The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus is the causal agent of the coronavirus disease-2019 (COVID-19) pandemic and has already claimed more than 4.73 million lives worldwide. Vaccination programs have begun in many countries, but low- and middle-income countries (LMICs) are still lacking in the availability of vaccine doses.

Study: Safety and Immunogenicity of an Inactivated Recombinant Newcastle Disease Virus Vaccine Expressing SARS-CoV-2 Spike: Interim Results of a Randomised, Placebo-Controlled, Phase 1/2 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 Newcastle disease virus vaccine expressing the spike protein of SARS-CoV-2 and is being developed in Thailand, Vietnam, and Brazil.

A new study presents initial results from a randomized, placebo-controlled phase 1/2 trial in Thailand. A preprint version of the study is available on the medRxiv* server while the article undergoes peer review.

Background

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

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

A new study

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

Researchers observed that over four weeks after vaccination, all formulations were very well-tolerated with mild injection site pain and tenderness. Initial analysis of the clinical data raised no safety concerns, and the vaccine was strongly immunogenic in a formulation and dose-dependent manner. However, it was noted that the adjuvant benefit was uncertain as to the small sample size limited precision

Irrespective of the dose level, the vaccine-elicited neutralizing antibodies against two variants of concern (VoC), namely, B.1.351 and P.1. B.1.351 variant, is currently regarded as the worst-case example of immune evasion. Researchers observed that antibody titers decreased modestly against P.1 and more markedly against B.1.351, and this reduction depended on the assay used. This result was expected and in line with the range observed with sera from recipients of the vaccines BNT162b2 and mRNA-1273.

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

Strengths and limitations

The study has some key strengths that should be highlighted. The vaccine construct presents a novel platform. It expresses pre-fusion stabilized S-protein (generation 2) in a membrane-bound trimeric conformation. Researchers hypothesize that these features impart notable immunogenicity, even without the CpG1018 adjuvant. They contrasted the induction of anti-S binding and neutralizing antibodies with mean levels in human convalescent serum and found the former superior (dose-dependent).

Although the preliminary findings are encouraging, the study has several limitations. The key limitation was the small sample size that limited the precision of estimates. Evaluations were limited to 43 days for immunogenicity and 57 days for reactogenicity and safety, which meant that researchers were only constrained to considering acute outcomes. There are other difficulties of conducting phase 1 trials and analyzing data in the middle of a pandemic scenario. Still, researchers wanted to publish the data early as clinical trials with similar vaccines are underway in Vietnam (NCT04830800) and Brazil (NCT04993209).

Conclusion

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

Based on the promising results and acknowledging the importance of maximizing the output of vaccine doses, the 3 µg and 3 µg+CpG1018 formulations were selected for further assessment in the phase 2 stage of the ongoing clinical trial.

In future studies, scientists wish to contrast the NDV-HXP-S vaccine to an authorized comparator, which will enable them to derive the relative immunogenicity evidence.

*Important Notice

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