Engaging the public in decisions about emergency vaccine deployment strategies: Lessons from scenario-based discussions in Sierra Leone.

ABSTRACTThe COVID-19 pandemic has amplified discussions on emergency vaccine deployment strategies, with current perspectives often neglecting extensive community involvement in ethical, logistical and political aspects. Existing social science literature predominantly delves into factors influencing trust, overlooking the untapped potential for community engagement.Our study examines community preparedness in Sierra Leone's Kambia District, exploring diverse viewpoints on vaccine deployment strategies, emphasising Ebola and COVID-19 vaccinations. Utilising extensive ethnographic research from the Ebola vaccine trials (EBOVAC Salone) conducted in Kambia District from 2015 to 2021, including participant observation and tailored focus group discussions, we investigated various deployment scenarios with community leaders and citizens.Our findings underscore the multifaceted contributions of social science research with communities in shaping emergency vaccination strategies. These contributions span logistical insights, aligning campaigns with local livelihoods and social structures, and grounded ethical concerns assessing social justice outcomes across epidemic scenarios. This study emphasises the imperative of integrating discussions on vaccine confidence and deployment. It highlights communities' proficiency in epidemiological reasoning and their ability to bring this in conversation with salient socio-cultural, economic and religious dimensions. We therefore promote the cultivation of public dialogue, collaborative creation of impactful vaccination initiatives alongside relevant communities in recognition of their invaluable perspectives .

Helminth exposure and immune response to the two-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen.

BACKGROUND: The exposure to parasites may influence the immune response to vaccines in endemic African countries. In this study, we aimed to assess the association between helminth exposure to the most prevalent parasitic infections, schistosomiasis, soil transmitted helminths infection and filariasis, and the Ebola virus glycoprotein (EBOV GP) antibody concentration in response to vaccination with the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen in African and European participants using samples obtained from three international clinical trials. METHODS/PRINCIPAL FINDINGS: We conducted a study in a subset of participants in the EBL2001, EBL2002 and EBL3001 clinical trials that evaluated the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen against EVD in children, adolescents and adults from the United Kingdom, France, Burkina Faso, Cote d'Ivoire, Kenya, Uganda and Sierra Leone. Immune markers of helminth exposure at baseline were evaluated by ELISA with three commercial kits which detect IgG antibodies against schistosome, filarial and Strongyloides antigens. Luminex technology was used to measure inflammatory and activation markers, and Th1/Th2/Th17 cytokines at baseline. The association between binding IgG antibodies specific to EBOV GP (measured on day 21 post-dose 2 and on Day 365 after the first dose respectively), and helminth exposure at baseline was evaluated using a multivariable linear regression model adjusted for age and study group. Seventy-eight (21.3%) of the 367 participants included in the study had at least one helminth positive ELISA test at baseline, with differences of prevalence between studies and an increased prevalence with age. The most frequently detected antibodies were those to Schistosoma mansoni (10.9%), followed by Acanthocheilonema viteae (9%) and then Strongyloides ratti (7.9%). Among the 41 immunological analytes tested, five were significantly (p < .003) lower in participants with at least one positive helminth ELISA test result: CCL2/MCP1, FGFbasic, IL-7, IL-13 and CCL11/Eotaxin compared to participants with negative helminth ELISA tests. No significant association was found with EBOV-GP specific antibody concentration at 21 days post-dose 2, or at 365 days post-dose 1, adjusted for age group, study, and the presence of any helminth antibodies at baseline. CONCLUSIONS/SIGNIFICANCE: No clear association was found between immune markers of helminth exposure as measured by ELISA and post-vaccination response to the Ebola Ad26.ZEBOV/ MVA-BN-Filo vaccine regimen. TRIAL REGISTRATION: NCT02416453, NCT02564523, NCT02509494. ClinicalTrials.gov.

Impact of pneumococcal conjugate vaccination on pneumococcal nasopharyngeal carriage in the Gambia: Population-based cross-sectional surveys.

BACKGROUND: The introduction of pneumococcal conjugate vaccines (PCV) has reduced carriage of vaccine-type (VT) pneumococci in many settings. We determined the impact of The Gambia's national PCV programme on carriage of VT pneumococci in the population. METHODS: Seven-valent PCV (PCV7) was introduced in August 2009 without catch-up and with doses scheduled at 2, 3, 4 months of age; it was replaced by PCV13 in May 2011. We did cross-sectional carriage surveys in 2009, 2015, and 2017 in age-stratified, population-based samples. Nasopharyngeal specimens were collected and processed according to WHO guidelines. We calculated observed and adjusted prevalence ratios (PR) of VT carriage before and after PCV introduction. FINDINGS: We enrolled 2988, 3162, and 2709 participants in 2009, 2015, and 2017 respectively. The baseline (2009) prevalence of VT pneumococcal carriage among children aged 0-4 years was 42.6 %, which declined to 14.9 % and 17.5 % in 2015 and 2017 respectively (adjPR 0.32 [95 % CI 0.27, 0.38] and 0.38 [0.31, 0.46] respectively). VT prevalence among children aged 5-14 years was 16.6 %, 15.1 %, and 15.8 % in the three surveys (2017 vs 2009, adjPR 0.70 [0.58, 0.83]). VT prevalence among 15-44 year-olds was 6.4 %, 5.7 %, and 7.1 % in the three surveys (2017 vs 2009, adjPR 0.59 [0.46, 0.75]), while in those aged ≥ 45 years it was 4.5 %, 6.5 %, and 4.5 % respectively. Non-VT carriage increased in all age-groups. Prevalent residual serotypes were 34 and 15B (age 0-4 years), 3 and 34 (age 5-14 years), and 3 and 16F (age ≥ 15 years). CONCLUSIONS: Introduction of PCV was associated with reduced VT pneumococcal carriage in young, and older children, although with substantial residual prevalence. Persisting VT, and non-VT, carriage indicate significant, persistent transmission of pneumococci in the population.

