahlen B , Desai M , Madanitsa M , Kalilani-Phiri L , Ashorn P , Maleta K , Tshefu-Kitoto A , Mueller I , Stanisic D , Cates J , Van Eijk AM , Ome-Kaius M , Aitken EH , Rogerson SJ . Sci Rep 2023 13 (1) 10310 In areas of moderate to intense Plasmodium falciparum transmission, malaria in pregnancy remains a significant cause of low birth weight, stillbirth, and severe anaemia. Previously, fetal sex has been identified to modify the risks of maternal asthma, pre-eclampsia, and gestational diabetes. One study demonstrated increased risk of placental malaria in women carrying a female fetus. We investigated the association between fetal sex and malaria in pregnancy in 11 pregnancy studies conducted in sub-Saharan African countries and Papua New Guinea through meta-analysis using log binomial regression fitted to a random-effects model. Malaria infection during pregnancy and delivery was assessed using light microscopy, polymerase chain reaction, and histology. Five studies were observational studies and six were randomised controlled trials. Studies varied in terms of gravidity, gestational age at antenatal enrolment and bed net use. Presence of a female fetus was associated with malaria infection at enrolment by light microscopy (risk ratio 1.14 [95% confidence interval 1.04, 1.24]; P = 0.003; n = 11,729). Fetal sex did not associate with malaria infection when other time points or diagnostic methods were used. There is limited evidence that fetal sex influences the risk of malaria infection in pregnancy. |
Increased levels of anti-PfCSP antibodies in post-pubertal females versus males immunized with PfSPZ Vaccine does not translate into increased protective efficacy
Kc N , Church LWP , Riyahi P , Chakravarty S , Seder RA , Epstein JE , Lyke KE , Mordmüller B , Kremsner PG , Sissoko MS , Healy S , Duffy PE , Jongo SA , Nchama Vunn , Abdulla S , Mpina M , Sirima SB , Laurens MB , Steinhardt LC , Oneko M , Li M , Murshedkar T , Billingsley PF , Sim BKL , Richie TL , Hoffman SL . Front Immunol 2022 13 1006716 BACKGROUND: While prior research has shown differences in the risk of malaria infection and sickness between males and females, little is known about sex differences in vaccine-induced immunity to malaria. Identifying such differences could elucidate important aspects of malaria biology and facilitate development of improved approaches to malaria vaccination. METHODS: Using a standardized enzyme-linked immunosorbent assay, IgG antibodies to the major surface protein on Plasmodium falciparum (Pf) sporozoites (SPZ), the Pf circumsporozoite protein (PfCSP), were measured before and two weeks after administration of a PfSPZ-based malaria vaccine (PfSPZ Vaccine) to 5-month to 61-year-olds in 11 clinical trials in Germany, the US and five countries in Africa, to determine if there were differences in vaccine elicited antibody response between males and females and if these differences were associated with differential protection against naturally transmitted Pf malaria (Africa) or controlled human malaria infection (Germany, the US and Africa). RESULTS: Females ≥ 11 years of age made significantly higher levels of antibodies to PfCSP than did males in most trials, while there was no indication of such differences in infants or children. Although adult females had higher levels of antibodies, there was no evidence of improved protection compared to males. In 2 of the 7 trials with sufficient data, protected males had significantly higher levels of antibodies than unprotected males, and in 3 other trials protected females had higher levels of antibodies than did unprotected females. CONCLUSION: Immunization with PfSPZ Vaccine induced higher levels of antibodies in post-pubertal females but showed equivalent protection in males and females. We conclude that the increased antibody levels in post-pubertal females did not contribute substantially to improved protection. We hypothesize that while antibodies to PfCSP (and PfSPZ) may potentially contribute directly to protection, they primarily correlate with other, potentially protective immune mechanisms, such as antibody dependent and antibody independent cellular responses in the liver. |
