# Attenuated viral strains of priority pathogens for potential use in controlled human infection model studies: A scoping review

## TL;DR

This paper reviews weakened versions of high-risk viruses that could be used in human challenge studies to develop vaccines and treatments before potential pandemics.

## Contribution

The study identifies specific attenuated viral strains suitable for controlled human infection models for two priority pathogens.

## Key findings

- Four attenuated strains were identified for chikungunya and Rift Valley fever viruses.
- VLA1553 for chikungunya is a licensed vaccine suitable for use in CHIM.
- No major safety concerns were found for the identified attenuated strains in clinical studies.

## Abstract

There are several known pathogens and families identified as high risk for pandemic potential. It is essential to study these pathogens and develop medical countermeasures to mitigate disease prior to potential pandemics. Controlled human infection models (CHIMs) using attenuated viral strains may offer an efficient and safe way to do this.

Our aim was to systematically examine the literature for attenuated, but replication competent, strains of Coalition for Epidemic Preparedness Innovations (CEPI) identified priority pathogens (Ebola, Lassa virus, Nipah virus, Rift Valley fever virus, chikungunya virus and Middle East respiratory syndrome-related coronavirus) that have been administered to humans.

A comprehensive literature search of multiple databases was performed by an information specialist. All search results were screened by two authors against inclusion/exclusion criteria from a pre-specified protocol. The primary outcome was confirmation that the administered viral strain could subsequently be recovered from participants. The secondary outcome was attenuated virus safety.

Our searches yielded 13078 results and 5998 articles remained for screening after removing duplicates and animal studies. Subsequently, 351 articles were selected for full text review and nine were included for data extraction. Four distinct attenuated strains were identified across two priority pathogens – TSI-GSD-218 and VLA1553 for chikungunya virus and MP-12 and hRVFV-4s for Rift Valley Fever virus. Attenuated virus was recovered for each strain except hRVFV-4s. There were no major safety concerns for these identified strains in Phase 1–3 studies.

We have identified three attenuated viral strains that may be amenable to development into novel CHIMs for two priority pathogens. Of these, VLA1553 for chikungunya is a licenced and commercially available vaccine product suitable for use in CHIM. There is a research gap for the creation of new attenuated mutants that could be utilised in CHIM for other priority pathogens.

There are several families of viruses that scientists predict are most likely to cause a future pandemic, such as coronaviruses or Ebola. Studying these viruses ahead of time might mean we have vaccines or drugs already available before an outbreak occurs.

Human challenge studies involve exposing healthy volunteers to germs that might make them sick and can be an efficient way of testing vaccines or treatments. It wouldn’t be safe to do that for many illnesses that could cause a pandemic. However, it may be possible to use weakened versions of these viruses instead. We have performed a thorough search of scientific papers to look for candidates of weakened viruses to see if we could use them like this. The most promising is a version of the chikungunya virus that is currently used as a vaccine.