Are Additional Boosters Needed? It Is a Matter of When

Over the past 19 months of the COVID-19 pandemic, we have learned much about vaccines. The great news is that we have safe, effective vaccines, many of which prevent over 90% of severe disease against all variants. This is spectacular, a major scientific feat. However, the question is whether we are going to need additional booster shots in the future. What happens if protection diminishes over time? What if current vaccines prove less effective against new variants?

To answer these questions, we need to understand how vaccines work. Vaccines trigger our body’s immune system to produce T-cells and antibodies specific to the virus. In the case of mRNA (Pfizer and Moderna) and adeno-vectored vaccines (AstraZeneca, Johnson & Johnson, Sputnik V), the spike protein of the SARS-CoV-2 is the target antigen. This is because the virus uses spike protein to bind to our cell surface receptor (ACE2) and enter the cells; antibodies can block this interaction. These mRNA and viral vaccines consist of nucleic acid inside a vehicle (RNA in lipid nanoparticles, DNA in adenovirus capsid).

Once inside the host cell, the nucleic acid serves as the template for the host cell machinery to produce the spike protein, which is detected by our immune system to trigger T-cell and antibody responses. This process of stimulating T-cells (which become killer cells) and B-cells (which produce antibodies) takes a week or two to kick in. After the first shot of vaccine, the immune system generates pretty good levels of antibodies that can block incoming virus. However, this first shot is not very effective against the emerging viral variants, which have sufficiently mutated the spike protein to evade the antibody responses generated against the original strain of SARS-CoV-2 (which is used in vaccines). Moreover, the delta variant is highly transmissible, rendering the single shot even less effective in preventing infection and disease.

This is where the second shot comes in. People who got the first shot of vaccine are given the second shot (21 days later in the case of Pfizer, 28 days later for Moderna) to increase the level, function and duration of immunity. The second dose triggers memory T- and B-cells to make even better killer T-cell and antibody responses. Because the second jab induces higher amounts of anti-bodies, even if they are not perfectly matched to the spikes on variants, they are good enough to block the virus infection. So far, the real-world data tell us that two doses of the Pfizer vaccine are 85% to 90% effective against symptomatic infection with the delta variant and that two doses of the AstraZeneca vaccines are 61%-72% effective. Studies also indicate that immune responses induced by vaccines are likely long lasting.

So, will we ever need additional booster shots in the future? It is a matter of when. It is all about keeping your immune responses above the threshold of protection against the circulating variant. Below, I share my own opinion on the need for boosters in various categories of individuals based on my own understanding of the transmission, immunology and vaccine effectiveness. This may not exactly align with what is being recommended by the Centers for Disease Control and Prevention at this time, but I hope it will inform future recommendations.

If you are immunocompetent and fully vaccinated, you may not need a booster now but will likely need a booster in the future to maintain high levels of immune defense. However, if you are immunocompromised due to cancer, transplants or HIV, a third shot of mRNA vaccines will help elevate the antibody levels above the threshold in some. Other immunocompromised persons may require extra help to prevent protection, such as monoclonal antibodies. If you are older than 65 years of age, you will benefit from the third dose of vaccine. If you received the J&J vaccine (a single shot), you will benefit from the booster (second) shot. Studies have shown that the adenoviral-vectored vaccine (like J&J) followed by an mRNA vaccine provides more robust antibody responses. Even if you are an immunocompetent, fully mRNA vaccinated person, if you are at high risk of exposure with virus (such as front-line workers and health care workers), or if you frequently come into contact with individuals at high risk of developing severe disease, a booster shot may help prevent transmission.

In addition, should a variant that further evades antibody responses arise in the future, a booster will help (see red dotted line in figure). Our work has demonstrated that a previously infected person who received two doses of mRNA vaccines has much more cross-protective neutralizing antibodies against the beta and gamma variants than those who are vaccinated without prior infection. These data suggest that a third dose of vaccine may similarly elevate antibody levels against such variants. Even if no such variants are around, an additional shot will boost the waning immune responses sometime in the future.

In theory, the booster does not have to be the same as the prior vaccine. In fact, evidence is emerging that a mix-and-match strategy may be more effective. However, more research is needed to provide a definitive answer as to the safety and optimal timing of these shots. Importantly, in addition to considering booster shots, we should be focusing on giving the first shot to the rest of the world with no access to vaccines.