Case fatality risk among individuals vaccinated with rVSVΔG-ZEBOV-GP: a retrospective cohort analysis of patients with confirmed Ebola virus disease in the Democratic Republic of the Congo.

BACKGROUND: The rVSVΔG-ZEBOV-GP vaccine constitutes a valuable tool to control Ebola virus disease outbreaks. This retrospective cohort study aimed to assess the protective effect of the vaccine against death among patients with confirmed Ebola virus disease. METHODS: In this retrospective cohort analysis of patients with confirmed Ebola virus disease admitted to Ebola health facilities in the Democratic Republic of the Congo between July 27, 2018, and April 27, 2020, we performed univariate and multivariate analyses to assess case fatality risk and cycle threshold for nucleoprotein according to vaccination status, Ebola virus disease-specific treatments (eg, mAb114 and REGN-EB3), and other risk factors. FINDINGS: We analysed all 2279 patients with confirmed Ebola virus disease. Of these 2279 patients, 1300 (57%) were female and 979 (43%) were male. Vaccination significantly lowered case fatality risk (vaccinated: 25% [106/423] vs not vaccinated: 56% [570/1015]; p<0·0001). In adjusted analyses, vaccination significantly lowered the risk of death compared with no vaccination, with protection increasing as time elapsed from vaccination to symptom onset (vaccinated ≤2 days before onset: 27% [27/99], adjusted relative risk 0·56 [95% CI 0·36-0·82, p=0·0046]; 3-9 days before onset: 20% [28/139], 0·44 [0·29-0·65, p=0·0001]; ≥10 days before onset: 18% [12/68], 0·40 [0·21-0·69; p=0·0022]; vaccination date unknown: 33% [39/117], 0·69 [0·48-0·96; p=0·0341]; and vaccination status unknown: 52% [441/841], 0·80 [0·70-0·91, p=0·0011]). Longer time from symptom onset to admission significantly increased risk of death (49% [1117/2279], 1·03 [1·02-1·05; p<0·0001]). Cycle threshold values for nucleoprotein were significantly higher-indicating lower viraemia-among patients who were vaccinated compared with those who were not vaccinated; the highest difference was observed among those vaccinated 21 days or longer before symptom onset (median 30·0 cycles [IQR 24·6-33·7]) compared with patients who were not vaccinated (21·4 cycles [18·4-25·9], p<0·0001). INTERPRETATION: To our knowledge, this is the first observational study describing the protective effect of rVSVΔG-ZEBOV-GP vaccination against death among patients with confirmed Ebola virus disease admitted to an Ebola health facility. Vaccination was protective against death for all patients, even when adjusted for Ebola virus disease-specific treatment, age group, and time from symptom onset to admission. FUNDING: Médecins Sans Frontières. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Implementation of targeted cholera response activities, Cameroon.

Objective: To describe the implementation of case-area targeted interventions to reduce cholera transmission using a rapid, localized response in Kribi district, Cameroon. Methods: We used a cross-sectional design to study the implementation of case-area targeted interventions. We initiated interventions after rapid diagnostic test confirmation of a case of cholera. We targeted households within a 100-250 metre perimeter around the index case (spatial targeting). The interventions package included: health promotion, oral cholera vaccination, antibiotic chemoprophylaxis for nonimmunized direct contacts, point-of-use water treatment and active case-finding. Findings: We implemented eight targeted intervention packages in four health areas of Kribi between 17 September 2020 and 16 October 2020. We visited 1533 households (range: 7-544 per case-area) hosting 5877 individuals (range: 7-1687 per case-area). The average time from detection of the index case to implementation of interventions was 3.4 days (range: 1-7). Oral cholera vaccination increased overall immunization coverage in Kribi from 49.2% (2771/5621 people) to 79.3% (4456/5621 people). Interventions also led to the detection and prompt management of eight suspected cases of cholera, five of whom had severe dehydration. Stool culture was positive for Vibrio cholerae O1 in four cases. The average time from onset of symptoms to admission of a person with cholera to a health facility was 1.2 days. Conclusion: Despite challenges, we successfully implemented targeted interventions at the tail-end of a cholera epidemic, after which no further cases were reported in Kribi up until week 49 of 2021. The effectiveness of case-area targeted interventions in stopping or reducing cholera transmission needs further investigation.

