With SARS-CoV-2 still infecting, sickening, and killing a staggering number of people worldwide, and only limited quantities of recently authorized vaccines available, countries are considering ways to vaccinate more people as quickly as possible.
One way to achieve this is to overcome logistical hurdles that have hampered the administration of available vaccine. Another way is to stretch the vaccine supply. As strategies for doing this are being considered and, in some cases, implemented, it has spurred debate among scientists about whether it is wise to stray from the precise regimens that were studied in clinical trials, and how doing so may affect the overall efficacy of the vaccines.
At the end of last year, the U.K. announced that it would allow a gap of up to 12 weeks between administering the two doses of two COVID-19 vaccines—an mRNA-based vaccine developed by Pfizer/BioNTech and a chimpanzee adenovirus vector-based vaccine developed by AstraZeneca and Oxford University.
Recently, there was also discussion among U.S. scientists and the company Moderna
about cutting the two doses of their mRNA vaccine in half for people ages 18-55 in an effort to double the available doses. This suggestion was based on data from earlier stage clinical trials of this vaccine.
For now, the U.S. Food and Drug Administration (FDA) is opposed to any changes to the dosing regimens. In a statement
issued on January 4th
, the agency, which granted an Emergency Use Authorization to both the Pfizer/BioNtech and Moderna mRNA COVID-19 vaccines in December, said that altering the dose, reducing the number of doses, or extending the time between doses of these vaccines are reasonable questions to consider and evaluate in clinical trials. “However, at this time, suggesting changes to the FDA-authorized dosing or schedules of these vaccines is premature and not rooted solidly in available evidence.” The AstraZeneca vaccine has not been submitted to the FDA yet for authorization, however, it was authorized already in the U.K., India, and other countries.
But others argue that these strategies to free up more vaccine are warranted given the terrifying course of the pandemic. “As long as there is a shortage of vaccine, protection of the largest number of people against death and disability in the shortest time should take priority over formalism and insufficiency of conclusive data,” says Stanley Plotkin, veteran vaccine developer, Emeritus Professor of Pediatrics at the University of Pennsylvania, and founding board chair of the Human Vaccines Project. “This is an emergency, not a time to stick to routine rules.”
Furthermore, Plotkin argues that there is actually an immunological benefit to delaying vaccine doses. “The optional delay for non-live vaccines is four to six months,” he says.
Thomas Evans, Chief Scientific Officer and Board Director of Vaccitech, who was involved in the development of the AstraZeneca vaccine, agrees. “The longer the interval, the better the boost you’re going to get. You can’t show me any case where waiting doesn’t give you a higher boost,” says Evans.
Most vaccines are administered in two or more doses. The first acts as a prime, gearing up the immune system to produce various infection-fighting cells, including B cells that can produce antibodies that are effective at neutralizing the virus. The booster vaccination, administered sometime later, augments this process and typically stimulates the production of even more virus-specific antibodies.
This is true for the COVID-19 vaccines that are now available. “We know there is a big jump in the antibody response after the second shot,” says Mark Slifka, professor at the Oregon National Primate Research Center. This response peaks, then goes through a period of decline before plateauing. Researchers suspect that neutralizing antibodies are the reason these COVID-19 vaccines are effective, but they do not know what level of antibodies correlate with this efficacy. The goal is to have the antibody levels plateau at a level above that which is required for protection.
Evans cites a study by Shane Crotty
of the La Jolla Institute for Immunology and colleagues that shows that memory B cells specific to SARS-CoV-2—the type a vaccine would ideally induce as they are long-lasting cells that can quickly reactivate in the future— increase in frequency for the first 120 days following natural infection, before plateauing, which, he says, suggests that boosting after a longer time interval would be even more effective.
This was, in fact, what was observed with the AstraZeneca vaccine. Sub-group analyses indicate that vaccine efficacy was actually higher among volunteers who received the second vaccine dose later rather than sooner, according to the Public Assessment Report
issued by the U.K.’s Medicines & Healthcare products Regulatory Agency. Volunteers received two doses of the AstraZeneca vaccine at intervals between 4 to 26 weeks apart. Efficacy was higher if the second dose came 8 to 11 weeks after the first, and, was higher still among volunteers who received the second dose of vaccine more than 11 weeks after the first. Data suggest dosing interval was a more significant factor in determining efficacy of this vaccine than dose.
The benefits of delaying the second dose of the mRNA vaccines are less clear given these are the first vaccines of their kind ever authorized. Yet, Evans is confident that there would be a better boosting response for these vaccines too if the second shot is delayed longer than the three or four weeks it was in the Pfizer/BioNTech and Moderna studies, respectively. “I’m in favor of what they’re doing in England,” he says.
Slifka agrees that increasing the time between vaccinations with more traditional vaccines, including those that use a live or weakened virus or a viral protein to spur an immune response, generally improves the overall immune response. But when it comes to mRNA vaccines, he isn’t so sure. “There is a risk for the mRNA vaccines of losing vaccine efficacy if the second shot is delayed, with the bottom line being we just don’t know,” says Slifka.
John P. Moore, professor of microbiology and immunology at Weill Cornell Medicine, also argued against altering the FDA-approved COVID-19 vaccine regimens. He shared his thoughts in a recent commentary on a blog of the BMJ
. “Some flexibility in timing the second dose would be appropriate, but vaccine failures will surely increase with the length of delay,” he wrote. Moore called the clinical trial evidence to support delaying the second dose of the Pfizer/BioNTech and AstraZeneca vaccines, or even allowing for two doses of different vaccines, “flimsy or non-existent.”
Slifka notes that it took about 10-12 days for the protective immune response to build up after the first shot of the Pfizer/BioNTech vaccine. Given the booster was administered three weeks after the primary dose in the efficacy trial, there isn’t really any data on how long the initial, priming immune response will last. “Especially with these new mRNA vaccines, there isn’t enough information in human subjects about how durable the immune responses are between a primary vaccination and a boost. These aren’t traditional vaccines and so there is still a lot that we need to learn.”
Moore notes that if the immune response after a single dose is poorly protective, it could drive the emergence of resistant viral variants in infected vaccine recipients. Viral variants that are now circulating around the globe are already raising concerns
Altering regimens from what was ultimately found to be effective could also sew mistrust among the public. “Making such changes that are not supported by adequate scientific evidence may ultimately be counterproductive to public health,” according to the FDA’s statement.
With SARS-CoV-2, Slifka and Evans both say that the dosing interval was largely chosen based on the urgency to develop and test vaccines, and not immunologic mechanisms. However, Evans says that these are the types of questions that need to be studied so that decisions about optimal doses and dosing intervals in the future are based more on immunology, and less on empirical data.
There are various factors that may explain why boosting improves the immune response, but, like many things in immunology, the precise mechanism isn’t fully understood. “We don’t understand how boosts work,” Evans says. “I don’t know the answer, but the answer is to do the right science. We need to think about dosing and boosting in a more immunological way.” And this is exactly what he’s submitted a recent grant proposal to do.
In the meantime, Johnson & Johnson is expected to report efficacy data this month from the Phase III trial of their viral vector-based COVID-19 vaccine, which has the distinct advantage of being a single shot. This could offer logistical advantages and help bolster vaccine supply. But Slifka and Evans are skeptical that the durability of the immune responses induced by a single-shot vaccine will be as favorable. “I don’t think it’s going to be sufficiently durable,” Evans says, predicting that they will likely have to go back and administer a booster shot. For that, only time will tell.
By Kristen Jill Abboud