Urgent considerations for booster vaccination strategies against Ebola virus disease.

With two endorsed and prophylactic vaccines against Zaire ebolavirus (referred to hereafter as EBOV), the number of individuals vaccinated against EBOV worldwide is estimated to range between 500 000 and 1 000 000 individuals, increasing with every renewed EBOV threat and vaccination campaign. Therefore, re-exposure of previously vaccinated health-care workers, and possibly community members, could become more frequent. In the absence of long-term data on vaccine efficacy and duration of protection, we urgently need to understand revaccination strategies that could maximise the level of protection. In this Personal View, we highlight the scarcity of available evidence to guide revaccination recommendations for the accumulating groups of previously vaccinated communities or front-line health-care workers that could be redeployed or re-exposed in the next EBOV outbreak(s). This evidence base is crucial to identify optimal target populations and the frequency of booster doses, and guide vaccine interchangeability (especially in settings with limited or unpredictable vaccine supplies), while preventing vaccine mistrust, equity concerns, and exclusion of vulnerable populations. We discuss five priority gaps (to whom, when, and how frequently, to provide booster doses; long-term correlates and thresholds of protection; the effect of vector-directed immunity and viral variant protection; comparative research in mix-and-match schedules; and implementation concerns) that should be urgently tackled to adapt the initial EBOV prophylactic vaccination strategies considering potential booster dose vaccinations.

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 .

Implementing focused echocardiography and AI-supported analysis in a population-based survey in Lesotho: implications for community-based cardiovascular disease care models.

In settings where access to expert echocardiography is limited, focused echocardiography, combined with artificial intelligence (AI)-supported analysis, may improve diagnosis and monitoring of left ventricular hypertrophy (LVH). Sixteen nurses/nurse-assistants without prior experience in echocardiography underwent a 2-day hands-on intensive training to learn how to assess parasternal long axis views (PLAX) using an inexpensive hand-held ultrasound device in Lesotho, Southern Africa. Loops were stored on a cloud-drive, analyzed using deep learning algorithms at the University Hospital Basel, and afterwards confirmed by a board-certified cardiologist. The nurses/nurse-assistants obtained 756 echocardiograms. Of the 754 uploaded image files, 628 (83.3%) were evaluable by deep learning algorithms. Of those, results of 514/628 (81.9%) were confirmed by a cardiologist. Of the 126 not evaluable by the AI algorithm, 46 (36.5%) were manually evaluable. Overall, 660 (87.5%) uploaded files were evaluable and confirmed. Following short-term training of nursing cadres, a high proportion of obtained PLAX was evaluable using AI-supported analysis. This could be a basis for AI- and telemedical support in hard-to-reach areas with minimal resources.

Immunogenicity and Vaccine Shedding After 1 or 2 Doses of rVSVΔG-ZEBOV-GP Ebola Vaccine (ERVEBO®): Results From a Phase 2, Randomized, Placebo-controlled Trial in Children and Adults.

