Lassa fever research priorities: towards effective medical countermeasures by the end of the decade.

In 2016, WHO designated Lassa fever a priority disease for epidemic preparedness as part of the WHO Blueprint for Action to Prevent Epidemics. One aspect of preparedness is to promote development of effective medical countermeasures (ie, diagnostics, therapeutics, and vaccines) against Lassa fever. Diagnostic testing for Lassa fever has important limitations and key advancements are needed to ensure rapid and accurate diagnosis. Additionally, the only treatment available for Lassa fever is ribavirin, but controversy exists regarding its effectiveness. Finally, no licensed vaccines are available for the prevention and control of Lassa fever. Ongoing epidemiological and behavioural studies are also crucial in providing actionable information for medical countermeasure development, use, and effectiveness in preventing and treating Lassa fever. This Personal View provides current research priorities for development of Lassa fever medical countermeasures based on literature published primarily in the last 5 years and consensus opinion of 20 subject matter experts with broad experience in public health or the development of diagnostics, therapeutics, and vaccines for Lassa fever. These priorities provide an important framework to ensure that Lassa fever medical countermeasures are developed and readily available for use in endemic and at-risk areas by the end of the decade.

Measures to prevent and treat Nipah virus disease: research priorities for 2024-29.

Nipah virus causes highly lethal disease, with case-fatality rates ranging from 40% to 100% in recognised outbreaks. No treatments or licensed vaccines are currently available for the prevention and control of Nipah virus infection. In 2019, WHO published an advanced draft of a research and development roadmap for accelerating development of medical countermeasures, including diagnostics, therapeutics, and vaccines, to enable effective and timely emergency response to Nipah virus outbreaks. This Personal View provides an update to the WHO roadmap by defining current research priorities for development of Nipah virus medical countermeasures, based primarily on literature published in the last 5 years and consensus opinion of 15 subject matter experts with broad experience in development of medical countermeasures for Nipah virus or experience in the epidemiology, ecology, or public health control of outbreaks of Nipah virus. The research priorities are organised into four main sections: cross-cutting issues (for those that apply to more than one category of medical countermeasures), diagnostics, therapeutics, and vaccines. The strategic goals and milestones identified in each section focus on key achievements that are needed over the next 6 years to ensure that the necessary tools are available for rapid response to future outbreaks of Nipah virus or related henipaviruses.

Defeating meningitis by 2030 - an ambitious target.

Acute bacterial meningitis remains a major cause of mortality and morbidity, especially in lower-income countries. Thus, in 2017, a group of people concerned with this continuing problem came together to plan a way forward. A task force was established, a baseline situation analysis undertaken and a road map for a new initiative 'Defeating Meningitis by 2030' prepared. This road map will be launched officially in September 2021. Additional finances for meningitis control will be needed, together with the support of many different institutions and people with different skills, if the 'Defeating Meningitis by 2030' initiative is to achieve its ambitious goals.

Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.

BACKGROUND: World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS: We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS: At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS: These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).

Baseline mapping of severe fever with thrombocytopenia syndrome virology, epidemiology and vaccine research and development.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly emergent tick-borne bunyavirus first discovered in 2009 in China. SFTSV is a growing public health problem that may become more prominent owing to multiple competent tick-vectors and the expansion of human populations in areas where the vectors are found. Although tick-vectors of SFTSV are found in a wide geographic area, SFTS cases have only been reported from China, South Korea, Vietnam, and Japan. Patients with SFTS often present with high fever, leukopenia, and thrombocytopenia, and in some cases, symptoms can progress to severe outcomes, including hemorrhagic disease. Reported SFTSV case fatality rates range from ~5 to >30% depending on the region surveyed, with more severe disease reported in older individuals. Currently, treatment options for this viral infection remain mostly supportive as there are no licensed vaccines available and research is in the discovery stage. Animal models for SFTSV appear to recapitulate many facets of human disease, although none of the models mirror all clinical manifestations. There are insufficient data available on basic immunologic responses, the immune correlate(s) of protection, and the determinants of severe disease by SFTSV and related viruses. Many aspects of SFTSV virology and epidemiology are not fully understood, including a detailed understanding of the annual numbers of cases and the vertebrate host of the virus, so additional research on this disease is essential towards the development of vaccines and therapeutics.

