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Twelve-year-old Samekh Nadeem, right, watches as his brother Sion Nadeem, 13, receive his Pfizer COVID-19 vaccination at the Embassy Grand Convention Centre in Brampton, Ont. on May 25, 2021.Fred Lum/the Globe and Mail

If you’re lucky, getting your second dose of a COVID-19 vaccine may make you feel worse than some people feel after getting infected with the virus itself.

This apparent paradox is one of the consequences of how the vaccines currently available to Canadians are designed to work. And it relates directly to why the virus is so dangerous and insidious in the first place.

At the most basic level, a virus is little more than a package of genetic information that has evolved to hijack our cells in order to make copies of itself. To achieve this goal, the virus that causes COVID-19 carries some additional instructions besides the bare minimum it needs to reproduce. Those extra instructions allow it to delay the body’s initial immune response, which can buy the infection time to get established and start spreading.

In comparison, the COVID-19 vaccines – particularly those that employ messenger RNA as the active ingredient – are even more minimalist. When the vaccine RNA is delivered to cells, it carries only the instructions to make the spike protein that is the virus’s calling card. This ultimately will allow the immune system to recognize the real virus if it ever shows up.

Since there is nothing in the vaccine RNA that is made to hinder an immune response, the body springs into its infection-fighting position right away. For many people, that will mean feeling under the weather in the first day or two after getting a shot – but that’s not necessarily a bad thing.

“Feeling poorly for a couple of days is assurance that the vaccine has worked,” said Cecile King, an immunologist and associate professor at the University of New South Wales in Australia. “The effect is temporary and not dangerous.”

In a paper published this past week in the journal Science Immunology, Dr. King and a colleague sum up the current knowledge and questions that surround how people are reacting to COVID-19 vaccines.

Vaccines made by Pfizer-BioNTech and Moderna – by far the most widely administered in Canada – are known to produce side effects that include headache, fever, aches and a general malaise in about 60 per cent of recipients. The reaction is often more pronounced after a second dose. By then, Dr. King said, the immune system knows what a COVID-19 spike protein looks like “and you’re going to have a lot more cells that are activated … which will contribute to the whole effect.”

A key player in this process is a class of molecules called interferons, which are released as soon as foreign RNA is detected inside cells. As the name suggests, the role of interferons is to interfere with viral replication. They also trigger a host of other responses that explain many of the reactions people experience after a receiving a vaccine. This includes changes to the vascular system that can cause headaches, a shift in body-temperature regulation that manifests as fever and a flood of immune chemicals called cytokines, which course through the body and lead to aching joints.

According to Eleanor Fish, a University of Toronto immunologist who specializes in the action of interferons, that list of side effects should sound very familiar to anyone who has ever received interferon as a drug.

“Am I surprised that people are experiencing these symptoms following an RNA vaccine? Not at all. That’s the interferon response,” she said.

Over the past year, Dr. Fish has been involved in clinical trials of interferon as a treatment for fighting COVID-19 infection – in order to counteract the virus’s ability to shut down interferon production. After vaccination, interferon is unleashed naturally and it helps prime the immune system to achieve the vaccine’s ultimate goal, which is to form long-term immunity to the virus.

That longer-term response generally takes two weeks to reach its peak. By then, the immune system will have generated antibodies that can block the coronavirus by attaching to the spike protein. It will also have developed special immune cells that can recognize and eliminate other cells infected with the virus.

However, that doesn’t mean people who had very little initial reaction to a vaccine are unprotected. The intensity of the reaction varies greatly between individuals, and it tends to be stronger in females and younger recipients with more robust immune systems. Genetics also play a role, as do the microbes we carry around with us, which fine tune and individualize our immune systems.

For those who received an AstraZeneca vaccine, which operates using a somewhat different strategy, there appears to be more potential for a strong reaction at first dose. Those who are mixing vaccine types may therefore be getting the best – or worst – of both worlds, depending on how you look at it. The upside is that mixing doses appears to provide a strong immune response in the long run.

Other types of vaccines appear to exhibit different response profiles. This past week, researchers at the VIDO-Intervac infectious disease research facility at the University of Saskatchewan announced successful results from their Phase I clinical trial of a protein-based vaccine developed there. According to director Volker Gerdts, the results indicate the severity and number of reactions to the vaccine were lower for the second dose.

Regardless of the side effects, the data are clear that second doses are important.

Also, results from the CanPath COVID-19 antibody study, based on blood samples from 6,000 individuals, showed that 10 per cent of those who received a single dose of an mRNA vaccine and 30 per cent of those who received the AstraZeneca vaccine did not show signs of antibodies against the virus. Antibodies were also lower in recipients over the age of 60.

“We don’t know if there’s a one-to-one relationship between antibodies and protection … but what we’re seeing is that there’s a lot of individual variability in response,” said study director Philip Awadalla, who is based at the Ontario Institute for Cancer Research in Toronto.

Shehzad Iqbal, Canadian medical director for Moderna, said a second dose of the vaccine boosts antibodies and stimulates the immune system to selectively generate a higher proportion of the antibodies that appear to be most effective.

“Vaccines offer a good deal of protection, but you need two doses to get the full level of immunity that can be offered,” Dr. Iqbal said.

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