BACKGROUND: The rVSVΔG-ZEBOV-GP vaccine (ERVEBO®) is a single-dose, live-attenuated, recombinant vesicular stomatitis virus vaccine indicated for the prevention of Ebola virus disease (EVD) caused by Zaire ebolavirus in individuals 12 months of age and older. METHODS: The Partnership for Research on Ebola VACcination (PREVAC) is a multicenter, phase 2, randomized, double-blind, placebo-controlled trial of 3 vaccine strategies in healthy children (ages 1-17) and adults, with projected 5 years of follow-up (NCT02876328). Using validated assays (GP-ELISA and PRNT), we measured antibody responses after 1-dose rVSVΔG-ZEBOV-GP, 2-dose rVSVΔG-ZEBOV-GP (given on Day 0 and Day 56), or placebo. Furthermore, we quantified vaccine virus shedding in a subset of children's saliva using RT-PCR. RESULTS: In total, 819 children and 783 adults were randomized to receive rVSVΔG-ZEBOV-GP (1 or 2 doses) or placebo. A single dose of rVSVΔG-ZEBOV-GP increased antibody responses by Day 28 that were sustained through Month 12. A second dose of rVSVΔG-ZEBOV-GP given on Day 56 transiently boosted antibody concentrations. In vaccinated children, GP-ELISA titers were superior to placebo and non-inferior to vaccinated adults. Vaccine virus shedding was observed in 31.7% of children, peaking by Day 7, with no shedding observed after Day 28 post-dose 1 or any time post-dose 2. CONCLUSIONS: A single dose of rVSVΔG-ZEBOV-GP induced robust antibody responses in children that was non-inferior to the responses induced in vaccinated adults. Vaccine virus shedding in children was time-limited and only observed after the first dose. Overall, these data support the use of rVSVΔG-ZEBOV-GP for the prevention of EVD in at-risk children. Clinical Trials Registration. The study is registered at ClinicalTrials.gov (NCT02876328), the Pan African Clinical Trials Registry (PACTR201712002760250), and the European Clinical Trials Register (EudraCT number: 2017-001798-18).

Community-based models of care for management of type 2 diabetes mellitus among non-pregnant adults in sub-Saharan Africa: A scoping review.

INTRODUCTION: The prevalence of type 2 diabetes mellitus (T2DM) and associated morbidity and mortality are increasing in sub-Saharan Africa (SSA). To facilitate access to quality care and improve treatment outcomes, there is a need for innovative community care models and optimized use of non-physician healthcare workers bringing diagnosis and care closer to patients' homes. AIM: We aimed to describe with a scoping review different models of community-based care for non-pregnant adults with T2DM in SSA, and to synthesize the outcomes in terms of engagement in care, blood sugar control, acceptability, and end-organ damage. We further aimed to critically appraise the different models of care and compare community-based to facility-based care if data were available. METHODS: We searched Medline, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Scopus, supplemented with backward and forward citation searches. We included cohort studies, randomized trials and case-control studies that reported on non-pregnant individuals diagnosed with T2DM in SSA, who received a substantial part of care in the community. Only studies which reported at least one of our outcomes of interest were included. A narrative analysis was done, and comparisons made between community-based and facility-based models, where within-study comparison was reported. RESULTS: We retrieved 5,335 unique studies, four of which met our inclusion criteria. Most studies were excluded because interventions were facility-based; community care interventions described in the studies were only add-on features of a primarily facility-based care; and studies did not report outcomes of interest. The included studies reported on a total of 383 individuals with T2DM. Three different community care models were identified. 1) A community-initiated model where diagnosis, treatment and monitoring occurred primarily in the community. This model reported a higher linkage and engagement in care at 9 months compared to the corresponding facility model, but only slight reductions of average blood glucose levels at six months compared to baseline. 2) A facility-originated community model where after treatment initiation, a substantial part of follow-up was offered at community level. Two studies reported such a model of care, both had as core component home-delivery of medication. Acceptability of this approach was high. But neither study found improved T2DM control when compared to facility care 3) An eHealth model with high acceptability scores for both patients and care providers, and an absolute 1.76% reduction in average HbA1c levels at two months compared to baseline. There were no reported outcomes on end-organ damage. All four studies were rated as being at high risk for bias. CONCLUSION: Evidence on models of care for persons with T2DM in SSA where a substantial part of care is shifted to the community is scant. Whereas available literature indicates high acceptability of community-based care, we found no conclusive data on their effectiveness in controlling blood sugar and preventing complications. Evidence from larger scale studies, ideally randomized trials with clinically relevant endpoints is needed before roll-out of community-based T2DM care can be recommended in SSA.

Continuity and Rupture in Crisis: from Ebola to COVID-19 in Sierra Leone and the eastern Democratic Republic of the Congo.

