Safety and Immunogenicity of Accelerated Heterologous Two-dose Ebola Vaccine Regimens in Adults With and Without HIV in Africa.

BACKGROUND: Shorter prophylactic vaccine schedules may offer more rapid protection against Ebola in resource-limited settings. METHODS: This randomized, observer-blind, placebo-controlled, phase 2 trial conducted in five sub-Saharan African countries included people without HIV (PWOH, n = 249) and people living with HIV (PLWH, n = 250). Adult participants received one of two accelerated Ebola vaccine regimens (MVA-BN-Filo, Ad26.ZEBOV administered 14 days apart [n = 79] or Ad26.ZEBOV, MVA-BN-Filo administered 28 days apart [n = 322]) or saline/placebo (n = 98). The primary endpoints were safety (adverse events [AEs]) and immunogenicity (Ebola virus [EBOV] glycoprotein-specific binding antibody responses). Binding antibody responders were defined as participants with a > 2.5-fold increase from baseline or the lower limit of quantification if negative at baseline. RESULTS: The mean age was 33.4 years, 52% of participants were female, and among PLWH, the median (interquartile range) CD4+ cell count was 560.0 (418.0-752.0) cells/µL. AEs were generally mild/moderate with no vaccine-related serious AEs or remarkable safety profile differences by HIV status. At 21 days post-dose 2, EBOV glycoprotein-specific binding antibody response rates in vaccine recipients were 99% for the 14-day regimen (geometric mean concentrations [GMCs]: 5168 enzyme-linked immunosorbent assay units (EU)/mL in PWOH; 2509 EU/mL in PLWH), and 98% for the 28-day regimen (GMCs: 6037 EU/mL in PWOH; 2939 EU/mL in PLWH). At 12 months post-dose 2, GMCs in PWOH and PLWH were 635 and 514 EU/mL, respectively, for the 14-day regimen and 331 and 360 EU/mL, respectively, for the 28-day regimen. CONCLUSIONS: Accelerated 14- and 28-day Ebola vaccine regimens were safe and immunogenic in PWOH and PLWH in Africa. TRIAL REGISTRATION: NCT02598388.

A Multinational Trial of Prasugrel for Sickle Cell Vaso-Occlusive Events.

BACKGROUND: Sickle cell anemia is an inherited blood disorder that is characterized by painful vaso-occlusive crises, for which there are few treatment options. Platelets mediate intercellular adhesion and thrombosis during vaso-occlusion in sickle cell anemia, which suggests a role for antiplatelet agents in modifying disease events. METHODS: Children and adolescents 2 through 17 years of age with sickle cell anemia were randomly assigned to receive oral prasugrel or placebo for 9 to 24 months. The primary end point was the rate of vaso-occlusive crisis, a composite of painful crisis or acute chest syndrome. The secondary end points were the rate of sickle cell-related pain and the intensity of pain, which were assessed daily with the use of pain diaries. RESULTS: A total of 341 patients underwent randomization at 51 sites in 13 countries across the Americas, Europe, Asia, and Africa. The rate of vaso-occlusive crisis events per person-year was 2.30 in the prasugrel group and 2.77 in the placebo group (rate ratio, 0.83; 95% confidence interval, 0.66 to 1.05; P=0.12). There were no significant differences between the groups in the secondary end points of diary-reported events. The safety end points, including the frequency of bleeding events requiring medical intervention, of hemorrhagic and nonhemorrhagic adverse events that occurred while patients were taking prasugrel or placebo, and of discontinuations due to prasugrel or placebo, did not differ significantly between the groups. CONCLUSIONS: Among children and adolescents with sickle cell anemia, the rate of vaso-occlusive crisis was not significantly lower among those who received prasugrel than among those who received placebo. There were no significant between-group differences in the safety findings. (Funded by Daiichi Sankyo and Eli Lilly; ClinicalTrials.gov number, NCT01794000.).

Longitudinal estimation of Plasmodium falciparum prevalence in relation to malaria prevention measures in six sub-Saharan African countries.