Spatiotemporal Analysis of Serogroup C Meningococcal Meningitis Spread in Niger and Nigeria and Implications for Epidemic Response.

BACKGROUND: After the re-emergence of serogroup C meningococcal meningitis (MM) in Nigeria and Niger, we aimed to re-evaluate the vaccination policy used to respond to outbreaks of MM in the African meningitis belt by investigating alternative strategies using a lower incidence threshold and information about neighboring districts. METHODS: We used data on suspected and laboratory-confirmed cases in Niger and Nigeria from 2013 to 2017. We calculated global and local Moran's I-statistics to identify spatial clustering of districts with high MM incidence. We used a Pinner model to estimate the impact of vaccination campaigns occurring between 2015 and 2017 and to evaluate the impact of 3 alternative district-level vaccination strategies, compared with that currently used. RESULTS: We found significant clustering of high incidence districts in every year, with local clusters around Tambuwal, Nigeria in 2013 and 2014, Niamey, Niger in 2016, and in Sokoto and Zamfara States in Nigeria in 2017.We estimate that the vaccination campaigns implemented in 2015, 2016, and 2017 prevented 6% of MM cases. Using the current strategy but with high coverage (85%) and timely distribution (4 weeks), these campaigns could have prevented 10% of cases. This strategy required the fewest doses of vaccine to prevent a case. None of the alternative strategies we evaluated were more efficient, but they would have prevented the occurrence of more cases overall. CONCLUSIONS: Although we observed significant spatial clustering in MM in Nigeria and Niger between 2013 and 2017, there is no strong evidence to support a change in methods for epidemic response in terms of lowering the intervention threshold or targeting neighboring districts for reactive vaccination.

Eliminating Meningococcal Epidemics From the African Meningitis Belt: The Case for Advanced Prevention and Control Using Next-Generation Meningococcal Conjugate Vaccines.

The introduction and rollout of a meningococcal serogroup A conjugate vaccine, MenAfriVac, in the African meningitis belt has eliminated serogroup A meningococcal infections for >300 million Africans. However, serogroup C, W, and X meningococci continue to circulate and have been responsible for focal epidemics in meningitis belt countries. Affordable multivalent meningococcal conjugate vaccines are being developed to prevent these non-A epidemics. This article describes the current epidemiologic situation and status of vaccine development and highlights questions to be addressed to most efficiently use these new vaccines.

Status of the Rollout of the Meningococcal Serogroup A Conjugate Vaccine in African Meningitis Belt Countries in 2018.

BACKGROUND: A novel meningococcal serogroup A conjugate vaccine (MACV [MenAfriVac]) was developed as part of efforts to prevent frequent meningitis outbreaks in the African meningitis belt. The MACV was first used widely and with great success, beginning in December 2010, during initial deployment in Burkina Faso, Mali, and Niger. Since then, MACV rollout has continued in other countries in the meningitis belt through mass preventive campaigns and, more recently, introduction into routine childhood immunization programs associated with extended catch-up vaccinations. METHODS: We reviewed country reports on MACV campaigns and routine immunization data reported to the World Health Organization (WHO) Regional Office for Africa from 2010 to 2018, as well as country plans for MACV introduction into routine immunization programs. RESULTS: By the end of 2018, 304 894 726 persons in 22 of 26 meningitis belt countries had received MACV through mass preventive campaigns targeting individuals aged 1-29 years. Eight of these countries have introduced MACV into their national routine immunization programs, including 7 with catch-up vaccinations for birth cohorts born after the initial rollout. The Central African Republic introduced MACV into its routine immunization program immediately after the mass 1- to 29-year-old vaccinations in 2017 so no catch-up was needed. CONCLUSIONS: From 2010 to 2018, successful rollout of MACV has been recorded in 22 countries through mass preventive campaigns followed by introduction into routine immunization programs in 8 of these countries. Efforts continue to complete MACV introduction in the remaining meningitis belt countries to ensure long-term herd protection.

