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Symvivo, a clinical-stage gene therapy company founded in Burnaby, B.C., in 2013, is working toward creating an oral vaccine for COVID-19.

Symvivo Corporation

Canadian researchers are part of the all-hands-on-deck global effort to develop a COVID-19 vaccine.

With several vaccine candidates on the go, part of the research effort is directed, not only at finding the right formula to stimulate a safe, effective immune response but also how to get the vaccine into the body in the most efficient way.

Although Pfizer Inc.'s announcement this week of an early indication of 90-per-cent effectiveness in its vaccine offers hope, it is important that vaccine researchers continue their work, experts say.

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“The scientific community has come together to look at all options … to try to come up with the best solutions” for different situations, says Karina Top, an investigator at the Canadian Center for Vaccinology and an associate professor of pediatrics and community health and epidemiology at Dalhousie University. “So, casting that wide net is the best approach.”

There are many researchers working on injectable vaccines and nasal sprays, but in Canada a couple of projects are aimed at developing other delivery methods – a vaccine that can be inhaled and one that can be ingested.

Some basics

There are many ways our bodies jump into action to defend us from harmful viruses, such as SARS-CoV-2, which causes COVID-19. In order to get a sense of the goals of research on COVID-19 vaccines, it’s helpful to know some basic facts about viral infection, the body’s defence mechanisms and how vaccines help.

“The purpose of any vaccine is to train the immune system to recognize a virus or bacteria that causes an infection, so when [you] encounter that infection, your immune system can fight it off before it can make you sick,” says Dr. Top.

When a virus enters the body, it has are certain defences, which include antibodies and T-cells.

Antibodies and antigens: One defence is the production of antibodies, which are proteins that latch onto antigens, or the molecules on foreign substances, such as the SARS-CoV-2 virus. Antibodies can recognize and inactivate specific antigens.

T cells: When viruses infect cells in the body, hijacking them to make more copies of themselves, killer T cells attack those infected cells. “The ideal vaccine would stimulate both arms of the immune system,” Dr. Top says.

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Vaccines and spike proteins: In order for a vaccine to train the immune system to recognize and attack a virus, it needs to introduce to the body a safe version of the virus or parts of the virus or genetic instructions to make the virus. For instance, Dr. Top notes, many vaccine candidates target the spike proteins that stick out of the surface of the SARS-CoV-2 virus and attach themselves to our cells, which is how the virus invades cells and makes copies of itself.

Carriers: Antigens, such as spike protein, or instructions to make spike protein need to be introduced to the body through a carrier, which include a bacterium or another virus that will not harm the body.

Scientists also choose the method of administering the vaccine. The following research projects are developing methods that are more unusual:

An inhalable vaccine

Dr. Zhou Xing, a vaccine immunologist at McMaster University in Hamilton.

Handout

Dr. Zhou Xing, a vaccine immunologist at McMaster University in Hamilton, is the lead scientist on a project focused on producing an inhaled aerosol vaccine.

The researchers on the project are developing two viral vector vaccines, which means the antigens, or molecules, they want the immune system to react to are delivered by viruses. One is a human adenovirus, a common virus that can cause such illnesses as the common cold or an intestinal illness. The other is an adenovirus derived from chimpanzees, which has the advantage of being new to the human body, so we do not already carry an immune response to it, potentially masking any responses to SARS-CoV-2 antigens.

Both are recombinant viral vector vaccines, meaning the delivery viruses are engineered to carry genetic instructions to cells in the body. These instructions guide the cells to produce the SARS-CoV-2 antigen targets for our immune systems to react to.

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“These [COVID-19] vaccines are engineered to express multiple select SARS-CoV-2 antigens, including the spike protein, with a goal to induce both antibody and T-cell immunity,” Dr. Xing says. “We believe that by combining the two arms of immunity, we may have the best chance of controlling COVID-19.”

These vaccines are designed to be inhaled, much in the way people with asthma use inhalers.

Over the past couple of years, the research team has been working on tuberculosis vaccine strategies with the same inhaled-aerosol technology and have since pivoted to apply it to a COVID-19 vaccine.

The researchers decided on an inhalable delivery method for several reasons, Dr. Xing says. “We have come to understand that in order to accomplish the best level of immunity and protection against certain respiratory infections, such as COVID-19, … the respiratory-mucosal route of immunization is the way to go. That’s where you get all the protective mechanisms right at the site of infection.”

Meanwhile, Dr. Top points out the importance of the mucosal response. “The virus enters through the nasal passages, through the throat and sometimes through the eyes' mucous membrane, so any vaccine that we make will, ideally, produce immune responses in those target tissues – what we call mucosal immunity.”

