Safety and immunogenicity of a purified inactivated Zika virus vaccine candidate in adults primed with a Japanese encephalitis virus or yellow fever virus vaccine in the USA: a phase 1, randomised, double-blind, placebo-controlled clinical trial.

BACKGROUND: Zika virus infection is a threat to at-risk populations, causing major birth defects and serious neurological complications. Development of a safe and efficacious Zika virus vaccine is, therefore, a global health priority. Assessment of heterologous flavivirus vaccination is important given co-circulation of Japanese encephalitis virus and yellow fever virus with Zika virus. We investigated the effect of priming flavivirus naive participants with a licensed flavivirus vaccine on the safety and immunogenicity of a purified inactivated Zika vaccine (ZPIV). METHODS: This phase 1, placebo-controlled, double-blind trial was done at the Walter Reed Army Institute of Research Clinical Trials Center in Silver Spring, MD, USA. Eligible participants were healthy adults aged 18-49 years, with no detectable evidence of previous flavivirus exposure (by infection or vaccination), as measured by a microneutralisation assay. Individuals with serological evidence of HIV, hepatitis B, or hepatitis C infection were excluded, as were pregnant or breastfeeding women. Participants were recruited sequentially into one of three groups (1:1:1) to receive no primer, two doses of intramuscular Japanese encephalitis virus vaccine (IXIARO), or a single dose of subcutaneous yellow fever virus vaccine (YF-VAX). Within each group, participants were randomly assigned (4:1) to receive intramuscular ZPIV or placebo. Priming vaccinations were given 72-96 days before ZPIV. ZPIV was administered either two or three times, at days 0, 28, and 196-234. The primary outcome was occurrence of solicited systemic and local adverse events along with serious adverse events and adverse events of special interest. These data were analysed in all participants receiving at least one dose of ZPIV or placebo. Secondary outcomes included measurement of neutralizing antibody responses following ZPIV vaccination in all volunteers with available post-vaccination data. This trial is registered at ClinicalTrials.gov, NCT02963909. FINDINGS: Between Nov 7, 2016, and Oct 30, 2018, 134 participants were assessed for eligibility. 21 did not meet inclusion criteria, 29 met exclusion criteria, and ten declined to participate. 75 participants were recruited and randomly assigned. 35 (47%) of 75 participants were male and 40 (53%) were female. 25 (33%) of 75 participants identified as Black or African American and 42 (56%) identified as White. These proportions and other baseline characteristics were similar between groups. There were no statistically significant differences in age, gender, race, or BMI between those who did and did not opt into the third dose. All participants received the planned priming IXIARO and YF-VAX vaccinations, but one participant who received YF-VAX dropped out before receipt of the first dose of ZPIV. 50 participants received a third dose of ZPIV or placebo, including 14 flavivirus-naive people, 17 people primed with Japanese encephalitis virus vaccine, and 19 participants primed with yellow fever vaccine. Vaccinations were well tolerated across groups. Pain at the injection site was the only adverse event reported more frequently in participants who received ZPIV than in those who received placebo (39 [65%] of 60 participants, 95% CI 51·6-76·9 who received ZPIV vs three [21·4%] of 14 who received placebo; 4·7-50·8; p=0·006). No patients had an adverse event of special interest or serious adverse event related to study treatment. At day 57, the flavivirus-naive volunteers had an 88% (63·6-98·5, 15 of 17) seroconversion rate (neutralising antibody titre ≥1:10) and geometric mean neutralising antibody titre (GMT) against Zika virus of 100·8 (39·7-255·7). In the Japanese encephalitis vaccine-primed group, the day 57 seroconversion rate was 31·6% (95% CI 12·6-56·6, six of 19) and GMT was 11·8 (6·1-22·8). Participants primed with YF-VAX had a seroconversion rate of 25% (95% CI 8·7-49·1, five of 20) and GMT of 6·6 (5·2-8·4). Humoral immune responses rose substantially following a third dose of ZPIV, with seroconversion rates of 100% (69·2-100; ten of ten), 92·9% (66·1-99·8; 13 of 14), and 60% (32·2-83·7, nine of 15) and GMTs of 511·5 (177·6-1473·6), 174·2 (51·6-587·6), and 79 (19·0-326·8) in the flavivirus naive, Japanese encephalitis vaccine-primed, and yellow fever vaccine-primed groups, respectively. INTERPRETATION: We found ZPIV to be well tolerated in flavivirus naive and primed adults but that immunogenicity varied significantly according to antecedent flavivirus vaccination status. Immune bias towards the flavivirus antigen of initial exposure and the timing of vaccination may have impacted responses. A third ZPIV dose overcame much, but not all, of the discrepancy in immunogenicity. The results of this phase 1 clinical trial have implications for further evaluation of ZPIV's immunisation schedule and use of concomitant vaccinations. FUNDING: Department of Defense, Defense Health Agency; National Institute of Allergy and Infectious Diseases; and Division of Microbiology and Infectious Disease.