This article examines the experience of healthcare professionals working in primary healthcare provision during the first wave of the COVID-19 pandemic in North Kivu, the Democratic Republic of the Congo, and in Kambia District, Sierra Leone. Drawing on ethnographic observation, interviews and focus groups, we explore everyday narratives of 'crisis' in these two regions which had recently seen Ebola epidemics. In describing the impact of COVID-19 on their life, work, and relationships with patients, healthcare workers made sense of the pandemic in relation to broader experiences of structural economic and political crisis, as well as differing experiences of recent Ebola epidemics. There were contradictory experiences of rupture and continuity: whilst COVID-19 disrupted routine health provision and exacerbated tensions with patients, the pandemic was also described as continuity, interacting with broader structural problems and longer-term experiences of 'crisis'. In effect, healthcare workers experienced the COVID-19 pandemic at the crossroads between the exceptional and the everyday, where states of exception brought by emergency measures shed new light on long-standing tensions and structural crisis.

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.

High Rates of Undiagnosed Target Organ Damage Among Adults with Elevated Blood Pressure or Diabetes Mellitus in a Community-Based Survey in Lesotho.

INTRODUCTION: Prevalence of elevated blood pressure (BP) and diabetes mellitus (DM) is increasing in sub-Saharan Africa. Data on target organ damage such as retinopathy, left ventricular hypertrophy (LVH), renal impairment and peripheral neuropathy (PN) among persons with elevated BP and/or DM in sub-Saharan Africa remain scarce. AIM: To determine at community-level the prevalence of retinopathy, LVH, renal impairment, and PN among adults with elevated BP and/or DM, and assess the association of elevated BP and/or DM with target organ damage in Lesotho. METHODS: During a household-based survey, a sub-sample of adults with elevated BP (≥ 140/90 mmHg) and/or DM (glycosylated hemoglobin ≥ 6.5%), as well as comparators (BP < 140/90 mmHg, HbA1c < 6.5%) were screened for retinopathy, LVH, renal impairment, and PN. We used multivariable logistic regression for inferential analysis. RESULTS: Out of 6108 participants screened during the survey, 420 with elevated BP only, 80 with DM only, 61 with elevated BP and DM, and 360 comparators were assessed for target organ damage. Among those with elevated BP, and among those with DM with or without elevated BP, prevalence of retinopathy was 34.6% (89/257) and 14.4% (15/104); renal impairment was 45.0% (156/347) and 42.4% (56/132), respectively. Among those with elevated BP, 2.3% (7/300) and 65.7% (224/341) had LVH and left ventricular concentric remodeling, respectively. PN, only assessed among those with DM, was present in 32.6% (42/129). Elevated BP was associated with increased odds of retinopathy (aOR, 19.13; 95% CI, 8.52-42.94; P < 0.001) and renal impairment (aOR, 1.80; 95% CI, 1.27-2.55; P = 0.001). Presence of both elevated BP and DM was associated with an increased odds of retinopathy (aOR, 16.30; 95%CI, 5.69-46.68; P < 0.001), renal impairment (aOR, 2.55; 95% CI, 1.35-4.81; P = 0.004), and PN (aOR, 2.13; 95% CI, 1.04-4.38; P = 0.040). CONCLUSION: We found a high prevalence of undiagnosed target organ damage among adults with elevated BP and/or DM during community-based screening. These findings emphasize the importance of regular prevention and screening activities in this setting.

Head-to-head comparison of the WHO STEPwise approach with immediate unattended and delayed unattended automated blood pressure measurements during household-based screening: a diagnostic accuracy study in Lesotho.

