Natalie E Dean

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).

Spread of Zika virus in the Americas

Significance Mathematical and computational modeling approaches can be essential in providing quantitative scenarios of disease spreading, as well as projecting the impact in the population. Here we analyze the spatial and temporal dynamics of the Zika virus epidemic in the Americas with a microsimulation approach informed by high-definition demographic, mobility, and epidemic data. The model provides probability distributions for the time and place of introduction of Zika in Brazil, the estimate of the attack rate, timing of the epidemic in the affected countries, and the projected number of newborns from women infected by Zika. These results are potentially relevant in the preparation and analysis of contingency plans aimed at Zika virus control. We use a data-driven global stochastic epidemic model to analyze the spread of the Zika virus (ZIKV) in the Americas. The model has high spatial and temporal resolution and integrates real-world demographic, human mobility, socioeconomic, temperature, and vector density data. We estimate that the first introduction of ZIKV to Brazil likely occurred between August 2013 and April 2014 (90% credible interval). We provide simulated epidemic profiles of incident ZIKV infections for several countries in the Americas through February 2017. The ZIKV epidemic is characterized by slow growth and high spatial and seasonal heterogeneity, attributable to the dynamics of the mosquito vector and to the characteristics and mobility of the human populations. We project the expected timing and number of pregnancies infected with ZIKV during the first trimester and provide estimates of microcephaly cases assuming different levels of risk as reported in empirical retrospective studies. Our approach represents a modeling effort aimed at understanding the potential magnitude and timing of the ZIKV epidemic and it can be potentially used as a template for the analysis of future mosquito-borne epidemics.

The ring vaccination trial: a novel cluster randomised controlled trial design to evaluate vaccine efficacy and effectiveness during outbreaks, with special reference to Ebola

A World Health Organization expert meeting on Ebola vaccines proposed urgent safety and efficacy studies in response to the outbreak in West Africa. One approach to communicable disease control is ring vaccination of individuals at high risk of infection due to their social or geographical connection to a known case. This paper describes the protocol for a novel cluster randomised controlled trial design which uses ring vaccination. In the Ebola ça suffit ring vaccination trial, rings are randomised 1:1 to (a) immediate vaccination of eligible adults with single dose vaccination or (b) vaccination delayed by 21 days. Vaccine efficacy against disease is assessed in participants over equivalent periods from the day of randomisation. Secondary objectives include vaccine effectiveness at the level of the ring, and incidence of serious adverse events. Ring vaccination trials are adaptive, can be run until disease elimination, allow interim analysis, and can go dormant during inter-epidemic periods.

Transmission dynamics of Ebola virus disease and intervention effectiveness in Sierra Leone

Significance Since the initial recognition of Ebola virus disease (EVD) in 1976, many epidemics have occurred in Africa. Serious concerns remain that the fatal disease may repeatedly reemerge. In this study, we used data from an unprecedented EVD outbreak in Sierra Leone to map spatiotemporal transmission patterns, identify influential factors, and assess the effects of interventions at the chiefdom level. Furthermore, we have quantified household transmissibility and the temporal association between interventions and household transmission. Our findings have deepened the understanding of the transmission dynamics of EVD and provided key information for future modeling efforts in forecasting future epidemics and establishing intervention strategies. Sierra Leone is the most severely affected country by an unprecedented outbreak of Ebola virus disease (EVD) in West Africa. Although successfully contained, the transmission dynamics of EVD and the impact of interventions in the country remain unclear. We established a database of confirmed and suspected EVD cases from May 2014 to September 2015 in Sierra Leone and mapped the spatiotemporal distribution of cases at the chiefdom level. A Poisson transmission model revealed that the transmissibility at the chiefdom level, estimated as the average number of secondary infections caused by a patient per week, was reduced by 43% [95% confidence interval (CI): 30%, 52%] after October 2014, when the strategic plan of the United Nations Mission for Emergency Ebola Response was initiated, and by 65% (95% CI: 57%, 71%) after the end of December 2014, when 100% case isolation and safe burials were essentially achieved, both compared with before October 2014. Population density, proximity to Ebola treatment centers, cropland coverage, and atmospheric temperature were associated with EVD transmission. The household secondary attack rate (SAR) was estimated to be 0.059 (95% CI: 0.050, 0.070) for the overall outbreak. The household SAR was reduced by 82%, from 0.093 to 0.017, after the nationwide campaign to achieve 100% case isolation and safe burials had been conducted. This study provides a complete overview of the transmission dynamics of the 2014−2015 EVD outbreak in Sierra Leone at both chiefdom and household levels. The interventions implemented in Sierra Leone seem effective in containing the epidemic, particularly in interrupting household transmission.

Transmissibility and Pathogenicity of Ebola Virus: A Systematic Review and Meta-analysis of Household Secondary Attack Rate and Asymptomatic Infection.

Factors affecting our ability to control an Ebola outbreak include transmissibility of the virus and the proportion of transmissions occurring asymptomatically. We performed a meta-analysis of Ebola household secondary attack rate (SAR), disaggregating by type of exposure (direct contact, no direct contact, nursing care, direct contact but no nursing care). The estimated overall household SAR is 12.5% (95% confidence interval [CI], 8.6%-16.3%). Transmission was driven by direct contact, with little transmission occurring in its absence (SAR, 0.8% [95% CI, 0%-2.3%]). The greatest risk factor was the provision of nursing care (SAR, 47.9% [95% CI, 23.3%-72.6%]). There was evidence of a decline in household SAR for direct contact between 1976 and 2014 (P = .018). We estimate that 27.1% (95% CI, 14.5%-39.6%) of Ebola infections are asymptomatic. Our findings suggest that surveillance and containment measures should be effective for controlling Ebola.