Investigating outbreaks of initially unknown aetiology in complex settings: findings and recommendations from 10 case studies.

BACKGROUND: Outbreaks of unknown aetiology in complex settings pose challenges and there is little information about investigation methods. We reviewed investigations into such outbreaks to identify methods favouring or impeding identification of the cause. METHODS: We used two approaches: reviewing scientific literature and soliciting key informants. Case studies were developed through interviews with people involved and triangulated with documents available from the time of the investigation. RESULTS: Ten outbreaks in African or Asian countries within the period 2007-2017 were selected. The cause was identified in seven, of which two had an unclear mode of transmission, and in three, neither origin nor transmission mode was identified. Four events were caused by infectious agents and three by chemical poisoning. Despite differences in the outbreaks, similar obstacles were noted: incomplete or delayed description of patients, comorbidities confounding clinical pictures and case definitions wrongly attributed. Repeated rounds of data collection and laboratory investigations were common and there was limited capacity to ship samples. DISCUSSION: It was not possible to define activities that led to prompt identification of the cause in the case studies selected. Based on the observations, we conclude that basing case definitions on precise medical observations, implementing initial comprehensive data collection, including environmental, social and behavioural information; and involving local informants could save precious time and hasten implementation of control measures.

Implementation of targeted cholera response activities, Cameroon

Objective To describe the implementation of case-area targeted interventions to reduce cholera transmission using a rapid, localized response in Kribi district, Cameroon. Methods We used a cross-sectional design to study the implementation of case-area targeted interventions. We initiated interventions after rapid diagnostic test confirmation of a case of cholera. We targeted households within a 100­250 metre perimeter around the index case (spatial targeting). The interventions package included: health promotion, oral cholera vaccination, antibiotic chemoprophylaxis for nonimmunized direct contacts, point-of-use water treatment and active case-finding. Findings We implemented eight targeted intervention packages in four health areas of Kribi between 17 September 2020 and 16 October 2020. We visited 1533 households (range: 7­544 per case-area) hosting 5877 individuals (range: 7­1687 per case-area). The average time from detection of the index case to implementation of interventions was 3.4 days (range: 1­7). Oral cholera vaccination increased overall immunization coverage in Kribi from 49.2% (2771/5621 people) to 79.3% (4456/5621 people). Interventions also led to the detection and prompt management of eight suspected cases of cholera, five of whom had severe dehydration. Stool culture was positive for Vibrio cholerae O1 in four cases. The average time from onset of symptoms to admission of a person with cholera to a health facility was 1.2 days. Conclusion Despite challenges, we successfully implemented targeted interventions at the tail-end of a cholera epidemic, after which no further cases were reported in Kribi up until week 49 of 2021. The effectiveness of case-area targeted interventions in stopping or reducing cholera transmission needs further investigation

Effectiveness of case-area targeted interventions including vaccination on the control of epidemic cholera: protocol for a prospective observational study.

INTRODUCTION: Cholera outbreaks in fragile settings are prone to rapid expansion. Case-area targeted interventions (CATIs) have been proposed as a rapid and efficient response strategy to halt or substantially reduce the size of small outbreaks. CATI aims to deliver synergistic interventions (eg, water, sanitation, and hygiene interventions, vaccination, and antibiotic chemoprophylaxis) to households in a 100-250 m 'ring' around primary outbreak cases. METHODS AND ANALYSIS: We report on a protocol for a prospective observational study of the effectiveness of CATI. Médecins Sans Frontières (MSF) plans to implement CATI in the Democratic Republic of the Congo (DRC), Cameroon, Niger and Zimbabwe. This study will run in parallel to each implementation. The primary outcome is the cumulative incidence of cholera in each CATI ring. CATI will be triggered immediately on notification of a case in a new area. As with most real-world interventions, there will be delays to response as the strategy is rolled out. We will compare the cumulative incidence among rings as a function of response delay, as a proxy for performance. Cross-sectional household surveys will measure population-based coverage. Cohort studies will measure effects on reducing incidence among household contacts and changes in antimicrobial resistance. ETHICS AND DISSEMINATION: The ethics review boards of MSF and the London School of Hygiene and Tropical Medicine have approved a generic protocol. The DRC and Niger-specific versions have been approved by the respective national ethics review boards. Approvals are in process for Cameroon and Zimbabwe. The study findings will be disseminated to the networks of national cholera control actors and the Global Task Force for Cholera Control using meetings and policy briefs, to the scientific community using journal articles, and to communities via community meetings.