Lessons from the Meningitis Vaccine Project.

From 2001 to 2017 the Meningitis Vaccine Project (MVP), a Gates Foundation funded partnership between PATH and the World Health Organization (WHO), successfully developed, tested, licensed, and introduced an affordable new Group A meningococcal conjugate vaccine, MenAfriVac, in sub-Saharan Africa. The vaccine was well received, and from 2010 to 2016, over 260 million Africans have received a dose of the vaccine in campaigns largely directed at 1­29-year olds. The public health impact has been dramatic with the elimination of Group A meningococcal infections wherever the vaccine has been used at public health scale. Over its 16-year life span, MVP faced many challenges, and lessons were learned that may be of interest to other groups seeking to develop vaccine products for resource-poor countries. We have chosen to highlight six elements that were keys to the success of the project: (a) country and African regional engagement during all phases of the project; (b) the evolution of the WHO/PATH partnership; (c) funding the introduction of MenAfriVac in meningitis belt countries; (d) regulatory challenges; (e) clinical trials in Africa and India; and (f ) the realities of vaccine development partnerships.

Successful African introduction of a new Group A meningococcal conjugate vaccine: Future challenges and next steps.

The introduction of a new Group A meningococcal conjugate vaccine, MenAfriVacR, has been a important public health success. Group A meningococcal meningitis has disappeared in all countries where the new Men A conjugate vaccine has been used at public health scale. However, continued control of Group A disease in sub-Saharan Africa will require that community immunity against Group A meningococci be maintained. Modeling studies have shown that unless herd immunity is maintained Group A meningococcal disease will return. To ensure that African populations remain protected birth cohorts must be protected with an EPI formulation of MenAfriVacR (5 mcg) given at 9 months with Measles 1. In addition, populations born after the initial 1-29 year old campaigns and consequently not yet immunized with the new Men A conjugate vaccine, will have to be immunized in country-specific catch-up campaigns. Countries with poor EPI coverage (Measles 1 coverage < 60%) will likely need quinquennial vaccination campaigns aimed at covering 1-4 year olds. Implementing these strategies is the only sure way of ensuring that Group A meningococcal meningitis epidemics will not recur. A second problem that requires urgent attention is the challenge of dealing with Non-A meningococcal meningitis epidemics in sub-Saharan Africa. Groups C, W and X meningococci are well-established circulating strains in sub-Saharan Africa and are responsible for yearly focal meningitis epidemics that vary in severity and remain unpredictable as to size and geographic distribution. For this reason, polyvalent meningococcal conjugate vaccines that are affordable and appropriate for the African context must be developed and introduced. These new meningococcal vaccines when combined with more affordable pneumococcal conjugate vaccines offer the promise of a meningitis-free Sub-Saharan Africa.

Elimination of Epidemic Meningitis in the African Region: Progress and Challenges: 2010-2016.

BACKGROUND: Epidemics of meningococcal disease constitute a major public health challenge in Africa, affecting mostly the 24 countries of the meningitis belt. These epidemics led to a call for a call for a safe, effective and affordable conjugate vaccine against the major serogroup responsible for recent epidemics by leaders of the region. OBJECTIVE: This paper documents experiences with efforts at eliminating epidemic meningitis in the African Region. METHOD: The meningoccocal serogroup A conjugate vaccine was developed, licensed and offered to more than 235 million people through mass vaccination campaigns in 16 countries since 2010. Future plans include providing the vaccine to the remaining countries in the African Meningitis Belt and, to implement the vaccine into routine national infant immunization programme and to organise catch-up immunization campaigns every 5 years for unvaccinated <5 year-olds who had missed their routine vaccinations. RESULTS: The success of the project is evidenced by the large declines in cases of group A meningococcal disease since 2010, with no cases reported in vaccinated persons across the 16 countries, reflecting the highly effective nature of the vaccine. The successful control of serogroup A meningococcal disease has highlighted the need to tackle other meningococcal serogroups through development of polyvalent conjugate vaccines with the aim of eliminating epidemics of meningococcal meningitis in the African region.

