B. Draguez

Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial

BACKGROUND A recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV) is a promising Ebola vaccine candidate. We report the results of an interim analysis of a trial of rVSV-ZEBOV in Guinea, west Africa. METHODS For this open-label, cluster-randomised ring vaccination trial, suspected cases of Ebola virus disease in Basse-Guinée (Guinea, west Africa) were independently ascertained by Ebola response teams as part of a national surveillance system. After laboratory confirmation of a new case, clusters of all contacts and contacts of contacts were defined and randomly allocated 1:1 to immediate vaccination or delayed (21 days later) vaccination with rVSV-ZEBOV (one dose of 2 × 10(7) plaque-forming units, administered intramuscularly in the deltoid muscle). Adults (age ≥18 years) who were not pregnant or breastfeeding were eligible for vaccination. Block randomisation was used, with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 vs >20 individuals). The study is open label and masking of participants and field teams to the time of vaccination is not possible, but Ebola response teams and laboratory workers were unaware of allocation to immediate or delayed vaccination. Taking into account the incubation period of the virus of about 10 days, the prespecified primary outcome was laboratory-confirmed Ebola virus disease with onset of symptoms at least 10 days after randomisation. The primary analysis was per protocol and compared the incidence of Ebola virus disease in eligible and vaccinated individuals in immediate vaccination clusters with the incidence in eligible individuals in delayed vaccination clusters. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193. FINDINGS Between April 1, 2015, and July 20, 2015, 90 clusters, with a total population of 7651 people were included in the planned interim analysis. 48 of these clusters (4123 people) were randomly assigned to immediate vaccination with rVSV-ZEBOV, and 42 clusters (3528 people) were randomly assigned to delayed vaccination with rVSV-ZEBOV. In the immediate vaccination group, there were no cases of Ebola virus disease with symptom onset at least 10 days after randomisation, whereas in the delayed vaccination group there were 16 cases of Ebola virus disease from seven clusters, showing a vaccine efficacy of 100% (95% CI 74·7-100·0; p=0·0036). No new cases of Ebola virus disease were diagnosed in vaccinees from the immediate or delayed groups from 6 days post-vaccination. At the cluster level, with the inclusion of all eligible adults, vaccine effectiveness was 75·1% (95% CI -7·1 to 94·2; p=0·1791), and 76·3% (95% CI -15·5 to 95·1; p=0·3351) with the inclusion of everyone (eligible or not eligible for vaccination). 43 serious adverse events were reported; one serious adverse event was judged to be causally related to vaccination (a febrile episode in a vaccinated participant, which resolved without sequelae). Assessment of serious adverse events is ongoing. INTERPRETATION The results of this interim analysis indicate that rVSV-ZEBOV might be highly efficacious and safe in preventing Ebola virus disease, and is most likely effective at the population level when delivered during an Ebola virus disease outbreak via a ring vaccination strategy. FUNDING WHO, with support from the Wellcome Trust (UK); Médecins Sans Frontières; the Norwegian Ministry of Foreign Affairs through the Research Council of Norway; and the Canadian Government through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre, and Department of Foreign Affairs, Trade and Development.

Efficacy and Effectiveness of an rVSV-Vectored Vaccine in Preventing Ebola Virus Disease: Final Results from the Guinea Ring Vaccination, Open-Label, Cluster-Randomised Trial (Ebola Ça Suffit!)