Feasibility and safety of rVSV-ZEBOV vaccination of humanitarian health workers against Ebola virus disease: an observational study.

BACKGROUND AND RATIONALE: Geneva University Hospitals were granted a temporary authorization to administer the recombinant live vesicular stomatitis virus rVSV-ZEBOV (Ervebo®) vaccine to expatriate humanitarian frontline workers (FLWs) prior to mission deployment. OBJECTIVES: Our aims were to assess the feasibility of FLW vaccination before deployment and to report adverse events (AEs). METHODS: FLWs received a single injection of rVSV-ZEBOV (>7.2E7 plaque forming unit) during their pre-deployment medical check-up at the Travel Medicine Clinic of the Geneva University Hospitals (Day 0). A safety questionnaire regarding potential AEs was emailed to FLWs on Days 3 and 21. Early and delayed AEs were those starting within 3 or 21 days of vaccination, respectively. RESULTS: Between 1 August 2019 and 30 June 2020, 124 FLWs received the rVSV-ZEBOV vaccine. Eighty-six volunteers (86/124; 69%) received a concomitant vaccine. The response rate to the follow-up questionnaire was 88 and 55% at Days 3 and 21, respectively. Most respondents (105/109; 96.3%), experienced at least one AE, with a mean of three (±SD 1.75) AEs per person. The most common AE was injection site pain, followed by fever (53/109; 48.6%), fatigue (51/109; 46.7%) and myalgia (49/109; 44.9%). Most early AEs (360/377; 95.4%) resolved within 3 days, reflecting vaccine reactogenicity. Delayed AEs were reported by 6/69 (7.2%) subjects, the median time to symptom onset was 11 days (range: 5-14); half of them were joint-related AEs (3/6). Four serious adverse events (SAE) were observed: two cases of high grade fever, one rash and one case of arthritis. Two suspected unexpected serious adverse reactions were observed: one case of continuing recurrent transient dizziness and fatigue considered related to the vaccine; and one case of presbyopia that was deemed unrelated. CONCLUSION: AEs to rVSV-ZEBOV were common but in general transient and were well tolerated, pre-deployment rVSV-ZEBOV vaccination in FLW is feasible and can be included with pre-mission check-up.

Potential use of microarray patches for vaccine delivery in low- and middle- income countries.

Microarray patches (MAPs), also referred to as microneedle patches, are a novel methodology that have the potential to overcome barriers to vaccine delivery in low- and middle-income countries (LMICs), and transform the way that vaccines are delivered within immunization programs. The World Health Organization's Initiative for Vaccine Research and its partners are working to understand how MAPs could ease vaccine delivery and increase equitable access to vaccines in LMICs. Global stakeholders have been engaged to evaluate technical, economic, and programmatic challenges; to validate assumptions where possible; and to propose areas of focus to facilitate future vaccine-MAP product development. This report summarizes those learnings.

A post-conflict vaccination campaign, Central African Republic.

OBJECTIVE: To rapidly increase childhood immunization through a preventive, multi-antigen, vaccination campaign in Mambéré-Kadéï prefecture, Central African Republic, where a conflict from 2012 to 2015 reduced vaccination coverage. METHODS: The three-round campaign took place between December 2015 and June 2016 using: (i) oral poliomyelitis vaccine (OPV); (ii) combined diphtheria, tetanus and pertussis (DTP) vaccine, Haemophilus influenza type B (Hib) and hepatitis B (DTP-Hib-hepatitis B) vaccine; (iii) pneumococcal conjugate vaccine (PCV); (iv) measles vaccine; and (v) yellow fever vaccine. Administrative data were collected on vaccines administered by age group and vaccination coverage surveys were carried out before and after the campaign. FINDINGS: Overall, 294 054 vaccine doses were administered. Vaccination coverage for children aged 6 weeks to 59 months increased to over 85% for the first doses of OPV, DTP-Hib-hepatitis B vaccine and PCV and, in children aged 9 weeks to 59 months, to over 70% for the first measles vaccine dose. In children aged 6 weeks to 23 months, coverage of the second doses of OPV, DTP-Hib-hepatitis B vaccine and PCV was over 58% and coverage of the third doses of OPV and DTP-Hib-hepatitis B vaccine was over 20%. Moreover, 61% (5804/9589) of children aged 12 to 23 months had received two PCV doses and 90% (25933/28764) aged 24 to 59 months had received one dose. CONCLUSION: A preventive, multi-antigen, vaccination campaign was effective in rapidly increasing immunization coverage in a post-conflict setting. To sustain high coverage, routine immunization must be reinforced.

