Development of a new oral poliovirus vaccine for the eradication end game using codon deoptimization

Abstract

Enormous progress has been made in global efforts to eradicate poliovirus, using live-attenuated Sabin oral poliovirus vaccine (OPV). However, as the incidence of disease due to wild poliovirus has declined, vaccine-derived poliovirus (VDPV) has emerged in areas of low-vaccine coverage. Coordinated global cessation of routine, type 2 Sabin OPV (OPV2) use has not resulted in fewer VDPV outbreaks, and continued OPV use in outbreak-response campaigns has seeded new emergences in low-coverage areas. The limitations of existing vaccines and current eradication challenges warranted development of more genetically stable OPV strains, most urgently for OPV2. Here, we report using codon deoptimization to further attenuate Sabin OPV2 by changing preferred codons across the capsid to non-preferred, synonymous codons. Additional modifications to the 5′ untranslated region stabilized known virulence determinants. Testing of this codon-deoptimized new OPV2 candidate (nOPV2-CD) in cell and animal models demonstrated that nOPV2-CD is highly attenuated, grows sufficiently for vaccine manufacture, is antigenically indistinguishable from Sabin OPV2, induces neutralizing antibodies as effectively as Sabin OPV2, and unlike Sabin OPV2 is genetically stable and maintains an attenuation phenotype. In-human clinical trials of nOPV2-CD are ongoing, with potential for nOPV strains to serve as critical vaccine tools for achieving and maintaining polio eradication.npj Vaccines (2020) 5:26 ; https://doi.

Safety and immunogenicity of two novel type 2 oral poliovirus vaccine candidates compared with a monovalent type 2 oral poliovirus vaccine in children and infants: two clinical trials

“…Both candidates have been engineered to improve the genetic stability of the attenuation sites of the poliovirus and so minimise the risk of reversion to neurovirulence. 11,12 Safety and immunogenicity of both candidates shown in a phase 1 study in adults, done in strict containment conditions to avoid possible environmental contamination with the novel viruses, 13 has been confirmed by a larger non-contained study in adults. 14 Both studies also provided a preliminary assessment of the genetic stability in virus shed in stools, sufficient to pave the way for the present study in children and infants.…”

“…Both candidate strains included different combinations of five distinct modifications of the Sabin-2 genome, including changes to the RNA sequence in the 5′ untranslated region of polio genome, the capsid protein coding region (P1), the non-structural protein 2C, and the polymerase 3D. 11 , 12 Only changes to polymerase 3D result in a change in the amino acid sequence. Each novel OPV2 candidate was administered as either a low dose in two drops (0·1 mL) containing 10 5 CCID 50 in infants using a supplied dropper, or a high dose containing 10 6 CCID 50 administered as 20 drops (1·0 mL) measured from a syringe to infants and children.…”

“…10 A consortium established to ensure the development and research of such poliovirus vaccines has produced two candidates, novel OPV2-c1 and novel OPV2-c2, with further genetic modifications introduced to enhance the stability of the Sabin attenuations and substantially mitigate the risk of reversion to neurovirulence while maintaining immunogenicity. 11,12 Our previously re ported phase 1 study showed the safety, immunogenicity, shedding, and stability of both novel OPV2 candidates in healthy adults, in conditions of biological containment. 13 Following the preliminary assessment, and confir mation in larger adult studies of the safety of monovalent OPV2 and both novel OPV2 candidates, 14 we did the present studies to confirm their safety and immuno genicity in fully immunised young children and in infants.…”

Engineering the Live-Attenuated Polio Vaccine to Prevent Reversion to Virulence

“…Candidate vaccines that incorporate design elements coming from the molecular and epidemiological understanding of virus biology, such as the nOPV2 developed here and other alternative vaccine candidate designs developed in the context of our Bill and Melinda Gate Foundation Consortium ( Konopka-Anstadt et al, 2020 ), should be a game-changer in the efforts to contribute to the complete and permanent global eradication of poliovirus type 2. Application of similar knowledge-based strategies to vaccine design should also enable us to rationally design live-attenuated vaccines for other polio-serotypes as well as related emerging pathogenic enteroviruses, including enterovirus D68 (EV-D68) and enterovirus A71 (EV-A71).…”

Case of Poliomyelitis Caused by Significantly Diverged Derivative of the Poliovirus Type 3 Vaccine Sabin Strain Circulating in the Orphanage

“…Consequently, urgent completion of work on a new and improved vaccine is needed, aimed at creating not only humoral, but also mucosal immunity, on the one hand, that is safer than Sabin strains on the other hand. Investigations in this direction are being actively carried out by several research groups [53][54][55][56]. Switching exclusively to IPV, in a situation wherein the possibility of introducing any type of Sabin-related viruses and their further spread and transformation into VDPVs is not completely ruled out, can lead to a disaster.…”