For millions of vulnerable people, COVID-19 is far from over

Immunocompromised patients remain frightened and frustrated that vaccines aren’t offering enough protection as everyone else moves on. Scientists are racing to figure out what will work.

Janet Handal was feeling optimistic when she booked her flight to Texas in early 2021. The 71-year-old New York City resident had just scheduled her first COVID-19 vaccine appointment amid news that the mRNA vaccines available in the U.S. were highly effective. She carefully counted the days until she would be safe to travel, eager to see family for the first time in over 18 months.

But that optimism was short-lived.

A blood sample taken a month after her second shot revealed that Handal had developed nearly no antibodies against COVID-19. The two vaccine doses being recommended for mRNA shots didn’t confer the same robust immunity as they had for tens of thousands of vaccine trial participants. That’s because she has been on immune-suppressing drugs due to a kidney transplant she received in 2010.

“It was really a punch to the gut,” she says. “I never imagined that I was not going to be protected [in the same way].”

Handal is among the estimated 10 million people in the U.S. with a compromised immune system. Unlike everyone else, they mount a much weaker immune response to several vaccines. But when pharmaceutical companies first began testing COVID-19 vaccines in 2020 and 2021, the clinical trials excluded immunocompromised individuals and issued the same vaccination recommendations for them without conducting separate trials.

“When a new vaccine comes out, the recommendation for an immunocompromised patient is the same as that for everyone else,” says Deepali Kumar, a transplant infectious diseases physician at the University of Toronto. It isn’t until later that those recommendations are adjusted, in part because the burden of providing data for immunocompromised individuals falls on the shoulders of independent scientists, not the vaccine makers, and it can take months to years to conduct the studies. “It’s a long-standing issue,” she says.

Even now it remains unclear whether more vaccine doses will help protect the severely immunocompromised. The U.S. Food and Drug Administration authorized a third dose in August 2021 for certain immunocompromised people. Some transplant recipients have since been vaccinated with a fourth shot and a smaller subset have secured a fifth dose. But Kumar says more may not always be better, and additional studies are needed to prove that further doses are effective.

The irony is that the third dose may not have been authorized if not for people like Handal taking matters into their own hands.

Without robust protection from two shots, Handal knew her weak immune system meant greater chances of severe disease or death from exposure to the SARS-CoV-2 virus. So she and some others like her got a third COVID-19 shot—well before the FDA authorized its use. But not all immunocompromised people did, making things tricky in May 2021 as the Centers for Disease Control and Prevention was saying “no masks for the fully vaccinated.”

“I know three people myself who were transplant recipients who’ve died because they listened to the message of take your masks off,” Handal says. “Many, many, many, of us just decided we were going to get our [additional] vaccines early because we knew we weren’t protected.”

Why COVID-19 vaccines don’t work well in immunocompromised people

When our bodies receive a COVID-19 shot, the immune system springs into action. It stimulates the production of antibodies—which can bind to the virus and prevent it from infecting cells. It also activates specialized immune cells called T cells, as well as memory cells that “remember” how to respond when a COVID-19 infection occurs.

But those immune responses are blunted in immunocompromised people, including those taking immunosuppressive drugs for autoimmune diseases, organ transplants, cancers, HIV infections, and other conditions.

When a transplant patient receives an organ from another human, their immune system sees it as foreign and immediately tries to reject it. To counter these attacks doctors use immunosuppressants to dial down the activity of the patient’s immune system and stop it from attacking the new organ. “It’s always this really careful balance in leaving some of the immune system intact, obviously, and wanting to leave it suppressed enough so it doesn’t cause harm,” says Dorry Segev, a transplant surgeon at Johns Hopkins University. “But it also reduces the ability to respond to the vaccine.”

Several studies have suggested that two shots of an mRNA vaccine were grossly inadequate for several immunocompromised individuals, particularly kidney transplant recipients. One study published in May 2021 found that 46 percent of 658 kidney, lung, liver, and heart transplant individuals in the U.S. had no antibody response after receiving one or two doses of the mRNA vaccines. Compared to everyone else, transplant patients vaccinated with two doses had an 82-fold higher risk of breakthrough infections and 485-fold increased risk of hospitalization or dying.

