Vaccines against the virus that causes COVID-19 play a critical role in addressing the ongoing pandemic. For those of us with normally functioning immune systems, vaccines have all but assured us that we will not ultimately die from this terrible virus, and have even given us some comfort that our chances of getting COVID-19 can be quite low — if we follow other guidelines like masking indoors in public places.
Sadly, there are millions of people in the United States who have not been able to celebrate the magic of COVID-19 vaccines. This is because vaccines rely on myriad components of the immune system to do their thing, and many people lack some of these components, including people with conditions that directly impact the immune system as well as those who take medications to purposefully suppress the immune system. But as of this week, thanks to a recent Food and Drug Administration (FDA) authorization and Centers for Disease Control and Prevention (CDC) guidance, our vulnerable family and friends and neighbors might have some renewed hope.
Disheartening evidence has been mounting since March that solid organ transplant recipients have suboptimal responses to COVID-19 vaccines. While the vaccines are generally considered safe and recommended in this population, only 17 percent of transplant recipients had detectable anti-spike antibodies after a first dose of mRNA vaccine (in stark contrast to 100 percent of people with normally functioning immune systems), only 54 percent had detectable antibodies after a full 2-dose series of mRNA vaccine, and only 17 percent had detectable antibodies after receiving the Janssen adenovirus vaccine. This translates to an 82-fold higher risk of breakthrough infection and 485-fold higher risks of breakthrough infection with associated hospitalization and death in fully-vaccinated transplant recipients compared to the fully-vaccinated general public.
Similar evidence exists for other immunosuppressed populations, including those with rheumatic and musculoskeletal diseases such as systemic lupus erythematosus, those with hematologic malignancies, those undergoing treatment for solid tumors, those with inflammatory bowel disease, among a number of other conditions delineated by the recent CDC guidance.
In the context of suboptimal protection, immunosuppressed people started taking matters into their own hands, seeking additional doses in the hopes of activating more robust immune responses. This makes intuitive sense: If 17 percent of transplant patients had antibodies after one dose and 54 percent after two doses, then perhaps more would have antibodies after three doses. By June, enough people had gone down this road that we were able to study their immune responses, and it turns out that they were right — kind of.
Among transplant recipients who reached a low-positive level of antibodies after two doses, all were boosted to high-positive after a third dose. And even among those who started negative, for whom some might have lost hope, 33 percent reached positive antibody levels after the third dose — but 67 percent did not. These findings were subsequently confirmed in reports from France and Canada.
In addition to increasing antibody levels, there is new evidence that that third doses can also increase neutralizing capability versus variants of concern, including the Delta variant, and there is a new NIH-funded clinical trial aimed at better understanding these deeper immune responses.
The term "booster" has been loosely attributed to any additional vaccine beyond the established regimens. People who did not achieve a good immune response initially need what might be termed a supplement booster: additional doses to get their immune response to the level that those of us with normally functioning immune systems achieved with two doses. This type of boosting is urgent given the strong evidence that immunosuppressed people had suboptimal immune responses which translate to much higher risk of infection and severe consequences. And it is this type of boosting that FDA and CDC have recently authorized and recommended.
Not everyone needs a supplement booster, but it is very likely that everyone will ultimately need a durability booster: a reminder to our immune system to keep up the good work protecting us from COVID-19, a confirmation that we're not done with this virus any time soon. When the strong initial immune response will wane, and in whom and at what point we need a re-up, remains a very active area of study.
It is also very possible that the virus will mutate to the point that the original vaccines are less relevant, and at that point we may need a variant booster: a vaccine redesigned to detect and attack a new protein sequence that better characterizes a new variant. Fortunately, the current vaccines seem to remain quite powerful against the Delta variant, but other variants are no doubt around the corner.
Helping the immunosuppressed reach a level of immune response comparable to those with normally functioning immune systems is critical and high-priority: Without this, we are denying millions of people the opportunity to fully benefit from the magic of vaccination. The FDA and CDC are commended for their nimble and thoughtful response to the growing evidence, paving the way for individualized risk/benefit decisions between people and their medical teams — and hopefully the development of organized and efficient distribution logistics to help with the inevitable future boosters for all of us.
Dorry Segev, MD, Ph.D., is a professor of surgery at Johns Hopkins University School of Medicine and Professor of Epidemiology at Johns Hopkins Bloomberg School of Public Health. Segev has been leading an observational study of COVID-19 vaccine responses in immunosuppressed people since December 2020 and is the principal Investigator of the NIH/NIAID-funded interventional trial "COVID-19 Protection After Transplantation (CPAT)." Follow him on Twitter: @dorry_segev