Highlight
– First-in-human, observer-masked phase 1 trial shows novel type 1 and type 3 oral poliovirus vaccines (nOPV1, nOPV3) are well tolerated in healthy adults.
– Immunogenicity (homotypic neutralising antibody responses) after a single dose was high (86–100% seroconversion for nOPV; 86–93% for mOPV); seroprotection at 28 days reached 100%.
– Faecal viral shedding kinetics and peak detection by PCR were similar between nOPV and Sabin monovalent OPV (mOPV); peak shedding reached 100% by PCR on day 8 in IPV recipients.
– Results support advancement of nOPV1 and nOPV3 into phase 2 trials, while further evaluation in children, immunocompromised hosts, and population-level genetic stability remains essential.
Background
Poliomyelitis eradication efforts have dramatically reduced global paralytic polio incidence, largely through widespread use of oral poliovirus vaccines (OPV) and inactivated poliovirus vaccine (IPV). However, rare but important safety challenges persist with live attenuated Sabin-strain OPVs: vaccine-associated paralytic poliomyelitis (VAPP) in recipients or close contacts and emergences of circulating vaccine-derived polioviruses (cVDPVs) when genetically unstable vaccine strains revert toward neurovirulence and sustain transmission in under-immunised populations. These residual risks motivated the development of next-generation, genetically stabilized novel OPV candidates (nOPV) engineered to reduce reversion risk while retaining the mucosal immunogenicity and ease of administration that underpin OPV’s outbreak-control advantages.
nOPV2 previously received emergency use listing for outbreak response under WHO guidance, and the current study reports first-in-human evaluation of nOPV1 and nOPV3—monovalent live attenuated candidates designed for types 1 and 3—with the stated intent to reduce risks of reversion to neurovirulence compared with Sabin-strain mOPVs.
Study design
This was a first-in-human, observer-masked, multicentre, phase 1 randomised controlled trial conducted at four sites in the USA (ClinicalTrials.gov NCT04529538). Key design elements:
– Population: Healthy adult volunteers stratified by prior polio vaccination history: participants who had received IPV only (IPV participants) and those with any OPV-containing regimen in their history (OPV participants).
– Randomisation: Block-randomised and stratified by site and vaccination history; observers were masked to allocation.
– Interventions and cohorts: IPV participants received a single dose of either nOPV1 or homotypic Sabin monovalent OPV1 (mOPV1) (cohort 1) or nOPV3 or mOPV3 (cohort 3). OPV-experienced participants received two doses 28 days apart of nOPV1 or mOPV1 (cohort 2) or nOPV3 or mOPV3 (cohort 4).
– Primary outcome: Safety among vaccinated participants, including solicited and unsolicited adverse events and serious adverse events (SAEs).
– Secondary outcomes: Homotypic serum neutralising antibody responses measured at baseline and 28 days after each dose in a per-protocol population; faecal viral shedding monitored up to 56 days mainly among IPV participants, assessed by PCR and culture.
– Sample size and enrollment: 377 screened, 226 randomised, and 205 participants received at least one dose: nOPV1 (n=70), mOPV1 (n=45), nOPV3 (n=54), mOPV3 (n=36).
Key findings
Safety
– No serious adverse events attributable to vaccination were observed across any groups.
– Most adverse events were mild; severe solicited events were uncommon and balanced across groups. Severe solicited events were mostly fatigue (1–4% across groups; none reported in mOPV1 group), with single severe events of nausea/vomiting (mOPV1) and abdominal pain (nOPV1).
– Severe unsolicited events within 28 days were rare: two participants (3%) in combined nOPV1 groups (one with severe fatigue, headache and myalgia; one with abdominal pain) and one participant (2%) in the mOPV1 groups (kidney infection). Investigators did not identify a pattern of vaccine-related SAEs.
Immunogenicity
– Baseline homotypic seroprotection (presumably neutralising antibody titres above protective thresholds) was nearly 100% in this adult cohort.
– At 28 days after the first dose, homotypic seroprotection reached 100% across groups.
– Homotypic seroconversion rates after a single dose were high and similar between nOPV and mOPV: for nOPV groups, rates ranged from 86% to 100%; for mOPV groups, from 86% to 93%.
– Results indicate that a single dose of either novel or Sabin monovalent OPV elicits robust boosting of neutralising antibodies in adults with prior immunity.
Viral shedding
– Faecal shedding profiles measured by PCR and (where reported) by culture were similar for nOPV and mOPV recipients.
– Among IPV participants, PCR-detected shedding peaked at 100% on day 8 post-dose across groups, indicating widespread intestinal replication sufficient for detection by molecular methods.
– The reported data do not indicate substantial differences in peak shedding rates or gross duration between nOPV and mOPV in this adult cohort.
