First-in-human, phase 1, randomized, observer-blind, controlled trial to assess the safety and immunogenicity of novel live attenuated type 1 and type 3 oral poliomyelitis vaccines in healthy adults

BackgroundReducing the risks of vaccine-derived polioviruses and vaccine-associated paralytic poliomyelitis from type 1 or 3 Sabin-strain oral poliovirus vaccines (OPVs) motivated the development of novel type 1 and 3 OPVs (nOPV1, nOPV3), designed to have similar safety and immunogenicity and improved genetic stability to reduce risk of reversion to neurovirulence. In this first-in-human trial, we assessed safety and immunogenicity of nOPV1 and nOPV3 in healthy adults. MethodsWe conducted a multi-site, randomized, observer-blind, controlled trial in healthy adults in the United States. Participants were stratified according to poliovirus vaccination history (exclusive inactivated polio vaccine [IPV] or including OPV) and randomized to receive either nOPV or homotypic Sabin-strain monovalent OPV (mOPV); IPV participants received a single dose and OPV participants received two doses. The primary objective was to assess safety measured by adverse events. The secondary objectives were to assess serum neutralizing antibody responses measured before and 28 days after each dose and fecal viral shedding assessed up to 56 days post-first dose. This study was registered with ClinicalTrials.gov, NCT04529538. FindingsBetween May 2021 and February 2023, 205 healthy adults were enrolled and received at least one dose: 70 nOPV1, 45 mOPV1, 56 nOPV3, and 38 mOPV3. Most events were mild, severe events were rare, and solicited events were balanced. Homotypic seroprotection was nearly 100% at baseline and was 100% after the first dose. Homotypic seroconversion rates after a single dose were high and similar for nOPV and mOPV (from 86 to 100%), with no statistically significant differences. Similar rates of viral shedding were observed among participants receiving nOPV or mOPV. InterpretationBoth nOPV1 and nOPV3 were well tolerated and demonstrated similar immunogenicity and shedding profiles to mOPV1 and mOPV3, respectively, supporting progression to phase 2 studies. nOPVs may be an important tool for achieving eradication of poliovirus. FundingGates Foundation. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSSabin-strain vaccine-derived polio virus (cVDPVs) and vaccine-associated paralytic polio (VAPP) are now a substantial proportion of paralytic poliomyelitis worldwide. To reduce the seeding of type 2 cVDPVs (cVDPV2), a more genetically stable novel oral polio vaccine (nOPV2) was developed to control outbreaks. WHO granted use under emergency use listing (EUL) in 2020 and prequalified the vaccine in 2023. More than one billion doses have been distributed since March 2021, with surveillance data demonstrating a promising safety and effectiveness profile. Sabin-strain types 1 and 3 present similar risks for cVDPVs and VAPP. In pre-clinical studies chimeric viruses with nOPV2s non-structural regions, including changes to the RNA sequence in the 5 untranslated region, the non-structural protein 2C, and the polymerase 3D, coupled with the coding region for the type-specific Sabin-strain capsid proteins have demonstrated similar immunogenicity, antigenicity, and lower neurovirulence compared to Sabin. Added value of this studyThis first-in-human trial includes safety and immunogenicity data in adults with a history of either exclusive inactivated polio vaccine (IPV) or prior exposure to OPV. We found that nOPV1 and nOPV3 are safe, well tolerated, and induce similar immunogenicity to their Sabin controls. The magnitude and durations of nOPV shedding was not higher than Sabin controls. We also observed induction of mucosal immunity, evidenced by reduced viral shedding post second vaccination. Implications of all the available evidenceThe successful deployment of nOPV2 to combat cVDPV2s previously demonstrated that use of such novel vaccines can be effective in the control of cVDPV outbreaks after the cessation of Sabin-strain types 1 and 3. nOPVs can thus support the polio endgame strategy by providing outbreak response vaccines less likely to be associated with VAPP and seeding of new cVDPVs. The safety and immunogenicity evidence generated for nOPV1 and nOPV3 in this phase 1 clinical study were sufficiently strong to justify phase 2 studies in geographically relevant target populations of previously vaccinated children and infants, as well as vaccine naive neonates.