Safety, tolerability, and immunogenicity of the chimpanzee adenovirus type 3-vectored Marburg virus (cAd3-Marburg) vaccine in healthy adults in the USA: a first-in-human, phase 1, open-label, dose-escalation trial.

BACKGROUND: WHO has identified Marburg virus as an emerging virus requiring urgent vaccine research and development, particularly due to its recent emergence in Ghana. We report results from a first-in-human clinical trial evaluating a replication-deficient recombinant chimpanzee adenovirus type 3 (cAd3)-vectored vaccine encoding a wild-type Marburg virus Angola glycoprotein (cAd3-Marburg) in healthy adults. METHODS: We did a first-in-human, phase 1, open-label, dose-escalation trial of the cAd3-Marburg vaccine at the Walter Reed Army Institute of Research Clinical Trials Center in the USA. Healthy adults aged 18-50 years were assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 1010 or 1 × 1011 particle units (pu). Primary safety endpoints included reactogenicity assessed for the first 7 days and all adverse events assessed for 28 days after vaccination. Secondary immunogenicity endpoints were assessment of binding antibody responses and T-cell responses against the Marburg virus glycoprotein insert, and assessment of neutralising antibody responses against the cAd3 vector 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT03475056. FINDINGS: Between Oct 9, 2018, and Jan 31, 2019, 40 healthy adults were enrolled and assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 1010 pu (n=20) or 1 × 1011 pu (n=20). The cAd3-Marburg vaccine was safe, well tolerated, and immunogenic. All enrolled participants received cAd3-Marburg vaccine, with 37 (93%) participants completing follow-up visits; two (5%) participants moved from the area and one (3%) was lost to follow-up. No serious adverse events related to vaccination occurred. Mild to moderate reactogenicity was observed after vaccination, with symptoms of injection site pain and tenderness (27 [68%] of 40 participants), malaise (18 [45%] of 40 participants), headache (17 [43%] of 40 participants), and myalgia (14 [35%] of 40 participants) most commonly reported. Glycoprotein-specific antibodies were induced in 38 (95%) of 40 participants 4 weeks after vaccination, with geometric mean titres of 421 [95% CI 209-846] in the 1 × 1010 pu group and 545 [276-1078] in the 1 × 1011 pu group, and remained significantly elevated at 48 weeks compared with baseline titres (39 [95% CI 13-119] in the 1 ×1010 pu group and 27 [95-156] in the 1 ×1011 pu group; both p<0·0001). T-cell responses to the glycoprotein insert and neutralising responses against the cAd3 vector were also increased at 4 weeks after vaccination. INTERPRETATION: This first-in-human trial of this cAd3-Marburg vaccine showed the agent is safe and immunogenic, with a safety profile similar to previously tested cAd3-vectored filovirus vaccines. 95% of participants produced a glycoprotein-specific antibody response at 4 weeks after a single vaccination, which remained in 70% of participants at 48 weeks. These findings represent a crucial step in the development of a vaccine for emergency deployment against a re-emerging pathogen that has recently expanded its reach to new regions. FUNDING: National Institutes of Health.

Systematic review of Marburg virus vaccine nonhuman primate studies and human clinical trials.