Efficacy of RTS,S/AS01(E) malaria vaccine administered according to different full, fractional, and delayed third or early fourth dose regimens in children aged 5-17 months in Ghana and Kenya: an open-label, phase 2b, randomised controlled trial
Samuels AM , Ansong D , Kariuki SK , Adjei S , Bollaerts A , Ockenhouse C , Westercamp N , Lee CK , Schuerman L , Bii DK , Osei-Tutu L , Oneko M , Lievens M , Attobrah Sarfo MA , Atieno C , Morelle D , Bakari A , Sang T , Jongert E , Kotoh-Mortty MF , Otieno K , Roman F , Buabeng PBY , Ntiamoah Y , Ofori-Anyinam O , Agbenyega T . Lancet Infect Dis 2022 22 (9) 1329-1342 BACKGROUND: Controlled infection studies in malaria-naive adults suggest increased vaccine efficacy for fractional-dose versus full-dose regimens of RTS,S/AS01. We report first results of an ongoing trial assessing different fractional-dose regimens in children, in natural exposure settings. METHODS: This open-label, phase 2b, randomised controlled trial is conducted at the Malaria Research Center, Agogo, Ashanti Region (Ghana), and the Kenya Medical Research Institute and the US Centers for Disease Control and Prevention site in Siaya County (Kenya). We enrolled children aged 5-17 months without serious acute or chronic illness who had previously received three doses of diphtheria, tetanus, pertussis, and hepatitis B vaccine and at least three doses of oral polio vaccine. Children were randomly assigned (1:1:1:1:1) using a web-based randomisation system with a minimisation procedure accounting for centre to receive rabies control vaccine (M012 schedule) or two full doses of RTS,S/AS01(E) at month 0 and month 1, followed by either full doses at months 2 and 20 (group R012-20 [standard regimen]), full doses at months 2, 14, 26, and 38 (R012-14), fractional doses at months 2, 14, 26, and 38 (Fx012-14), or fractional doses at months 7, 20, and 32 (Fx017-20). The fractional doses were administered as one fifth (0·1 mL) of the full RTS,S dose (0·5 mL) after reconstitution. All vaccines were administered by intramuscular injection in the left deltoid. The primary outcome was occurrence of clinical malaria cases from month 2·5 until month 14 for the Fx012-14 group versus the pooled R012-14 and R012-20 groups in the per-protocol set. We assessed incremental vaccine efficacy of the Fx012-14 group versus the pooled R012-14 and R012-20 group over 12 months after dose three. Safety was assessed in all children who received at least one vaccine dose. This trial is registered with ClinicalTrials.gov, NCT03276962. FINDINGS: Between Sept 28, 2017, and Sept 25, 2018, 2157 children were enrolled, of whom 1609 were randomly assigned to a treatment group (322 to each RTS,S/AS01(E) group and 321 to the rabies vaccine control group). 1500 children received at least one study vaccine dose and the per-protocol set comprised 1332 children. Over 12 months after dose three, the incremental vaccine efficacy in the Fx012-14 group versus the pooled R012-14 and R12-20 groups was -21% (95% CI -57 to 7; p=0·15). Up to month 21, serious adverse events occurred in 48 (16%) of 298 children in the R012-20 group, 45 (15%) of 294 in the R012-14 group, 47 (15%) of 304 in the Fx012-14 group, 62 (20%) of 311 in the Fx017-20 group, and 71 (24%) of 293 in the control group, with no safety signals observed. INTERPRETATION: The Fx012-14 regimen was not superior to the standard regimen over 12 months after dose three. All RTS,S/AS01(E) regimens provided substantial, similar protection against clinical malaria, suggesting potential flexibility in the recommended dosing regimen and schedule. This, and the effect of annual boosters, will be further evaluated through 50 months of follow-up. FUNDING: GlaxoSmithKline Biologicals; PATH's Malaria Vaccine Initiative. |
The burden of influenza among Kenyan pregnant and postpartum women and their infants, 2015-2020