Pneumococcal conjugate vaccination schedules in infants-acquisition, immunogenicity, and pneumococcal conjugate and yellow fever vaccine co-administration study: statistical analysis plan.

RATIONALE: The effectiveness of immunisation with pneumococcal conjugate vaccine (PCV) has been demonstrated in many countries. However, the global impact of PCV is limited by its cost, which has prevented its introduction in some countries. Reducing the cost of PCV programmes will facilitate further vaccine introductions and improve the sustainability of PCV in low-income countries when they transition from subsidised vaccine supply. We are conducting a large, population-level, cluster-randomised field trial (PVS) of an alternative reduced-dose schedule of PCV compared to the standard schedule. We are also conducting a nested sub-study at the individual level to investigate the immunogenicity of the two schedules and their effects on pneumococcal carriage acquisition (PVS-AcqImm). METHODS AND DESIGN: PVS-AcqImm is a prospective, cluster-randomised trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months compared to the standard of three primary doses scheduled at 6, 10, and 14 weeks of age. Sub-groups within the alternative schedule group receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) concentrations of vaccine-type anti-pneumococcal IgG at 18 months of age, (b) proportions with yellow fever neutralising antibody titre ≥ 1:8 4 weeks after separate or co-administration of PCV and yellow fever vaccines, and (c) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 10-14 months of age. Participants and field staff are not masked to group allocation while measurement of the laboratory endpoints is masked. Approximately equal numbers of participants are resident in each of 28 randomly allocated geographic clusters (14 clusters in each group); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. PURPOSE: This statistical analysis plan (SAP) describes the PVS-AcqImm cohort and follow-up criteria to be used in different analyses. The SAP defines the endpoints and describes how adherence to the interventions will be presented. We describe the approach to analyses and how we will account for the effect of clustering. Defining the SAP prior to the conduct of analysis will avoid bias in analyses that may arise from prior knowledge of trial findings. TRIAL REGISTRATION: ISRCTN, ISRCTN7282161328. Registered on 28 November 2019. https://www.isrctn.com/ISRCTN72821613 . PROTOCOL: MRCG SCC number 1670, LSHTM Ref 17683. Current protocol version: 6.0, 24 May 2021. Version: 1.0 (5 April 2023); SAP revisions-none.

Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial.

BACKGROUND: Recently, we found that a new malaria vaccine, R21/Matrix-M, had over 75% efficacy against clinical malaria with seasonal administration in a phase 2b trial in Burkina Faso. Here, we report on safety and efficacy of the vaccine in a phase 3 trial enrolling over 4800 children across four countries followed for up to 18 months at seasonal sites and 12 months at standard sites. METHODS: We did a double-blind, randomised, phase 3 trial of the R21/Matrix-M malaria vaccine across five sites in four African countries with differing malaria transmission intensities and seasonality. Children (aged 5-36 months) were enrolled and randomly assigned (2:1) to receive 5 µg R21 plus 50 µg Matrix-M or a control vaccine (licensed rabies vaccine [Abhayrab]). Participants, their families, investigators, laboratory teams, and the local study team were masked to treatment. Vaccines were administered as three doses, 4 weeks apart, with a booster administered 12 months after the third dose. Half of the children were recruited at two sites with seasonal malaria transmission and the remainder at standard sites with perennial malaria transmission using age-based immunisation. The primary objective was protective efficacy of R21/Matrix-M from 14 days after third vaccination to 12 months after completion of the primary series at seasonal and standard sites separately as co-primary endpoints. Vaccine efficacy against multiple malaria episodes and severe malaria, as well as safety and immunogenicity, were also assessed. This trial is registered on ClinicalTrials.gov, NCT04704830, and is ongoing. FINDINGS: From April 26, 2021, to Jan 12, 2022, 5477 children consented to be screened, of whom 1705 were randomly assigned to control vaccine and 3434 to R21/Matrix-M; 4878 participants received the first dose of vaccine. 3103 participants in the R21/Matrix-M group and 1541 participants in the control group were included in the modified per-protocol analysis (2412 [51·9%] male and 2232 [48·1%] female). R21/Matrix-M vaccine was well tolerated, with injection site pain (301 [18·6%] of 1615 participants) and fever (754 [46·7%] of 1615 participants) as the most frequent adverse events. Number of adverse events of special interest and serious adverse events did not significantly differ between the vaccine groups. There were no treatment-related deaths. 12-month vaccine efficacy was 75% (95% CI 71-79; p<0·0001) at the seasonal sites and 68% (61-74; p<0·0001) at the standard sites for time to first clinical malaria episode. Similarly, vaccine efficacy against multiple clinical malaria episodes was 75% (71-78; p<0·0001) at the seasonal sites and 67% (59-73; p<0·0001) at standard sites. A modest reduction in vaccine efficacy was observed over the first 12 months of follow-up, of similar size at seasonal and standard sites. A rate reduction of 868 (95% CI 762-974) cases per 1000 children-years at seasonal sites and 296 (231-362) at standard sites occurred over 12 months. Vaccine-induced antibodies against the conserved central Asn-Ala-Asn-Pro (NANP) repeat sequence of circumsporozoite protein correlated with vaccine efficacy. Higher NANP-specific antibody titres were observed in the 5-17 month age group compared with 18-36 month age group, and the younger age group had the highest 12-month vaccine efficacy on time to first clinical malaria episode at seasonal (79% [95% CI 73-84]; p<0·001) and standard (75% [65-83]; p<0·001) sites. INTERPRETATION: R21/Matrix-M was well tolerated and offered high efficacy against clinical malaria in African children. This low-cost, high-efficacy vaccine is already licensed by several African countries, and recently received a WHO policy recommendation and prequalification, offering large-scale supply to help reduce the great burden of malaria in sub-Saharan Africa. FUNDING: The Serum Institute of India, the Wellcome Trust, the UK National Institute for Health Research Oxford Biomedical Research Centre, and Open Philanthropy.