Impact of MenAfriVac in nine countries of the African meningitis belt, 2010-15: an analysis of surveillance data.

BACKGROUND: In preparation for the introduction of MenAfriVac, a meningococcal group A conjugate vaccine developed for the African meningitis belt, an enhanced meningitis surveillance network was established. We analysed surveillance data on suspected and confirmed cases of meningitis to quantify vaccine impact. METHODS: We compiled and analysed surveillance data for nine countries in the meningitis belt (Benin, Burkina Faso, Chad, Côte d'Ivoire, Ghana, Mali, Niger, Nigeria, and Togo) collected and curated by the WHO Inter-country Support Team between 2005 and 2015. The incidence rate ratios (IRRs) of suspected and confirmed cases in vaccinated and unvaccinated populations were estimated with negative binomial regression models. The relative risk of districts reaching the epidemic threshold of ten per 100 000 per week was estimated according to district vaccination status. FINDINGS: The incidence of suspected meningitis cases declined by 57% (95% CI 55-59) in vaccinated compared with unvaccinated populations, with some heterogeneity observed by country. We observed a similar 59% decline in the risk of a district reaching the epidemic threshold. In fully vaccinated populations, the incidence of confirmed group A disease was reduced by more than 99%. The IRR for non-A serogroups was higher after completion of MenAfriVac campaigns (IRR 2·76, 95% CI 1·21-6·30). INTERPRETATION: MenAfriVac introduction has led to substantial reductions in the incidence of suspected meningitis and epidemic risk, and a substantial effect on confirmed group A meningococcal meningitis. It is important to continue strengthening surveillance to monitor vaccine performance and remain vigilant against threats from other meningococcal serogroups and other pathogens. FUNDING: World Health Organization.

Prevalence and epidemiology of meningococcal carriage in Southern Ethiopia prior to implementation of MenAfriVac, a conjugate vaccine.

BACKGROUND: Neisseria meningitidis colonizes humans and transmits mainly by asymptomatic carriage. We sought to determine the prevalence and epidemiology of meningococcal carriage in Ethiopia prior to the introduction of MenAfriVac, a serogroup A meningococcal conjugate vaccine. METHODS: A cross-sectional meningococcal carriage study was conducted in Arba Minch, southern Ethiopia. A total of 7479 oropharyngeal samples were collected from 1 to 29 year old volunteers, between March and October, 2014. The swabs were cultured for N. meningitidis and Neisseria lactamica in Ethiopia. N. meningitidis isolates were confirmed and characterized by their serogroup, sequence type (ST) and PorA:FetA profile in Norway. RESULTS: Overall carriage prevalence was 6.6 %. There was no significant difference in overall carriage between male (6.7 %) and female (6.4 %) participants. Highest carriage prevalence (10.9 %) for females was found in the 15-19 years of age, while prevalence among males was highest (11.3 %) in the 20-24 age group. Non-groupable isolates dominated (76.4 %), followed by serogroups X (14.0 %) and W (5.9 %) isolates. No serogroup A was found. Most non-groupable isolates were ST-192. Serogroup W isolates were assigned to the ST-11 clonal complex, and serogroup X isolates to the ST-181 and ST-41/44 clonal complexes. Overall carriage prevalence of N. lactamica was 28.1 %. Carriage of N. meningitidis and N. lactamica varied depending on age and geographic area, but there was no association between carriage of the two species. CONCLUSIONS: Epidemic strains of serogroups W and X were circulating in this area of Ethiopia. As no serogroup A was found among the carriage isolates the immediate impact of mass-vaccination with MenAfriVac on transmission of N. meningitidis in this population is expected to be marginal.

