When it came to coronavirus vaccination, the third time was the charm for Esther Jones, a dialysis nurse in rural Oregon. After two doses of the Pfizer-BioNTech vaccine failed to jolt her immune system into producing antibodies, she sought out a third, this time the Moderna shot.
It worked. Blood tests revealed a reasonable antibody response, although lower than what would be detected in healthy people. She received a fourth dose last month in hopes of boosting the levels even more.
Ms. Jones, 45, had a kidney transplant in 2010. To prevent rejection of the organ, she has taken drugs that suppress the immune response ever since. She expected to have trouble responding to a coronavirus vaccine, and enrolled in one of the few studies so far to test the utility of a third dose in people with weak immune systems.
Since April, health care providers in France have routinely given a third dose of a two-dose vaccine to people with certain immune conditions. The number of organ transplant recipients who had antibodies increased to 68 percent four weeks after the third dose from 40 percent after the second dose, one team of French researchers recently reported.
The study in which Ms. Jones enrolled has turned up similar results in 30 organ transplant recipients who procured third doses on their own.
Being vulnerable to infection even after inoculation is “very scary and frustrating” for immunocompromised people, said Dr. Dorry Segev, a transplant surgeon at Johns Hopkins University who led the study. “They have to continue to act unvaccinated until we figure out a way to give them better immunity.”
But in the United States, there is no concerted effort by federal agencies or vaccine manufacturers to test this approach, leaving people with low immunity with more questions than answers. The Centers for Disease Control and Prevention, the Food and Drug Administration and the National Institutes of Health in fact recommend even against testing to find out who is protected. And academic scientists are stymied by the rules that limit access to the vaccines.
“There should be already a national study looking at post-transplant patients getting booster shots,” said Dr. Balazs Halmos, an oncologist at the Montefiore Medical Center in the Bronx, who led a study showing that some cancer patients did not respond to the vaccines. “It shouldn’t be our little team here in the Bronx trying to figure this out.”
An estimated 5 percent of the population is considered to be immunocompromised. The list of causes is long: some cancers, organ transplants, chronic liver disease, kidney failure and dialysis, and drugs like Rituxan, steroids and methotrexate, which are taken by roughly 5 million people for disorders from rheumatoid arthritis and psoriasis to some forms of cancer.
“These are the people being left behind,” said Dr. Jose U. Scher, a rheumatologist at NYU Langone Health who led a study of methotrexate’s effect on the vaccines.
Not everyone who has one of these risk factors is affected. But without more research, it’s impossible to know who might need extra doses of the vaccines, and how many. Besides the risk of Covid-19, there is also evidence that low immunity may allow the virus to continue to replicate in the body for long periods, potentially leading to new variants.
An infusion of monoclonal antibodies may help some people who don’t produce antibodies on their own — but again, the idea is not being thoroughly explored, said John Moore, a virologist at Weill Cornell Medicine in New York.
Use of monoclonal antibodies “makes great sense for this group of people, so I would like to see the companies be more active in this area,” he said. “Government support or pressure would also help.”
The third-dose approach has widespread support among researchers because there is clear precedent. Immunocompromised people are given booster doses of vaccines for hepatitis B and influenza, for example. And discontinuing methotrexate after getting a flu vaccine is known to improve the vaccine’s potency — evidence that compelled the American College of Rheumatology to recommend pausing methotrexate use for one week before being immunized against the coronavirus.
Several studies have indicated that a third coronavirus vaccine dose might succeed in patients who did not have detectable antibodies after the first or second dose. But research has lagged.
Moderna is gearing up to test a third dose in 120 organ transplant recipients, and Pfizer — which produces some immunosuppressant medications — is planning a study of 180 adults and 180 children with an immune condition.
The companies turned down at least two independent teams who hoped to study the effects of a third dose.
The N.I.H. is recruiting 400 immunocompromised people for a trial that would track their levels of antibodies and immune cells for up to 24 months — but has no trials looking at a third dose.
“It takes time, unfortunately, especially as a government agency,” said Emily Ricotta, an epidemiologist at the National Institute of Allergy and Infectious Diseases. “We have to go through a lot of regulatory and approval processes to do these sorts of projects.”
But that explanation does not satisfy some researchers. Many medical centers already have groups of patients who did not respond to the vaccines, so federal agencies could organize a clinical trial without too much difficulty, Dr. Scher noted. “It’s a very simple study,” he said. “There’s no rocket science here.”
Earlier studies suggested that many people with cancer would not respond to the vaccines, but those analyses were done after the patients had received a single dose. A new study published this month by Dr. Halmos of Montefiore Medical Center and his colleagues laid some of those fears to rest. The vaccines seem to work well in patients with a wide range of solid and liquid tumors, according to the large analysis.
But 15 percent of those who had blood cancers and 30 percent of those who took drugs that suppress the immune system had no detectable antibodies after the second dose. Dr. Halmos said he and his colleagues were eager to test whether a third dose could benefit those individuals, but have not yet been able to gain access to the vaccines.
Dr. Segev’s team found in an earlier study that less than half of 658 organ transplant recipients had measurable antibodies after both doses of an mRNA vaccine made by Pfizer-BioNTech or Moderna. But to follow up on the finding, they had to resort to recruiting volunteers like Ms. Jones who had obtained third doses on their own.
The scientists found that a third dose amped up antibody levels in all 30 organ transplant recipients who had low or undetectable levels of antibodies.
Ms. Jones said many people like her felt they had been abandoned by the federal government — especially with the threat of more contagious variants circulating in the United States.
Some members of a Facebook group for immunocompromised people desperate for protection have gotten a third dose at mass vaccination sites where providers don’t check records, or have even crossed state lines, she said. Even so, most continue to wear masks to protect themselves — and have sometimes had to endure harassment as a result.
“It really saddens me that so many people in this world have made masking like, this super political thing when it should never have been,” she said. “It makes it so it’s harder for us to take care of ourselves.”