Inactivated egg-based vaccine against Newcastle disease virus expressing SARS-CoV-2 spike protein

The coronavirus-2 severe acute respiratory syndrome virus (SARS-CoV-2) is the causative agent of the coronavirus disease-2019 (COVID-19) pandemic and has already claimed more than 4.73 million lives in the world. Immunization programs have started in many countries, but low- and middle-income countries (LMICs) are still short of available vaccine doses.

Study: Safety and Immunogenicity of an Inactivated Recombinant Newcastle Disease Virus Vaccine Expressing the SARS-CoV-2 Peak: Interim Results of a Phase 1/2 Randomized, Placebo-Controlled Trial. Image Credit: creativeneko / Shutterstock

It is imperative to produce good quality and affordable vaccines in LMICs. NDV-HXP-S is one such inactivated egg-based vaccine against Newcastle disease virus expressing the SARS-CoV-2 spike protein and is under development in Thailand, Vietnam and in Brazil.

A new study presents the first results of a phase 1/2 randomized, placebo-controlled trial in Thailand. A pre-printed version of the study is available on the website medRxiv* server while the article is subject to peer review.

Background

There is an imbalance in the global distribution of COVID-19 vaccines. A sustainable increase in the supply of vaccines in LMICs must be achieved if the pandemic is to be contained. The manufacturing capacity of inactivated egg-based influenza vaccines (IVVs) is one of the largest in the world. Some of these facilities operate less than half the year and use embryonated eggs to make more than a billion doses per year of affordable human vaccines.

To use these facilities, scientists have developed a COVID-19 vaccine for egg production. This vaccine is based on a Newcastle disease virus (NDV) expressing the ectodomain of a new spike protein construct SARS-CoV-2 stabilized by pre-fusion and anchored in the membrane (NDV-HXP-S). Between September and November 2020, manufacturers in Thailand, Vietnam and Brazil changed their IIV manufacturing process and achieved high yields.

A new study

Scientists evaluated a range of vaccine doses (1 µg, 3 µg, 10 µg) with potency quantified in µg of SARS-CoV-2 spike protein anchored in the viral envelope. Doses were evaluated in formulations with and without the TLR-9 agonist CpG1018 as an adjuvant to the vaccine.

The researchers observed that more than four weeks after vaccination, all formulations were very well tolerated with slight pain and tenderness at the injection site. Initial analysis of the clinical data did not raise any safety concerns, and the vaccine was strongly immunogenic in one formulation and in a dose-dependent manner. However, it was noted that the adjuvant benefit was uncertain about the limited precision of the small sample size.

Regardless of the dose level, the neutralizing antibodies elicited by the vaccine against two variants of concern (VoC), namely, B.1.351 and P.1. B.1.351, is currently considered the worst case of immune evasion. The researchers observed that antibody titers decreased modestly against P.1 and more markedly against B.1.351, and this reduction depended on the test used. This result was expected and consistent with the range observed with the sera of recipients of the BNT162b2 and mRNA-1273 vaccines.

NDV-HXP-S is expected to have neutralizing activity against the widely circulating delta variant (B.1.617.2). The T cell response showed a bias towards a TH1 response, thereby alleviating concerns about the increased disease associated with a TH2 response. The first results are promising and suggest that the memory of T lymphocytes induced by the vaccine is capable of antiviral response.

Strengths and limitations

The study has strengths that should be highlighted. Vaccine construction presents a new platform. It expresses the stabilized S protein before fusion (generation 2) in a membrane-bound trimeric conformation. The researchers hypothesize that these characteristics confer significant immunogenicity, even without the adjuvant CpG1018. They compared the induction of neutralizing and anti-S binding antibodies to average levels in convalescent human serum and found the former to be higher (dose dependent).

Although the preliminary results are encouraging, the study has several limitations. The main limitation was the small sample size which limited the precision of the estimates. Ratings were limited to 43 days for immunogenicity and 57 days for reactogenicity and safety, which meant researchers were only forced to consider acute results. There are other challenges in conducting Phase 1 trials and analyzing data in the midst of a pandemic scenario. Still, the researchers wanted to publish the data as soon as clinical trials with similar vaccines were underway in Vietnam (NCT04830800) and Brazil (NCT04993209).

Conclusion

The mean anti-S IgG ELISA vaccine responses normalized to the mean in convalescent sera suggest that NDV-HXP-S vaccine will have significant clinical benefit. The vaccine can be produced at low cost in LMICs and could help resolve the global imbalance in vaccine availability.

Based on the promising results and recognizing the importance of maximizing vaccine dose production, the 3 µg and 3 µg + CpG1018 formulations were selected for further evaluation in Phase 2 of the ongoing clinical trial.

In future studies, scientists want to compare the NDV-HXP-S vaccine to a licensed comparator, which will allow them to derive evidence of relative immunogenicity.

*Important Notice

medRxiv publishes preliminary scientific reports which are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behavior, or treated as established information.