Why are so many COVID-19 booster shots necessary and how can we make vaccines even better?

One dose is rarely enough

People often think – or expect – vaccines provide complete protection for everyone after they get their first dose. “This common perception of what vaccines can do isn’t accurate or realistic,” explains Dr. Marc-André Langlois, CoVaRR-Net’s Executive Director, a Professor at the University of Ottawa, and former Canada Research Chair in Molecular Virology and Intrinsic Immunity. “Although vaccines are one of the most formidable contributions of modern medicine, they don’t fully protect everyone who is vaccinated in terms of preventing infection, whether it’s vaccination for polio, measles, chickenpox, or human papilloma virus. Most vaccines also require multiple doses or boosters to provide effective and lasting immune protection.”

mRNA vaccines have saved millions of lives, but protection could be improved

COVID-19 vaccines and especially mRNA vaccines have been remarkably successful in protecting against severe disease, hospitalizations, and deaths, saving tens of millions of lives around the world since their rollout a mere two years ago. Vaccines are the reason Canadians – and people around the world – are leading somewhat “normal” lives again, even as the pandemic persists.

“The mRNA vaccines are phenomenal tools that significantly reduce the likelihood of severe disease,” explains Dr. Langlois. “However, the question many have is: why do we need constant boosting for COVID-19, perhaps more frequently than with other vaccines? Basically, it’s a tall order for the vaccines and our immune system to deal with a respiratory virus that is highly transmissible, evolves very rapidly, and can cause lasting chronic symptoms, called Long COVID, even in mild cases of the disease.”

Here, we’ll go into more detail however, as to why.

Boosters needed to top-up waning immunity

For acute viral infections, like SARS-CoV-2 (the virus that causes COVID-19), getting a booster dose of an mRNA vaccine increases the level of neutralizing antibodies secreted by the immune system’s B cells. Neutralizing antibodies protect cells from infection by attaching to the surface spike protein of the coronavirus and preventing the virus from entering cells. But the levels of these neutralizing antibodies naturally decrease over several months (also known as waning). New variants, such as Omicron and its subvariants, have proven to partially evade antibody recognition and attachment of these antibodies, and that is why regular boosters are therefore required to compensate and help reduce virus transmission.

Vaccination and boosters also induce immunological memory: the ability of the immune system to remember and respond more rapidly and effectively to parts of a pathogen that has been encountered before either through infection or vaccination. Memory is the key to long-term protection against COVID-19. The challenge with SARS-CoV-2 is that the virus evolves very quickly and therefore some parts of the virus that the immune system remembers may no longer be there in new variants. The immune system’s memory B cells and memory T cells work collaboratively to neutralize pathogens in the bloodstream, mucosae and other tissues through antibodies, and to eliminate virally infected cells through cell mediated immunity to prevent progression to severe disease, hospitalization, and death. Memory T cells recognize and eliminate infected cells, but are not the main actors in preventing infection.

“The current vaccine strategy is to top up the antibody response with frequent boosters to help us navigate the different waves of evolving variants of the virus,” says Dr. Jörg Fritz, Deputy, CoVaRR-Net’s Computational Biology and Modelling Pillar, and Associate Professor, Department of Microbiology and Immunology, McGill University. “But this approach is not very effective at preventing infection and transmission, and new variants of concern can evade some of these antibodies. We need to develop and optimize other vaccination strategies to stop transmission and to provide longer-lasting immune protection by inducing stronger and more durable B cell and T cell memory against conserved parts of the virus.”

More research into new vaccines is required

Mucosal vaccines

An important and promising strategy to prevent infection and transmission of SARS-CoV-2 more effectively is to boost immunity in the mucosal lining of our airways where the virus first enters our bodies, using sprays delivered through the nose or mouth. Mucosal boosters, as a complement to injected vaccines, also stimulate higher levels of neutralizing IgA (immunoglobulin A) antibodies that reside within the mucosal surfaces of the nose and throat than do injected vaccines. Mucosal IgA antibodies seem to provide even better protection against infection by the virus and its diverse variants than IgG (immunoglobulin G) antibodies, which are most abundant in blood.

“The goal of the mucosal vaccine strategy is to provide immediate and durable protection at the point of entry and site of infection. Researchers are also investigating whether mucosal boosters will be able to generate an effective long-term memory response in B cells and T cells, so we don’t need boosters as frequently,” says Dr. Fritz.

More than a dozen mucosal vaccines are being tested in clinical trials around the world. Researchers at Canada’s McMaster University have also developed and are now testing in clinical trials an inhaled spray vaccine, which triggers an immune response in mucosal cells in the lining of the lungs. “The mucosal immunity approach is very promising and less invasive than a needle, but more research is urgently required to make this next-generation booster available in the near future to complement mRNA vaccines,” says Dr. Langlois, whose own lab is developing a nasal spray protein-based vaccine prototype made in plants.

Vaccines that target multiple viral proteins to increase memory

Another promising strategy aimed at offering more durable protection against a virus that’s rapidly evolving is to develop injected COVID-19 vaccines that target multiple viral proteins. “The current mRNA vaccine regimen that includes a primary series of vaccines and a first booster dose mounts a very good T cell response. But additional boosts that target only the spike protein don’t seem to further strengthen the T cell response significantly or make it last very long,” explains Dr. Hélène Decaluwe, Deputy of CoVaRR-Net’s Immunology & Vaccine Protection Pillar, Associate Professor at Université de Montréal and Clinician Scientist, CHU Sainte-Justine Research Centre.

“Researchers are developing and testing vaccines that target not only the spike protein but other viral proteins for increasing both B cell and T cell immunity. These include the N protein (nucleocapsid protein) and M protein (membrane protein). If this approach can increase the quality, strength, diversity and persistence of B cell and T cell responses, it could generate immune memory cells to protect people for a very long time,” says Dr. Decaluwe, noting that not only mRNA but other vaccine platforms can be used to target multiple viral proteins.

Studies also suggest a diversified vaccination strategy where people receive booster doses from a mix of different mRNA vaccines (currently Pfizer and Moderna) or different vaccine platforms – an mRNA vaccine and a modified adenovirus vaccine, for example – to enhance the immune response. “The data shows that heterogenous vaccines and platforms increase the strength of B-cell and T-cell immune responses. Further research is needed to determine whether mixing vaccines and platforms is significantly more effective and could provide a longer-lasting immune response,” adds Dr. Decaluwe. 

Investing in next-generation vaccines for all Canadians, especially those at higher risk of severe COVID-19

Developing next-generation vaccines that can prevent infection, stop transmission, and provide more durable protection is important for everyone, but especially for older adults and those who are immunocompromised – populations which generally don’t respond as well to current COVID-19 vaccines due to their weakened immune systems, says Dr. Decaluwe. Moreover, next-generation vaccines could also keep more people out of hospital by reducing the likelihood of developing chronic illnesses due to long COVID, allowing countries to regain a delicate equilibrium with healthcare services and keep people in school and at work, maintaining the economy’s effectiveness.

“Funding agencies must continue investing in research to develop diversified and improved intramuscular and mucosal vaccines,” says Dr. Langlois. “By using both strategies together in a complementary way, the next generation of vaccines could be much more effective in blocking infection and transmission, and may offer broader, longer-lasting protection against new SARS-CoV-2 variants and related coronaviruses for all Canadians including those at higher risk.”

To arrange an interview with Hélène Decaluwe, Jörg Fritz, or Marc-André Langlois, please contact:
media@covarrnet.ca