BACKGROUND: Plasmodium falciparum prevalence (PfPR) is a widely used metric for assessing malaria transmission intensity. This study was carried out concurrently with the RTS,S/AS01 candidate malaria vaccine Phase III trial and estimated PfPR over ≤ 4 standardized cross-sectional surveys. METHODS: This epidemiology study (NCT01190202) was conducted in 8 sites from 6 countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, and Tanzania), between March 2011 and December 2013. Participants were enrolled in a 2:1:1 ratio according to age category: 6 months-4 years, 5-19 years, and ≥ 20 years, respectively, per year and per centre. All sites carried out surveys 1-3 while survey 4 was conducted only in 3 sites. Surveys were usually performed during the peak malaria parasite transmission season, in one home visit, when medical history and malaria risk factors/prevention measures were collected, and a blood sample taken for rapid diagnostic test, microscopy, and haemoglobin measurement. PfPR was estimated by site and age category. RESULTS: Overall, 6401 (survey 1), 6411 (survey 2), 6400 (survey 3), and 2399 (survey 4) individuals were included in the analyses. In the 6 months-4 years age group, the lowest prevalence (assessed using microscopy) was observed in 2 Tanzanian centres (4.6% for Korogwe and 9.95% for Bagamoyo) and Lambaréné, Gabon (6.0%), while the highest PfPR was recorded for Nanoro, Burkina Faso (52.5%). PfPR significantly decreased over the 3 years in Agogo (Ghana), Kombewa (Kenya), Lilongwe (Malawi), and Bagamoyo (Tanzania), and a trend for increased PfPR was observed over the 4 surveys for Kintampo, Ghana. Over the 4 surveys, for all sites, PfPR was predominantly higher in the 5-19 years group than in the other age categories. Occurrence of fever and anaemia was associated with high P. falciparum parasitaemia. Univariate analyses showed a significant association of anti-malarial treatment in 4 surveys (odds ratios [ORs]: 0.52, 0.52, 0.68, 0.41) and bed net use in 2 surveys (ORs: 0.63, 0.68, 1.03, 1.78) with lower risk of malaria infection. CONCLUSION: Local PfPR differed substantially between sites and age groups. In children 6 months-4 years old, a significant decrease in prevalence over the 3 years was observed in 4 out of the 8 study sites. Trial registration Clinical Trials.gov identifier: NCT01190202:NCT. GSK Study ID numbers: 114001.

Longitudinal and Cross-sectional Analyses of Asymptomatic HIV-1/Malaria Co-infection in Kisumu County, Kenya.

Individuals infected with HIV-1 experience more frequent and more severe episodes of malaria and are likely to harbor asymptomatic parasitemia, thus potentially making them more efficient reservoirs of malaria. Two studies (cross-sectional and longitudinal) were designed in sequence between 2015-2018 and 2018-2020, respectively, to test the hypothesis that HIV-1 infected individuals have higher prevalence of asymptomatic parasitemia and gametocytemia than the HIV-1 negatives. This article describes the overall design of the two studies, encompassing data for the longitudinal study and additional data to the previously published baseline data for the cross-sectional study. In the cross-sectional study, HIV-1 positive participants were significantly older, more likely to be male, and more likely to have parasitemia relative to HIV-1 negatives (P < 0.01). In the longitudinal study, 300 participants were followed for 6 months. Of these, 102 were HIV-1 negative, 106 were newly diagnosed HIV-1 positive, and 92 were HIV-1 positive and on antiretroviral therapy, including antifolates, at enrollment. Overall parasitemia positivity at enrollment was 17.3% (52/300). Of these, 44% (23/52) were HIV-1 negative, 52% (27/52) were newly diagnosed HIV-1 positives, and only 4% (2/52) were HIV-1 positive and on treatment. Parasitemia for those on stable antiretroviral therapy was significantly lower (hazard ratio: 0.51, P < 0.001), compared with the HIV-1-negatives. On follow-up, there was a significant decline in parasitemia prevalence (hazard ratio: 0.74, P < 0.001) among the HIV patients newly initiated on antiretroviral therapy including trimethoprim-sulfamethoxasole. These data highlight the impact of HIV-1 and HIV treatment on asymptomatic parasitemia over time.

