A next-generation COVID-19 vaccine will be puffed in the nose

Getting inoculated against COVID-19 with a jab into the upper arm has proven to be reliable, but the appearance of new, troublesome SARS-COV-2 variants continues to threaten the efficacy of existing vaccines. A better strategy, some say, is a multivalent vaccine delivered directly into the respiratory tract by inhalation, as it can provide broader protection and greater durability.

A team of investigators from McMaster University in Canada claims that nasal administration, which targets the lungs and upper airways where respiratory viruses first enter the body, is far superior at inducing a protective immune response.

“What we’ve discovered from many years’ research is that the vaccine delivered into the lung induces all-around protective respiratory mucosal immunity, a property that the injected vaccine is lacking,” according to co-lead investigator Dr Zhou Xing, a professor at the McMaster Immunology Research Centre and Department of Medicine.

In designing their vaccine, Xing and his team said that producing one that would keep up with mutations and work well against any variant was also a priority. So, they looked at a recombinant viral-vectored multivalent vaccine amenable to respiratory mucosal immunization.

Such a vaccine, according to the team, would not only contain the spike antigen but also express additional conserved SARS-CoV-2 antigens to broaden T-cell immunity to target both ancestral and variants of SARS-CoV-2. Furthermore, when delivered via the respiratory tract, the vaccine should confer protection via eliciting mucosal tissue-resident trained innate and adaptive immunity at the site of viral entry. [Nat Rev Immunol 2020;20:615-632; Nat Rev Immunol 2021;21:195-197; J Leukoc Biol 2020;108:825-834; Cell 2018;175:1634-1650.e17]

Trinity of protection

Built upon the adenoviral vectors of human (Tri:HuAd) or chimpanzee (Tri:ChAd) origin, the vaccines developed by Xing and his team express three SARS-CoV-2 antigens (spike protein 1, full-length nucleocapsid protein, and truncated polymerase) and are suitable for respiratory mucosal delivery.

In a preclinical testing involving murine models, single-dose intranasal immunization was more effective than intramuscular immunization at inducing the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells, and mucosal trained innate immunity. [Cell 2022;doi:10.1016/j.cell.2022.02.005]

There were other notable observations. First, the choice of adenoviral vector seemed to play an important role, with the Tri:ChAd outperforming the Tri:HuAd vaccine. Also, the inclusion of both the spike and conserved internal T-cell antigens in vaccine design was necessary for optimal protection against ancestral SARS-CoV-2 and two variants of concern, namely Alpha (B.1.1.7) and Beta (B.1.351).

“We have revealed in our report that besides neutralizing antibodies and T-cell immunity, the vaccine delivered into the lungs stimulates a unique form of immunity known as trained innate immunity, which is able to provide very broad protection against many lung pathogens besides SARS-CoV-2,” Xing said.

Keeping up

Taken together, the findings indicate that an inhaled adenoviral-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccination strategy to induce all-around mucosal immunity against current and future VOCs, according to the investigators.

“We can remain ahead of the virus with our vaccine strategy,” stated co-lead investigator Dr Matthew Miller, an associate professor at McMaster’s Michael G. DeGroote Institute for Infectious Disease Research. “Current vaccines are limited because they will need to be updated and will always be chasing the virus.”

Another merit to an inhaled vaccine, aside from being needle- and pain-free, is that it is so efficient at targeting the lungs and upper airways that it can achieve maximum protection with a small fraction of the dose of current vaccines, possibly as little as 1 percent, Miller and Xing noted.

That means that with the alternative delivery method, a single batch of vaccine has the potential to go 100 times farther and extend supply in a larger context, which could be a game changer in a pandemic setting, the investigators added.