In July 2024 the Centre for Infectious Disease Research and Policy (CIDRAP) announced an updated roadmap for Nipah virus (NiV) research and development. The project began in 2019 and was interrupted by the COVID-19 pandemic. Now, with funding from the Wellcome Trust, CIDRAP engaged a working group to update previous efforts and reflect more recent literature and knowledge. The roadmap is intended to provide a 6-year framework for “identifying the vision, underpinning strategic goals, and prioritising areas and activities” to accelerate the development of medical countermeasures against NiV infection. Here we consider the vaccine section of the roadmap.
Vaccine barriers
The term “barriers” in this context describes “inherent obstacles or technical challenges that may influence the likelihood of success at various stages”. For vaccine development this includes:
- Large clinical efficacy trials are “likely not feasible” – while “typically required” for vaccine licensure, large clinical efficacy trials are complicated by the “sporadic and unpredictable nature” of NiV outbreaks and low case numbers when they occur.
- We have limited experience with “nontraditional regulatory pathways”, which will be needed in the absence of large clinical efficacy trials, and “few successful models” for authorisation and approval.
- Limited commercial value of NiV vaccines may “impede industry’s involvement” in vaccine development and production without “significant” financial support.
- The affordability of creating and maintaining an NiV vaccine stockpile and deploying vaccines in outbreaks is a “key issue” for LMICs; additional funding will likely be needed to ensure vaccine preparedness.
- The absence of improved diagnostic assays for the timely diagnosis of infection creates an “important challenge” as it delays the implementation of a rapid reactive vaccination strategy for outbreak control.
Vaccine gaps
The authors refer to “gaps”, meaning “key unresolved issues or limitations in knowledge” that are “critical” to vaccine development and can be addressed through targeted R&D activities.
- NiV vaccines must be “readily accessible with adequate supply chains”, especially in low-resourced areas, should protect against different NiV strains, and provide “rapid onset of immunity” for effective outbreak prevention and control.
- Use cases for NiV vaccines should be “better defined”.
- Reference standards for NiV antibodies are needed for candidate vaccine evaluation.
- Expanded partnerships among researchers, funders, and regulators are needed to advance the development of promising candidates.
- NiV vaccine candidates in preclinical development target the fusion (F) and attachment (G) glycoproteins with a variety of platform technologies under consideration.
- Demonstrating vaccine-induced protection against NiV infection or disease in an animal model will require an immune correlate of protection (CoP) or immune surrogate to predict the likelihood of protective efficacy and reflect the protective immune responses generated in humans.
- Accurate and reliable CoPs have not yet been identified.
- Once we have identified the protective threshold for neutralising antibodies, “appropriate and feasible” assays must be identified and standardised for use in animal models.
- NiV vaccines can also be protective in the absence of detectable neutralising antibodies, which implies the presence of other mechanisms of protection. Research is required to better understand these.
- Research is needed to “better define” other potential CoPs, which could be important for next-generation vaccines.
- Most current NiV vaccine candidates target the immunodominant F and G glycoproteins, but data are needed on the potential role of additional immunogens.
- Further research should address some key elements of protective immunity:
- The relative contributions of innate, cell-mediated, and humoral immune responses.
- Specific cell types and interactions between different immune compartments in achieving viral clearance, surviving acute disease, and modulating chronic infection.
- The roles of neutralising and non-neutralising or binding antibodies in protecting against NiVD.
- Mechanisms and cell subsets of cellular immune responses that contribute to cross-neutralising protection against co-circulating strains.
- If researchers and regulators agree on the need for a nontraditional regulatory pathway, several issues should be addressed:
- A fully characterised and controlled virus challenge stock to assess vaccines in animal models should be generated.
- At least one animal model suitable for vaccine efficacy should be characterised.
- Challenge strain and dose should be standardised, and most appropriate lethal dose determined.
- The most appropriate CoP or surrogate marker should be determined.
- NiV vaccine efficacy data should be bridged from animal models to humans.
- If the accelerated approval process is deemed an acceptable regulatory approval pathway, we will need plans to conduct “well-controlled” clinical trials.