BACKGROUND: Recent deadly outbreaks of Marburg virus underscore the need for an effective vaccine. A summary of the latest research is needed for this WHO priority pathogen. This systematic review aimed to determine progress towards a vaccine for Marburg virus. METHODS: Article search criteria were developed to query PubMed for peer-reviewed articles from 1990 through 2019 on Marburg virus vaccine clinical trials in humans and pre-clinical studies in non-human primates (NHP). Abstracts were reviewed by two authors. Relevant articles were reviewed in full. Discrepancies were resolved by a third author. Data abstracted included year, author, title, vaccine construct, number of subjects, efficacy, and demographics. Assessment for risk of bias was performed using the Syrcle tool for animal studies, and the Cochrane Collaboration risk of bias tool for human studies. RESULTS: 101 articles were identified; 27 were related to Marburg vaccines. After full text review, 21 articles were selected. 215 human subjects were in three phase 1 clinical trials, and 203 NHP in 18 studies. Vaccine constructs were DNA plasmids, recombinant vesicular stomatitis virus (VSV) vectors, adenovirus vectors, virus-like particles (VLP), among others. Two human phase 1 studies of DNA vaccines had 4 adverse effects requiring vaccine discontinuation among 128 participants and 31-80% immunogenicity. In NHP challenge studies, 100% survival was seen in 6 VSV vectored vaccines, 2 DNA vaccines, 2 VLP vaccines, and in 1 adenoviral vectored vaccine. CONCLUSION: In human trials, two Marburg DNA vaccines provided either low immunogenicity or a failure to elicit durable immunity. A variety of NHP candidate Marburg vaccines demonstrated favorable survival and immunogenicity parameters, to include VSV, VLP, and adenoviral vectored vaccines. Elevated binding antibodies appeared to be consistently associated with protection across the NHP challenge studies. Further human trials are needed to advance vaccines to limit the spread of this highly lethal virus.

Enhancing Global Health Security: US Africa Command's Disaster Preparedness Program.

US Africa Command's Disaster Preparedness Program (DPP), implemented by the Center for Disaster and Humanitarian Assistance Medicine, partnered with US Government agencies and international organizations to promote stability and security on the African continent by engaging with African Partner Nations' (PN) civil and military authorities to improve disaster management capabilities. From 2008 to 2015, DPP conducted disaster preparedness and response programming with 17 PNs. DPP held a series of engagements with each, including workshops, strategic planning, developing preparedness and response plans, tabletop exercises, and prioritizing disaster management capability gaps identified through the engagements. DPP partners collected data for each PN to further capacity building efforts. Thus far, 9 countries have completed military pandemic plans, 10 have developed national pandemic influenza plans, 9 have developed military support to civil authorities plans, and 11 have developed disaster management strategic work plans. There have been 20 national exercises conducted since 2009. DPP was cited as key in implementation of Ebola response plans in PNs, facilitated development of disaster management agencies in DPP PNs, and trained nearly 800 individuals. DPP enhanced PNs' ability to prepare and respond to crises, fostering relationships between international agencies, and improving civil-military coordination through both national and regional capacity building. (Disaster Med Public Health Preparedness. 2019;13:319-329).

Economic Community of West African States Disaster Preparedness Tabletop Exercise: Building Regional Capacity to Enhance Health Security.

OBJECTIVE: The West African Disaster Preparedness Initiative held a disaster preparedness tabletop exercise with representatives from the Economic Community of West African States (ECOWAS) in November 2015. The tabletop exercise was hosted by the Republic of Ghana's National Disaster Management Organization and partners in Accra, Ghana. METHODS: ECOWAS Commission delegates and representatives from 10 member states were confronted with a series of simulated crises. Participants utilized existing national preparedness plans and web-based information technologies to research and communicate about internal disaster threats and those from neighboring countries. After each of the exercise's three phases, facilitators distributed participant surveys. RESULTS: A total of 106 individuals participated in the tabletop exercise. During the exercise, national teams utilizing well-developed disaster contingency plans and emergency operations center (EOC) standard operating procedures (SOPs) reached out to help less-prepared national teams. Key issues identified in the survey were language and cultural issues as barriers, effectiveness of disaster management agencies linked to heads of state, and the need for data sharing and real-time communication for situational awareness and multisector coordination. CONCLUSION: This tabletop exercise helped improve and refine the ECOWAS regional and member states' national SOPs that teams will employ to prepare for, respond to, and recover from future disasters. (Disaster Med Public Health Preparedness. 2019;13:400-404).