Seasonal vaccination with RTS,S/AS01E vaccine with or without seasonal malaria chemoprevention in children up to the age of 5 years in Burkina Faso and Mali: a double-blind, randomised, controlled, phase 3 trial.

BACKGROUND: Seasonal vaccination with the RTS,S/AS01E vaccine combined with seasonal malaria chemoprevention (SMC) prevented malaria in young children more effectively than either intervention given alone over a 3 year period. The objective of this study was to establish whether the added protection provided by the combination could be sustained for a further 2 years. METHODS: This was a double-blind, individually randomised, controlled, non-inferiority and superiority, phase 3 trial done at two sites: the Bougouni district and neighbouring areas in Mali and Houndé district, Burkina Faso. Children who had been enrolled in the initial 3-year trial when aged 5-17 months were initially randomly assigned individually to receive SMC with sulphadoxine-pyrimethamine and amodiaquine plus control vaccines, RTS,S/AS01E plus placebo SMC, or SMC plus RTS,S/AS01E. They continued to receive the same interventions until the age of 5 years. The primary trial endpoint was the incidence of clinical malaria over the 5-year trial period in both the modified intention-to-treat and per-protocol populations. Over the 5-year period, non-inferiority was defined as a 20% increase in clinical malaria in the RTS,S/AS01E-alone group compared with the SMC alone group. Superiority was defined as a 12% difference in the incidence of clinical malaria between the combined and single intervention groups. The study is registered with ClinicalTrials.gov, NCT04319380, and is complete. FINDINGS: In April, 2020, of 6861 children originally recruited, 5098 (94%) of the 5433 children who completed the initial 3-year follow-up were re-enrolled in the extension study. Over 5 years, the incidence of clinical malaria per 1000 person-years at risk was 313 in the SMC alone group, 320 in the RTS,S/AS01E-alone group, and 133 in the combined group. The combination of RTS,S/AS01E and SMC was superior to SMC (protective efficacy 57·7%, 95% CI 53·3 to 61·7) and to RTS,S/AS01E (protective efficacy 59·0%, 54·7 to 62·8) in preventing clinical malaria. RTS,S/AS01E was non-inferior to SMC (hazard ratio 1·03 [95% CI 0·95 to 1·12]). The protective efficacy of the combination versus SMC over the 5-year period of the study was very similar to that seen in the first 3 years with the protective efficacy of the combination versus SMC being 57·7% (53·3 to 61·7) and versus RTS/AS01E-alone being 59·0% (54·7 to 62·8). The comparable figures for the first 3 years of the study were 62·8% (58·4 to 66·8) and 59·6% (54·7 to 64·0%), respectively. Hospital admissions for WHO-defined severe malaria were reduced by 66·8% (95% CI 40·3 to 81·5), for malarial anaemia by 65·9% (34·1 to 82·4), for blood transfusion by 68·1% (32·6 to 84·9), for all-cause deaths by 44·5% (2·8 to 68·3), for deaths excluding external causes or surgery by 41·1% (-9·2 to 68·3), and for deaths from malaria by 66·8% (-2·7 to 89·3) in the combined group compared with the SMC alone group. No safety signals were detected. INTERPRETATION: Substantial protection against malaria was sustained over 5 years by combining seasonal malaria vaccination with seasonal chemoprevention, offering a potential new approach to malaria control in areas with seasonal malaria transmission. FUNDING: UK Joint Global Health Trials and PATH's Malaria Vaccine Initiative (through a grant from the Bill & Melinda Gates Foundation). TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Post-discharge malaria chemoprevention in children admitted with severe anaemia in malaria-endemic settings in Africa: a systematic review and individual patient data meta-analysis of randomised controlled trials.