Background: WHO introduced the STEPwise approach to surveillance (STEPS) to monitor trends in non-communicable diseases. For arterial hypertension, the STEPS protocol takes the average of the last two out of three standard blood pressure measurements (SBPM). This study assesses the diagnostic accuracy of SBPM, same-day and next-day unattended automated measurement (uABP), with 24 h ambulatory measurement (24 h-ABPM) as reference. Methods: This diagnostic accuracy study was done within a population-based household survey on cardiovascular risk factors in two districts in Northern Lesotho. Adults (aged ≥ 18 years) with elevated SBPM (defined as ≥140/90 mmHg), and 2:1 age- and sex-matched participants with normal SBPM during the survey were recruited. Following SBPM, first uABP readings were obtained on survey day. Afterwards, participants received a 24 h-ABPM device. Second uABP readings were taken 24 h later, after retrieval of the 24 h-ABPM. The main outcome was overall diagnostic accuracy of all screening measurements (SBPM, first uABP, and second uABP), determined using area under the receiver operating characteristic curve (AUROC), with 24 h-ABPM as a reference. Findings: Between November 2, 2021 and August 31, 2022, 275 participants (mean age 58 years (SD: 16 years), 163 (59%) female) were enrolled, 183 of whom had elevated and 92 had normal SBPM. Mean difference between systolic daytime 24 h-ABPM and screening measurements was highest for SBPM (mean difference: -13 mmHg; 95% CI: -14 to -11). Mean difference between diastolic daytime 24 h-ABPM and diastolic SBPM was -2 mmHg (95% CI: -4 to -1), whereas no difference was found for mean diastolic first uABP (mean difference: -1 mmHg; 95% CI: -2.0 to 0.3); and mean diastolic second uABP (mean difference: 1.0 mmHg; 95% CI: -0.4 to 2.3). White coat hypertension was highest with SBPM (55 [20%]), followed by first uABP (27 [9.8%]), and second uABP (18 [6.5%]). Using systolic daytime 24 h-ABPM as a reference, the uABPs had higher AUROC (first uABP: 87% [95% CI: 83-91]; second uABP: 88% [95% CI: 84-92]); SBPM: (79% [95% CI: 74-85]). This difference was significant between first uABP and SBPM (P = 0.0024), and between second uABP and SBPM (P = 0.0017). Interpretation: uABP had better diagnostic performance than SBPM. Integration of uABP into STEPS protocol should be considered. Funding: Swiss Agency for Development and Cooperation under the ComBaCaL project, and the World Diabetes Foundation.

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.

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 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.

Randomized Trial of Vaccines for Zaire Ebola Virus Disease.

BACKGROUND: Questions remain concerning the rapidity of immune responses and the durability and safety of vaccines used to prevent Zaire Ebola virus disease. METHODS: We conducted two randomized, placebo-controlled trials - one involving adults and one involving children - to evaluate the safety and immune responses of three vaccine regimens against Zaire Ebola virus disease: Ad26.ZEBOV followed by MVA-BN-Filo 56 days later (the Ad26-MVA group), rVSVΔG-ZEBOV-GP followed by placebo 56 days later (the rVSV group), and rVSVΔG-ZEBOV-GP followed by rVSVΔG-ZEBOV-GP 56 days later (the rVSV-booster group). The primary end point was antibody response at 12 months, defined as having both a 12-month antibody concentration of at least 200 enzyme-linked immunosorbent assay units (EU) per milliliter and an increase from baseline in the antibody concentration by at least a factor of 4. RESULTS: A total of 1400 adults and 1401 children underwent randomization. Among both adults and children, the incidence of injection-site reactions and symptoms (e.g., feverishness and headache) was higher in the week after receipt of the primary and second or booster vaccinations than after receipt of placebo but not at later time points. These events were largely low-grade. At month 12, a total of 41% of adults (titer, 401 EU per milliliter) and 78% of children (titer, 828 EU per milliliter) had a response in the Ad26-MVA group; 76% (titer, 992 EU per milliliter) and 87% (titer, 1415 EU per milliliter), respectively, had a response in the rVSV group; 81% (titer, 1037 EU per milliliter) and 93% (titer, 1745 EU per milliliter), respectively, had a response in the rVSV-booster group; and 3% (titer, 93 EU per milliliter) and 4% (titer, 67 EU per milliliter), respectively, had a response in the placebo group (P<0.001 for all comparisons of vaccine with placebo). In both adults and children, antibody responses with vaccine differed from those with placebo beginning on day 14. CONCLUSIONS: No safety concerns were identified in this trial. With all three vaccine regimens, immune responses were seen from day 14 through month 12. (Funded by the National Institutes of Health and others; PREVAC ClinicalTrials.gov number, NCT02876328; EudraCT numbers, 2017-001798-18 and 2017-001798-18/3rd; and Pan African Clinical Trials Registry number, PACTR201712002760250.).