On a path to accelerate access to Ebola vaccines: The WHO's research and development efforts during the 2014-2016 Ebola epidemic in West Africa.

During 2014 and 2015 an outbreak of Ebola deemed a Public Health Emergency of International Concern affected a number of West African countries. The outbreak underscored the need for a vaccine against Ebola. An unprecedented and to great extent collaborative effort built on the availability of a number of candidate vaccines that could enter into clinical phase evaluation. A series of international consultations and activities were led by WHO as a contribution to the unprecedented global efforts to develop and assess an Ebola vaccine. WHO consulted widely, and immediately fostered interactions with the international scientific, ethics, regulatory, vaccine development, public health partners, industry and funders' communities and participated in consortia to facilitate Ebola vaccine assessments. WHO also fostered key activities to ensure the optimal policy and deployment of Ebola vaccines, if licensed. WHO has convened a broad global coalition of experts to develop a Blueprint and a platform for accelerated R&D, in order to avert full-blown epidemics.

Ethical Challenges and Lessons Learned During the Clinical Development of a Group A Meningococcal Conjugate Vaccine.

BACKGROUND: The group A meningococcal vaccine (PsA-TT) clinical development plan included clinical trials in India and in the West African region between 2005 and 2013. During this period, the Meningitis Vaccine Project (MVP) accumulated substantial experience in the ethical conduct of research to the highest standards. METHODS: Because of the public-private nature of the sponsorship of these trials and the extensive international collaboration with partners from a diverse setting of countries, the ethical review process was complex and required strategic, timely, and attentive communication to ensure the smooth review and approval for the clinical studies. Investigators and their site teams fostered strong community relationships prior to, during, and after the studies to ensure the involvement and the ownership of the research by the participating populations. As the clinical work proceeded, investigators and sponsors responded to specific questions of informed consent, pregnancy testing, healthcare, disease prevention, and posttrial access. RESULTS: Key factors that led to success included (1) constant dialogue between partners to explore and answer all ethical questions; (2) alertness and preparedness for emerging ethical questions during the research and in the context of evolving international ethics standards; and (3) care to assure that approaches were acceptable in the diverse community contexts. CONCLUSIONS: Many of the ethical issues encountered during the PsA-TT clinical development are familiar to groups conducting field trials in different cultural settings. The successful approaches used by the MVP clinical team offer useful examples of how these problems were resolved. CLINICAL TRIALS REGISTRATION: ISRCTN17662153 (PsA-TT-001); ISRTCN78147026 (PsA-TT-002); ISRCTN87739946 (PsA-TT-003); ISRCTN46335400 (PsA-TT-003a); ISRCTN82484612 (PsA-TT-004); CTRI/2009/091/000368 (PsA-TT-005); PACTR ATMR2010030001913177 (PsA-TT-006); PACTR201110000328305 (PsA-TT-007).

Community Perspectives Associated With the African PsA-TT (MenAfriVac) Vaccine Trials.

BACKGROUND: The Meningitis Vaccine Project (MVP) was established to address epidemic meningitis as a public health problem in sub-Saharan Africa and, to that end, worked to develop a group A meningococcal conjugate vaccine, PsA-TT. METHODS: Experiences in 4 clinical trial sites are described. Culturally sensitive collaborative strategies were adopted to manage acceptable communication methods, peculiarities with the consent process, participant medical issues, community care, and death. RESULTS: The clinical trials were completed successfully through community acceptance and active community collaboration. The trials also strengthened the capacities in the participating communities, and actively worked to resolve community problems. CONCLUSIONS: The understanding and integration of sociocultural realities of communities were major assets in the conduct and acceptance of these trials. MVP succeeded in these sites and provided a sound example for future clinical studies in Africa. CLINICAL TRIALS REGISTRATION: ISRTCN78147026 (PsA-TT 002); ISRCTN87739946 (PsA-TT 003); ISRCTN82484612 (PsA-TT 004); PACTR ATMR2010030001913177 (PsA-TT 006); and PACTR201110000328305 (PsA-TT 007).