BACKGROUND: Severe anaemia is associated with high in-hospital mortality among young children. In malaria-endemic areas, surviving children also have an increased risk of mortality or readmission after hospital discharge. We conducted a systematic review and individual patient data meta-analysis to determine the efficacy of monthly post-discharge malaria chemoprevention in children recovering from severe anaemia. METHODS: This analysis was conducted according to PRISMA-IPD guidelines. We searched multiple databases on Aug 28, 2023, without date or language restrictions, for randomised controlled trials comparing monthly post-discharge malaria chemoprevention with placebo or standard of care among children (aged <15 years) admitted with severe anaemia in malaria-endemic Africa. Trials using daily or weekly malaria prophylaxis were not eligible. The investigators from all eligible trials shared pseudonymised datasets, which were standardised and merged for analysis. The primary outcome was all-cause mortality during the intervention period. Analyses were performed in the modified intention-to-treat population, including all randomly assigned participants who contributed to the endpoint. Fixed-effects two-stage meta-analysis of risk ratios (RRs) was used to generate pooled effect estimates for mortality. Recurrent time-to-event data (readmissions or clinic visits) were analysed using one-stage mixed-effects Prentice-Williams-Peterson total-time models to obtain hazard ratios (HRs). This study is registered with PROSPERO, CRD42022308791. FINDINGS: Our search identified 91 articles, of which 78 were excluded by title and abstract, and a further ten did not meet eligibility criteria. Three double-blind, placebo-controlled trials, including 3663 children with severe anaemia, were included in the systematic review and meta-analysis; 3507 (95·7%) contributed to the modified intention-to-treat analysis. Participants received monthly sulfadoxine-pyrimethamine until the end of the malaria transmission season (mean 3·1 courses per child [range 1-6]; n=1085; The Gambia), monthly artemether-lumefantrine given at the end of weeks 4 and 8 post discharge (n=1373; Malawi), or monthly dihydroartemisinin-piperaquine given at the end of weeks 2, 6, and 10 post discharge (n=1049; Uganda and Kenya). During the intervention period, post-discharge malaria chemoprevention was associated with a 77% reduction in mortality (RR 0·23 [95% CI 0·08-0·70], p=0·0094, I2=0%) and a 55% reduction in all-cause readmissions (HR 0·45 [95% CI 0·36-0·56], p<0·0001) compared with placebo. The protective effect was restricted to the intervention period and was not sustained after the direct pharmacodynamic effect of the drugs had waned. The small number of trials limited our ability to assess heterogeneity, its sources, and publication bias. INTERPRETATION: In malaria-endemic Africa, post-discharge malaria chemoprevention reduces mortality and readmissions in recently discharged children recovering from severe anaemia. Post-discharge malaria chemoprevention could be a valuable strategy for the management of this group at high risk. Future research should focus on methods of delivery, options to prolong the protection duration, other hospitalised groups at high risk, and interventions targeting non-malarial causes of post-discharge morbidity. FUNDING: The Research-Council of Norway and the Bill-&-Melinda-Gates-Foundation through the Worldwide-Antimalarial-Research-Network.

Feasibility and safety of integrating mass drug administration for helminth control with seasonal malaria chemoprevention among Senegalese children: a randomized controlled, observer-blind trial.

BACKGROUND: The overlap in the epidemiology of malaria and helminths has been identified as a potential area to exploit for the development of an integrated control strategy that may help to achieve elimination of malaria and helminths. A randomized, controlled, observer-blind trial was conducted to assess the feasibility and safety of combining mass drug administration (MDA) for schistosomiasis and soil transmitted helminths (STH) with seasonal malaria chemoprevention (SMC) among children living in Senegal. METHODS: Female and male children aged 1-14 years were randomized 1:1:1, to receive Vitamin A and Zinc on Day 0, followed by SMC drugs (sulfadoxine-pyrimethamine and amodiaquine) on Days 1-3 (control group); or praziquantel and Vitamin A on Day 0, followed by SMC drugs on Days 1-3 (treatment group 1); or albendazole and praziquantel on Day 0, followed by SMC drugs on Days 1-3 (treatment group 2). Safety assessment was performed by collecting adverse events from all children for six subsequent days following administration of the study drugs. Pre- and post-intervention, blood samples were collected for determination of haemoglobin concentration, malaria microscopy, and PCR assays. Stool samples were analyzed using Kato-Katz, Merthiolate-iodine-formalin and PCR methods. Urine filtration, PCR and circulating cathodic antigen tests were also performed. RESULTS: From 9 to 22 June 2022, 627 children aged 1-14 years were randomized into the three groups described above. Mild, transient vomiting was observed in 12.6% (26/206) of children in treatment group 2, in 10.6% (22/207) in group 1, and in 4.2% (9/214) in the control group (p = 0.005). Pre-intervention, the geometric mean value of Plasmodium falciparum parasite density was highest among children who received albendazole, praziquantel with SMC drugs. Post-intervention, the parasite density was highest among children who received SMC drugs only. Children who received praziquantel and SMC drugs had a lower risk of developing severe anaemia than their counterparts who received SMC drugs alone (OR = 0.81, 95% CI 0.13-5.00, p = 0.63). CONCLUSIONS: Integration of MDA for helminths with SMC drugs was safe and feasible among Senegalese children. These findings support further evaluation of the integrated control model. TRIAL REGISTRATION: The study is registered at Clinical Trial.gov NCT05354258.

Safety and immunogenicity of an Ad26.ZEBOV booster vaccine in Human Immunodeficiency Virus positive (HIV+) adults previously vaccinated with the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen against Ebola: A single-arm, open-label Phase II clinical trial in Kenya and Uganda.