Longitudinal impact of asymptomatic malaria/HIV-1 co-infection on Plasmodium falciparum gametocyte transcript expression and transmission to Anopheles mosquitoes.

Despite significant developments towards malaria reduction, parasite transmission in the common context of HIV-1 co-infection and treatment for one or both infections has not been fully characterized. This is particularly important given that HIV-1 and malaria chemotherapies have the potential to alter gametocyte burden and mosquito infectivity. In this study, we examined 782 blood samples collected from a longitudinal cohort of 300 volunteers with asymptomatic parasitemia seeking HIV testing or treatment in the endemic region of Kisumu, Kenya, to define the impacts of HIV-1-malaria co-infection, antiretroviral therapy (ART) plus trimethoprim-sulfamethoxazole (TS) and the antimalarials artemether/lumefantrine (AL) on Plasmodium falciparum gametocyte transcript prevalence and parasite transmission to the African malaria mosquito Anopheles gambiae. Volunteers were assigned to three distinct HIV-1 groups: HIV-1 positive on treatment, HIV-1 positive newly diagnosed, and HIV-1 negative. Volunteers were monitored monthly over the course of six months. Using our highly sensitive digital droplet PCR (ddPCR) assay of three gametocyte specific transcript markers, we detected gametocyte transcripts in 51.1% of 18S positive volunteers across all study groups and time points. After correcting for multiple comparisons, the factors of HIV-1 status, time, CD4+ T-cell levels and hematocrit were not predictive of gametocyte prevalence or transmission. However, among those volunteers who were newly diagnosed with HIV-1 and malaria positive by rapid diagnostic test (RDT) at enrollment, the initiation of ART/TS and AL treatment was associated with a significant reduction in gametocyte transcript prevalence in the subsequent month when compared to HIV-1 negative volunteers treated with AL. To assess gametocyte transmissibility, volunteer blood samples were used in standard membrane feeding assays (SFMA) with laboratory-reared A. gambiae, with evidence of transmission confirmed by at least one of 25 dissected mosquitoes per sample positive for at least one midgut oocyst. HIV-1 status, CD4+ T-cell levels and hematocrit were not significantly associated with successful transmission to A. gambiae. Analysis of SMFA blood samples revealed that 50% of transmission-positive blood samples failed to test positive by Plasmodium-specific 18S ribosomal RNA quantitative PCR (qPCR) and 35% failed to test positive for any gametocyte specific transcript marker by droplet digital (ddPCR), documenting that transmission occurred in the absence of molecular parasite/gametocyte detection. Overall, these findings highlight the complexity of HIV-1 malaria co-infection and the need to further define the unpredictable role of asymptomatic parasitemia in transmission to mosquitoes.

Initiation of anti-retroviral/Trimethoprim-Sulfamethoxazole therapy in a longitudinal cohort of HIV-1 positive individuals in Western Kenya rapidly decreases asymptomatic malarial parasitemia.

