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Review 1: "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 The comparator arm uses a vaccine that is obsolete and not currently recommended.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 1: "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:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: In response to COVID-19 and future emerging infectious diseases, accelerating vaccine development and improving access and equity are crucial. The develop and evaluation of NDV-HXP-S vaccine demonstrate a potential platform and technical reserve for this objective, which can be worldwide manufactured at low production cost in embryonated chicken eggs (including low- and middle-income countries), and stored at 2~8℃ for years. The NDV-HXP-S vaccine uses the Newcastle disease virus as its viral vector, which can be present in live or inactivated forms. The vaccine had been separately evaluated for its safety profile and immunogenicity in Thailand, Brazil, the United States, Mexico and Vietnam, some of the studies had been reported (EClinicalMedicine. 2022 Mar 8;45:101323; NPJ Vaccines. 2023 May 10;8(1):67; Vaccine. 2022 Jun 9;40(26):3621-3632). However, the relevant findings have NOT been comprehensively discussed in this manuscript.

The current study was conducted from August 11, 2021 to March 11, 2022, and partly coincided with the Delta and Omicron variant epidemics in Vietnam. The immunity induced by SARS-CoV-2 infection should have a significant impact on the assessment of immunogenicity. It is noteworthy that, in the COVIVAC and AstraZeneca vaccine group, the PNA antibody GMTs in six months after second dose were unusually high compared to the level of 14 days after second dose, especially among the participants aged 18-59 years (Figure 2, Supplement Table 4). Paired comparison of antibody titer, especially between D43 and D197, should be assessed to find extreme outliers (abnormal rising of antibody level which indicate possible unnoticed infection during the period). Furthermore, a post-hoc sensitivity analysis, excluding extreme outliers, is strong recommended to show the antibody dynamics.

A wealth of evidence indicated that the ongoing evolution of SARS-CoV-2 variants, especially Omicron sub-lineages, had led to a rapid decline in the effectiveness of marketed COVID-19 vaccines. As mentioned by the authors in the manuscript, vaccines containing ancestral spike antigens are now considered obsolete. While this study found that the point values of PNA antibodies (for Wuhan-Hu-1 strain) induced by COVIVAC were higher than that induced by the AstraZeneca vaccine, it offers limited information for evaluating the value of this vaccine during the pandemic of JN.1 strain. Additionally, another study (Sci Transl Med. 2023 Feb 15;15(683):eabo2847) indicated that, for the wild type (USA-WA01/2020), neutralizing activities of NDV-HXP-S were higher or comparable than that of BNT162b2. However, for Delta or Beta strains, neutralizing activities of NDV-HXP-S were lower than that of BNT162b2.

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