Safety of the novel oral poliovirus vaccine type 2 (nOPV2) in infants and young children aged 1 to <5 years and lot-to-lot consistency of the immune response to nOPV2 in infants in The Gambia: a phase 3, double-blind, randomised controlled trial

Abstract

Background: Novel oral poliovirus vaccine type 2 (nOPV2) has been engineered to improve the genetic stability of Sabin oral poliovirus vaccine (OPV) and reduce the emergence of circulating vaccine-derived polioviruses. This trial aimed to provide key safety and immunogenicity data required for nOPV2 licensure and WHO prequalification.

Methods: This phase 3 trial recruited infants aged 18 to <52 weeks and young children aged 1 to <5 years in The Gambia. Infants randomly assigned to receive one or two doses of one of three lots of nOPV2 or one lot of bivalent OPV (bOPV). Young children were randomised to receive two doses of nOPV2 lot 1 or bOPV. The primary immunogenicity objective was to assess lot-to-lot equivalence of the three nOPV2 lots based on one-dose type 2 poliovirus neutralising antibody seroconversion rates in infants. Equivalence was declared if the 95% CI for the three pairwise rate differences was within the -10% to 10% equivalence margin. Tolerability and safety were assessed based on the rates of solicited adverse events to 7 days, unsolicited adverse events to 28 days, and serious adverse events to 3 months post-dose. Stool poliovirus excretion was examined. The trial was registered as PACTR202010705577776 and is completed.

Findings: Between February and October, 2021, 2345 infants and 600 young children were vaccinated. 2272 (96·9%) were eligible for inclusion in the post-dose one per-protocol population. Seroconversion rates ranged from 48·9% to 49·2% across the three lots. The minimum lower bound of the 95% CIs for the pairwise differences in seroconversion rates between lots was -5·8%. The maximum upper bound was 5·4%. Equivalence was therefore shown. Of those seronegative at baseline, 143 (85·6%) of 167 (95% CI 79·4-90·6) infants and 54 (83·1%) of 65 (71·7-91·2) young children seroconverted over the two-dose nOPV2 schedule. The post-two-dose seroprotection rates, including participants who were both seronegative and seropositive at baseline, were 604 (92·9%) of 650 (95% CI 90·7-94·8) in infants and 276 (95·5%) of 289 (92·4-97·6) in young children. No safety concerns were identified. 7 days post-dose one, 78 (41·7%) of 187 (95% CI 34·6-49·1) infants were excreting the type 2 poliovirus.

Interpretation: nOPV2 was immunogenic and safe in infants and young children in The Gambia. The data support the licensure and WHO prequalification of nOPV2.

Funding: Bill & Melinda Gates Foundation.

Figure 1

Trial profile (A) Infants trial profile. (B) Young children trial profile. All young children randomly assigned to nOPV2 received lot 1 of the vaccine. bOPV=bivalent oral poliovirus vaccine. nOPV2=novel oral poliovirus vaccine type 2.

Figure 2

Poliovirus type 2 serum neutralising antibody seroprotection rates, geometric mean titres, and seroconversion rates in infants and young children (A) Infant seroprotection rates and geometric mean poliovirus type 2 neutralising antibody concentrations. (B) Infant post-dose one and post-dose two overall seroconversion rates and seroconversion rates in baseline seronegative and baseline seropositive infants. (C) Young children seroprotection rates and geometric mean poliovirus type 2 neutralising antibody concentrations. (D) Young children post-dose one and post-dose two overall seroconversion rates and seroconversion rates in baseline seronegative and baseline seropositive young children. Solid bars indicate seroprotection or seroconversion rates (left axis). Lines represent geometric mean type 2 serum neutralising antibody titres (right axis). Geometric mean titres and 95% CIs are estimated via the maximum likelihood based on survival methods including censoring at the lower limit of quantification and upper limit of quantification when appropriate. Seroprotection is defined as the percentage of participants with a reciprocal serum neutralising antibody titre of 8 or higher. Seroconversion (baseline seronegative) is defined as the percentage of participants with a post-dose reciprocal serum neutralising antibody titre of 8 or higher among those participants with a baseline reciprocal serum neutralising antibody titre of less than 8. Seroconversion (baseline seropositive) is defined as the percentage of participants with a post-dose four-fold rise in reciprocal serum neutralising antibody titres among those with a baseline reciprocal serum neutralising antibody titre of 8 or higher. This includes only those participants in whom a four-fold rise in reciprocal neutralising antibody titres was evaluable based on the baseline titre and upper limit of quantification for the assay. Seroconversion overall combined the seronegative and seropositive participants undergoing seroconversion. Exact Clopper-Pearson CIs are provided for seroprotection and seroconversion rates.