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Review 2: "Safety and Immunogenicity of an Inactivated Recombinant Newcastle Disease Virus Vaccine Expressing SARS-CoV-2 Spike: A Randomised, Comparator-Controlled, Phase 2 Trial"

The reviewers express important concern. Among them, they point out that the main outcome reported in the paper is not the same one that was pre-registered. The comparator arm uses a vaccine that is obsolete and not currently recommended.

Published onJun 04, 2024
Review 2: "Safety and Immunogenicity of an Inactivated Recombinant Newcastle Disease Virus Vaccine Expressing SARS-CoV-2 Spike: A Randomised, Comparator-Controlled, Phase 2 Trial"
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key-enterThis Pub is a Review of
Safety and Immunogenicity of an Inactivated Recombinant Newcastle Disease Virus Vaccine Expressing SARS-CoV-2 Spike: A Randomised, Comparator-Controlled, Phase 2 Trial
Safety and Immunogenicity of an Inactivated Recombinant Newcastle Disease Virus Vaccine Expressing SARS-CoV-2 Spike: A Randomised, Comparator-Controlled, Phase 2 Trial
Description

Summary Background Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and lower-middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A public sector manufacturer in Vietnam assessed the immunogenicity of NDV-HXP-S (COVIVAC) relative to an authorized vaccine.Methods This phase 2 stage of a randomised, observer-blind, controlled, phase 1/2 trial was conducted at three community health centers in Thai Binh Province, Vietnam. Healthy males and non-pregnant females, 18 years of age and older, were eligible. Participants were randomised by age (18-59, ≥60 years) to receive one of three treatments by intramuscular injection twice, 28 days apart: COVIVAC at 3 µg or 6 µg, or AstraZeneca COVID-19 vaccine VAXZEVRIA. Participants and personnel assessing outcomes were masked to treatment. The main outcome was the induction of 50% neutralising antibody titers against vaccine-homologous pseudotyped virus 14 days (day 43) and 6 months (day 197) after the second vaccination by age group. The primary immunogenicity and safety analyses included all participants who received one dose of the vaccine. ClinicalTrials.govNCT05940194.Findings During August 10-23, 2021, 737 individuals were screened, and 374 were randomised (124-125 per group); all received dose one, and three missed dose two. On day 43, the geometric mean fold rise of 50% neutralising antibody titers for subjects age 18-59 years was 31·20 (COVIVAC 3 μg N=82, 95% CI 25·14-38·74), 35·80 (COVIVAC 6 μg; N=83, 95% CI 29·03-44·15), 18·85 (VAXZEVRIA; N=82, 95% CI 15·10-23·54), and for subjects age ≥60 years was 37·27 (COVIVAC 3 μg; N=42, 95% CI 27·43-50·63), 50·10 (COVIVAC 6 μg; N=40, 95% CI 35·46-70·76), 16·11 (VAXZEVRIA; N=40, 95% CI 11·73-22·13). Among subjects seronegative for anti-S IgG at baseline, the day 43 geometric mean titer ratio of neutralising antibody (COVIVC 6 μg/VAXZEVRIA) was 1·77 (95% CI 1·30-2·40) for subjects age 18-59 years and 3·24 (95% CI 1·98-5·32) for subjects age ≥60 years. On day 197, the age-specific ratios were 1·11 (95% CI 0·51-2·43) and 2·32 (0·69-7·85). Vaccines were well tolerated; reactogenicity was predominantly mild and transient. The percentage of subjects with unsolicited adverse events (AEs) during 28 days after vaccinations was similar among treatments (COVIVAC 3 μg 29·0%, COVIVAC 6 μg 23·2%, VAXZEVRIA 31·2%); no vaccine-related AE was reported.Interpretation Considering that induction of neutralising antibodies against SARS-CoV-2 has been correlated with the efficacy of COVID-19 vaccines, including VAXZEVRIA, our results suggest that vaccination with COVIVAC may afford clinical benefit matching or exceeding that of the VAXZEVRIA vaccine.Funding Vietnam’s Institute of Vaccines and Medical Biologicals (including support from Vietnam’s national COVID-19 vaccine fund and a charitable contribution from the Thien Tam fund of Vin group), Coalition for Epidemic Preparedness Innovations, a charitable contribution from Bayer AG, US National Institutes of Health.

RR:C19 Evidence Scale rating by reviewer:

  • Misleading. Serious flaws and errors in the methods and data render the study conclusions misinformative. The results and conclusions of the ideal study are at least as likely to conclude the opposite of its results and conclusions than agree. Decision-makers should not consider this evidence in any decision.

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Review: This is an interesting study reporting the results of an initial phase I/II trial of a recombinant vaccine for COVID-19 conducted in Vietnam in August of 2021. Unfortunately, the results at this point are of limited utility, given that the circulating strain of virus is completely different at this time and the fact that the comparator vaccine has been discontinued from the market and was demonstrated to be inferior to other available vaccines. It is not at all clear why there has been a 3 year delay to submit these results for publication on a preprint server?

In addition, the study overstates the results of the intended analysis. The registered study design clearly lists the safety outcomes as primary and all other immunologic outcomes as secondary outcomes. The study was clearly not designed a priori to evaluate superiority and should not be presented as such. The secondary objectives were clearly noted as exploratory and the manuscript should more clearly reflect that. The abstract currently says that the main outcome was the induction of 50% neutralizing antibody – which is clearly not the primary outcome listed in the trial registration.

Additional comments below:

  • The abstract should include dates of study, inclusion and exclusion criteria, more clearly align with a priori registered analysis plan.

  • Line 88-889 suggests that the study aimed to demonstrate superiority – this was not clearly noted in the registration of the analysis plan – remove.

  • Inclusion and exclusion criteria must be included in the manuscript.

  • It is not clear if participants received prior covid vaccines? If so, this should be noted and included in table one by arm (number, type and time since prior vaccination).

  • Line 134 – please reference assay validation documentation.

  • NOTE – line 203-204 suggests that the analysis of immunogenicity included seropositive subjects. Please document the number of participants in each arm with evidence of seropositivity at baseline. This is potentially problematic as it is possible that participants who developed infection during the study would have demonstrated increased evidence of immunogenicity as a result of infection, not vaccination, and if the number of seropositive individuals differed by arm at baseline, then the likelihood of infection would also differ.

  • The authors note that the funders had no role in the data collection, analysis or manuscript writing – yet there are authors included from the funding agency. Please clarify.

  • The cellular immunity data are not well described – please add to the presentation of results and discussion.

  • The discussion overstates the findings of this study (as noted above) based on the a priori defined statistical analysis plan.

  • Data access not in line with international requirements or standards.

Comments
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