BACKGROUND: People living with HIV constitute an important part of the population in regions at risk of Ebola virus disease outbreaks. The two-dose Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen induces strong immune responses in HIV-positive (HIV+) adults but the durability of this response is unknown. It is also unclear whether this regimen can establish immune memory to enable an anamnestic response upon re-exposure to antigen. METHODS: This paper describes an open-label, phase 2 trial, conducted in Kenya and Uganda, of Ad26.ZEBOV booster vaccination in HIV+ participants who had previously received the Ad26.ZEBOV, MVA-BN-Filo primary regimen. HIV+ adults with well-controlled infection and on highly active antiretroviral therapy were enrolled, vaccinated with booster, and followed for 28 days. The primary objectives were to assess Ad26.ZEBOV booster safety and antibody responses against the Ebola virus glycoprotein using the Filovirus Animal Non-Clinical Group ELISA. RESULTS: The Ad26.ZEBOV booster was well-tolerated in HIV+ adults with mostly mild to moderate symptoms. No major safety concerns or serious adverse events were reported. Four and a half years after the primary regimen, 24/26 (92 %) participants were still classified as responders, with a pre-booster antibody geometric mean concentration (GMC) of 726 ELISA units (EU)/mL (95 %CI 447-1179). Seven days after the booster, the GMC increased 54-fold to 38,965 EU/mL (95 %CI 23532-64522). Twenty-one days after the booster, the GMC increased 176-fold to 127,959 EU/mL (95 %CI 93872-174422). The responder rate at both post-booster time points was 100 %. CONCLUSIONS: The Ad26.ZEBOV booster is safe and highly immunogenic in HIV+ adults with well-controlled infection. The Ad26.ZEBOV, MVA-BN-Filo regimen can generate long-term immune memory persisting for at least 4·5 years, resulting in a robust anamnestic response. TRIAL REGISTRATION: Pan African Clinical Trial Registry (PACTR202102747294430). CLINICALTRIALS: gov (NCT05064956).

Safety and immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in infants: a phase 2, randomised, double-blind, active-controlled trial in Guinea and Sierra Leone.

BACKGROUND: This study assessed the safety and immunogenicity of the Ad26.ZEBOV and MVA-BN-Filo Ebola virus (EBOV) vaccine regimen in infants aged 4-11 months in Guinea and Sierra Leone. METHODS: In this phase 2, randomised, double-blind, active-controlled trial, we randomly assigned healthy infants (1:1 in a sentinel cohort, 5:2 for the remaining infants via an interactive web response system) to receive Ad26.ZEBOV followed by MVA-BN-Filo (Ebola vaccine group) or two doses of meningococcal quadrivalent conjugate vaccine (control group) administered 56 days apart. Infants were recruited at two sites in west Africa: Conakry, Guinea, and Kambia, Sierra Leone. All infants received the meningococcal vaccine 8 months after being randomly assigned. The primary objective was safety. The secondary objective was immunogenicity, measured as EBOV glycoprotein-binding antibody concentration 21 days post-dose 2, using the Filovirus Animal Non-Clinical Group ELISA. This study is registered with ClinicalTrials.gov (NCT03929757) and the Pan African Clinical Trials Registry (PACTR201905827924069). FINDINGS: From Aug 20 to Nov 29, 2019, 142 infants were screened and 108 were randomly assigned (Ebola vaccine n=75; control n=33). The most common solicited local adverse event was injection-site pain (Ebola vaccine 15 [20%] of 75; control four [12%] of 33). The most common solicited systemic adverse events with the Ebola vaccine were irritability (26 [35%] of 75), decreased appetite (18 [24%] of 75), pyrexia (16 [21%] of 75), and decreased activity (15 [20%] of 75). In the control group, ten (30%) of 33 had irritability, seven (21%) of 33 had decreased appetite, three (9%) of 33 had pyrexia, and five (15%) of 33 had decreased activity. The frequency of unsolicited adverse events was 83% (62 of 75 infants) in the Ebola vaccine group and 85% (28 of 33 infants) in the control group. No serious adverse events were vaccine-related. In the Ebola vaccine group, EBOV glycoprotein-binding antibody geometric mean concentrations (GMCs) at 21 days post-dose 2 were 27 700 ELISA units (EU)/mL (95% CI 20 477-37 470) in infants aged 4-8 months and 20 481 EU/mL (15 325-27 372) in infants aged 9-11 months. The responder rate was 100% (74 of 74 responded). In the control group, GMCs for both age groups were less than the lower limit of quantification and the responder rate was 3% (one of 33 responded). INTERPRETATION: Ad26.ZEBOV and MVA-BN-Filo was well tolerated and induced strong humoral responses in infants younger than 1 year. There were no safety concerns related to vaccination. FUNDING: Janssen Vaccines & Prevention and Innovative Medicines Initiative 2 Joint Undertaking. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Invasive bacterial disease in young infants in rural Gambia: Population-based surveillance.

Background: Invasive bacterial diseases (IBD) cause significant mortality in young infants. There are limited population-based data on IBD in young infants in Sub-Saharan Africa. Methods: We conducted population-based surveillance for IBD among infants aged 0-90 days in a demographic surveillance area in rural Gambia between 1 March 2011 and 31 December 2017. Infants admitted to health facilities within the study area had standardised clinical evaluation plus conventional microbiological investigation. We defined IBD as isolation of pathogenic bacteria from blood, cerebrospinal fluid, lung, or pleural aspirate. We determined incidence, aetiology and case-fatality of IBD. Results: A total of 3794 infants were admitted and 3605 (95%) had at least one sample collected for culture. We detected 254 (8.0%) episodes of IBD (bacteraemia 241; meningitis 14; pneumonia seven). The incidence of IBD in infants aged 0-90 days was 25 episodes/1000 person-years (95% confidence interval (CI) = 22-28), the incidence in neonates was 50 episodes/1000 person-years (95% CI = 43-58) and the incidence in infants aged 29-90 days was 12 episodes/1000 person-years (95% CI = 9-15). The most common pathogens causing IBD were Staphylococcus aureus (n = 102, 40%), Escherichia coli (n = 37, 15%), Streptococcus pneumoniae (n = 24, 9%) and Klebsiella pneumoniae (n = 12, 5%). Case-fatality was 29% (95% CI = 23-37) in neonates and 19% (95% CI = 11-29) in infants aged 29-90 days. A minimum of 7.3% of all young infant deaths in the population were caused by IBD. Conclusions: IBD are common in young infants in rural Gambia and have a high case-fatality. Strategies are needed to prevent IBD in young infants. Overcoming barriers to widespread implementation of existing vaccines and developing new vaccines against the most common pathogens causing IBD should be among top priorities for reducing the high mortality rate in young infants.