Interactions between malaria and HIV-1 have important public health implications. Our previous cross-sectional studies showed significant associations between HIV-1 positivity and malarial parasitemia with an increased risk of gametocytemia. In this follow-up longitudinal study, we evaluated these associations to determine the magnitude of asymptomatic parasitemia over time, and to examine the effects of initiating Antiretroviral Therapy (ART) together with the broad-spectrum antibiotic Trimethoprim Sulfamethoxazole (TS) on asymptomatic parasitemia. 300 adult volunteers in a malaria holoendemic region in Western Kenya were enrolled and followed for six months. The study groups were composed of 102 HIV-1 negatives, 106 newly diagnosed HIV-1 positives and 92 HIV-1 positives who were already stable on ART/TS. Blood samples were collected monthly and asymptomatic malarial parasitemia determined using sensitive 18S qPCR. Results showed significantly higher malaria prevalence in the HIV-1 negative group (61.4%) (p=0.0001) compared to HIV-1 positives newly diagnosed (36.5%) and those stable on treatment (31.45%). Further, treatment with ART/TS had an impact on incidence of asymptomatic parasitemia. In volunteers who were malaria PCR-negative at enrollment, the median time to detectable asymptomatic infection was shorter for HIV-1 negatives (149 days) compared to the HIV-1 positives on treatment (171 days) (p=0.00136). Initiation of HIV treatment among the newly diagnosed led to a reduction in malarial parasitemia (expressed as 18S copy numbers/µl) by over 85.8% within one week of treatment and a further reduction by 96% after 2 weeks. We observed that while the impact of ART/TS on parasitemia was long term, treatment with antimalarial Artemether/Lumefantrine (AL) among the malaria RDT positives had a transient effect with individuals getting re-infected after short periods. As was expected, HIV-1 negative individuals had normal CD4+ levels throughout the study. However, CD4+ levels among HIV-1 positives who started treatment were low at enrollment but increased significantly within the first month of treatment. From our association analysis, the decline in parasitemia among the HIV-1 positives on treatment was attributed to TS treatment and not increased CD4+ levels per se. Overall, this study highlights important interactions between HIV-1 and malaria that may inform future use of TS among HIV-infected patients in malaria endemic regions.

Asymptomatic falciparum and Non-falciparum Malarial Parasitemia in Adult Volunteers with and without HIV-1 Coinfection in a Cohort Study in Western Kenya.

Asymptomatic malarial parasitemia represents the largest reservoir of infection and transmission, and the impact of coinfection with HIV-1 on this reservoir remains incompletely described. Accordingly, we sought to determine the prevalence of asymptomatic malarial parasitemia in Kombewa, Western Kenya, a region that is endemic for both malaria and HIV-1. A total of 1,762 dried blood spots were collected from asymptomatic adults in a cross-sectional study. The presence of parasitemia was first determined by a sensitive Plasmodium genus-specific 18S assay, followed by less sensitive species-specific DNA-based quantitative polymerase chain reaction (PCR) assays. The prevalence of asymptomatic malarial parasitemia by 18S genus-specific PCR assay was 64.4% (1,134/1,762). Of the 1,134 malaria positive samples, Plasmodium falciparum was the most prevalent species (57.4%), followed by Plasmodium malariae (3.8%) and Plasmodium ovale (2.6%) as single or mixed infections. As expected, the majority of infections were below the detection limit of microscopy and rapid diagnostic tests. HIV-1 prevalence was 10.6%, and we observed a significant association with malarial parasitemia by χ2 analysis (P = 0.0475). Seventy-one percent of HIV-1 infected volunteers were positive for Plasmodium 18S (132/186), with only 29% negative (54/186). In HIV-1-negative volunteers, the proportion was lower; 64% were found to be positive for 18S (998/1,569) and 36% were negative (571/1,569). Overall, the prevalence of asymptomatic malarial parasitemia in Western Kenya is high, and knowledge of these associations with HIV-1 infection are critically important for malaria elimination and eradication efforts focused on this important reservoir population.

Clinical laboratory hematology reference values among infants aged 1month to 17 months in Kombewa Sub-County, Kisumu: A cross sectional study of rural population in Western Kenya.