COVID-19 Vaccine Acceptability Among Healthcare Facility Workers in Sierra Leone, the Democratic Republic of Congo and Uganda: A Multi-Centre Cross-Sectional Survey.

Objectives: This cross-sectional survey explored COVID-19 vaccine acceptability among public healthcare facility workers in Kambia (Sierra Leone), Goma (Democratic Republic of Congo) and Masaka (Uganda). Methods: Questionnaire-based interviews conducted between April-October 2021 explored participants' knowledge and perceptions of, and attitudes towards, the COVID-19 pandemic and COVID-19 vaccines, as well as COVID-19 vaccine acceptability (defined as uptake of ≥1 dose or intent to get vaccinated). Results: Whilst most (n = 444; 81.8%) of the 543 participants had one or more concerns about COVID-19 vaccines, 487 (89.7%) nonetheless perceived that they were important for pandemic control. Most participants from Kambia or Masaka either were vaccinated (n = 137/355; 38.6%) or intended to get vaccinated (n = 211/355; 59.4%) against COVID-19. In Goma, all 188 participants were unvaccinated; only 81 (43.1%) participants intended to get vaccinated, and this was associated with positive perceptions about COVID-19 vaccines. In Goma, the most common reasons for not wanting a COVID-19 vaccine were concerns that the vaccines were new (n = 75/107; 70.1%) and fear of side effects (n = 74/107; 69.2%). Conclusion: Reported COVID-19 vaccine acceptability was high among healthcare facility workers in Kambia and Masaka. The lower vaccine acceptability in Goma may highlight the importance of social mobilisation and accurate, accessible information that addresses specific concerns.

Prevalence of malaria and helminth infections in rural communities in northern Sierra Leone, a baseline study to inform Ebola vaccine study protocols.

INTRODUCTION: Recurrent parasitic infections may influence the immune response to vaccines. In the Partnership for Research on Ebola VACcinations extended follow-UP and clinical research capacity build-UP (PREVAC-UP) study being undertaken in Mambolo, northern Sierra Leone, participants are being followed up to assess the potential impact of exposure to malaria and/or helminth infections on long-term immune response to two Ebola vaccines. To support the development of the assays that will be used in this evaluation, a parasitological survey was conducted in Mambolo between November 2019 and February 2020. METHODS: Healthy individuals aged ≥1 year who were resident in Mambolo Chiefdom were selected using a stratified sampling approach and questionnaires were administered to explore their sociodemographic characteristics. Microscopy was used to detect malaria parasites, intestinal helminths and urinary schistosome infections. Rapid blood tests were used to detect infections with Onchocerca volvulus and Wuchereria bancrofti. We estimated the overall prevalence of these infections and used adjusted logistic regression models to explore risk factors for malaria and hookworm infection. RESULTS: Eight hundred and fifteen (815) residents, 50.9% of whom were female were surveyed. Overall, 309 (39.1%) of 791 persons tested for malaria had a positive blood slide; Plasmodium falciparum was the dominant species. Helminth infection was detected in 122 (15.0%) of 815 stool samples including three mixed infections. The helminth infections comprised 102 (12.5%) cases of hookworm, 11 (1.3%) cases of Trichuris trichiura, 10 (1.2%) cases of Schistosoma mansoni and two (0.2%) cases of Ascaris lumbricoides. Being male (OR = 2.01, 95% CI 1.15-3.50) and residing in a non-riverine community (OR = 4.02, 95%CI 2.32-6.98) were the factors associated with hookworm infection. Onchocerca volvulus and Wuchereria bancrofti infections were found in 3.3% and 0.4% of participants respectively. CONCLUSION: Malaria and hookworm are the most prevalent parasite infections and those most likely to influence long-term immune response to Ebola vaccines among the trial participants.