Otieno NA , Nyawanda BO , McMorrow M , Oneko M , Omollo D , Lidechi S , Widdowson MA , Flannery B , Chaves SS , Azziz-Baumgartner E , Emukule GO . Influenza Other Respir Viruses 2022 16 (3) 452-461 BACKGROUND: 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 <31 weeks of gestation and conducted weekly follow-up until 6-month postpartum to identify acute respiratory illnesses (ARIs). We defined ARI among mothers as reported cough, rhinorrhoea or sore throat and among infants as maternal-reported cough, difficulty breathing, rhinorrhoea or clinician diagnosis of respiratory illness. We collected nasal/nasopharyngeal and oropharyngeal swabs from mothers/infants with ARI and tested for influenza A and B using molecular assays. We calculated antenatal incidence of laboratory-confirmed influenza among mothers and postnatal incidence among mothers and infants. RESULTS: During June 2015 to May 2020, we analysed data from 3,026 pregnant women at a median gestational age of 16weeks (interquartile range [IQR], 13, 18) and followed 2,550 infants. Incidence of laboratory-confirmed influenza during pregnancy (10.3 episodes per 1,000person-months [95% confidence interval {CI} 8.6-11.8]) was twofold higher than in the postpartum period (4.0 [95% CI 2.6-5.5]; p<0.01). Incidence was significantly higher among human immunodeficiency virus (HIV)-infected pregnant women (15.6 [95% CI 11.0-20.6] vs. 9.1 [95% CI 7.5-10.8]; p<0.01). Incidence among young infants was 4.4 (95% CI 3.0-5.9) and similar among HIV-exposed and HIV-unexposed infants. CONCLUSION: Our findings suggest a substantial burden of influenza illnesses during pregnancy, with a higher burden among HIV-infected mothers. Kenyan authorities should consider the value of vaccinating pregnant women, especially if HIV infected. |
Safety, immunogenicity and efficacy of PfSPZ vaccine against malaria in infants in western Kenya: a double-blind, randomized, placebo-controlled phase 2 trial
Oneko M , Steinhardt LC , Yego R , Wiegand RE , Swanson PA , Kc N , Akach D , Sang T , Gutman JR , Nzuu EL , Dungani A , Kim Lee Sim B , Oloo PN , Otieno K , Bii DK , Billingsley PF , James ER , Kariuki S , Samuels AM , Jongo S , Chebore W , Abdulla S , Daubenberger C , Mpina M , Styers D , Potter GE , Abarbanell G , Richie TL , Hoffman SL , Seder RA . Nat Med 2021 27 (9) 1636-1645 The radiation-attenuated Plasmodium falciparum sporozoite (PfSPZ) vaccine provides protection against P. falciparum infection in malaria-naïve 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 × 10(5), 9.0 × 10(5) or 1.8 × 10(6) 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 × 10(5) 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. |
Caregiver and community perceptions and experiences participating in an infant malaria prevention trial of PfSPZ Vaccine administered by direct venous inoculation: a qualitative study in Siaya County, western Kenya
Achieng F , Rosen JG , Cherop RY , Kariuki S , Hoffman SL , Seder R , Oneko M , Steinhardt LC . Malar J 2020 19 (1) 226 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. |
Feasibility of direct venous inoculation of the radiation-attenuated Plasmodium falciparum whole sporozoite vaccine in children and infants in Siaya, western Kenya
Oneko M , Cherop YR , Sang T , Gutman JR , Wiegand R , Nyang'au EM , Odila AD , Akach D , Hamel MJ , Samuels AM , Kariuki S , Abebe Y , Nzuu EL , Wijayalath W , James ER , Sim BKL , Billingsley PF , Richie TL , Hoffman SL , Seder RA , Steinhardt LC . Vaccine 2020 38 (29) 4592-4600 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 (<0.5 mL), and in 10/511 (2.0%) venous access was not obtained. The rate of complete injections by single DVI for infants improved from 77.1% in part 1 to 92.8% in part 2. No crying occurred in 51/59 (86.4%) vaccinations in 5-9-year-olds, 25/86 (29.1%) vaccinations in 13-59-month-olds and 172/1067 (16.1%) vaccinations in infants. Mean administration time ranged from 2.6 to 4.6 minutes and was longer for younger age groups. These data show that vaccination by DVI was feasible and well tolerated in infants and children in this rural hospital in western Kenya, when performed by skilled injectors. We also report that shipping and storage in liquid nitrogen vapor phase was simple and efficient. (Clinicaltrials.gov NCT02687373). |
Neurodevelopmental outcomes of infants with congenital cytomegalovirus infection in Western Kenya