Containing Ebola at the Source with Ring Vaccination

Interim results from the Guinea Ebola ring vaccination trial suggest high efficacy of the rVSV-ZEBOV vaccine. These findings open the door to the use of ring vaccination strategies in which the contacts and contacts of contacts of each index case are promptly vaccinated to contain future Ebola virus disease outbreaks. To provide a numerical estimate of the effectiveness of ring vaccination strategies we introduce a spatially explicit agent-based model to simulate Ebola outbreaks in the Pujehun district, Sierra Leone, structurally similar to previous modelling approaches. We find that ring vaccination can successfully contain an outbreak for values of the effective reproduction number up to 1.6. Through an extensive sensitivity analysis of parameters characterising the readiness and capacity of the health care system, we identify interventions that, alongside ring vaccination, could increase the likelihood of containment. In particular, shortening the time from symptoms onset to hospitalisation to 2–3 days on average through improved contact tracing procedures, adding a 2km spatial component to the vaccination ring, and decreasing human mobility by quarantining affected areas might contribute increase our ability to contain outbreaks with effective reproduction number up to 2.6. These results have implications for future control of Ebola and other emerging infectious disease threats.

The epidemiology and transmissibility of Zika virus in Girardot and San Andres island, Colombia, September 2015 to January 2016

Transmission of Zika virus (ZIKV) was first detected in Colombia in September 2015. As of April 2016, Colombia had reported over 65,000 cases of Zika virus disease (ZVD). We analysed daily surveillance data of ZVD cases reported to the health authorities of San Andres and Girardot, Colombia, between September 2015 and January 2016. ZVD was laboratory-confirmed by reverse transcription-polymerase chain reaction (RT-PCR) in the serum of acute cases within five days of symptom onset. We use daily incidence data to estimate the basic reproductive number (R0) in each population. We identified 928 and 1,936 reported ZVD cases from San Andres and Girardot, respectively. The overall attack rate for reported ZVD was 12.13 cases per 1,000 residents of San Andres and 18.43 cases per 1,000 residents of Girardot. Attack rates were significantly higher in females in both municipalities (p < 0.001). Cases occurred in all age groups with highest rates in 20 to 49 year-olds. The estimated R0 for the Zika outbreak was 1.41 (95% confidence interval (CI): 1.15–1.74) in San Andres and 4.61 (95% CI: 4.11–5.16) in Girardot. Transmission of ZIKV is ongoing in the Americas. The estimated R0 from Colombia supports the observed rapid spread.

Projected spread of Zika virus in the Americas

We use a data-driven global stochastic epidemic model to project past and future spread of the Zika virus (ZIKV) in the Americas. The model has high spatial and temporal resolution, and integrates real-world demographic, human mobility, socioeconomic, temperature, and vector density data. We estimate that the first introduction of ZIKV to Brazil likely occurred between August 2013 and April 2014 (90% credible interval). We provide simulated epidemic profiles of incident ZIKV infections for several countries in the Americas through February 2017. The ZIKV epidemic is characterized by slow growth and high spatial and seasonal heterogeneity, attributable to the dynamics of the mosquito vector and to the characteristics and mobility of the human populations. We project the expected timing and number of pregnancies infected with ZIKV during the first trimester, and provide estimates of microcephaly cases assuming different levels of risk as reported in empirical retrospective studies. Our approach represents an early modeling effort aimed at projecting the potential magnitude and timing of the ZIKV epidemic that might be refined as new and more accurate data from the region become available.

Ring vaccination with rVSV-ZEBOV under expanded access in response to an outbreak of Ebola virus disease in Guinea, 2016: an operational and vaccine safety report.

Summary Background In March, 2016, a flare-up of Ebola virus disease was reported in Guinea, and in response ring vaccination with the unlicensed rVSV-ZEBOV vaccine was introduced under expanded access, the first time that an Ebola vaccine has been used in an outbreak setting outside a clinical trial. Here we describe the safety of rVSV-ZEBOV candidate vaccine and operational feasibility of ring vaccination as a reactive strategy in a resource-limited rural setting. Methods Approval for expanded access and compassionate use was rapidly sought and obtained from relevant authorities. Vaccination teams and frozen vaccine were flown to the outbreak settings. Rings of contacts and contacts of contacts were defined and eligible individuals, who had given informed consent, were vaccinated and followed up for 21 days under good clinical practice conditions. Findings Between March 17 and April 21, 2016, 1510 individuals were vaccinated in four rings in Guinea, including 303 individuals aged between 6 years and 17 years and 307 front-line workers. It took 10 days to vaccinate the first participant following the confirmation of the first case of Ebola virus disease. No secondary cases of Ebola virus disease occurred among the vaccinees. Adverse events following vaccination were reported in 47 (17%) 6–17 year olds (all mild) and 412 (36%) adults (individuals older than 18 years; 98% were mild). Children reported fewer arthralgia events than adults (one [<1%] of 303 children vs 81 [7%] of 1207 adults). No severe vaccine-related adverse events were reported. Interpretation The results show that a ring vaccination strategy can be rapidly and safely implemented at scale in response to Ebola virus disease outbreaks in rural settings. Funding WHO, Gavi, and the World Food Programme.