There is an urgent need for reliable region-specific hematological reference values for clinical monitoring. Laboratory reference ranges are important for assessing study participant eligibility, toxicity grading and management of adverse events in clinical trials and clinical diagnosis. Most clinical laboratories in Kenya rely on hematological reference values provided by instrument manufacturers and/or textbooks, which are based on population from Europe or North America. The use of such values in medical practice could result in improper patient management, selection bias in selection of appropriate participants for clinical trials and flawed classification of the clinical adverse events when applied to African populations. The aim of this study was to establish local laboratory hematological reference values in infants aged 1 month to 17 months from Kombewa Sub-county that could be true representative of the existing rural population. The study participants in the current study were those who had previously been recruited from GSK-sponsored study. This study was a phase III, Double Blind, Randomized, GSK-sponsored, Malaria Vaccine Clinical Trial that was conducted in infants aged 1month to 17months. 1,509 participants were included in the study analysis. Data were partitioned into 3 different age groups (1-6 months[m], 6-12 m and 12-17 m) and differences between gender were compared within each group. Data were analyzed using Graphpad prism V5 to generate 95% reference ranges (2.5th-97.5th percentile). There was evidence of gender differences in hemoglobin values (p = 0.0189) and platelet counts (p = 0.0005) in the 1 to 6m group. For the 12-17m group, there were differences in MCV (p<0.0001) and MCH (p = 0.0003). Comparing gender differences for all age groups, differences were noted in percent lymphocytes (p = 0.0396), percent monocytes (p = 0.0479), percent granulocytes (p = 0.0044), hemoglobin (p = 0.0204), hematocrit (p = 0.0448), MCV (p = 0.0092), MCH (p = 0.0089), MCHC (p = 0.0336) and absolute granulocytes (p = 0.0237). In 1 to 6m age group and all age groups assessed, for WBCs, hemoglobin, hematocrit, MCV and lymphocytes absolute counts, both 2.5th and 97.5th percentiles for Kisumu infants were higher than those from Kilifi. Platelet ranges for Kisumu children were narrower compared to Kilifi ranges. Kisumu hematology reference ranges were observed to be higher than the ranges of Tanzanian children for the WBCs, absolute lymphocyte and monocyte counts, hemoglobin, hematocrit and MCV. Higher ranges of WBCs, absolute lymphocyte and monocyte counts were observed compared to the values in US/Europe. Wider ranges were observed in hemoglobin, hematocrit, and MCV. Wider ranges were observed in platelet counts in Kisumu infants compared to the US/Europe ranges. Compared to Harriet Lane Handbook reference values that are used in the area, higher counts were observed in WBC counts, both absolute and percent lymphocyte counts, as well as monocyte counts for current study. Wider ranges were observed in RBC, platelets and RDW, while lower ranges noted in the current study for hemoglobin, hematocrit and granulocyte counts. This study underscores the importance of using locally established hematology reference ranges of different age groups in support of proper patient management and for clinical trials.

HIV-1 Infection Is Associated With Increased Prevalence and Abundance of Plasmodium falciparum Gametocyte-Specific Transcripts in Asymptomatic Adults in Western Kenya.

As morbidity and mortality due to malaria continue to decline, the identification of individuals with a high likelihood of transmitting malaria is needed to further reduce the prevalence of malaria. In areas of holoendemic malaria transmission, asymptomatically infected adults may be infected with transmissible gametocytes. The impact of HIV-1 on gametocyte carriage is unknown, but co-infection may lead to an increase in gametocytemia. In this study, a panel of qPCR assays was used to quantify gametocyte stage-specific transcripts present in dried blood spots obtained from asymptomatic adults seeking voluntary HIV testing in Kombewa, Kenya. A total of 1,116 Plasmodium-specific 18S-positive samples were tested and 20.5% of these individuals had detectable gametocyte-specific transcripts. Individuals also infected with HIV-1 were 1.82 times more likely to be gametocyte positive (P<0.0001) and had significantly higher gametocyte copy numbers when compared to HIV-negative individuals. Additionally, HIV-1 positivity was associated with higher gametocyte prevalence in men and increased gametocyte carriage with age. Overall, these data suggest that HIV-positive individuals may have an increased risk of transmitting malaria parasites in regions with endemic malaria transmission and therefore should be at a higher priority for treatment with gametocidal antimalarial drugs.

Plasmodium falciparum DHFR and DHPS Mutations Are Associated With HIV-1 Co-Infection and a Novel DHPS Mutation I504T Is Identified in Western Kenya.