Provider and User Acceptability of Integrated Treatment for the Control of Malaria and Helminths in Saraya, South-Eastern Senegal.

Integration of vertical programs for the control of malaria, schistosomiasis, and soil-transmitted helminthiasis has been recommended to achieve elimination of malaria and neglected tropical diseases (NTD) by 2030. This qualitative study was conducted within the context of a randomized controlled trial to explore the perceptions and views of parents/caregivers of at-risk children and healthcare providers to determine their acceptability of the integrated malaria-helminth treatment approach. Randomly selected parents/caregivers of children enrolled in the trial, healthcare providers, trial staff, malaria, and NTD program managers were interviewed using purpose-designed topic guides. Transcripts obtained from the interviews were coded and common themes identified using content analysis were triangulated. Fifty-seven study participants comprising 26 parents/caregivers, 10 study children aged ≥ 10 years, 15 trial staff, four healthcare providers, and two managers from the Senegal Ministry of Health were interviewed. Thirty-eight of the participants (66.7%) were males, and their ages ranged from 10 to 65 years. Overall, the integrated malaria-helminth treatment approach was considered acceptable, but the study participants expressed concerns about the taste, smell, and side effects associated with amodiaquine and praziquantel in the combination package. Reluctance to accept the medications was also observed among children aged 10 to 14 years due to peer influence and gender-sensitive cultural beliefs. Addressing concerns about the taste and smell of amodiaquine and praziquantel is needed to optimize the uptake of the integrated treatment program. Also, culturally appropriate strategies need to be put in place to cater for the inclusion of children aged 10 to 14 years in this approach.

The Effect of Previous Exposure to Malaria Infection and Clinical Malaria Episodes on the Immune Response to the Two-Dose Ad26.ZEBOV, MVA-BN-Filo Ebola Vaccine Regimen.

We assessed whether the immunogenicity of the two-dose Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen with a 56-day interval between doses was affected by exposure to malaria before dose 1 vaccination and by clinical episodes of malaria in the period immediately after dose 1 and after dose 2 vaccinations. Previous malaria exposure in participants in an Ebola vaccine trial in Sierra Leone (ClinicalTrials.gov: NCT02509494) was classified as low, intermediate, and high according to their antibody responses to a panel of Plasmodium falciparum antigens detected using a Luminex MAGPIX platform. Clinical malaria episodes after vaccinations were recorded as part of the trial safety monitoring. Binding antibody responses against the Ebola virus (EBOV) glycoprotein (GP) were measured 57 days post dose 1 and 21 days post dose 2 by ELISA and summarized as Geometric Mean Concentrations (GMCs). Geometric Mean Ratios (GMRs) were used to compare groups with different levels of exposure to malaria. Overall, 587 participants, comprising 188 (32%) adults (aged ≥ 18 years) and 399 (68%) children (aged 1-3, 4-11, and 12-17 years), were included in the analysis. There was no evidence that the anti-EBOV-GP antibody GMCs post dose 1 and post dose 2 differed between categories of previous malaria exposure. There was weak evidence that the GMC at 57 days post dose 1 was lower in participants who had had at least one episode of clinical malaria post dose 1 compared to participants with no diagnosed clinical malaria in the same period (GMR = 0.82, 95% CI: 0.69-0.98, p-value = 0.02). However, GMC post dose 2 was not reduced in participants who experienced clinical malaria post-dose 1 and/or post-dose 2 vaccinations. In conclusion, the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen is immunogenic in individuals with previous exposure to malaria and in those who experience clinical malaria after vaccination. This vaccine regimen is suitable for prophylaxis against Ebola virus disease in malaria-endemic regions.

Delivery strategies for malaria vaccination in areas with seasonal malaria transmission.

BACKGROUND: Seasonal vaccination with the RTS,S/AS01E malaria vaccine given alongside seasonal malaria chemoprevention (SMC) substantially reduces malaria in young children. The WHO has recommended the use of RTS,S/AS01E, including seasonal vaccination, in areas with seasonal malaria transmission. This study aimed to identify potential strategies to deliver RTS,S/AS01E, and assess the considerations and recommendations for delivery of seasonal malaria vaccination in Mali, a country with highly seasonal malaria. METHODS: Potential delivery strategies for RTS,S/AS01E in areas with seasonal malaria were identified through a series of high level discussions with the RTS,S/AS01E plus SMC trial investigators, international and national immunisation and malaria experts, and through the development of a theory of change. These were explored through qualitative in-depth interviews with 108 participants, including national-level, regional-level and district-level malaria and immunisation programme managers, health workers, caregivers of children under 5 years of age, and community stakeholders. A national-level workshop was held to confirm the qualitative findings and work towards consensus on an appropriate strategy. RESULTS: Four delivery strategies were identified: age-based vaccination delivered via the Essential Programme on Immunisation (EPI); seasonal vaccination via EPI mass vaccination campaigns (MVCs); a combination of age-based priming vaccination doses delivered via the EPI clinics and seasonal booster doses delivered via MVCs; and a combination of age-based priming vaccination doses and seasonal booster doses, all delivered via the EPI clinics, which was the preferred strategy for delivery of RTS,S/AS01E in Mali identified during the national workshop. Participants recommended that supportive interventions, including communications and mobilisation, would be needed for this strategy to achieve required coverage. CONCLUSIONS: Four delivery strategies were identified for administration of RTS,S/AS01E alongside SMC in countries with seasonal malaria transmission. Components of these delivery strategies were defined as the vaccination schedule, and the delivery system(s) plus the supportive interventions needed for the strategies to be effective. Further implementation research and evaluation is needed to explore how, where, when and what effective coverage is achievable via these new strategies and their supportive interventions.