Liberia national disaster preparedness coordination exercise: Implementing lessons learned from the West African disaster preparedness initiative.

OBJECTIVE: In light of the recent Ebola outbreak, there is a critical need for effective disaster management systems in Liberia and other West African nations. To this end, the West Africa Disaster Preparedness Initiative held a disaster management exercise in conjunction with the Liberian national government on November 24-25, 2015. DESIGN: During this tabletop exercise (TTX), interactions within and between the 15 counties and the Liberian national government were conducted and observed to refine and validate the county and national standard operating procedures (SOPs). SETTING: The exercise took place in three regional locations throughout Liberia: Monrovia, Buchanan, and Bong. The TTX format allowed counties to collaborate utilizing open-source software platforms including Ushahidi, Sahana, QGIS, and KoBoCollect. PARTICIPANTS: Four hundred sixty-seven individuals (representing all 15 counties of Liberia) identified as key actors involved with emergency operations and disaster preparedness participated in the exercise. MAIN OUTCOME MEASURES: A qualitative survey with open-ended questions was administered to exercise participants to determine needed improvements in the disaster management system in Liberia. RESULTS: Key findings from the exercise and survey include the need for emergency management infrastructure to extend to the community level, establishment of a national disaster management agency and emergency operations center, customized local SOPs, ongoing surveillance, a disaster exercise program, and the need for effective data sharing and hazard maps. CONCLUSIONS: These regional exercises initiated the process of validating and refining Liberia's national and county-level SOPs. Liberia's participation in this exercise has provided a foundation for advancing its preparedness, response, and recovery capacities and could provide a template for other countries to use.

The West Africa Disaster Preparedness Initiative: Strengthening National Capacities for All-Hazards Disaster Preparedness.

OBJECTIVE: The Ebola outbreak demonstrated the need for improved disaster response throughout West Africa. The West Africa Disaster Preparedness Initiative was a training and assessment effort led by US Africa Command and partners to strengthen capacities among 12 West African partner nations (PNs). METHODS: Series of 3-week training sessions with representatives from each PN were held from 13 July through 20 November 2015 at the Kofi Annan International Peacekeeping Training Centre in Accra, Ghana. A team conducted Disaster Management Capabilities Assessments (DMCAs) for each PN, including a review of key data, a survey for leaders, and in-person interviews of key informants. RESULTS: All 12 PNs generated a national Ebola Preparedness and Response Plan and Emergency Operations Center standard operating procedures. DMCA metrics were generated for each PN. Top performers included Ghana, with a plan rated good/excellent, and Benin and Burkina Faso, which both achieved a satisfactory rating for their plans. More than 800 people from 12 nations were trained. CONCLUSION: PNs have improved disaster management capabilities and awareness of their strengths and weaknesses. The Economic Community of West African States has increased its lead role in this and future planned initiatives. (Disaster Med Public Health Preparedness. 2017;11:431-438).

Republic of Senegal Disaster Preparedness and Response Exercise: Lessons Learned and Progress Toward Key Goals.

OBJECTIVE: The Republic of Senegal Disaster Preparedness and Response Exercise was held from June 2-6, 2014, in Dakar, Senegal. The goal was to assist in familiarizing roles and responsibilities within 3 existing plans and to update the National Disaster Management Strategic Work Plan. METHODS: There were 60 participants in the exercise, which was driven by a series of evolving disaster scenarios. During the separate Disaster Management Strategic Work Plan review, participants refined a list of projects, including specific tasks to provide a "road map" for completing each project, project timelines, and estimated resource requirements. Project staff administered a survey to conference participants. RESULTS: A total of 86% of respondents had improved knowledge of Senegal disaster plans as a result of the exercise. A total of 89% of respondents had a better understanding of their ministry's role in disaster response, and 92% had a better understanding of the role of the military during a pandemic. Participants also generated ideas for disaster management system improvement in Senegal through a formal "gap analysis." CONCLUSIONS: Participants were in strong agreement that the exercise helped them to better understand the contents of their disaster response plans, build relationships across ministerial lines, and effectively enhance future disaster response efforts. (Disaster Med Public Health Preparedness. 2017;11:183-189).