Nipah Virus Therapeutics: A Systematic Review to Support Prioritisation for Clinical Trials

Nipah virus disease is a bat-borne zoonosis with person-to-person transmission, a case fatality rate of 38-75%, and recognised pandemic potential. The first reported outbreak occurred in Malaysia and Singapore in 1998, since followed by multiple outbreaks in Bangladesh and India. No therapeutics or vaccines have been licensed to date, and only few candidates are in development. This systematic review aimed to assess the evidence for the safety and efficacy of therapeutic options (monoclonal antibodies and small molecules) for Nipah virus and other henipaviral diseases in order to support candidate prioritisation for further evaluation in clinical trials. At present, there is sufficient evidence to trial only m102.4 and remdesivir (singly and/or in combination) for prophylaxis and early treatment of Nipah virus disease. In addition to well-designed clinical efficacy trials, in vivo pharmacokinetic-pharmacodynamic studies to optimise selection and dosing of therapeutic candidates in animal challenge and natural human infection are needed. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSNipah virus infection is a bat-borne zoonosis with person-to-person transmission, a case fatality rate of 38-75%, and recognised pandemic potential. No therapeutics or vaccines have been licensed to date, and only few candidates are in development. We conducted this systematic review to assess the evidence for the safety and efficacy of therapeutic options (monoclonal antibodies and small molecules) for Nipah virus and other henipaviral diseases to support candidate prioritisation for further evaluation in clinical trials. We searched bibliographic databases for journal articles, conference abstracts, and patents: PubMed, Ovid Embase, Ovid CAB Abstracts, Ovid Global Health, Scopus, Web of Science (all databases), and the WHO Global Index Medicus. "Henipavirus" or "Nipah" or "Hendra" along with "therapeutics" or "monoclonal" were the title, abstract, and subject heading keywords, with synonyms and variant spellings as additional search terms. We searched trial registries for clinical trials of Henipavirus, Nipah virus, and Hendra virus at all stages of recruitment: Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform. We searched the Trip database and WHO website for guidelines and reports. All searches were conducted on 30 May 2022. We did not apply language or publication date limits. Studies were included if they contained primary data on the safety and/or efficacy of monoclonal antibodies (in vivo) or small molecules (in vivo or in vitro) for the treatment and/or prophylaxis of Nipah, Hendra, and related Henipaviridae. Almost all had critical or high risk of bias. Added value of this studyThis is the most detailed systematic review and analysis of the Nipah virus therapeutics landscape to date, including all available in vivo and related in vitro data on the safety, efficacy, and pharmaco-kinetics of monoclonal antibodies and small molecules with the specific aim of supporting prioritisation for clinical trials. We also present a roadmap for how in vivo development of Nipah therapeutics could be strengthened to achieve greater equity, efficiency, and effectiveness. Implications of the available evidenceAt present, there is sufficient evidence to trial only m102.4 and remdesivir for prophylaxis and early treatment of Nipah virus infection. Well-designed clinical efficacy trials as well as in vivo pharmacokinetic-pharmacodynamic studies to optimise selection and dosing of therapeutic candidates in animal challenge and natural human infection are needed.