Researchers confirm newly developed inhaled vaccine delivers broad protection against SARS-CoV-2, variants of concern

Scientists at McMaster University who have developed an inhaled form of COVID vaccine have confirmed it can provide broad, long-lasting protection against the original strain of SARS-CoV-2 and variants of concern.

The research, recently published in the journal Cell, reveals the immune mechanisms and significant benefits of vaccines being delivered directly into the respiratory tract, rather than by traditional injection.

Because inhaled vaccines target the lungs and upper airways where respiratory viruses first enter the body, they are far more effective at inducing a protective immune response, the researchers report.

The reported preclinical study, which was conducted on animal models, has provided the critical proof of concept to enable a Phase 1 clinical trial that is currently under way to evaluate inhaled aerosol vaccines in healthy adults who had already received two doses of a COVID mRNA vaccine.

The tested COVID vaccine strategy was built upon a robust tuberculosis vaccine research program established by Zhou Xing, a co-lead author of the new study and a professor at the McMaster Immunology Research Centre and Department of Medicine.

"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," Xing says.

Currently authorized COVID vaccines are all injected.

"We wanted, first and foremost, to design a vaccine that would work well against any variant," explains the study's co-lead author Matthew Miller, an associate professor at McMaster's Michael G. DeGroote Institute for Infectious Disease Research.

The McMaster COVID vaccine represents one of only a handful developed in Canada. The urgent work is a critical mission of Canada's Global Nexus for Pandemics and Biological Threats, which is based at McMaster.

Researchers compared two types of adenovirus platforms for the vaccine. The viruses serve as vectors that can deliver vaccine directly to the lungs without causing illness themselves.

"We can remain ahead of the virus with our vaccine strategy," says Miller. "Current vaccines are limited because they will need to be updated and will always be chasing the virus."

Both types of the new McMaster vaccine are effective against highly transmissible variants because they are designed to target three parts of the virus, including two that are highly conserved among coronaviruses and do not mutate as quickly as spike. All COVID vaccines currently approved in Canada target only the spike protein, which has shown a remarkable ability to mutate.

"This vaccine might also provide pre-emptive protection against a future pandemic, and that's really important because as we've seen during this pandemic -- and as we saw in 2009 with the swine flu -- even when we are able to rapidly make a vaccine for a pandemic virus, it's already way too late. Millions of people died, even though we were able to make a vaccine in record time," says Miller.

"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 adds.

In additional to being needle and pain-free, an inhaled vaccine 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 per cent -- meaning a single batch of vaccine could go 100 times further, the researchers say.

"This pandemic has shown us that vaccine supply can be a huge challenge. Demonstrating that this alternative delivery method can significantly extend vaccine supply could be a game changer, particularly in a pandemic setting," says Brian Lichty, an associate professor in the Department of Medicine who co-led the preclinical study along with Miller, Xing and the senior trainees Sam Afkhami and Michael D'Agostino, who are the joint first authors of the study.

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Respiratory viruses that hijack immune mechanisms may have Achilles' heel

One viral protein could provide information to deter pneumonia causing the body's exaggerated inflammatory response to respiratory viruses, including the virus that causes COVID-19.

That viral protein is NS2 of Respiratory Syncytial Virus (RSV), and a study has found that if the virus lacks this protein, the human body's immune response can destroy the virus before exaggerated inflammation begins. The research, conducted at Washington State University's College of Veterinary Medicine, was published Jan. 18 in the journal MBio.

Like other respiratory viruses, including the COVID-19-causing SARS-CoV-2 virus, RSV infects the lung cells responsible for exchanging gases and uses them as factories to make more viruses. Uncontrollable virus multiplication in these cells leads to their destruction and manifestation of severe inflammation; lung diseases like pneumonia; and sometimes death.

"Exaggerated inflammation clogs the airways and makes breathing difficult," said Kim Chiok, a WSU post-doctoral researcher who led the study. "This is why people who have these long-term and severe inflammatory responses get pneumonia and need help breathing, and it's why they end up in the hospital in the ICU."

Chiok and fellow WSU researchers are laying the framework to break that cycle by understanding how respiratory viruses, like RSV, persist in the cell. RSV causes 160,000 deaths annually primarily in infants, children, elderly and immune-compromised individuals, according to National Institute of Allergy and Infectious Diseases.

The research was conducted in the laboratory of Professor Santanu Bose, who is part of WSU's Veterinary Microbiology and Pathology research unit. Chiok, a Fulbright Scholar from Peru who completed her Ph.D. at WSU, has spent the past two and a half years in the Bose laboratory exploring the mechanisms that regulate the virus-host battle.

The researchers first determined viral proteins' functions by using viruses lacking genes that code for different viral proteins and comparing them to a wild strain of the virus.

"The virus has a series of tools, some tools with multiple functions, we wanted to learn about these tools by essentially taking them away," Chiok said.

Each tool is a different viral protein.

Chiok identified the viral NS2 protein as a key regulator of autophagy, a cellular process that modulates immune defense during virus infection. Autophagy is mediated by a cellular protein known as Beclin1.

When the virus enters the cell, Beclin1 can recognize and clear the threat from the cell. It does this by attaching to certain smaller gene proteins through a process known as ISGylation. It is almost like Beclin1 is putting on a suit of armor, Chiok said.

The study showed that RSV's NS2 protein removes this "armor" from Beclin1 which allows the virus to persist and replicate within the cell, spreading to other cells and causing damage that initiates an exaggerated inflammatory response from the body that culminates in airway diseases like pneumonia. Without the NS2 protein, the virus is routinely destroyed by Beclin1.

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