Oneko M , Otieno NA , Dollard SC , Lanzieri TM . J Clin Virol 2020 128 104367 Recent studies in Africa have shown an increased prevalence of congenital CMV infection among HIV-exposed infants compared with HIV-unexposed infants, despite near universal maternal use of highly active antiretroviral therapy. [1,2] However, data on the burden of congenital CMV-related sequelae among HIV-exposed and -unexposed children in Africa are limited. In this letter, we report updated estimates of prevalence by HIV-exposure status and clinical outcomes of CMV-positive children identified by screening 1078 newborns in western Kenya during 2015–2017. [1] |
Exploration of risk factors for ceftriaxone resistance in invasive non-typhoidal Salmonella infections in western Kenya
Luvsansharav UO , Wakhungu J , Grass J , Oneko M , Nguyen V , Bigogo G , Ogola E , Audi A , Onyango D , Hamel MJ , Montgomery JM , Fields PI , Mahon BE . PLoS One 2020 15 (3) e0229581 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. |
Safety and immunogenicity of the RTS,S/AS01 malaria vaccine in infants and children identified as HIV-infected during a randomized trial in sub-Saharan Africa
Otieno L , Guerra Mendoza Y , Adjei S , Agbenyega T , Agnandji ST , Aide P , Akoo P , Ansong D , Asante KP , Berkley JA , Gesase S , Hamel MJ , Hoffman I , Kaali S , Kamthunzi P , Kariuki S , Kremsner P , Lanaspa M , Lell B , Lievens M , Lusingu J , Malabeja A , Masoud NS , Mtoro AT , Njuguna P , Ofori-Anyinam O , Otieno GA , Otieno W , Owusu-Agyei S , Schuerman L , Sorgho H , Tanner M , Tinto H , Valea I , Vandoolaeghe P , Sacarlal J , Oneko M . Vaccine 2019 38 (4) 897-906 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. |
The impact of maternal HIV and malaria infection on the prevalence of congenital cytomegalovirus infection in Western Kenya
Otieno NA , Nyawanda BO , Otiato F , Oneko M , Amin MM , Otieno M , Omollo D , McMorrow M , Chaves SS , Dollard SC , Lanzieri TM . J Clin Virol 2019 120 33-37 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. |
Safety, tolerability, and immunogenicity of PfSPZ Vaccine administered by direct venous inoculation to infants and young children: findings from an age de-escalation, dose-escalation double-blinded randomized, controlled study in western Kenya
Steinhardt LC , Richie TL , Yego R , Akach D , Hamel MJ , Gutman JR , Wiegand RE , Nzuu EL , Dungani A , Kc N , Murshedkar T , Church LWP , Sim BKL , Billingsley PF , James ER , Abebe Y , Kariuki S , Samuels AM , Otieno K , Sang T , Kachur SP , Styers D , Schlessman K , Abarbanell G , Hoffman SL , Seder RA , Oneko M . Clin Infect Dis 2019 71 (4) 1063-1071 BACKGROUND: The whole 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 (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: 1.35x105, 2.7x105, 4.5x105, 9.0x105, and 1.8x106Plasmodium falciparum sporozoites (PfSPZ), with the two highest doses given twice, 8 weeks apart. Solicited adverse events (AEs) were monitored for eight days after vaccination; unsolicited AEs for 29 days; and serious AEs (SAEs) throughout the study. Blood taken pre-vaccination and one-week post-vaccination was tested for IgG antibodies to Pf circumsporozoite protein (PfCSP) using enzyme-linked immunosorbent assay (ELISA). 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, SAEs, or grade 3 laboratory abnormalities occurred. Most (79.0%) vaccinations were administered by a single DVI. Among those in the 9.0x105 and 1.8x106 PfSPZ groups, 36/45 (80.0%) vaccinees and 4/21 (19.0%) placebo controls developed antibodies to PfCSP, p<0.001. CONCLUSIONS: PfSPZ Vaccine in doses as high as 1.8x106 can be administered to infants and children by DVI, and was safe, well tolerated, and immunogenic. |
Safety profile of the RTS,S/AS01 malaria vaccine in infants and children: additional data from a phase III randomized controlled trial in sub-Saharan Africa
Guerra Mendoza Y , Garric E , Leach A , Lievens M , Ofori-Anyinam O , Pircon JY , Stegmann JU , Vandoolaeghe P , Otieno L , Otieno W , Owusu-Agyei S , Sacarlal J , Masoud NS , Sorgho H , Tanner M , Tinto H , Valea I , Mtoro AT , Njuguna P , Oneko M , Otieno GA , Otieno K , Gesase S , Hamel MJ , Hoffman I , Kaali S , Kamthunzi P , Kremsner P , Lanaspa M , Lell B , Lusingu J , Malabeja A , Aide P , Akoo P , Ansong D , Asante KP , Berkley JA , Adjei S , Agbenyega T , Agnandji ST , Schuerman L . Hum Vaccin Immunother 2019 15 (10) 1-13 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. |