Effects of proactive vs fixed community health care delivery on child health and access to care: a cluster randomised trial secondary endpoint analysis.

Background: Professional community health workers (CHWs) can help achieve universal health coverage, although evidence gaps remain on how to optimise CHW service delivery. We conducted an unblinded, parallel, cluster randomised trial in rural Mali to determine whether proactive CHW delivery reduced mortality and improved access to health care among children under five years, compared to passive delivery. Here we report the secondary access endpoints. Methods: Beginning from 26-28 February 2017, 137 village-clusters were offered care by CHWs embedded in communities who were trained, paid, supervised, and integrated into a reinforced public-sector health system that did not charge user fees. Clusters were randomised (stratified on primary health centre catchment and distance) to care during CHWs during door-to-door home visits (intervention) or based at a fixed village site (control). We measured outcomes at baseline, 12-, 24-, and 36-month time points with surveys administered to all resident women aged 15-49 years. We used logistic regression with cluster-level random effects to estimate intention-to-treat and per-protocol effects over time on prompt (24-hour) treatment within the health sector. Results: Follow-up surveys between February 2018 and April 2020 generated 20 105 child-year observations. Across arms, prompt health sector treatment more than doubled compared to baseline. At 12 months, children in intervention clusters had 22% higher odds of receiving prompt health sector treatment than those in control (cluster-specific adjusted odds ratio (aOR) = 1.22; 95% confidence interval (CI) = 1.06, 1.41, P = 0.005), or 4.7 percentage points higher (adjusted risk difference (aRD) = 0.047; 95% CI = 0.014, 0.080). We found no evidence of an effect at 24 or 36 months. Conclusions: CHW-led health system redesign likely drove the 2-fold increase in rapid child access to care. In this context, proactive home visits further improved early access during the first year but waned afterwards. Registration: ClinicalTrials.gov NCT02694055.

Immune response of a two-dose heterologous Ebola vaccine regimen: summary of three African clinical trials using a single validated Filovirus Animal Nonclinical Group enzyme-linked immunosorbent assay in a single accredited laboratory.

BACKGROUND: This analysis evaluated the immune response to the two-dose, heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccine regimen, administered 56-days apart, from multiple African sites based on results from one analytic laboratory. METHODS: Immunogenicity across three trials (EBL2002, EBL2004/PREVAC, EBL3001) conducted in East and West Africa is summarised. Vaccine-induced Ebola glycoprotein-binding antibody concentrations were analysed by Q2 Solutions laboratory at baseline, 21 days (EBL2002 and EBL3001) or 28 days (EBL2004) post-dose 2 (regimen completion), and 12 months post-dose 1 using the validated Filovirus Animal Nonclinical Group Ebola glycoprotein enzyme-linked immunosorbent assay (ELISA). Responders were defined as those with a >2.5-fold increase from baseline or the lower limit of quantification (LLOQ) if 

Prevalence of malaria-helminth co-infections among children living in a setting of high coverage of standard interventions for malaria and helminths: Two population-based studies in Senegal.

Background: Concurrent infections of Plasmodium falciparum with Soil Transmitted Helminths (STH) and Schistosoma spp are still a major public health problem among children living in Sub-Saharan Africa. We conducted two prospective studies among children living in urban and rural settings of Senegal, where control programmes for malaria, STH and schistosomiasis have been sustained, to determine the prevalence of malaria-helminth co-infection. Methods: We enrolled 910 children aged 1-14 years from Saraya and Diourbel districts of Senegal in June and November 2021, respectively. We collected finger-prick blood samples from the children for malaria parasite detection using microscopy and PCR methods. Stool samples were also collected and Kato-Katz and PCR methods were used to detect STH and S. mansoni; and Merthiolate-iodine-formalin (MIF) test for other intestinal protozoans. Urine samples were analyzed using a filtration test, Point of Care Circulating Cathodic Antigens (POC-CCA) and PCR methods for detection of S. haematobium. Statistical analyses were performed to compare the continuous and categorical variables across the two study sites and age groups, as well as using the adjusted Odds ratios (aOR) to explore risk factors for malaria-helminth co-infections. Results: The overall prevalence of polyparasitism with P. falciparum, STH, S. haematobium and S. mansoni among children in the two study sites was 2.2% (20/910) while prevalence of P. falciparum-S. haematobium co-infection was 1.1% (10/910); P. falciparum-S. mansoni 0.7% (6/910) and P. falciparum with any intestinal protozoan 2.4% (22/910). Co-infection was slightly higher among 5-14 year old children (17/629, 2.7%; 95% CI: 1.43-3.97) than 1-4 years (3/281, 1.1%; 95% CI: -0.12-2.32) and, in boys (13/567, 2.3%; 95% CI: 1.27-3.96) than girls (7/343, 2.1%; 95% CI: 0.52-3.48). Children aged 5-14 years (aOR = 3.37; 95% CI: 0.82-13.77, p = 0.09), who were boys (aOR = 1.44; 95% CI: 0.48-4.36, p = 0.51) and lived in Saraya (aOR = 1.27; 95% CI: 0.24-6.69, p = 0.77) had a higher risk of malaria-helminth co-infection than other age group, in girls and those who lived in Diourbel. Living in houses with spaces between the walls and roofs as well as frequent contacts with water during swimming were statistically significant risk factors for malaria-helminth co-infection. Conclusions: The prevalence of malaria-helminth co-infection is low in two districts in Senegal, possibly due to sustained implementation of effective control measures for malaria and NTDs. These findings could help to develop and implement strategies that would lead to elimination of malaria and helminths in the study areas.