- Post-licensure clinical trials will be needed to confirm clinical benefit of vaccines approved via nontraditional pathways.
- Research is also needed to:
- Clarify vaccine attributes and determine safety profiles
- Identify alternative vaccine delivery approaches to facilitate rapid deployment in response to outbreaks in low-resource settings
- Evaluate optimal NiV antigen combinations and antigen/vaccine platform combinations for “rapid and durable” responses to infection
- Determine in animal models if vaccine candidates are cross-protective between different strains
- Mathematical modelling and forecasting might enable assessment of whether disease incidence is high enough in endemic areas to conduct clinical trials, simulate various epidemiological scenarios, estimate potential vaccine impact, estimate disease risk, and estimate vaccine quantity to maintain stockpiles.
- Researchers should consider efforts towards the development of pan-henipavirus vaccines to maximise potential benefit.
- Public communication outreach strategies should address possible vaccine uptake hesitancy and guidance for community sensitisation and promotion.
- Once vaccines available, we will need:
- Guidance on the use of NiV vaccines including strategies for special populations, different epidemiological scenarios, and different vaccine attributes
- Enhanced surveillance capacity to assess vaccination programmes and refine strategies
- Strategic planning for stockpiling and deploying vaccines
Vaccine strategic goals
“Strategic goals” are “long-range high-level research priorities” that the roadmap’s actions should address within the stated timeframe. These are supported with “milestones”, actions that will enable the strategic goals including target dates and reflecting SMART criteria.
- Develop the tools and policies necessary for evaluating and potentially approving one or more NiV candidate vaccines through a nontraditional regulatory pathway:
- By 2024 – generate a fully characterised and controlled virus challenge stock to assess candidates in animal models.
- By 2025 – generate standardised assays to measure immunoglobulin G (IgG) antibodies for NiV vaccine R&D, focusing on assays for regulatory approval via nontraditional pathways.
- By 2025 – Work with regulatory authorities to establish benchmark parameters for candidate testing in well-characterised animal models, focusing on meeting necessary criteria for approval via a nontraditional pathway.
- By 2025 – describe the range of possible protective thresholds against NiV infection for serum neutralising antibodies or other functional CoPs for use in animal studies and immunobridging to humans.
- Continue to move the current NiV vaccine pipeline forward through clinical trials:
- By 2024 – complete current phase I clinical trials for at least 3 promising candidates.
- By 2025 – define use cases for NiV vaccines to inform vaccine deployment and manufacturing plans.
- By 2025 – initiate phase II clinical trials, preferably in infected areas, to further assess immunogenicity and safety for at least 2 promising candidates.
- By 2028 – conduct further well-controlled phase II clinical trials in affected areas to assess a surrogate endpoint in human subjects – including children and pregnant women – for at least 2 candidates.
- By 2029 – complete a regulatory dossier for licensure or emergency use for a least 1 candidate based on a suitable animal model with subsequent immunobridging to humans for review via a nontraditional approval pathway.
Countermeasures against catastrophe
Dr Stephen Luby of Stanford University, contributing author, described the virus as “important”, with a “very high” case-fatality rate.
“The current roadmap appreciates the risk this represents so works to develop a set of countermeasures that helps prevent a catastrophe.”
Dr Luby hopes the roadmap will produce a “clear vision of where to go”. Dr Kristine Moore, lead author, reflected that the COVID-19 pandemic “dramatically demonstrated” that new virus strains can emerge “far more transmissible than their genetically related predecessors”.
“We need to be prepared for this possibility with Nipah virus, particularly given the high case-fatality rate.”
Dr Moore thanked the “many” subject experts who offered input and identified gaps in progress so that those issues can be addressed in the report. Dr Michael Osterholm, director of CIDRAP and principal investigator of the roadmap, emphasised that “we can only anticipate based on growing human populations, challenges in food supplies, which can lead to more human-animal interactions”.
“Owing in part to the greater likelihood of exposures, the risk for these infectious diseases causing more serious illness and death only goes up and not down…Time is of the essence.”
Dr Emily Gurley of Johns Hopkins University, coauthor, believes the roadmap represents an opportunity.
“The roadmap is a way to move the ball forward.”
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