Malaria, malnutrition, and birthweight: A meta-analysis using individual participant data
Cates JE , Unger HW , Briand V , Fievet N , Valea I , Tinto H , D'Alessandro U , Landis SH , Adu-Afarwuah S , Dewey KG , Ter Kuile FO , Desai M , Dellicour S , Ouma P , Gutman J , Oneko M , Slutsker L , Terlouw DJ , Kariuki S , Ayisi J , Madanitsa M , Mwapasa V , Ashorn P , Maleta K , Mueller I , Stanisic D , Schmiegelow C , Lusingu JPA , van Eijk AM , Bauserman M , Adair L , Cole SR , Westreich D , Meshnick S , Rogerson S . PLoS Med 2017 14 (8) e1002373 BACKGROUND: Four studies previously indicated that the effect of malaria infection during pregnancy on the risk of low birthweight (LBW; <2,500 g) may depend upon maternal nutritional status. We investigated this dependence further using a large, diverse study population. METHODS AND FINDINGS: We evaluated the interaction between maternal malaria infection and maternal anthropometric status on the risk of LBW using pooled data from 14,633 pregnancies from 13 studies (6 cohort studies and 7 randomized controlled trials) conducted in Africa and the Western Pacific from 1996-2015. Studies were identified by the Maternal Malaria and Malnutrition (M3) initiative using a convenience sampling approach and were eligible for pooling given adequate ethical approval and availability of essential variables. Study-specific adjusted effect estimates were calculated using inverse probability of treatment-weighted linear and log-binomial regression models and pooled using a random-effects model. The adjusted risk of delivering a baby with LBW was 8.8% among women with malaria infection at antenatal enrollment compared to 7.7% among uninfected women (adjusted risk ratio [aRR] 1.14 [95% confidence interval (CI): 0.91, 1.42]; N = 13,613), 10.5% among women with malaria infection at delivery compared to 7.9% among uninfected women (aRR 1.32 [95% CI: 1.08, 1.62]; N = 11,826), and 15.3% among women with low mid-upper arm circumference (MUAC <23 cm) at enrollment compared to 9.5% among women with MUAC ≥ 23 cm (aRR 1.60 [95% CI: 1.36, 1.87]; N = 9,008). The risk of delivering a baby with LBW was 17.8% among women with both malaria infection and low MUAC at enrollment compared to 8.4% among uninfected women with MUAC ≥ 23 cm (joint aRR 2.13 [95% CI: 1.21, 3.73]; N = 8,152). There was no evidence of synergism (i.e., excess risk due to interaction) between malaria infection and MUAC on the multiplicative (p = 0.5) or additive scale (p = 0.9). Results were similar using body mass index (BMI) as an anthropometric indicator of nutritional status. Meta-regression results indicated that there may be multiplicative interaction between malaria infection at enrollment and low MUAC within studies conducted in Africa; however, this finding was not consistent on the additive scale, when accounting for multiple comparisons, or when using other definitions of malaria and malnutrition. The major limitations of the study included availability of only 2 cross-sectional measurements of malaria and the limited availability of ultrasound-based pregnancy dating to assess impacts on preterm birth and fetal growth in all studies. CONCLUSIONS: Pregnant women with malnutrition and malaria infection are at increased risk of LBW compared to women with only 1 risk factor or none, but malaria and malnutrition do not act synergistically. |
First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies
Dellicour S , Sevene E , McGready R , Tinto H , Mosha D , Manyando C , Rulisa S , Desai M , Ouma P , Oneko M , Vala A , Ruperez M , Macete E , Menendez C , Nakanabo-Diallo S , Kazienga A , Valea I , Calip G , Augusto O , Genton B , Njunju EM , Moore KA , d'Alessandro U , Nosten F , Ter Kuile F , Stergachis A . PLoS Med 2017 14 (5) e1002290 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. |
Evaluation of TaqMan Array Card (TAC) for the Detection of Central Nervous System Infections in Kenya.