Following a third shot, one study found that 77 out of 197 people with kidney transplants developed COVID-19-specific antibodies after producing none from two doses. In another study, 26 out of 60 organ transplant recipients who were given the third dose produced antibodies at levels nearly equivalent to those seen in people with healthy immune systems who’d gotten two doses.

But for some immunocompromised people, such as those who are older or taking certain immunosuppression drugs or high doses of it, even the third or fourth vaccine dose has proven limited.

“I have two patients who’ve had the fourth dose critically ill with COVID-19 because they didn’t mount a sufficient antibody response even with the fourth dose,” says Ayelet Grupper, a nephrologist at Israel’s Tel Aviv Medical Center. “And it’s getting more complicated—I’m not sure what level of antibodies are needed to fight against Omicron and new variants that might come.”

Like living under house arrest

Segev has been measuring post-vaccination antibody responses among organ transplant recipients, including Handal, since last year. While her blood work indicated an increase in antibody levels following a third dose in April 2021, the response was still weak compared to that seen in people with healthy immune systems.

So in October 2021—six months after her third dose—Handal got a fourth. Some of Segev’s patients still didn’t mount a robust immune response and needed a fifth shot. In a recent study, he recorded an increase in antibodies at dose five among some patients who didn’t have a sufficient response at four. “There are people out there who need two doses, there are people out there who need five doses, and there people in between,” Segev says.

But, theoretically, too many doses of the same vaccine could create a “problem of tolerance,” he says, meaning a potential lukewarm immune response following multiple vaccine doses. “Your body can say, I know this vaccine, I don’t need to do anything.”

Feeling unprotected, several of his patients have lived far more isolated lives during the pandemic than everyone else. “Essentially you’ve been living under house arrest,” Handal says. “You haven’t been able to participate in your family’s lives or be with your friends.” Getting additional shots hasn’t been easy either. It created dissonance for almost everyone who chose to do it, Handal says, especially if the shots were not yet officially authorized by the CDC and FDA.

“We are building the plane as we fly it,” Segev says, “and we’ve been doing that through the entire pandemic.”

Clinical trials spark hope

Scientists are conducting clinical trials and are exploring alternative strategies to boost the immune response for the immunocompromised.

Segev, for instance, is leading a randomized clinical trial involving kidney and liver transplant recipients who have failed to produce antibodies after two, three, or four mRNA vaccine doses and giving them an additional dose. In some participants he’s also reducing their immunosuppressive medication one week before and two weeks after giving them the additional COVID-19 shot to see if such an adjustment improves the immune response, similar to what researchers have observed in people with autoimmune diseases.

At the University of California, Davis, Transplant Center, Aileen Wang is leading a similar clinical trial specifically with kidney transplant recipients for whom the second or third mRNA vaccine doses weren’t adequate. Before and after giving an additional shot, she and her colleagues plan to halve the dose of one immunosuppressive drug called mycophenolate, which prevents the recipient’s body from rejecting a transplant organ.

Grupper, who isn’t involved in these studies, feels the research will be informative. But she emphasizes the delicate balance between increasing a transplant recipient’s immune response to the vaccine while still preventing organ rejection. Monitoring clinical trial participants’ health closely is key, she says.

As this work continues and researchers recruit more participants, transplant recipients may have to wait at least another three months, if not more, to find out if Segev, Wang, and their colleague’s approach is successful.

In the meantime, as COVID-19 continues to be a serious risk for many immunocompromised individuals, they’re also struggling to access Evusheld—the only monoclonal antibody authorized for prevention of COVID-19 in people who can’t take the vaccine due to a severe allergy or an immunocompromised condition. The intramuscular injection must be given once every six months while the virus circulates, and supplies are extremely limited. Last week the FDA revised its initial dosing regimen in light of Omicron to a higher dose.

“People have driven hours, sometimes eight to 10 hours, to get the injection,” Handal says. Alongside finding ways to access additional vaccine doses, “we’re also strategizing about how to get Evusheld.”

With several states rolling back masking mandates and pushing for a return to normalcy, Handal and others remain frustrated. “We know we’re not safe,” she says, “and there isn’t adequate treatment if you get sick.” She’s planning on getting her fifth dose very soon.

Editor's Note: This story originally misspelled the name of the transplant surgeon at Johns Hopkins University. It is Dorry Segev.

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