The new WHO decision-making framework on vaccine use in acute humanitarian emergencies: MSF experience in Minkaman, South Sudan.

INTRODUCTION: The main causes of death during population movements can be prevented by addressing the population's basic needs. In 2013, the World Health Organization (WHO) issued a framework for decision making to help prioritize vaccinations in acute humanitarian emergencies. This article describes MSF's experience of applying this framework in addition to addressing key population needs in a displacement setting in Minkaman, South Sudan. CASE DESCRIPTION: Military clashes broke out in South Sudan in December 2013. By May 2014, Minkaman, a village in the Lakes State, hosted some 85,000 displaced people. MSF arrived in Minkaman on 28 December 2013 and immediately provided interventions to address the key humanitarian needs (health care, access to drinking water, measles vaccination). The WHO framework was used to identify priority vaccines: those preventing outbreaks (measles, polio, oral cholera vaccine, and vaccine against meningococcal meningitis A (MenAfrivac®)) and those reducing childhood morbidity and mortality (pentavalent vaccine that combines diphtheria, tetanus, whooping cough, hepatitis B, and Haemophilus influenzae type B; pneumococcal vaccine; and rotavirus vaccine). By mid-March, access to primary and secondary health care was ensured, including community health activities and the provision of safe water. Mass vaccination campaigns against measles, polio, cholera, and meningitis had been organized. Vaccination campaigns against the main deadly childhood diseases, however, were not in place owing to lack of authorization by the Ministry of Health (MoH). CONCLUSIONS: The first field use of the new WHO framework for prioritizing vaccines in acute emergencies is described. Although MSF was unable to implement the full package of priority vaccines because authorization could not be obtained from the MoH, a series of mass vaccination campaigns against key epidemic-prone diseases was successfully implemented within a complex emergency context. Together with covering the population's basic needs, this might have contributed to reducing mortality levels below the emergency threshold and to the absence of epidemics. For the WHO framework to be used to its full potential it must not only be adapted for field use but, most importantly, national decision makers should be briefed on the framework and its practical implementation.

Long distance control of MHC class II expression by multiple distal enhancers regulated by regulatory factor X complex and CIITA.

MHC class II (MHC-II) genes are regulated by an enhanceosome complex containing two gene-specific transcription factors, regulatory factor X complex (RFX) and CIITA. These factors assemble on a strictly conserved regulatory module (S-X-X2-Y) found immediately upstream of the promoters of all classical and nonclassical MHC-II genes as well as the invariant chain (Ii) gene. To identify new targets of RFX and CIITA, we developed a computational approach based on the unique and highly constrained architecture of the composite S-Y motif. We identified six novel S'-Y' modules situated far away from the promoters of known human RFX- and CIITA-controlled genes. Four are situated at strategic positions within the MHC-II locus, and two are found within the Ii gene. These S'-Y' modules function as transcriptional enhancers, are bona fide targets of RFX and CIITA in B cells and IFN-gamma-induced cells, and induce broad domains of histone hyperacetylation. These results reveal a hitherto unexpected level of complexity involving long distance control of MHC-II expression by multiple distal regulatory elements.

Chromatin remodeling and extragenic transcription at the MHC class II locus control region.

In vivo, a wild-type pattern of major histocompatibility complex (MHC) class II expression requires a locus control region (LCR). Whereas the role of promoter-proximal MHC class II regulatory sequences is well established, the function of the distal LCR remained obscure. We show here that this LCR is bound by the MHC class II-specific transactivators regulatory factor X (RFX) and class II transactivator (CIITA). Binding of these factors induces long-range histone acetylation, RNA polymerase II recruitment and the synthesis of extragenic transcripts within the LCR. The finding that RFX and CIITA regulate the function of the MHC class II LCR reveals an unexpected degree of complexity in the mechanisms controlling MHC class II gene expression.