Assessment of genetic changes and neurovirulence of shed Sabin and novel type 2 oral polio vaccine viruses

Rahnuma Wahid,Andrew Macadam,Ricardo Rüttimann,Sarah Carlyle,Jennifer L Konopka-Anstadt,Koert J Stittelaar,William C Weldon,Majid Laassri,Laura Stephens,Svetlana Petrovskaya,M Steven Oberste,Konstantin Chumakov,Pierre Van Damme,Ilse De Coster,Christopher J Van Der Gast ,Laina D Mercer ,Javier Martı́n ,Ananda S Bandyopadhyay ,Saskia L Smits,John Konz

doi:10.1038/s41541-021-00355-y

Abstract

Sabin-strain oral polio vaccines (OPV) can, in rare instances, cause disease in recipients and susceptible contacts or evolve to become circulating vaccine-derived strains with the potential to cause outbreaks. Two novel type 2 OPV (nOPV2) candidates were designed to stabilize the genome against the rapid reversion that is observed following vaccination with Sabin OPV type 2 (mOPV2). Next-generation sequencing and a modified transgenic mouse neurovirulence test were applied to shed nOPV2 viruses from phase 1 and 2 studies and shed mOPV2 from a phase 4 study. The shed mOPV2 rapidly reverted in the primary attenuation site (domain V) and increased in virulence. In contrast, the shed nOPV2 viruses showed no evidence of reversion in domain V and limited or no increase in neurovirulence in mice. Based on these results and prior published data on safety, immunogenicity, and shedding, the nOPV2 viruses are promising alternatives to mOPV2 for outbreak responses.

Highlights

Despite tremendous progress in the reduction of the incidence of poliomyelitis, global eradication remains elusive
One of the challenges is the genetic instability of the Sabin oral polio vaccine (OPV) strains, which can lead to vaccine-associated paralytic polio (VAPP) in recipients or their immediate contacts and, in regions with persistently under-immunized populations, virulent circulating vaccine-derived poliovirus strains that cause outbreaks
The results demonstrate the suitability of the methods to readily detect reversion mutations and discriminate shed novel OPV2 (nOPV2) from shed mOPV2 strains, affirming the potential of these novel strains

Summary

INTRODUCTION

Despite tremendous progress in the reduction of the incidence of poliomyelitis, global eradication remains elusive. One of the challenges is the genetic instability of the Sabin oral polio vaccine (OPV) strains, which can lead to vaccine-associated paralytic polio (VAPP) in recipients or their immediate contacts and, in regions with persistently under-immunized populations, virulent circulating vaccine-derived poliovirus (cVDPV) strains that cause outbreaks. In 2011, a research consortium initiated efforts to combine different approaches to stabilize the attenuation, leading to selection of two novel OPV2 (nOPV2) candidates for clinical development[15,16]. In both candidates, domain V is genetically stabilized through the replacement of all U–G pairs with C–G or U–A pairs while maintaining a similar thermostability of the RNA structure as the Sabin strain (Supplementary Fig. 1a)[11]. The results demonstrate the suitability of the methods to readily detect reversion mutations and discriminate shed nOPV2 from shed mOPV2 strains, affirming the potential of these novel strains

RESULTS

DISCUSSION

METHODS

Findings

CODE AVAILABILITY