Two nOPV2 vaccine candidates have been developed as attenuated serotype 2 polioviruses derived from a modified Sabin 2 infectious complementary deoxyribonucleic acid (cDNA) clone. nOPV2 Candidate 1 (S2/cre5/S15domV/rec1/hifi3) and nOPV2 Candidate 2 (S2/S15domV/CpG40) were generated by modifying the Sabin-2 ribonucleic acid (RNA) sequence to improve phenotypic stability and make the strains less prone to reversion to virulence.
Due to the withdrawal of Sabin monovalent oral polio vaccine type 2 (mOPV2) and prohibition of its use from April 2016 onwards, well before the availability of nOPV2 for clinical testing, Phase 4 trials have been conducted with Sabin mOPV2 to provide control data on safety, immunogenicity, against which data for nOPV2 in subsequent Phase I and II studies will be evaluated and compared. The Phase 4 trials of Sabin mOPV2 were designed to parallel the expected design of Phase 1 and 2 nOPV2 studies with respect to the overall design, the inclusion of similar study cohorts. As for these reasons head to head comparison of nOPV2 and mOPV2 is not possible, the overall clinical development plan with the Phase I and II studies was designed taking into consideration the unique situation of OPV2 cessation in April 2016, and the global public health need of a vaccine with lower risk of vaccine-associated paralytic poliomyelitis (VAPP) and vaccine-derived type-2 poliovirus (cVDPV2) (VDPV2) for outbreak response in the post-cessation era.
This first-in-human phase 1 study is designed to evaluate in contained conditions the safety, immunogenicity, shedding, and genetic stability of both nOPV2 vaccine candidates in IPV-primed adults before testing in a larger adult and adolescent (> 15 y of age) population, and then in young children and infants.
This Phase 1 study will include 30 IPV-only vaccinated adults to be vaccinated with the study vaccines (15 subjects per candidate vaccine) and followed in contained conditions (28 days) to obtain safety, immunogenicity, shedding, and genetic stability data relevant to the decision to advance to future studies with testing in un-contained conditions.
Participants were isolated in a purpose-built containment facility named Poliopolis at the University of Antwerp Hospital (Antwerp, Belgium), to minimize the risk of environmental release of the novel OPV2 candidates. Volunteers were enrolled sequentially in two groups, with each group receiving one of the two vaccine candidates, to avoid cross-contamination, after which they were confined to Poliopolis for 28 days, with further monitoring until the end of shedding. A final safety follow-up call (for those no longer shedding) or visit (for those still shedding) was made 42 days after vaccine administration.
Findings
On July 13, 2019, The Lancet published the findings of the clinical trial.
Between May 22 and Aug 22, 2017, 48 volunteers were screened, of whom 15 (31%) volunteers were excluded for reasons relating to the inclusion or exclusion criteria, three (6%) volunteers were not treated because of restrictions to the number of participants in each group, and 30 (63%) volunteers were sequentially allocated to groups (15 participants per group). Both novel OPV2 candidates were immunogenic and increased the median blood titre of serum neutralising antibodies; all participants were seroprotected after vaccination. Both candidates had acceptable tolerability, and no serious adverse events occurred during the study. However, severe events were reported in six (40%) participants receiving candidate 1 (eight events) and nine (60%) participants receiving candidate 2 (12 events); most of these events were increased blood creatinine phosphokinase but were not accompanied by clinical signs or symptoms. Vaccine virus was detected in the stools of 15 (100%) participants receiving vaccine candidate 1 and 13 (87%) participants receiving vaccine candidate 2. Vaccine poliovirus shedding stopped at a median of 23 days (IQR 15-36) after candidate 1 administration and 12 days (1-23) after candidate 2 administration. Total shedding, described by the estimated median shedding index (50% cell culture infective dose/g), was observed to be greater with candidate 1 than candidate 2 across all participants (2·8 [95% CI 1·8-3·5] vs 1·0 [0·7-1·6]). Reversion to neurovirulence, assessed as paralysis of transgenic mice, was low in isolates from those vaccinated with both candidates, and sequencing of shed virus indicated that there was no loss of attenuation in domain V of the 5'-untranslated region, the primary site of reversion in Sabin OPV.
Interpretation: We found that the novel OPV2 candidates were safe and immunogenic in IPV-immunised adults, and our data support the further development of these vaccines to potentially be used for maintaining global eradication of neurovirulent type-2 polioviruses.