Onyango CO , Loparev V , Lidechi S , Bhullar V , Schmid DS , Radford K , Lo MK , Rota P , Johnson BW , Munoz J , Oneko M , Burton D , Black CM , Neatherlin J , Montgomery JM , Fields B . J Clin Microbiol 2017 55 (7) 2035-2044 ![]() 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 (CSF). The 21-pathogen TAC assays include two parasites (Balamuthia mandrillaris and Acanthamoeba), six bacterial pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Mycoplasma pneumoniae, Mycobacterium tuberculosis, and Bartonella) and 13 viruses (parechovirus, dengue, nipah, varicella zoster, mumps, measles, lyssa, herpes simplex virus 1 and 2, Epstein Barr virus, enterovirus, cytomegalovirus and chikungunya). The card also includes human RNAse P as a nucleic acid extraction control and an internal manufacturer control (glyceraldehyde 3-phosphate dehydrogenase (GAPDH)). This CNS-TAC can test up to eight samples for all 21 agents within 2.5 hours following nucleic acid extraction. The assay was validated for linearity, limit of detection, sensitivity and specificity by either using live viruses (dengue, mumps and measles) or nucleic acid material (nipah and chikungunya). Of the 120 samples tested by individual real-time PCR (IRTP), 35 were positive for eight different targets while CNS-TAC detected 37 positive samples across nine different targets. The TAC assays showed 85.6% sensitivity and 96.7% specificity across the assays. This assay may be useful for outbreak investigation and surveillance of suspected neurological disease. |
Congenital anomalies: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data
DeSilva M , Munoz FM , McMillan M , Kawai AT , Marshall H , Macartney KK , Joshi J , Oneko M , Rose AE , Dolk H , Trotta F , Spiegel H , Tomczyk S , Shrestha A , Kochhar S , Kharbanda EO . Vaccine 2016 34 (49) 6015-6026 Need for developing case definitions and guidelines for data collection, analysis, and presentation for congenital anomalies as an adverse event following immunization | Congenital anomalies, also commonly referred to as birth defects, congenital disorders, congenital malformations, or congenital abnormalities, are conditions of prenatal origin that are present at birth, potentially impacting an infant's health, development and/or survival. We will use the term congenital anomalies in this report. Congenital anomalies encompass a wide array of structural and functional abnormalities that can occur in isolation (i.e., single defect) or as a group of defects (i.e., multiple defects). Multiple defects may occur as part of well-described associations, such as the non-random co-occurrence of Vertebral anomalies, Anal atresia, Cardiac defects, Tracheoesophageal fistula, and/or Esophageal atresia, Renal and Radial anomalies, and Limb defects (VACTERL) [1]. | Congenital anomalies vary substantially in severity. Some congenital anomalies are associated with spontaneous abortion, stillbirth, or death in the early postnatal period. Global deaths due to congenital anomalies decreased from 750.6 thousand in 1990 to 632.1 thousand in 2013, with respective age-standardized death rates of 11.0 and 8.7 per 100,000 [2]. Subtypes of fatal congenital anomalies (with estimated number of global deaths in 2013 in thousands) are congenital heart anomalies (323.4), neural tube defects (68.9), Down's syndrome (36.4), and chromosomal unbalanced rearrangements (17.3) [2]. Other congenital anomalies may have little impact on survival. Anomalies which affect an infant's life expectancy, health status, physical or social functioning may be described as “major” anomalies. In contrast, “minor” anomalies are those with little or no impact on health or short-term or long-term function [3]. We have chosen to focus on major anomalies for this case definition due to their impact on public health and pre-existing structure for surveillance and reporting by large national and international organizations. |
Safety and immunogenicity of RTS,S/AS01 malaria vaccine in infants and children with WHO stage 1 or 2 HIV disease: a randomised, double-blind, controlled trial
