The COVID-19 pandemic made plain what many patients, clinicians and researchers have known for decades: people with weakened immune systems are much more vulnerable to infectious diseases. But immunocompromised patients are usually left out of large clinical trials that assess new treatments and vaccines, leaving a data gap that hampers clinical care.
On September 10, experts across disciplines, from infectious disease clinicians to regulators to representatives from the pharmaceutical industry, convened at the inaugural ImmunOptimize workshop in Bethesda, MD, to brainstorm strategies to address the unmet needs of immunocompromised patients.
“We need roots, not parachutes,” said Fred Hutch Cancer Center infectious disease expert Joshua Hill, MD, who headed the ImmunOptimize scientific committee. “We need a grassroots effort to address the unmet needs of immunocompromised patients. The time is right to bring the conversations to the forefront.”
According to the National Health Interview Survey conducted in 2021, about 7% of the U.S. population — or over 23 million people, a smidge more than the population of Florida — are immunosuppressed. A likely underestimation, this number has more than doubled since 2013.
But despite their swelling numbers, these patients are still shut out of lifesaving advances in infectious disease treatment and prevention.
“Our goal: How we can improve timely evidence generation for therapeutics to improve prevention and treatment of infectious diseases in immunocompromised individuals,” Hill said.
At the workshop, stakeholders from academia, industry and government, including the U.S. Food and Drug Administration and the National Institutes of Health discussed how to bridge the data gap that leaves immunocompromised patients and their clinicians unable to make evidence-based treatment decisions.
A clinical trials network, dedicated to testing drugs and vaccines against infectious diseases in immunocompromised patients, is the most pragmatic solution, experts argued. Such a program would offer the funding and administrative support necessary to support the scientists and clinicians who design, conduct, recruit for and analyze clinical trials.
The day after the workshop, a cadre of infectious disease specialists, patient representatives, and operations experts also discussed the scale of the problem — and the potential power of a clinical trials network — with select congresspeople and congressional staffers.
“We have the passion … these are the most vulnerable patients we see every day. We know the unmet need, we know there are a lot of gaps,” said workshop attendee and panelist Roy Chemaly, MD, MPH, chair of Infectious Diseases, Infection Control and Employee Health at the University of Texas MD Anderson Cancer Center. “We want to make sure during our lifetime that we’re making a difference for our patients.”
In the first wave of the COVID-19 pandemic in 2020, bone marrow transplant (BMT) recipients, whose immune systems are severely weakened by their cancer treatments, faced an up to 30% chance of dying within a month of an infection with SARS-CoV-2.
“That’s both striking and shocking,” Hill noted. “It was higher than the risk for 70- to 80-year- olds.”
BMT patients, whose immune systems must be reestablished after transplant, are among the most severely immunocompromised. But they’re not alone: solid organ transplant patients receive lifelong immunosuppressive drugs to prevent organ rejection. Advances in therapies for autoimmune conditions like rheumatoid arthritis and lupus, and some new cancer immunotherapies, can also leave patients with depressed immune function.
Although these patients need vaccines and antimicrobial drugs more than anyone, doctors often don’t have the data they need to make strong recommendations about regimens and dosage.
The COVID-19 pandemic highlighted this longstanding problem, said Michael Boeckh, MD, PhD, who heads Fred Hutch’s Infectious Disease Sciences Program.
“There were fantastic vaccine trials conducted with unprecedented speed, but immunocompromised patients were left out,” he said. Without data, clinicians had to make up recommendations.
“COVID brought it to the forefront, but it’s what we who work in the field have been dealing with for a long time,” Boeckh said.
He recalled a young mother he successfully treated for a blood cancer a few years before SARS-CoV-2 swept the globe. After recovering from her bone marrow transplant, the woman returned to her home in rural Washington state. But when she became infected with a common cold virus, it quickly progressed into pneumonia. Despite being air-lifted to a major medical center, she died.
“I call this a tragedy, but it happens every day to immunocompromised patients,” Boeckh said.
As more people receive cancer treatment, organ transplants and immune-suppressive drugs for autoimmune disorders, the number of people who are highly vulnerable to infection is growing.
“You can’t always tell by looking who is immunocompromised,” said Fred Hutch Medical Director for Infection Prevention Steven Pergam, MD, MPH. “Even riding the elevator in a cancer center, I can’t always tell who is the patient. And yet, this feels like a discarded population — despite them being everywhere in our society.”
Cancer survivors and those living with organ transplants and autoimmune diseases have jobs and families just like anyone with a robust immune system; they usually don’t have the luxury of hiding away from infection. And the COVID-19 pandemic showed us how damaging the long-term emotional effects of isolation can be.
A cancer survivor and organ transplant recipient himself, Pergam knows firsthand how dangerous — but necessary — social interaction is for people with weakened immune systems. As an essential health care worker and head of infection prevention at Fred Hutch, he masked up and went into work every day during the pandemic.