And compared with injectable vaccines, the dose needed for an inhalable vaccine can be up to 100 times smaller, Dr. Xing notes. Furthermore, inhalable delivery is pain-free and needle-free.

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The team, which includes scientists Fiona Smaill, Brian Lichty and Matt Miller, has refined the technology, Dr. Xing reports. The refinements include knowing how many minutes the vaccine should be inhaled and, because the technology also knows the size of the particles, how far the vaccine can travel down the respiratory tract.

“Not all vaccines can be delivered via the respiratory tract,” Dr. Xing explains.

Because many vaccines do not activate the immune system strongly enough, they require an adjuvant, or additional molecules, which may not be safe or effective enough for the respiratory route.

As well, when a vaccine is introduced to the body, there can be some local reactions, such as pain or swelling, which are not significant around the site of an injection but could be more dangerous in the respiratory tract.

The researchers are testing the safety of their vaccine candidate in rodents and whether it stimulates an immune response or not, Dr. Xing says. The next step is to test the protective ability of the vaccine by immunizing mice, then infecting them with SARS-CoV-2 to see if the vaccine induces protection in the mice. The team is hoping to get Health Canada approval to move into a Phase 1 clinical trial in human subjects in the spring. (Phase 1 trials test the safety, tolerability and best dose of a new drug in a small group.)

The project has received about $2-million from the Canadian Institutes of Health Research (CIHR), enough to complete a Phase 1 trial, but, according to Dr. Xing, not enough for the larger trials required to test the vaccine after that first phase.

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“Funding resources is always the biggest challenge for scientists,” he notes.

An oral vaccine

Imagine being able to take in pill form a COVID-19 vaccine at home. That is exactly what Symvivo – a clinical-stage gene therapy company founded in Burnaby, B.C., in 2013 – is working toward. The first volunteer for the project was dosed last week in a Phase 1 clinical trial underway in Australia.

“We have developed a novel way to deliver plasmid DNA to select sites in the body,” says Symvivo’s founder and chief executive officer, Alexander Graves.

Plasmid DNA is a small circle of DNA separate from the bacteria’s DNA that, in this case, has been manipulated to carry instructions for the body’s cells to produce SARS-CoV-2 spike proteins. Symvivo delivers the plasmid DNA through a modified bacterium.

“Bifidobacterium longum … is in everyone’s large intestine,” Mr. Graves points out. The company chose the method, he says, because it can effectively transit the gastrointestinal tract and deliver plasmid DNA to the lining of the large intestine.

“That spike protein, when expressed, will induce an immune response that, hopefully – and we are going to confirm this in the clinic – can provide protective immune responses against future SARS-CoV-2 infections.”

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The product – bacTRL-Spike – can also be delivered intravenously, but there are several benefits to oral administration, Mr. Graves says.

One advantage is that the lining of the intestine, like that of the respiratory tract, is a mucous membrane routinely exposed to harmful substances and provides the first line of defence where antibodies are secreted.

This method allows the researchers to observe a mucosal response to SARS-CoV-2 antigens, Mr. Graves notes, and if people are exposed to the virus, they would already have antibodies at the lining of the mucosal membranes that would prevent the virus from entering the body.

An oral vaccine would also allow people to take it themselves without the need for needles and trained personnel.

“We are moving toward a room-temperature stable product,” he explains. This is an important factor when distributing the vaccine globally, as there would be no need to keep it cold – “a bottleneck that is current in the vaccine industry,” he says.

He adds that the bacterial product could make it easier to produce on a global scale because it could be manufactured with few changes to existing infrastructure.

Symvivo received $2.8-million in funding from the National Research Council of Canada Industrial Research Assistance Program. If Phase 1 trials prove that the bacTRL-Spike vaccine candidate is safe to use, the next step is to evaluate whether it stimulates an effective immune response to SARS-CoV-2. The aim is to move to Phase 2 trials in the new year.

“The ultimate goal is to produce a vaccine that we can send to people’s homes [and can be] self-administered,” Mr. Graves says. “And if there is a need for repeat vaccinations, that [can also be] enabled using this technology.”

Still many unknowns

“There is still so much unknown with regard to the vaccines,” Dr. Xing cautions. “We anticipate that maybe the first generation of COVID-19 vaccines will only provide short-term protection.” And in that case, booster vaccinations may be needed.

“That is why it is important ... to understand how our immune system works in response to SARS-CoV-2 and to continue to develop further improved vaccine strategies,” he says.

“With COVID vaccines, the added challenge is that this is a disease that affects everybody in the world,” Dr. Top says. “And so, we need vaccines that can be safe and effective for all age groups and can be rolled out to people across the world.”

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