Evaluating stability of attenuated Sabin and two novel type 2 oral poliovirus vaccines in children

Abstract

Novel oral poliovirus vaccine type 2 (nOPV2) is being developed to reduce the rare occurrence of disease and outbreaks associated with the genetic instability of the Sabin vaccine strains. Children aged 1 to 5 years were enrolled in two related clinical studies to assess safety, immunogenicity, shedding rates and properties of the shed virus following vaccination with nOPV2 (two candidates) versus traditional Sabin OPV type 2 (mOPV2). The anticipated pattern of reversion and increased virulence was observed for shed Sabin-2 virus, as assessed using a mouse model of poliovirus neurovirulence. In contrast, there were significantly reduced odds of mouse paralysis for shed virus for both nOPV2 candidates when compared to shed Sabin-2 virus. Next-generation sequencing of shed viral genomes was consistent with and further supportive of the observed neurovirulence associated with shed Sabin-2 virus, as well as the reduced reversion to virulence of shed candidate viruses. While shed Sabin-2 showed anticipated A481G reversion in the primary attenuation site in domain V in the 5’ untranslated region to be associated with increased mouse paralysis, the stabilized domain V in the candidate viruses did not show polymorphisms consistent with reversion to neurovirulence. The available data from a key target age group for outbreak response confirm the superior genetic and phenotypic stability of shed nOPV2 strains compared to shed Sabin-2 and suggest that nOPV2 should be associated with less paralytic disease and potentially a lower risk of seeding new outbreaks.

Global epidemiology of vaccine-derived poliovirus 2016–2021: A descriptive analysis and retrospective case-control study

“…The nOPV2, a modified form of the original monovalent OPV2 (mOPV2), has been shown to confer considerable immunity while at the same time being more genetically stable with a lower risk of cVDPV2 emergence. 40 With its addition to the EULP and use as a primary vaccine option in response to cVDPV2 outbreaks, the nOPV2 holds much promise as a replacement of the mOPV2 in controlling and preventing further cVDPV2 outbreaks. 40 …”

“… 40 With its addition to the EULP and use as a primary vaccine option in response to cVDPV2 outbreaks, the nOPV2 holds much promise as a replacement of the mOPV2 in controlling and preventing further cVDPV2 outbreaks. 40 …”

Developing genetically stable live-attenuated vaccine candidates against type 1 and 3 poliovirus

“…In the context of two similar but non-contemporaneous clinical trials, 18-22-week-old infants and 1-5year-old children were immunized with nOPV2 or Sabin 2. Virus shed from vaccinees was isolated and nucleotide polymorphisms examined by next generation sequencing 23,27,30,31,39,40 . There is also considerable sequence data from Sabin 2 isolates shed by vaccinees and contacts.…”

“…The nOPV2 strain also includes relocation of the cis-acting replication element (cre) to the 5′UTR to protect the modi ed domain V from replacement through a single recombination event and two amino acid substitutions to the 3D polymerase to improve delity and reduce the frequency of recombination events 22 . Promising human safety, immunogenicity, viral shedding, and genetic stability results from Phase 1 and 2 studies of nOPV2 were recently reported [23][24][25][26][27] . Since March 2021, more than 500 million doses of nOPV2 have been administered in outbreak responses in 23 countries, and the new vaccine ended a polio outbreak that left 34 children paralyzed in Tajikistan.…”

“…Since March 2021, more than 500 million doses of nOPV2 have been administered in outbreak responses in 23 countries, and the new vaccine ended a polio outbreak that left 34 children paralyzed in Tajikistan. 7 Based on the superior performance of nOPV2 in both preclinical and clinical trials 22,23,[26][27][28][29][30][31] , we developed new vaccine candidates for types 1 and 3 polioviruses by replacing the capsid coding region of nOPV2 with that of Sabin 1 and 3. These render vaccine candidates that preserve the antigenic and immunogenic characteristics of the Sabin 1 and 3 strains and increase their safety by stabilizing determinants of attenuation.…”