How an inhaled COVID-19 vaccine might breathe life into fight against the pandemic

When volunteers show up in the coming weeks to test a pair of COVID-19 vaccines developed at McMaster University, there will be something missing from the standard setup for such a clinical trial: needles.

Instead of a jab in the arm, both vaccines are designed to be inhaled as a fine mist that is deposited into subjects’ lungs. Researchers behind the effort say the goal is to provide protection via the same route that the disease itself uses to enter the body.

“Airborne pathogens are first seen in the respiratory tract,” said Fiona Smaill, a professor of pathology and molecular medicine who is leading the trial in Hamilton. “We truly believe that this is the most robust way to develop an immune response.”

Last week, Dr. Smaill and her colleagues announced they have a green light from Health Canada to conduct a Phase 1 clinical trial with a small cohort of 30 healthy volunteers between the ages of 18 and 65 who have already had their first two doses of an authorized COVID-19 vaccine.

In the trial, subjects will be given one of the McMaster vaccines as a third dose to boost their immunity levels. Both of the vaccines that are being tested consist of a modified adenovirus that delivers genetic instructions for making proteins that are specific to the coronavirus that causes COVID-19.

The vaccines differ from each other only in the specific adenovirus that is used to carry the instructions. In each case, once the instructions are delivered and proteins are generated, they are recognized by the body’s immune system and used as a reference to help fight off the coronavirus.

As well as being inhaled, the McMaster vaccines represent a new approach in another way.

All of the COVID-19 vaccines approved for use in Canada so far are designed to exclusively recreate the COVID-19 spike protein – the part of the coronavirus that first latches onto human cells at the start of an infection. However, the McMaster vaccines are engineered to reproduce two additional proteins that are found in other parts of the coronavirus and its replication machinery.

Zhou Xing, a professor at McMaster’s immunology research centre who led that part of the vaccines’ development, said the strategy may provide better protection against COVID-19 variants of concern, including Omicron, which features many changes to the spike protein, but not as many mutations elsewhere.

Dr. Xing added that the McMaster team’s aim was to have the trial under way early in the new year.

Subjects who participate will wear nose plugs and then inhale one of the two vaccines being tested through a mouthpiece. The system, developed in Dr. Smaill’s lab, has previously been tested with a tuberculosis vaccine candidate that was in development before the pandemic began.

Dr. Smaill said that after participants receive their vaccine dose, their antibody levels will be monitored both in their blood and in samples of lung fluid. The latter will be crucial to understanding the magnitude of the immune response that the vaccines are able to stimulate in the respiratory tract, a property known as mucosal immunity.

Evidence suggests the strategy can be effective against COVID-19. In a paper published last month in the journal Nature Communications, a German-led research team working with mice reported that an inhaled booster vaccine following an initial injection of an mRNA vaccine offered better protection than two injected doses.

The researchers wrote that while the initial shot creates a comprehensive, systemwide immune response, the inhaled boost appeared to optimize a local response along the lining of the airways that serve as COVID-19′s point of entry.

“I think it’s a really good way to go, because you get the best of both worlds,” said Jennifer Gommerman, an immunologist at the University of Toronto whose lab is investigating mucosal immunity to COVID-19.

The reason is that such a vaccine can leverage the power of mucosal antibodies, which are found in the respiratory tract and which are structurally different from the types of antibodies that are generated to intercept viruses in the blood. The latter are usually Y-shaped molecules that are active only at the top ends of the Y.

In contrast, mucosal antibodies look more like dog bones or like pairs of Ys joined together at the base. This doubles the points at which they can attach to their targets and therefore increases their power at fighting respiratory infections.

In a recent study that is still awaiting publication, Dr. Gommerman and international colleagues show that significant levels of mucosal antibodies that are active against COVID-19 are present in only about 30 per cent of individuals who receive an mRNA vaccine, such as those made by Pfizer-BioNTech or Moderna.

“While we don’t know how important that response is for blocking infection, it may play a role,” she said. While not involved in the McMaster effort, Dr. Gommerman said the development of an inhaled COVID-19 vaccine “is exactly what we need.”

Meanwhile, Canadian and global research teams are advancing other strategies for next-generation vaccines that could help fight the continuing parade of COVID-19 variants.

In one such development, researchers at the Ottawa Hospital Research Institute recently published their results from animal studies of a COVID-19 vaccine that is carried by another virus which is partly active, and therefore able to replicate for a short time once it is in the body. In both mice and monkeys, the results suggest the vaccine improves the immune response by more closely resembling the progress of a real infection, though without using the coronavirus to do it.

“We found that we got tremendous immune responses that lasted for six months without any diminution,” said John Bell, a senior scientist at the institute who co-led the work.

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