Otieno L , Oneko M , Otieno W , Abuodha J , Owino E , Odero C , Mendoza YG , Andagalu B , Awino N , Ivinson K , Heerwegh D , Otsyula N , Oziemkowska M , Usuf EA , Otieno A , Otieno K , Leboulleux D , Leach A , Oyieko J , Slutsker L , Lievens M , Cowden J , Lapierre D , Kariuki S , Ogutu B , Vekemans J , Hamel MJ . Lancet Infect Dis 2016 16 (10) 1134-1144 BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: GlaxoSmithKline Biologicals SA and PATH Malaria Vaccine Initiative. |
Weekly miscarriage rates in a community-based prospective cohort study in rural western Kenya
Dellicour S , Aol G , Ouma P , Yan N , Bigogo G , Hamel MJ , Burton DC , Oneko M , Breiman RF , Slutsker L , Feikin D , Kariuki S , Odhiambo F , Calip G , Stergachis A , Laserson KF , Ter Kuile FO , Desai M . BMJ Open 2016 6 (4) e011088 OBJECTIVE: 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. DESIGN: This was a population-based prospective cohort. PARTICIPANTS AND SETTING: 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. OUTCOME MEASURE: Miscarriage. RESULTS: 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. CONCLUSIONS: 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. |
Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial
RTS S Clinical Trials Partnership , Hamel MJ , Kariuki S , Oneko M , Odero C , Otieno K , Awino N , Muturi-Kioi V , Omoto J , Sang T , Odhiambo S , Laserson KF , Slutsker L . Lancet 2015 386 (9988) 31-45 BACKGROUND: The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose. METHODS: From March 27, 2009, until Jan 31, 2011, children (age 5-17 months) and young infants (age 6-12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria. Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619. FINDINGS: 8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39-50) and young infants for 38 months (34-41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8-40·5) and 7396 occurred in the R3C group (28·3%, 23·3-32·9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%, 13·7 to 46·9) and 169 in the R3C group (1·1%, -23·0 to 20·5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25·9%, 95% CI 19·9-31·5) and 5444 occurred in the R3C group (18·3%, 11·7-24·4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17·3%, 95% CI -9·4 to 37·5) and 104 in the R3C group (10·3%, -17·9 to 31·8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387-2186) in the R3R group and 1363 per 1000 children (995-1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592-1337) in the R3R group and 558 (158-926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children. INTERPRETATION: RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3-4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission. FUNDING: GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative. |
Risks of miscarriage and inadvertent exposure to artemisinin derivatives in the first trimester of pregnancy: a prospective cohort study in western Kenya
Dellicour S , Desai M , Aol G , Oneko M , Ouma P , Bigogo G , Burton DC , Breiman RF , Hamel MJ , Slutsker L , Feikin D , Kariuki S , Odhiambo F , Pandit J , Laserson KF , Calip G , Stergachis A , Ter Kuile FO . Malar J 2015 14 (1) 461 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 <13 weeks gestation) was higher than among pregnancies unexposed to anti-malarials in the first trimester: hazard ratio (HR) = 1.70, 95 % CI (1.08-2.68) and HR = 1.61 (0.96-2.70). For confirmed ACT-exposures (primary analysis) the corresponding values were: HR = 1.24 (0.56-2.74) and HR = 0.73 (0.19-2.82) relative to unexposed women, and HR = 0.99 (0.12-8.33) and HR = 0.32 (0.03-3.61) relative to quinine exposure, but the numbers of quinine exposures were very small. CONCLUSION: ACT exposure in early pregnancy was more common than quinine exposure. Confirmed inadvertent artemisinin exposure during the potential embryo-sensitive period was not associated with increased risk of miscarriage. Confirmatory studies are needed to rule out a smaller than three-fold increase in risk. |
Emergence of community-acquired, multidrug-resistant invasive nontyphoidal Salmonella disease in rural western Kenya, 2009-2013
Oneko M , Kariuki S , Muturi-Kioi V , Otieno K , Otieno VO , Williamson JM , Folster J , Parsons MB , Slutsker L , Mahon BE , Hamel MJ . Clin Infect Dis 2015 61 Suppl 4 S310-6 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. |
Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial
White MT , Verity R , Griffin JT , Asante KP , Owusu-Agyei S , Greenwood B , Drakeley C , Gesase S , Lusingu J , Ansong D , Adjei S , Agbenyega T , Ogutu B , Otieno L , Otieno W , Agnandji ST , Lell B , Kremsner P , Hoffman I , Martinson F , Kamthunzu P , Tinto H , Valea I , Sorgho H , Oneko M , Otieno K , Hamel MJ , Salim N , Mtoro A , Abdulla S , Aide P , Sacarlal J , Aponte JJ , Njuguna P , Marsh K , Bejon P , Riley EM , Ghani AC . Lancet Infect Dis 2015 15 (12) 1450-8 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. |
A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants
Agnandji ST , Lell B , Fernandes JF , Abossolo BP , Methogo BG , Kabwende AL , Adegnika AA , Mordmüller B , Issifou S , Kremsner PG , Sacarlal J , Aide P , Lanaspa M , Aponte JJ , Machevo S , Acacio S , Bulo H , Sigauque B , Macete E , Alonso P , Abdulla S , Salim N , Minja R , Mpina M , Ahmed S , Ali AM , Mtoro AT , Hamad AS , Mutani P , Tanner M , Tinto H , D'Alessandro U , Sorgho H , Valea I , Bihoun B , Guiraud I , Kaboré B , Sombié O , Guiguemdé RT , Ouédraogo JB , Hamel MJ , Kariuki S , Oneko M , Odero C , Otieno K , Awino N , McMorrow M , Muturi-Kioi V , Laserson KF , Slutsker L , Otieno W , Otieno L , Otsyula N , Gondi S , Otieno A , Owira V , Oguk E , Odongo G , Woods JB , Ogutu B , Njuguna P , Chilengi R , Akoo P , Kerubo C , Maingi C , Lang T , Olotu A , Bejon P , Marsh K , Mwambingu G , Owusu-Agyei S , Asante KP , Osei-Kwakye K , Boahen O , Dosoo D , Asante I , Adjei G , Kwara E , Chandramohan D , Greenwood B , Lusingu J , Gesase S , Malabeja A , Abdul O , Mahende C , Liheluka E , Malle L , Lemnge M , Theander TG , Drakeley C , Ansong D , Agbenyega T , Adjei S , Boateng HO , Rettig T , Bawa J , Sylverken J , Sambian D , Sarfo A , Agyekum A , Martinson F , Hoffman I , Mvalo T , Kamthunzi P , Nkomo R , Tembo T , Tegha G , Tsidya M , Kilembe J , Chawinga C , Ballou WR , Cohen J , Guerra Y , Jongert E , Lapierre D , Leach A , Lievens M , Ofori-Anyinam O , Olivier A , Vekemans J , Carter T , Kaslow D , Leboulleux D , Loucq C , Radford A , Savarese B , Schellenberg D , Sillman M , Vansadia P . N Engl J Med 2012 367 (24) 2284-95 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.). |
First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children
Agnandji ST , Lell B , Soulanoudjingar SS , Fernandes JF , Abossolo BP , Conzelmann C , Methogo BG , Doucka Y , Flamen A , Mordmüller B , Issifou S , Kremsner PG , Sacarlal J , Aide P , Lanaspa M , Aponte JJ , Nhamuave A , Quelhas D , Bassat Q , Mandjate S , Macete E , Alonso P , Abdulla S , Salim N , Juma O , Shomari M , Shubis K , Machera F , Hamad AS , Minja R , Mtoro A , Sykes A , Ahmed S , Urassa AM , Ali AM , Mwangoka G , Tanner M , Tinto H , D'Alessandro U , Sorgho H , Valea I , Tahita MC , Kaboré W , Ouédraogo S , Sandrine Y , Guiguemdé RT , Ouédraogo JB , Hamel MJ , Kariuki S , Odero C , Oneko M , Otieno K , Awino N , Omoto J , Williamson J , Muturi-Kioi V , Laserson KF , Slutsker L , Otieno W , Otieno L , Nekoye O , Gondi S , Otieno A , Ogutu B , Wasuna R , Owira V , Jones D , Onyango AA , Njuguna P , Chilengi R , Akoo P , Kerubo C , Gitaka J , Maingi C , Lang T , Olotu A , Tsofa B , Bejon P , Peshu N , Marsh K , Owusu-Agyei S , Asante KP , Osei-Kwakye K , Boahen O , Ayamba S , Kayan K , Owusu-Ofori R , Dosoo D , Asante I , Adjei G , Adjei G , Chandramohan D , Greenwood B , Lusingu J , Gesase S , Malabeja A , Abdul O , Kilavo H , Mahende C , Liheluka E , Lemnge M , Theander T , Drakeley C , Ansong D , Agbenyega T , Adjei S , Boateng HO , Rettig T , Bawa J , Sylverken J , Sambian D , Agyekum A , Owusu L , Martinson F , Hoffman I , Mvalo T , Kamthunzi P , Nkomo R , Msika A , Jumbe A , Chome N , Nyakuipa D , Chintedza J , Ballou WR , Bruls M , Cohen J , Guerra Y , Jongert E , Lapierre D , Leach A , Lievens M , Ofori-Anyinam O , Vekemans J , Carter T , Leboulleux D , Loucq C , Radford A , Savarese B , Schellenberg D , Sillman M , Vansadia P . N Engl J Med 2011 365 (20) 1863-75 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 .) |
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