A few months ago, transplant surgeon Dorry Segev was despondent about how COVID-19 vaccines were performing in patients like his, who have a donated organ and take powerful drugs to suppress their immune system. After one dose of a highly effective messenger RNA (mRNA) vaccine, for example, just 17% of those patients churned out protective antibodies against the pandemic coronavirus, and after the standard two doses, only 54% did. The very medications his patients took to protect their transplanted organ precluded them from mounting a healthy immune response after the vaccine. Even people who did make the antiviral antibodies often had very low levels, raising questions about how well they were shielded from COVID-19.
But now Segev, at Johns Hopkins University, has become cautiously optimistic. He and his colleagues have found that a third dose of vaccine may help: Among 24 organ transplant patients who had no antibodies after two doses, eight people generated protective antibodies after they sought out a third on their own. Six people who had few antibodies against the coronavirus after two doses all wound up with high levels after a third shot, the researchers reported today in the Annals of Internal Medicine. Although Segev didn’t conduct a systematic study—the 30 patients got combinations of different vaccines at different time intervals—“this gives hope, which is critical right now,” he says. “There is some encouraging evidence that we will be able to help the immune system do what it needs to do.”
The organ transplant recipients are participants in a research project Segev and his colleagues are running, studying COVID-19 vaccine responses in people with compromised immune systems. In this case, “We just got emails from people saying, ‘Hey, I’m getting a third dose, do you want my blood?’” Segev says. He jumped at the opportunity. (In the United States, determined individuals can secure extra vaccine doses despite the current authorized mRNA vaccines using just two.)
Segev’s study is the first to report outcomes after a third dose of vaccine, and it’s part of a broader discussion about whether and when to offer extra doses to vulnerable individuals. In France, health officials in April recommended a third dose for all of the country’s organ recipients. Because of that policy shift, 383 kidney transplant recipients at Strasbourg University Hospital have received a third dose of Moderna’s mRNA vaccine, and doctors have antibody results for 184 of them. Although the results aren’t yet published, they roughly match Segev’s small cohort: Twenty-eight percent of the French patients who had no antibodies after two doses developed them after the third shot, and 82% who had a weak reaction after two shots had a stronger response after the third, says Sophie Ohlmann, a nephrologist at the hospital.
In the United States, people with organ transplants number about 500,000, but they aren’t the only ones worrying about how well the vaccines are working for them—others include people with autoimmune diseases and those with cancer who got COVID-19 vaccines while their immune system was suppressed by chemotherapy. “It wouldn’t surprise me to see that higher doses work, but we have to do it systematically and find out,” says Deepali Kumar, director of transplant infectious diseases at Toronto General Hospital.
She argues that clinical trials studying third doses are crucial to provide clarity on ideal timing and potential risks in vulnerable populations. One of her concerns is whether an extra dose of vaccine, which revs up the immune system, could induce rejection of a donated organ; in Segev’s study, a heart transplant patient had a mild rejection episode 1 week after her third dose, though doctors can’t say whether it was linked to the additional dose. She recovered without incident.
Kumar expects results in July from a clinical trial she’s running in 120 transplant patients, only about one-third of whom had any antibodies after two doses of Moderna’s vaccine. The trial provided one-half of all participants a third dose 2 months after their second shot, and the rest got a placebo injection.
In Germany, 11 centers running a COVID-19 vaccine study are recruiting volunteers with a range of conditions that, by their nature or because of their medications, can affect immune functioning, including people with transplanted organ or autoimmune diseases, and those on kidney dialysis. Researchers will study antibodies and T cells after the second dose of vaccine, and may eventually offer some participants a third vaccine dose, says Leif Erik Sander, an infectious disease expert at the Charité University Hospital in Berlin, who is helping lead the work. And Segev is in discussions with the National Institutes of Health to start a trial this summer in transplant patients.
“We have a strong biologic rationale for a third dose in specific populations,” says Ravi Parikh, a health policy researcher and medical oncologist at the University of Pennsylvania. His patients haven’t asked him yet about third doses, but he imagines himself supporting that strategy for some.
When it comes to people with cancer, Parikh is not deeply worried about the effectiveness of two doses. Last month, a study in JAMA Oncology reported that 90% of a group of cancer patients on chemotherapy and other drugs produced antibodies after two doses of Pfizer’s mRNA vaccine. (Parikh co-wrote a commentary accompanying that paper.) Another study in Cancer Cell this month reported that 94% of 200 cancer patients had antibodies after vaccination. Those numbers are “excellent news,” says Salomon Stemmer, a medical oncologist at Tel Aviv University who led the JAMA Oncology study.
But in Stemmer’s cohort of 102 patients on treatment, antibody levels were between one-quarter and one-third of their healthy family members’ after they got a vaccine. The difference doesn’t strongly concern Stemmer, but because the level of SARS-CoV-2 antibodies declines naturally over time, he wonders whether they may drop worryingly low in cancer patients sooner, because they start from a lower level. Parikh agrees this is a big question: “We don’t know how quickly these antibody titers are going to fall,” he says.
Stemmer is continuing to follow his cohort and plans to test antibody levels every 2 to 3 months. He also wants to learn more about the small group of patients that produced no antibodies to SARS-CoV-2 at all: They include three women with breast cancer getting “dose-dense” chemotherapy, which means less time between treatments. Third vaccine doses might be helpful in some cases, but Stemmer says he would only offer them as part of a clinical trial.
Segev hopes more information to help these populations will come soon. Right now, he acknowledges, “There is a lack of guidance and a lack of knowledge.” In the meantime, Segev recognizes that some people may prefer to take matters into their own hands, whereas others would eagerly join a clinical trial—though he urges anyone considering a third vaccine dose to speak to their doctor first. “Whatever is happening out there, we are going to learn from as much as we possibly can,” he says.