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 Genetic variants were evaluated to assess which were important to ensure nOPV2 quality. The cDNA preparation and NGS method was validated through evaluating mixtures of Sabin-2 and nOPV2. Pre-specified validation criteria for linearity and precision were met at all positions. The method was assessed to be fit-for-purpose for vaccine lot release. Understanding the co-location of genetic variants was important to interpret NGS results.
Vaccination with Sabin, a live attenuated oral polio vaccine (OPV), results in robust intestinal and humoral immunity and has been key to controlling poliomyelitis. As with any RNA virus, OPV evolves rapidly to lose attenuating determinants critical to the reacquisition of virulence1–3 resulting in vaccine-derived, virulent poliovirus variants. Circulation of these variants within underimmunized populations leads to further evolution of circulating, vaccine-derived poliovirus with higher transmission capacity, representing a significant risk of polio re-emergence. A new type 2 OPV (nOPV2), with promising clinical data on genetic stability and immunogenicity, recently received authorization from the World Health Organization for use in response to circulating, vaccine-derived poliovirus outbreaks. Here we report the development of two additional live attenuated vaccine candidates against type 1 and 3 polioviruses. The candidates were generated by replacing the capsid coding region of nOPV2 with that from Sabin 1 or 3. These chimeric viruses show growth phenotypes similar to nOPV2 and immunogenicity comparable to their parental Sabin strains, but are more attenuated. Our experiments in mice and deep sequencing analysis confirmed that the candidates remain attenuated and preserve all the documented nOPV2 characteristics concerning genetic stability following accelerated virus evolution. Importantly, these vaccine candidates are highly immunogenic in mice as monovalent and multivalent formulations and may contribute to poliovirus eradication.
Poliovirus serotype 2 (PV2) has been declared eradicated and was removed from the live vaccine programme in 2016. WHO have developed the Global Action Plan (GAPIII) to describe containment conditions for laboratory work with poliovirus after eradication, and in the UK, all PV2 has been reclassified to hazard group 3 (HG3). Laboratory work involving live poliovirus will continue to be required years after eradication for the purposes of: vaccine testing; environmental surveillance; immunoglobulin testing; and for the development of new public health interventions. Compliance with GAPIII and HG3 containment conditions would impose financial burden and failure would lead to disruption to essential activities. Development of safer poliovirus strains for use outside of containment could overcome these issues. The S19 poliovirus strain, designed to be hyperattenuated and extremely genetically stable, was used as a cassette for the introduction of capsid proteins of other strains and serotypes (Knowlson et al. 2015), originally for vaccine production. S19 viruses are unable to infect transgenic mice (by intraspinal inoculation) or non-human primates (by mouth) at very high doses and are unlikely to infect humans at biological temperature. PV2 S19 strains have recently been approved for use outside of GAPIII containment requirements by the Containment Advisory Group. Validation of strains for laboratory assays and a highly sensitive QC assay based on NGS will be described.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.