Antifolate resistance is significant in Kenya and presumed to result from extensive use and cross-resistance between antifolate antimalarials and antibiotics, including cotrimoxazole/Bactrim used for HIV-1 chemotherapy. However, little is known about antifolate-resistant malaria in the context of newly diagnosed HIV-1 co-infection prior to administration of HIV-1 chemotherapy. Blood samples from a cross-sectional study of asymptomatic adult Kenyans enrolled during voluntary HIV testing were analyzed by PCR for Plasmodium spp. More than 95% of volunteers with identifiable parasite species (132 HIV-1 co-infected) were infected with Plasmodium falciparum alone or P. falciparum with Plasmodium ovale and/or Plasmodium malariae. Deep sequencing was used to screen for mutations in P. falciparum dihydrofolate reductase (dhfr) (N51I, C59R, S108N, I164L) and dihydropteroate synthase (dhps) (S436H, A437G, K540E, A581G) from 1133 volunteers. Individual mutations in DHPS but not DHFR correlated with HIV-1 status. DHFR haplotype diversity was significantly different among volunteers by gender and HIV-1 status. DHPS haplotype diversity by HIV-1 status was significantly different between volunteers paired by age and gender, indicating that patterns of resistance were independent of these variables. Molecular simulations for a novel DHPS mutation (I504T) suggested that the mutated protein has increased affinity for the endogenous ligand DHPPP and decreased affinity for drug binding. A sub-group of monoclonal infections revealed that age and parasitemia were not correlated and enabled identification of a rare septuple-mutant haplotype (IRNL-HGEA). In our study, adult Kenyans newly diagnosed with HIV-1 infection were predominantly infected with moderately resistant P. falciparum, with patterns of infecting parasite genotypes significantly associated with HIV-1 status. Together with the discovery of DHPS I504T, these data indicate that antifolate resistance continues to evolve in Kenya. Further, they highlight the need to understand the effects of associated mutations on both fitness and resistance of P. falciparum in the context of HIV-1 co-infection to better inform treatment for asymptomatic malaria.

Estimating Annual Fluctuations in Malaria Transmission Intensity and in the Use of Malaria Control Interventions in Five Sub-Saharan African Countries.

RTS,S/AS01E malaria vaccine safety, effectiveness, and impact will be assessed in pre- and post-vaccine introduction studies, comparing the occurrence of malaria cases and adverse events in vaccinated versus unvaccinated children. Because those comparisons may be confounded by potential year-to-year fluctuations in malaria transmission intensity and malaria control intervention usage, the latter should be carefully monitored to adequately adjust the analyses. This observational cross-sectional study is assessing Plasmodium falciparum parasite prevalence (PfPR) and malaria control intervention usage over nine annual surveys performed at peak parasite transmission. Plasmodium falciparum parasite prevalence was measured by microscopy and nucleic acid amplification test (quantitative PCR) in parallel in all participants, and defined as the proportion of infected participants among participants tested. Results of surveys 1 (S1) and 2 (S2), conducted in five sub-Saharan African countries, including some participating in the Malaria Vaccine Implementation Programme (MVIP), are reported herein; 4,208 and 4,199 children were, respectively, included in the analyses. Plasmodium falciparum parasite prevalence estimated using microscopy varied between study sites in both surveys, with the lowest prevalence in Senegalese sites and the highest in Burkina Faso. In sites located in the MVIP areas (Kintampo and Kombewa), PfPR in children aged 6 months to 4 years ranged from 24.8% to 27.3%, depending on the study site and the survey. Overall, 89.5% and 86.4% of children used a bednet in S1 and S2, of whom 68.7% and 77.9% used impregnated bednets. No major difference was observed between the two surveys in terms of PfPR or use of malaria control interventions.

A Spatiotemporal Analysis of HIV-Associated Mortality in Rural Western Kenya 2011-2015.