Summary Background rVSV-ZEBOV is a recombinant, replication competent vesicular stomatitis virus-based candidate vaccine expressing a surface glycoprotein of Zaire Ebolavirus. We tested the effect of rVSV-ZEBOV in preventing Ebola virus disease in contacts and contacts of contacts of recently confirmed cases in Guinea, west Africa. Methods We did an open-label, cluster-randomised ring vaccination trial (Ebola ça Suffit!) in the communities of Conakry and eight surrounding prefectures in the Basse-Guinée region of Guinea, and in Tomkolili and Bombali in Sierra Leone. We assessed the efficacy of a single intramuscular dose of rVSV-ZEBOV (2×107 plaque-forming units administered in the deltoid muscle) in the prevention of laboratory confirmed Ebola virus disease. After confirmation of a case of Ebola virus disease, we definitively enumerated on a list a ring (cluster) of all their contacts and contacts of contacts including named contacts and contacts of contacts who were absent at the time of the trial team visit. The list was archived, then we randomly assigned clusters (1:1) to either immediate vaccination or delayed vaccination (21 days later) of all eligible individuals (eg, those aged ≥18 years and not pregnant, breastfeeding, or severely ill). An independent statistician generated the assignment sequence using block randomisation with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 individuals vs >20 individuals). Ebola response teams and laboratory workers were unaware of assignments. After a recommendation by an independent data and safety monitoring board, randomisation was stopped and immediate vaccination was also offered to children aged 6–17 years and all identified rings. The prespecified primary outcome was a laboratory confirmed case of Ebola virus disease with onset 10 days or more from randomisation. The primary analysis compared the incidence of Ebola virus disease in eligible and vaccinated individuals assigned to immediate vaccination versus eligible contacts and contacts of contacts assigned to delayed vaccination. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193. Findings In the randomised part of the trial we identified 4539 contacts and contacts of contacts in 51 clusters randomly assigned to immediate vaccination (of whom 3232 were eligible, 2151 consented, and 2119 were immediately vaccinated) and 4557 contacts and contacts of contacts in 47 clusters randomly assigned to delayed vaccination (of whom 3096 were eligible, 2539 consented, and 2041 were vaccinated 21 days after randomisation). No cases of Ebola virus disease occurred 10 days or more after randomisation among randomly assigned contacts and contacts of contacts vaccinated in immediate clusters versus 16 cases (7 clusters affected) among all eligible individuals in delayed clusters. Vaccine efficacy was 100% (95% CI 68·9–100·0, p=0·0045), and the calculated intraclass correlation coefficient was 0·035. Additionally, we defined 19 non-randomised clusters in which we enumerated 2745 contacts and contacts of contacts, 2006 of whom were eligible and 1677 were immediately vaccinated, including 194 children. The evidence from all 117 clusters showed that no cases of Ebola virus disease occurred 10 days or more after randomisation among all immediately vaccinated contacts and contacts of contacts versus 23 cases (11 clusters affected) among all eligible contacts and contacts of contacts in delayed plus all eligible contacts and contacts of contacts never vaccinated in immediate clusters. The estimated vaccine efficacy here was 100% (95% CI 79·3–100·0, p=0·0033). 52% of contacts and contacts of contacts assigned to immediate vaccination and in non-randomised clusters received the vaccine immediately; vaccination protected both vaccinated and unvaccinated people in those clusters. 5837 individuals in total received the vaccine (5643 adults and 194 children), and all vaccinees were followed up for 84 days. 3149 (53·9%) of 5837 individuals reported at least one adverse event in the 14 days after vaccination; these were typically mild (87·5% of all 7211 adverse events). Headache (1832 [25·4%]), fatigue (1361 [18·9%]), and muscle pain (942 [13·1%]) were the most commonly reported adverse events in this period across all age groups. 80 serious adverse events were identified, of which two were judged to be related to vaccination (one febrile reaction and one anaphylaxis) and one possibly related (influenza-like illness); all three recovered without sequelae. Interpretation The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters. Funding WHO, UK Wellcome Trust, the UK Government through the Department of International Development, Médecins Sans Frontières, Norwegian Ministry of Foreign Affairs (through the Research Council of Norways GLOBVAC programme), and the Canadian Government (through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre and Department of Foreign Affairs, Trade and Development).

Is operational research delivering the goods? The journey to success in low-income countries

Operational research in low-income countries has a key role in filling the gap between what we know from research and what we do with that knowledge-the so-called know-do gap, or implementation gap. Planned research that does not tangibly affect policies and practices is ineffective and wasteful, especially in settings where resources are scarce and disease burden is high. Clear parameters are urgently needed to measure and judge the success of operational research. We define operational research and its relation with policy and practice, identify why operational research might fail to affect policy and practice, and offer possible solutions to address these shortcomings. We also propose measures of success for operational research. Adoption and use of these measures could help to ensure that operational research better changes policy and practice and improves health-care delivery and disease programmes.

Practicing medicine without borders: tele‐consultations and tele‐mentoring for improving paediatric care in a conflict setting in Somalia?

Objectives  In a district hospital in conflict‐torn Somalia, we assessed (i) the impact of introducing telemedicine on the quality of paediatric care, and (ii) the added value as perceived by local clinicians.

The published research paper: is it an important indicator of successful operational research at programme level?

Is a published research paper an important indicator of successful operational research at programme level in low‐income countries? In academia, publishing in peer‐reviewed scientific journals is highly encouraged and strongly pursued for academic recognition and career progression. In contrast, for those who engage in operational research at programme level, there is often no necessity or reward for publishing the results of research studies; it may even be criticized as being an unnecessary detraction from programme‐related work. We present arguments to support publishing operational research from low‐income countries; we highlight some of the main reasons for failure of publication at programme level and suggest ways forward.

Is mid-upper arm circumference alone sufficient for deciding admission to a nutritional programme for childhood severe acute malnutrition in Bangladesh?

OBJECTIVES Mid-upper arm circumference (MUAC) and weight-for-height Z-score (WHZ) identify different populations of children with severe acute malnutrition (SAM) with only some degree of overlap. In an urban slum in Bangladesh, we conducted a prospective cohort study on children assessed as being severely malnourished by WHZ (<-3) but not by MUAC (>115 mm), to: 1. Assess their nutritional outcomes, and 2. Report on morbidity and mortality. METHODS Children underwent 2-weekly prospective follow-up home visits for 3 months and their anthropometric evolution, morbidity and mortality were monitored. RESULTS Of 158 children, 21 did not complete follow-up (six were lost to follow-up and 15 changed residence). Of the remaining 137 children, nine (7%) required admission to the nutrition programme because of: MUAC dropping to <115 mm (5/9 children), weight loss ≥ 10% (1/9 children) and severe medical complications (3/9 children, of whom one died). Of the remaining 128 children who completed follow-up, 91 (66%) improved in nutritional status while 37 (27%) maintained a WHZ of <-3. Cough was less frequent among those whose nutritional status improved. CONCLUSIONS It seems acceptable to rely on MUAC as a single assessment tool for case finding and for admission of children with SAM to nutritional programmes.