“I knew from early data the rate of mortality [from COVID-19] in solid organ transplant patients was 20%. Still, as a transplant recipient, I did what I could to take care of patients. I couldn’t say, ‘No, I’m not doing this,’” Pergam said.
And even the most robust precautions may not be enough.
After a startling diagnosis of lymphoma just after her 28th birthday, Kaley Karaffa, JD, now a patient advocate and volunteer in Fred Hutch’s Patient and Family Engagement Program, did what she could to prevent infection.
“I found out, I’m not only a cancer patient, but I’m also immunocompromised,” said Karaffa, who was diagnosed in 2014 and is now in remission.
To protect herself, Karaffa upended her life: She minimized contact with her friends, family and even her dogs, halted travel, and had to forego her volunteer work as a court-appointed guardian for children in the foster care system.
“I had to all of a sudden stop doing all of the things that really brought me joy,” Karaffa said. But despite her precautions, she still contracted an infection that nearly derailed her care and put her life at risk.
People with weakened immune systems are usually excluded from clinical trials testing infection-preventing vaccines or infection-treating drugs. The few trials that do include immunocompromised patients tend to be too small to allow for recommendations that rise to the level of regulatory approval for inclusion in labeled indication from the FDA.
This means that when doctors need to make recommendations, they’re often left making educated guesses.
Karaffa felt lucky when she was able to participate in a novel clinical trial for her lymphoma, but days before a critical imaging procedure that would determine her future on the trial, Karaffa became severely neutropenic and spiked a high fever.
She recalled a moment during her eight-day hospitalization, when her doctors had tried every test and every treatment and still had no idea how to tackle the microbe that had infected her — or even what it was.
“I could see the panic in their eyes,” Karaffa said. “I knew they were diligent, and they really cared about me. … But all I could do was put my hope in their dedication.”
But even when she had recovered enough to go home, Karaffa wasn’t safe to continue her treatment. It was delayed by over a month — nearly long enough to disqualify her from the trial. Luckily, Karaffa was able to continue her trial participation with just days to spare and went into remission in 2015.
The small amount of data that researchers do have underscores one thing: vaccines and drugs don’t work as well in immunocompromised people as they do in people with robust immune systems. But without data, doctors don’t know whether to recommend that an individual patient get more doses, stronger doses or both. Or perhaps a different treatment or vaccine will work better — but who can say?
— Fred Hutch's Medical Director of Infection Prevention Dr. Steve Pergam
Natasha Halasa, MD, MPH, professor of pediatric infectious diseases at Vanderbilt University Medical Center who heads the Vanderbilt Infection Surveillance and Prevention Program (VISPR), understands how important the right regimen can be.
One of Halasa’s patients, a young girl, was cured of her inherited immune deficiency with a bone marrow transplant. But during her recovery, the girl developed mild graft-vs.-host disease. The steroids used to treat her GVHD put her at higher risk of infection. She received only a single shot of the standard-dose flu vaccine despite recent data that two doses of an available high-dose vaccine worked better.
She caught the flu, then developed a secondary pneumococcal infection, from which she died.
“For us [her care team], that was devastating,” said Halasa, who co-chaired a workshop session and presented to elected representatives and congressional staffers. “She’d received a lifesaving transplant, she’d been cured of her immune deficiency and then died of two vaccine-preventable diseases.”
Hill noted that there are new vaccine approaches on the horizon, such as self-replicating versions of the mRNA vaccines developed against COVID-19. Immunocompromised patients need access, and a trials network would help scientists build and sustain the momentum needed to advance the field, he said.
“We can’t leave these patients behind again,” Hill said.
Better options to prevent and treat infections will save lives and improve quality of life for people with weakened immune systems, who are also at higher risk for complications from infection. It will have positive downstream effects for society as well, experts argued.
A study of Medicare claims showed that of people admitted to the hospital for acute respiratory infections, 32% had an immunosuppressive condition, Hill noted. This disproportionate use of health care resources could be eased by prevention and treatment regimens developed with immunosuppressed people in mind.
The cost of lifesaving treatments like organ transplants dwarf the cost of a flu vaccine, but often insurance won’t cover a different regimen for immunocompromised people. This arises directly from the lack of clinical trial data, said Massachusetts General Hospital infectious disease specialist member Camille Kotton, MD. The Advisory Committee on Immunization Practices, on which Kotton sat, reviews clinical trial and other vaccine-related data to make recommendations to the Centers for Disease Control and Prevention (CDC).
Kotton, who is clinical director for MGH’s Transplant and Immunocompromised Host Infectious Diseases program, noted that the CDC does not conduct clinical trials: ACIP analyses are limited to data from trials conducted by others. Without data generated in specialized groups, ACIP members can’t recommend different dosing regimens that meet these groups’ needs. The FDA, in turn, can’t approve a special regimen without trial data, and insurers won’t cover it.
Pergam also reviews trial data and makes vaccine recommendations as a member of an important FDA committee.
“I was glad to vote to approve vaccines [for COVID-19 and RSV],” he said. “But it’s hard when I don’t know if they will protect my immunocompromised patients. I don’t even know if they’ll protect me.”
