Measles Resurgence and Drug Development

Abstract

Measles caused an estimated minimum of one million fatalities annually before vaccination. Outstanding progress towards controlling the virus has been made since the measles vaccine was introduced, but reduction of measles case-fatalities has stalled at around 100,000 annually for the last decade and a 2019 resurgence in several geographical regions threatens some of these past accomplishments. Whereas measles eradication through vaccination is feasible, a potentially open-ended endgame of elimination may loom. Other than doubling-down on existing approaches, is it worthwhile to augment vaccination efforts with antiviral therapeutics to solve the conundrum? This question is hypothetical at present, since no drugs have yet been approved specifically for the treatment of measles, or infection by any other pathogen of the paramyxovirus family. This article will consider obstacles that have hampered anti-measles and anti-paramyxovirus drug development, discuss MeV-specific challenges of clinical testing, and define drug properties suitable to address some of these problems.

Figure 1.

Timeline of MeV load, clinical signs (fever and rash), and immunosuppression phase during acute measles based on [59]. Approximate efficacy cut-offs for post-exposure vaccination and measles IgG PEP are shown.

Figure 2.

Docking pose of the MeV entry inhibitor AS-48 to MeV F. A ribbon model of the of the prefusion F trimer, colored by monomer, in complex with AS-48 is shown (PDB 5YZC). The prefusion head and stalk domains are highlighted. Docked AS-48 is depicted in magenta, resistance hot-spot N462 [89] is shown in black. The target membrane attack domain, the fusion peptides [90] are highlighted in red.

Figure 3.

Target site mapping of the MeV polymerase inhibitor ERDRP-0519. Homology model of the MeV L protein based on the coordinates reported for VSV L (PDB 5A22) and colored by functional domain. The catalytic center for phosphodiester bond formation (GDNQ) is shown with blue spheres, confirmed resistance sites are specified and shown in magenta.