Prevalence of immunoglobulin G and M to SARS-CoV-2 and other human coronaviruses in The Democratic Republic of Congo, Sierra Leone, and Uganda: A longitudinal study.

OBJECTIVES: We assessed the prevalence of immunoglobulin G (IgG) and IgM against four endemic human coronaviruses and two SARS-CoV-2 antigens among vaccinated and unvaccinated staff at health care centers in Uganda, Sierra Leone, and the Democratic Republic of Congo. METHODS: The government health facility staff who had patient contact in Goma (Democratic Republic of Congo), Kambia District (Sierra Leone), and Masaka District (Uganda) were enrolled. Questionnaires and blood samples were collected at three time points over 4 months. Blood samples were analyzed with the Luminex MAGPIXⓇ. RESULTS: Among unvaccinated participants, the prevalence of IgG/IgM antibodies against SARS-CoV-2 receptor-binding domain or nucleocapsid protein at enrollment was 70% in Goma (138 of 196), 89% in Kambia (112 of 126), and 89% in Masaka (190 of 213). The IgG responses against endemic human coronaviruses at baseline were not associated with SARS-CoV-2 sero-acquisition during follow-up. Among the vaccinated participants, those who had evidence of SARS-CoV-2 IgG/IgM at baseline tended to have higher IgG responses to vaccination than those who were SARS-CoV-2 seronegative at baseline, controlling for the time of sample collection since vaccination. CONCLUSION: The high levels of natural immunity and hybrid immunity should be incorporated into both vaccination policies and prediction models of the impact of subsequent waves of infection in these settings.

Safety and immunogenicity of an Ad26.ZEBOV booster dose in children previously vaccinated with the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen: an open-label, non-randomised, phase 2 trial.

BACKGROUND: Children account for a substantial proportion of cases and deaths during Ebola virus disease outbreaks. We aimed to evaluate the safety and immunogenicity of a booster dose of the Ad26.ZEBOV vaccine in children who had been vaccinated with a two-dose regimen comprising Ad26.ZEBOV as dose one and MVA-BN-Filo as dose two. METHODS: We conducted an open-label, non-randomised, phase 2 trial at one clinic in Kambia Town, Sierra Leone. Healthy children, excluding pregnant or breastfeeding girls, who had received the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen in a previous study, and were aged 1-11 years at the time of their first vaccine dose, received an intramuscular injection of Ad26.ZEBOV (5 × 1010 viral particles) and were followed up for 28 days. Primary outcomes were safety (measured by adverse events) and immunogenicity (measured by Ebola virus glycoprotein-specific IgG binding antibody geometric mean concentration) of the booster vaccine dose. Safety was assessed in all participants who received the booster vaccination; immunogenicity was assessed in all participants who received the booster vaccination, had at least one evaluable sample after the booster, and had no major protocol deviations that could have influenced the immune response. This trial is registered with ClinicalTrials.gov, NCT04711356. FINDINGS: Between July 8 and Aug 18, 2021, 58 children were assessed for eligibility and 50 (27 aged 4-7 years and 23 aged 9-15 years) were enrolled and received an Ad26.ZEBOV booster vaccination, more than 3 years after receiving dose one of the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen. The booster was well tolerated. The most common solicited local adverse event during the 7 days after vaccination was injection site pain, reported in 18 (36%, 95% CI 23-51) of 50 participants. The most common solicited systemic adverse event during the 7 days after vaccination was headache, reported in 11 (22%, 12-36) of 50 participants. Malaria was the most common unsolicited adverse event during the 28 days after vaccination, reported in 25 (50%, 36-64) of 50 participants. No serious adverse events were observed during the study period. 7 days after vaccination, the Ebola virus glycoprotein-specific IgG binding antibody geometric mean concentration was 28 561 ELISA units per mL (95% CI 20 255-40 272), which was 44 times higher than the geometric mean concentration before the booster dose. 21 days after vaccination, the geometric mean concentration reached 64 690 ELISA units per mL (95% CI 48 356-86 541), which was 101 times higher than the geometric mean concentration before the booster dose. INTERPRETATION: A booster dose of Ad26.ZEBOV in children who had received the two-dose Ad26.ZEBOV and MVA-BN-Filo vaccine regimen more than 3 years earlier was well tolerated and induced a rapid and robust increase in binding antibodies against Ebola virus. These findings could inform Ebola vaccination strategies in paediatric populations. FUNDING: Innovative Medicines Initiative 2 Joint Undertaking. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.