Next-generation COVID-19 vaccine provides robust immunity against SARS-CoV-2 in mice

Researchers in Canada have developed an adenoviral vector-based vaccine against coronavirus disease 2019 (COVID-19) that induced robust immune protection against the ancestral strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in mice.

The potential next-generation vaccine candidate also induced robust immunity against the UK B.1.1.7 (alpha) and South African B.1.315 (beta) variants of concern in the animals.

Furthermore, the researchers showed that respiratory mucosal administration of the vaccine was superior to the intramuscular route at inducing three-armed immunity, including local and systemic antibody responses, mucosal tissue-resident memory T cells, and mucosal trained innate immunity.

“To the best of our knowledge, our study represents the first to demonstrate the in vivo protective efficacy of a novel, multivalent next-generation vaccine strategy against both ancestral SARS-CoV-2 and emerging VOC [variants of concern] in animal models,” says the team from McMaster University in Hamilton, Oregon.

“These exciting findings warrant further clinical studies to evaluate inhaled aerosol delivery of our multivalent viral-vectored COVID-19 vaccine to the respiratory tract in humans,” writes Zhou Xing and colleagues.

A pre-print version of the research paper is available on the bioRxiv* server, while the article undergoes peer review.

The progress with vaccines so far

Approximately 18 months since the COVID-19 outbreak first began in Wuhan, China, in 2019, many countries are still struggling to prevent major waves of the disease.

In addition to measures implemented to contain the spread of SARS-CoV-2, the most effective way to control the pandemic is to establish herd immunity through vaccination.

To date, at least 100 vaccines candidates have been tested in clinical trials, and another 180 are in the preclinical pipeline.

These efforts have led to the emergency use authorization of several COVID-19 vaccines that are now being rolled out on a mass scale in many countries.

Several of these first-generation vaccines are based on recombinant adenoviral and messenger RNA (mRNA) platforms designed to express the spike protein of the ancestral SARS-CoV-2 strain.

The spike protein mediates the initial stage of the infection process when its receptor-binding domain (RBD) attaches to the host cell receptor angiotensin-converting enzyme 2. This spike is a primary target of neutralizing antibodies following natural infection or vaccination.

“Almost all first-generation recombinant COVID-19 vaccines were designed for intramuscular injections administration and to express only the spike protein,” writes Xing and colleagues.

SARS-CoV-2 variants pose a threat to vaccination efforts

The global rollout of COVID-19 vaccines has been highly effective at reducing viral transmission, hospitalizations, and deaths, particularly in countries that have achieved high vaccine coverage.

However, since September 2020, four SARS-CoV-2 variants of concern (VOC) have emerged with mutations in the spike protein that confer increased transmissibility and, in some cases, escape from infection- or vaccine-induced immunity.

These VOC include the B.1.1.7 (alpha) lineage that emerged in the UK, the B.1.351 (beta) lineage that arose in South Africa, P.1 (delta) that emerged in Brazil, and B.1.617 (gamma) that recently emerged in India.

While all of these VOC contain multiple spike mutations, B.1.351 and P.1 harbor three within the RBD (K417T, E484K and N501Y) that significantly increase resistance to neutralization by convalescent or vaccinated sera.

Importantly, several first-generation vaccines, including those developed by AstraZeneca (ChAdOx1 nCoV-19), Janssen (Ad26.COV2.S), Novavax (NVX-CoV2373), and Pfizer-BioNTech (BNT162b2) have all been shown to be less effective at protecting against mild-to-moderate COVID-19 caused by B.1.351.

Next-generation vaccine strategies are urgently needed

“To confront the challenges arising from VOC and uncertainty of the durability of first-generation vaccine-induced immunity, there is an urgent need to develop next-generation COVID-19 vaccine strategies,” says Xing and colleagues.

One such strategy is to develop recombinant viral-vectored multivalent vaccines that are amenable to respiratory mucosal immunization. These vaccines could express conserved SARS-CoV-2 antigens in addition to the spike protein and might provide more broad and long-lasting protection.

“Furthermore, adenoviral vectors delivered via the respiratory mucosal route induce protection by eliciting both mucosal tissue-resident innate immune memory/trained innate immunity and adaptive immunity at the site of viral entry,” writes the team.

What did the researchers do?

Using adenoviral vectors (Ad) of human and chimpanzee origin, the researchers developed Ad-vectored trivalent COVID-19 vaccines that expressed the original spike protein subunit S1, as well as the highly conserved T cell antigens nucleocapsid protein and RNA-dependent RNA polymerase.

The team evaluated the effectiveness of this next-generation vaccine strategy following a single intramuscular or intranasal dose in murine models.

What did they find?

The researchers showed that a single respiratory mucosal immunization via the intranasal route, particularly with the chimpanzee Ad-vectored vaccine, induced potent neutralizing antibodies both locally and systemically. Importantly, intranasal immunization elicited respiratory mucosal tissue-resident memory CD8+ T cells and trained resident alveolar macrophages.

This overall mucosal immunity conferred robust protection against not only the ancestral strain of SARS-CoV-2 but also the B.1.1.7 and B.1.351 VOC.

Furthermore, intranasal vaccination was found to be superior to the intramuscular route at eliciting protective mucosal immunity.

An important proof of concept for further clinical development

Xing and colleagues say the findings indicate that the single-dose respiratory mucosal delivery of an Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy against current and future VOC.

“Our study thus provides the important proof of concept for its further clinical development,” they write.

“If proven successful, the next-generation vaccine strategies such as ours may be deployed as a booster to bolster mucosal protective immunity against emerging VOC and to extend the durability of protective immunity following immunization with first-generation vaccines,” says the team.

*Important Notice

bioRxiv 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.

Journal reference:
Sally Robertson

Written by

Sally Robertson

Sally first developed an interest in medical communications when she took on the role of Journal Development Editor for BioMed Central (BMC), after having graduated with a degree in biomedical science from Greenwich University.


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