Ebola Virus Glycoprotein IgG Seroprevalence in Community Previously Affected by Ebola, Sierra Leone.

We explored the association of Ebola virus antibody seropositivity and concentration with potential risk factors for infection. Among 1,282 adults and children from a community affected by the 2014-2016 Ebola outbreak in Sierra Leone, 8% were seropositive for virus antibodies but never experienced disease symptoms. Antibody concentration increased with age.

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

BACKGROUND: Children account for a substantial proportion of cases and deaths from Ebola virus disease. We aimed to assess the safety and immunogenicity of a two-dose heterologous vaccine regimen, comprising the adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein (Ad26.ZEBOV) and the modified vaccinia Ankara vector-based vaccine, encoding glycoproteins from the Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus (MVA-BN-Filo), in a paediatric population in Sierra Leone. METHODS: This randomised, double-blind, controlled trial was done at three clinics in Kambia district, Sierra Leone. Healthy children and adolescents aged 1-17 years were enrolled in three age cohorts (12-17 years, 4-11 years, and 1-3 years) and randomly assigned (3:1), via computer-generated block randomisation (block size of eight), to receive an intramuscular injection of either Ad26.ZEBOV (5 × 1010 viral particles; first dose) followed by MVA-BN-Filo (1 × 108 infectious units; second dose) on day 57 (Ebola vaccine group), or a single dose of meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine (MenACWY; first dose) followed by placebo (second dose) on day 57 (control group). Study team personnel (except for those with primary responsibility for study vaccine preparation), participants, and their parents or guardians were masked to study vaccine allocation. The primary outcome was safety, measured as the occurrence of solicited local and systemic adverse symptoms during 7 days after each vaccination, unsolicited systemic adverse events during 28 days after each vaccination, abnormal laboratory results during the study period, and serious adverse events or immediate reportable events throughout the study period. The secondary outcome was immunogenicity (humoral immune response), measured as the concentration of Ebola virus glycoprotein-specific binding antibodies at 21 days after the second dose. The primary outcome was assessed in all participants who had received at least one dose of study vaccine and had available reactogenicity data, and immunogenicity was assessed in all participants who had received both vaccinations within the protocol-defined time window, had at least one evaluable post-vaccination sample, and had no major protocol deviations that could have influenced the immune response. This study is registered at ClinicalTrials.gov, NCT02509494. FINDINGS: From April 4, 2017, to July 5, 2018, 576 eligible children or adolescents (192 in each of the three age cohorts) were enrolled and randomly assigned. The most common solicited local adverse event during the 7 days after the first and second dose was injection-site pain in all age groups, with frequencies ranging from 0% (none of 48) of children aged 1-3 years after placebo injection to 21% (30 of 144) of children aged 4-11 years after Ad26.ZEBOV vaccination. The most frequently observed solicited systemic adverse event during the 7 days was headache in the 12-17 years and 4-11 years age cohorts after the first and second dose, and pyrexia in the 1-3 years age cohort after the first and second dose. The most frequent unsolicited adverse event after the first and second dose vaccinations was malaria in all age cohorts, irrespective of the vaccine types. Following vaccination with MenACWY, severe thrombocytopaenia was observed in one participant aged 3 years. No other clinically significant laboratory abnormalities were observed in other study participants, and no serious adverse events related to the Ebola vaccine regimen were reported. There were no treatment-related deaths. Ebola virus glycoprotein-specific binding antibody responses at 21 days after the second dose of the Ebola virus vaccine regimen were observed in 131 (98%) of 134 children aged 12-17 years (9929 ELISA units [EU]/mL [95% CI 8172-12 064]), in 119 (99%) of 120 aged 4-11 years (10 212 EU/mL [8419-12 388]), and in 118 (98%) of 121 aged 1-3 years (22 568 EU/mL [18 426-27 642]). INTERPRETATION: The Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen was well tolerated with no safety concerns in children aged 1-17 years, and induced robust humoral immune responses, suggesting suitability of this regimen for Ebola virus disease prophylaxis in children. FUNDING: Innovative Medicines Initiative 2 Joint Undertaking and Janssen Vaccines & Prevention BV.