Interpretation of results
– In healthy adults with high baseline immunity, nOPV1 and nOPV3 demonstrated comparable safety, immunogenicity, and shedding characteristics to conventional Sabin-strain monovalent OPV1 and OPV3.
– The absence of SAEs and the strong serologic responses support progression of these candidates to phase 2 studies where broader age groups and settings can be evaluated.
Expert commentary and context
Clinical and public health implications
– The primary public health rationale for nOPV development is to retain OPV’s capacity to induce intestinal immunity and interrupt transmission while reducing the probability of genetic reversion that leads to VAPP or cVDPV. Demonstrating comparable immunogenicity and shedding in adults is an essential first step; however, the populations most relevant to polio epidemiology and cVDPV risk are young children in low-immunity settings.
– High baseline seroprotection in this adult cohort limits assessment of primary immunogenicity; the trial effectively assessed boosting responses and short-term safety in previously primed adults. Observations in IPV-only adults are relevant for understanding mucosal replication and shedding when recipients lack prior live-mucosal exposure.
– Similar shedding rates by PCR do not directly equate to identical transmission risk; detailed comparisons of viral load by quantitative assays, culture positivity, duration of shedding, and sequencing to search for early reversion events are crucial for inferring population-level safety and cVDPV risk.
Mechanistic plausibility and prior experience
– nOPV candidates are engineered with stabilising changes in the 5′ untranslated region and other determinants that, in preclinical models, reduce the likelihood of reversion. A parallel precedent exists for nOPV2, which was deployed under emergency use listing after favourable safety and genetic stability data. Nevertheless, genetic behaviour at scale in varied epidemiological contexts must be monitored through environmental surveillance and molecular sequencing if nOPV1/3 are deployed more widely.
Limitations and remaining questions
– Study population: Healthy adults with near-universal baseline seroprotection are not representative of immunologically naive infants who will be the primary target for routine immunisation or outbreak response.
– Sample size and power: Phase 1 trials are designed for safety and immunogenicity signals, not to detect rare adverse events such as VAPP; larger phase 2/3 trials and post-licensure surveillance will be required.
– Shedding details: Reported shedding comparisons were summarized; quantitative viral loads, culture-positive proportions over time, and sequence-based assessments for reversion were not detailed in the summary and will be key endpoints in subsequent studies.
– Special populations: Immunocompromised hosts—who are at higher risk of prolonged shedding and potential evolution of vaccine-derived strains—require targeted evaluation.
Recommendations for next steps
– Proceed to phase 2 trials in children, including infants, in both IPV-primed and OPV-experienced populations to define primary immunogenicity, safety, and shedding kinetics in the epidemiologically critical age groups.
– Include longitudinal sequencing of shed virus and integration with environmental surveillance to evaluate genetic stability and reversion risk in real-world conditions.
– Plan studies that evaluate co-administration with routine childhood vaccines and performance in immunocompromised or malnourished populations where vaccine virus replication dynamics may differ.
Conclusion
This first-in-human phase 1 trial demonstrates that nOPV1 and nOPV3 are well tolerated in healthy adults and elicit robust homotypic neutralising antibody responses with shedding profiles similar to Sabin monovalent OPVs. These results support advancement to phase 2 testing, especially in infants and children, where the public health value of genetically stabilized OPV candidates would be greatest. Comprehensive downstream evaluation—particularly sequencing-based surveillance of shed virus, paediatric immunogenicity, and assessment in immunologically naive populations—will be required to determine whether nOPV1 and nOPV3 can meaningfully reduce the residual risks that complicate polio eradication.
Funding and trial registration
– Funded by the Bill & Melinda Gates Foundation.
– ClinicalTrials.gov registration: NCT04529538.
References
1. Mercer LD, Seña AC, Colgate ER, et al. Safety and immunogenicity of novel live attenuated type 1 and type 3 oral poliomyelitis vaccines in healthy adults in the USA: a first-in-human, observer-masked, multicentre, phase 1 randomised controlled trial. Lancet Infect Dis. 2025 Dec;25(12):1363-1376. doi:10.1016/S1473-3099(25)00285-3. PMID: 40818478; PMCID: PMC12630075.
2. World Health Organization. Polio vaccines: WHO position paper, March 2016. Weekly Epidemiol Rec. 2016;91(12):145–168. (WHO position papers summarise evidence about vaccine use and are available via WHO publications.)
3. Global Polio Eradication Initiative. What is vaccine-derived poliovirus (VDPV)? Available at: https://www.gpei.org (accessed November 2025). (GPEI provides up-to-date surveillance data and programmatic context for OPV and cVDPV risk.)
4. World Health Organization. Emergency Use Listing Procedure for nOPV2 and subsequent guidance on novel OPV use. Available at: https://www.who.int (accessed November 2025). (WHO guidance documents on nOPV2 provide precedents for regulatory and surveillance requirements relevant to other nOPV candidates.)