Plus, antibodies are not the only defense the body deploys to create immunity: We also make T cells, memory B cells, and others. The vaccine clinical trials didn’t attempt to measure the cell counts required to create an effective defense against the virus. They reported only clinical endpoints, such as whether someone became seriously ill or died from the disease. So focusing on antibodies alone may miss important parts of the immune response.
“I try not to use words like ‘you didn’t respond’ to the vaccine when someone isn’t making antibodies,” says Haidar, who is principal investigator on a larger study that is recruiting people with a range of immune deficits, including HIV, in order to study Covid vaccine response. “I worry that it might drive vaccine hesitancy if the messaging is that the vaccine isn’t working for you. I think we have to be a little more nuanced to account for the complexities that other elements of the immune system could have been revved up by the vaccines.”
Even in the few studies done so far, it’s clear that immune response to the vaccines varies, depending on the age of the patient, the type of immune deficit they are experiencing, the type of transplant they received, the specific drugs they take, the length of time since transplant or last dose, and a host of other factors. The likelihood of abundant antibody production appears higher, for instance, in patients who take immune-suppressing medications to treat chronic inflammatory diseases than it does in transplant and cancer patients. Studies done by Segev and team show better rates of antibody production in those patients after one and two doses. But a separate preprint, done by Washington University School of Medicine in St. Louis and UC San Francisco, shows a wide range of responses depending on which drug regimen a patient is taking.
That may provide a clue for managing patients’ vulnerability, so that they can get closer to the kind of immune protection that otherwise healthy people receive from Covid vaccines. “One thing we are telling patients who are in suppression, who haven’t gotten vaccinated yet, is to consider holding their medicine,” says Alfred H. J. Kim, that study’s senior author and an assistant professor of rheumatology and immunology at Washington University. “Obviously, if you hold medicines, you risk flares. And if you’re going to flare, this could make your vaccine side effects worse, or it could make the vaccine itself less effective. It’s a really tricky situation.”
And, legally, doctors currently can’t advise patients to seek extra doses of the Covid vaccine. The FDA has authorized only one or two doses for all the vaccines it has let enter the US market. For Segev’s team’s study, the doctors didn’t prescribe third doses—the patients found third doses on their own, in ways the study did not specify. The Hopkins team tracked the results.
Still, there’s some evidence in medical literature to support the utility of additional doses. For instance, the French government has recommended a third dose for anyone who is immunocompromised. And in the US, it’s been understood for years that a second dose of seasonal flu vaccine and larger doses of hepatitis B vaccine are required to create immunity in them.
But it will be necessary to gather more data to be sure. The Hopkins team is contemplating a larger trial in which immunosuppressed patients seeking third doses would be enrolled and tracked in a formal way. And despite the allure of higher protection, they’re not urging immune-damaged patients to start freelancing their own third shots. “There are risks to taking third doses,” Segev says. “There is a risk the third dose will activate your immune system and cause either an overt rejection or some sort of subclinical thing, where you start to develop a little more antibodies against your transplanted organ. It’s important that people who do go out and get third doses are either part of research protocols or are doing this in collaboration with their doctors who have evaluated the risks and benefits.”
If trials like this can yield data—another one, recently announced, is being conducted by the National Institutes of Health—they could do more than let the immunocompromised get back to everyday life. They could also illuminate aspects of the immune system and its interaction with vaccines that are still not very well understood. And that will be of benefit not just during this pandemic but for whatever we need to protect ourselves against next.
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