Operational Research during the Ebola Emergency

Operational research aims to identify interventions, strategies, or tools that can enhance the quality, effectiveness, or coverage of programs where the research is taking place. Médecins Sans Frontières admitted ≈5,200 patients with confirmed Ebola virus disease during the Ebola outbreak in West Africa and from the beginning nested operational research within its emergency response. This research covered critical areas, such as understanding how the virus spreads, clinical trials, community perceptions, challenges within Ebola treatment centers, and negative effects on non-Ebola healthcare. Importantly, operational research questions were decided to a large extent by returning volunteers who had first-hand knowledge of the immediate issues facing teams in the field. Such a method is appropriate for an emergency medical organization. Many challenges were also identified while carrying out operational research across 3 different countries, including the basic need for collecting data in standardized format to enable comparison of findings among treatment centers.

Severe malnutrition in children presenting to health facilities in an urban slum in Bangladesh.

SETTING An urban slum in Kamrangirchar, Bangladesh. OBJECTIVES Among children aged 6-59 months seeking medical care from the two Médecins Sans Frontières-supported primary health centres, to determine 1) the prevalence of severe acute malnutrition (SAM) and severe chronic malnutrition (SCM), and 2) the extent of overlap between SAM and SCM. DESIGN In a retrospective record review, data were analysed from out-patient registers on age, sex, height, weight and mid-upper arm circumference (MUAC) of children attending for medical care from April to September 2011. SAM was defined as weight for height < -3 Z scores of the median and/or MUAC <115 mm. SCM was defined as height for age < -3 Z scores of the median. World Health Organization growth standards were used as reference. RESULTS Data were complete in the records of 7318 (98%) children, of whom 322 (4%) had SAM and 1698 (23%) had SCM. Among the 322 children with SAM, 162 (50%) also had SCM. CONCLUSION In an urban Bangladesh slum, SAM and SCM co-exist, with a predominance of SCM. The current national guidelines for severe malnutrition, which focus on identification and management only for SAM, urgently need to be expanded to include SCM if substantial childhood morbidity and mortality are to be reduced.

Cholera in Haiti: please do not forget zinc

We commend Louise Ivers and colleagues (Dec 18, p 2048) for their thoughts around advocating for complementary public health inter ventions that could slow the cholera epidemic in Haiti. We are also particularly grateful to Partners In Health for the synergistic, helpful, and timely support provided to our medical action during the onset of the outbreak in the Artibonite region. Ivers and colleagues highlight the enormous potential benefi ts (shorter duration of illness, decreased volume of diarrhoea, and decreased duration of pathogen shedding) associated with the proper use of antibiotics. We concur, but would like to suggest the further need to add the systematic use of zinc for all paediatric patients (those younger than 15 years). Supplementation with zinc in children with cholera has been shown to present an additional benefi t over antimicrobial treatment by reducing the duration of diarrhoea and overall stool output. This eff ect can contribute substantially to decreased severity and a reduced overall burden of the disease. The US Centers for Disease Control and Prevention support the use of zinc for the paediatric population. Moreover, zinc has been proven to be eff ective in enhancing the T-cell and B-cell-driven sero conversion to vibriocidal antibodies in children given the oral inactivated cholera vaccine. This aspect is particularly crucial if we want to improve vaccine eff ectiveness and achieve, in the years to come, a meaningful preventive protection rate, aimed at saving thousands of lives.

Does the 65 cm height cut-off as age proxy exclude children eligible for nutritional assessment in Bangladesh?

SETTING Kamrangirchar slum, Dhaka, Bangladesh. OBJECTIVE During nutritional surveys and in circumstances when it is difficult to ascertain childrens age, length/height cut-offs are used as proxy for age to sample children aged 6-59 months. In a context of prevalent stunting, using data from primary health care centres where age and height parameters were well-recorded, we assessed the proportion of children aged between 6 and 59 months who would be excluded from nutritional assessment using a height cut-off of 65 cm as a proxy for age ≥6 months. DESIGN This was a secondary data analysis of primary health centre data. RESULTS A total of 2060 children were included in the analysis, with a median age of 24 months and a median height of 78 cm (SD 12.1, range 50-109 cm). There were 240 (12%, 95%CI 10-13) children aged between 6 and 29 months, with a height <65 cm. The majority (59%) of these children were females; 97.5% were aged 6-17 months. CONCLUSION In an urban slum setting in Bangladesh, the use of the current height cut-off as a proxy for age excludes vulnerable children from nutritional assessment and could also lead to underestimation of the prevalence of malnutrition in nutritional surveys.