BACKGROUND: Reliable data on the HIV epidemic is critical for the measurement of the impact of HIV response and for the implementation of further interventions. METHODS: We used mortality data from the Kombewa health and demographic surveillance systems (HDSS) from January 1, 2011 to December 31, 2015 to examine the space-time pattern of HIV-associated mortality. HIV mortality rate was calculated per 1000 persons living with HIV (for comparison with regional and national averages) and per 1000 person-years (p-y) for comparison with data from other HDSS sites. We used the Optimized Hot Spot Analysis to examine whether HIV-associated deaths would form statistically significant local aggregation in the 5-year period. P-value of <0.05 and <0.01 was considered significant. RESULTS: The HIV-associated mortality rate over the 5-year period was 9.8 per 1000 persons living with HIV (PLHIV). Mortality declined from 11.6 per 1000 PLHIV in 2011 to 7.3 per 1000 PLHIV by the end of 2015. The rates of HIV were highest among infants [hazard ratio (HR) = 2.39 (<0.001)]. Tuberculosis mortality rates were highest in the age group 5-14 years [HR = 2.29 (0.002)] and the age group 50-64 years [HR = 1.18 (0.531)]. The overall trend in HIV-associated mortality showed a decline from 1.8 per 1000 p-y in 2011 to 1.3 per 1000 p-y by the end of 2015. The hotspot analysis showed that 20.0% of the study area (72 km) was detected as hotspots (Z = 2.382-3.143, P ≤ 0.001) and 4.2% of the study area as cold spots (15 km). CONCLUSIONS: HIV attributable death in the HDSS population is substantial, although it is lower than both the national and the regional estimates.

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.

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.

Health & demographic surveillance system profile: The Kombewa health and demographic surveillance system (Kombewa HDSS).

The Kombewa Health and Demographic Surveillance System (HDSS) grew out of the Kombewa Clinical Research Centre in 2007 and has since established itself as a platform for the conduct of regulated clinical trials, nested studies and local disease surveillance. The HDSS is located in a rural part of Kisumu County, Western Kenya, and covers an area of about 369 km(2) along the north-eastern shores of Lake Victoria. A dynamic cohort of 141 956 individuals drawn from 34 718 households forms the HDSS surveillance population. Following a baseline survey in 2011, the HDSS continues to monitor key population changes through routine biannual household surveys. The intervening period between set-up and baseline census was used for preparatory work, in particular Global Positioning System (GPS) mapping. Routine surveys capture information on individual and households including residency, household relationships, births, deaths, migrations (in and out) and causes of morbidity (syndromic incidence and prevalence) as well as causes of death (verbal autopsy). The Kombewa HDSS platform is used to support health research activities, that is clinical trials and epidemiological studies evaluating diseases of public health importance including malaria, HIV and global emerging infectious diseases such as dengue fever.

Efficacy of pentavalent rotavirus vaccine in a high HIV prevalence population in Kenya.

BACKGROUND: Rotavirus gastroenteritis (RVGE) is a leading cause of death in African children. The efficacy of pentavalent rotavirus vaccine (PRV) against severe RVGE evaluated in Ghana, Kenya, and Mali in a randomized, double-blind, placebo-controlled trial, showed a combined regional efficacy of 39.3% (95% confidence interval [CI]: 19.1,54.7) in nearly 2 years of follow-up. This report concentrates on the Kenya findings. METHODS: Infants received 3 doses of PRV/placebo at approximately 6-, 10-, and 14-weeks of age. HIV testing was offered to all participants. Data on illness symptoms and signs were collected upon presentation to healthcare facilities, where stools were collected, and analyzed by rotavirus-specific enzyme-linked immunosorbent assay. The primary endpoint was severe RVGE (Vesikari score ≥ 11), occurring ≥ 14 days following the third dose. At monthly home visits, symptoms of illnesses during the past 2 weeks were solicited and limited physical exams were performed; dehydration was defined by WHO's Integrated Management of Childhood Illness. FINDINGS: Vaccine efficacy (VE) against severe RVGE through nearly 2 years of follow-up among 1308 Kenyan children was 63.9% (95% CI: -5.9,89.8). Through the first year of life, VE against severe RVGE was 83.4% (95% CI: 25.5,98.2). From home visits, VE against all-cause gastroenteritis with severe dehydration was 34.4% (95% CI: 5.3,54.6) through the first year and 29.7% (95% CI: 2.5,49.3) through the entire follow-up period. The reduction in incidence of gastroenteritis with severe dehydration in the community during the first year of life (19.0 cases/100 person-years) was almost six times greater than the reduction in severe RVGE presenting to the clinic (3.3/100 person-years). Oral rehydration solution use was lower among PRV recipients (VE 23.1%, 95% CI: 8.8,35.1). An estimated 41% of gastroenteritis with severe dehydration in the first year reported at home was rotavirus-related. CONCLUSIONS: PRV significantly reduced severe RVGE in Kenya. The impact of PRV might be greatest in rural Africa in protecting the many children who develop severe gastroenteritis and cannot access health facilities.