Safety and long-term immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in adults in Sierra Leone: a combined open-label, non-randomised stage 1, and a randomised, double-blind, controlled stage 2 trial.

BACKGROUND: The Ebola epidemics in west Africa and the Democratic Republic of the Congo highlight an urgent need for safe and effective vaccines to prevent Ebola virus disease. We aimed to assess the safety and long-term immunogenicity of a two-dose heterologous vaccine regimen, comprising the adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein (Ad26.ZEBOV) and the modified vaccinia Ankara vector-based vaccine, encoding glycoproteins from Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus (MVA-BN-Filo), in Sierra Leone, a country previously affected by Ebola. METHODS: The trial comprised two stages: an open-label, non-randomised stage 1, and a randomised, double-blind, controlled stage 2. The study was done at three clinics in Kambia district, Sierra Leone. In stage 1, healthy adults (aged ≥18 years) residing in or near Kambia district, received an intramuscular injection of Ad26.ZEBOV (5 × 1010 viral particles) on day 1 (first dose) followed by an intramuscular injection of MVA-BN-Filo (1 × 108 infectious units) on day 57 (second dose). An Ad26.ZEBOV booster vaccination was offered at 2 years after the first dose to stage 1 participants. The eligibility criteria for adult participants in stage 2 were consistent with stage 1 eligibility criteria. Stage 2 participants were randomly assigned (3:1), by computer-generated block randomisation (block size of eight) via an interactive web-response system, to receive either the Ebola vaccine regimen (Ad26.ZEBOV followed by MVA-BN-Filo) or an intramuscular injection of a single dose of meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine (MenACWY; first dose) followed by placebo on day 57 (second dose; control group). Study team personnel, except those with primary responsibility for study vaccine preparation, and participants were masked to study vaccine allocation. The primary outcome was the safety of the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen, which was assessed in all participants who had received at least one dose of study vaccine. Safety was assessed as solicited local and systemic adverse events occurring in the first 7 days after each vaccination, unsolicited adverse events occurring in the first 28 days after each vaccination, and serious adverse events or immediate reportable events occurring up to each participant's last study visit. Secondary outcomes were to assess Ebola virus glycoprotein-specific binding antibody responses at 21 days after the second vaccine in a per-protocol set of participants (ie, those who had received both vaccinations within the protocol-defined time window, had at least one evaluable post-vaccination sample, and had no major protocol deviations that could have influenced the immune response) and to assess the safety and tolerability of the Ad26.ZEBOV booster vaccination in stage 1 participants who had received the booster dose. This study is registered at ClinicalTrials.gov, NCT02509494. FINDINGS: Between Sept 30, 2015, and Oct 19, 2016, 443 participants (43 in stage 1 and 400 in stage 2) were enrolled; 341 participants assigned to receive the Ad26.ZEBOV and MVA-BN-Filo regimen and 102 participants assigned to receive the MenACWY and placebo regimen received at least one dose of study vaccine. Both regimens were well tolerated with no safety concerns. In stage 1, solicited local adverse events (mostly mild or moderate injection-site pain) were reported in 12 (28%) of 43 participants after Ad26.ZEBOV vaccination and in six (14%) participants after MVA-BN-Filo vaccination. In stage 2, solicited local adverse events were reported in 51 (17%) of 298 participants after Ad26.ZEBOV vaccination, in 58 (24%) of 246 after MVA-BN-Filo vaccination, in 17 (17%) of 102 after MenACWY vaccination, and in eight (9%) of 86 after placebo injection. In stage 1, solicited systemic adverse events were reported in 18 (42%) of 43 participants after Ad26.ZEBOV vaccination and in 17 (40%) after MVA-BN-Filo vaccination. In stage 2, solicited systemic adverse events were reported in 161 (54%) of 298 participants after Ad26.ZEBOV vaccination, in 107 (43%) of 246 after MVA-BN-Filo vaccination, in 51 (50%) of 102 after MenACWY vaccination, and in 39 (45%) of 86 after placebo injection. Solicited systemic adverse events in both stage 1 and 2 participants included mostly mild or moderate headache, myalgia, fatigue, and arthralgia. The most frequent unsolicited adverse event after the first dose was headache in stage 1 and malaria in stage 2. Malaria was the most frequent unsolicited adverse event after the second dose in both stage 1 and 2. No serious adverse event was considered related to the study vaccine, and no immediate reportable events were observed. In stage 1, the safety profile after the booster vaccination was not notably different to that observed after the first dose. Vaccine-induced humoral immune responses were observed in 41 (98%) of 42 stage 1 participants (geometric mean binding antibody concentration 4784 ELISA units [EU]/mL [95% CI 3736-6125]) and in 176 (98%) of 179 stage 2 participants (3810 EU/mL [3312-4383]) at 21 days after the second vaccination. INTERPRETATION: The Ad26.ZEBOV and MVA-BN-Filo vaccine regimen was well tolerated and immunogenic, with persistent humoral immune responses. These data support the use of this vaccine regimen for Ebola virus disease prophylaxis in adults. FUNDING: Innovative Medicines Initiative 2 Joint Undertaking and Janssen Vaccines & Prevention BV.