Safety of the pentavalent rotavirus vaccine (PRV), RotaTeq(®), in Kenya, including among HIV-infected and HIV-exposed infants.

Two multicenter Phase III trials were conducted in five countries from March 2007 to March 2009 to evaluate the safety and efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq(®), in Africa and Asia. In this report, we evaluate the safety of this vaccine, including among HIV-infected and HIV-exposed infants, in Kenya. 1308 Infants were randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age. HIV counseling and testing were offered to all participants. A positive PCR result indicated HIV infection; the presence of HIV antibody in PCR-negative children indicated HIV exposure without HIV infection. All serious adverse events (SAE) within 14 days of any dose, and vaccine-related SAEs, intussusception, and deaths occurring at any time during the study, were reported ("SAE surveillance"). In addition, 297 participants were followed for 42 days after any dose for any adverse event (AE), regardless of severity ("intensive safety surveillance"). The safety evaluation was stratified by HIV status. SAEs were reported in 20/649 vaccine recipients (3.1%) and 21/643 placebo recipients (3.3%) within 14 days following vaccination (p = 0.9). The most common SAE in the vaccinated group was pneumonia (1.7%). No individual SAE was significantly more common among vaccine vs. placebo recipients. Seventy-two deaths were reported, 38 (5.9%) and 34 (5.3%) among vaccine and placebo recipients, respectively (p = 0.66). No cases of intussusception were reported. During intensive safety surveillance, 137/147 (93.2%) vaccine recipients and 147/150 (98.0%) placebo recipients experienced one or more AEs (risk ratio = 0.95; 95% CI: 0.91-1.0; p = 0.05). 88.5% of the infants were tested for HIV infection; 21/581 (3.6%) children in the vaccine group and 17/577 (2.9%) in the placebo group were HIV-infected. Among the 37 HIV-infected infants with full safety follow-up, 5/21 (23.8%) vaccine recipients and 2/16 (12.5%) placebo recipients reported an SAE (p = 0.67). In total, 12 deaths occurred among identified HIV-infected infants: 8 (38%) receiving vaccine vs. 4 (23.5%) receiving placebo (RR = 1.6, 95% CI: 0.59-4.5). Among the 21 HIV-infected infants in the vaccine group, 2 of 8 deaths were gastroenteritis-related; among the 17 HIV-infected infants in the placebo group, 3 of 4 deaths were gastroenteritis-related. There were no significant differences in serious or non-serious AEs, including vaccine-related SAEs, between the 88 HIV-exposed vaccine recipients vs. the 89 HIV-exposed placebo recipients. PRV appears to be a safe intervention against rotavirus gastroenteritis among infants in Kenya. AEs, including serious AEs, were not associated with receipt of vaccine. Further, SAEs were not significantly more common among HIV-infected or HIV-exposed participants; however, the low number of HIV-infected infants did not provide sufficient power to fully assess safety in HIV-infected vaccine recipients.