Debunking highly prevalent health misinformation using audio dramas delivered by WhatsApp: evidence from a randomised controlled trial in Sierra Leone.

INTRODUCTION: Infectious disease misinformation is widespread and poses challenges to disease control. There is limited evidence on how to effectively counter health misinformation in a community setting, particularly in low-income regions, and unsettled scientific debate about whether misinformation should be directly discussed and debunked, or implicitly countered by providing scientifically correct information. METHODS: The Contagious Misinformation Trial developed and tested interventions designed to counter highly prevalent infectious disease misinformation in Sierra Leone, namely the beliefs that (1) mosquitoes cause typhoid and (2) typhoid co-occurs with malaria. The information intervention for group A (n=246) explicitly discussed misinformation and explained why it was incorrect and then provided the scientifically correct information. The intervention for group B (n=245) only focused on providing correct information, without directly discussing related misinformation. Both interventions were delivered via audio dramas on WhatsApp that incorporated local cultural understandings of typhoid. Participants were randomised 1:1:1 to the intervention groups or the control group (n=245), who received two episodes about breast feeding. RESULTS: At baseline 51% believed that typhoid is caused by mosquitoes and 59% believed that typhoid and malaria always co-occur. The endline survey was completed by 91% of participants. Results from the intention-to-treat, per-protocol and as-treated analyses show that both interventions substantially reduced belief in misinformation compared with the control group. Estimates from these analyses, as well as an exploratory dose-response analysis, suggest that direct debunking may be more effective at countering misinformation. Both interventions improved people's knowledge and self-reported behaviour around typhoid risk reduction, and yielded self-reported increases in an important preventive method, drinking treated water. CONCLUSION: These results from a field experiment in a community setting show that highly prevalent health misinformation can be countered, and that direct, detailed debunking may be most effective. TRIAL REGISTRATION NUMBER: NCT04112680.