While a high-dose flu vaccine was approved for people over 65, a 30-year-old BMT patient would have to pay out of pocket for the higher dose that would be more likely to offer some protection.
“We spend hundreds of thousands to protect people from cancer, but we won’t spend $200 to protect them from infection,” Pergam said.
This can put patients already strapped by expensive treatments in a difficult financial position, he noted: “People sometimes have to decide between protecting themselves from infection and putting food on the table.”
Protecting immunocompromised people is also a key consideration for those hoping to strengthen the response against the next pandemic. This would relieve the burden on the health care system but also help reduce development of new strains.
It’s likely that new SARS-CoV-2 strains arose in people whose immune systems could not clear the virus, which allowed it to mutate in ways that enabled further spread.
“And there are data showing that as our world becomes more global, there are increased opportunities for epidemics and pandemics to hit,” Hill said. “And so you've got this almost explosive combination as the population of immunocompromised individuals grows.”
At the workshop, experts agreed: immunocompromised patients need a clinical trials network, supported by a solid partnership between academic and industry interests, dedicated to assessing the best ways to treat or prevent infection.
Right now, though dedicated clinical trial networks exist, none are focused on preventing and treating infectious diseases in people with weakened immune systems. For example, the National Cancer Institute’s National Clinical Trials Network focuses on testing cancer treatments and the HIV Vaccine Trials Network tests HIV vaccines and preventive therapies. Infectious diseases in the broader community of immunocompromised patients fall through the cracks.
Individual investigators have attempted to fill the gap in data, but without the infrastructure and expertise offered by a trials network, it’s slow going.
During the COVID-19 pandemic, physicians and scientists learned firsthand how much the lack of data — and accompanying prescription restrictions — can hamper patient care. At the time, the terms of Paxlovid’s Emergency Use Authorization meant it could only be prescribed for five days in an outpatient setting.
One of Hill’s blood cancer patients had received an immunotherapy that weakened his body’s virus-fighting ability. After he first tested positive for COVID-19, the virus smoldered in the patient’s body for months. Hospitalized and receiving supplemental oxygen, he wasn’t eligible for Paxlovid under the EUA. Hill also suspected that five days wouldn’t be enough to quell the virus.
Over the course of three days, Hill and Fred Hutch and University of Washington colleagues across different hospital teams mobilized to submit a complex application to the FDA to give this individual patient a longer course of Paxlovid.
“We gave him a 20-day course of Paxlovid, and his symptoms went away without recurrence — but it was a Herculean effort,” Hill said. “It’s not sustainable to do that for every patient.”
Vanderbilt's VISPR director Halasa also recognizes the need for a national, well-funded and dedicated trials network. Such a network would provide the kind of data that could have expanded Paxlovid’s EUA recommendations to include immunocompromised patients.
“Right now, we’re reinventing the wheel every time,” Halasa said. “Through this eye-opening workshop and speaking with elected representatives and congressional staffers, I appreciate the value of a national network.”
VISPR aims to define and reduce the local and international burden of acute respiratory and gastrointestinal infections in children, particularly infants and immunocompromised children.
Twenty years ago, when she first attempted to generate vaccine data for immunocompromised patients, “there was no network — the network was my friends,” Halasa recalled.
She and VISPR researchers have completed trials seeking the optimal influenza-preventive vaccination strategy for children and adults who have received bone marrow or solid organ transplants.
“We showed that in bone marrow transplant patients, two doses of high-dose vaccine are superior to two doses of standard dose — but we realized we still don’t know the best strategy early in the transplant period,” she said.
Halasa has secured three NIH awards to address that question in adult and pediatric BMT patients and in lung transplant patients.
“We’ve been doing these types of studies for over a decade, but this concept started in 2019, and now, five years later, we’re about to enroll our first patient,” Halasa said. “We might not have an answer for another four years.”
But with the established infrastructure and experts of a trial network, Halasa estimates that the trials she has planned could be conducted concurrently, perhaps in as little as one year. And, such a network could enable the equally important dissemination of trial results to the clinicians making treatment and preventive recommendations, she said.
The ImmunOptimize workshop and concept is following a similar path lead by BMT experts that helped spur the formation of the NIH-funded Blood & Marrow Transplant Clinical Trials Network. Hill compared the state of clinical trials for infectious diseases in immunocompromised patients to the fragmented state of clinical trials for bone marrow transplant patients two decades prior.
“There were limited mechanisms to move promising findings made by individual investigators to the field for large-scale testing and validation. We have similar challenges now,” he said.
He hopes that the ImmunOptimize workshop will inspire a similar network. At the workshop, infectious disease clinicians and researchers, representatives from the FDA, BARDA (the Biomedical Advanced Research and Development Authority) and the CDC, pharmaceutical industry representatives and patient advocates met to discuss the barriers and solutions to the data gap faced by people with weakened immune systems.
Boeckh noted that while many important puzzle pieces already exist, the infrastructure that puts the pieces together in a sustainable, systematic way is missing.
“Investigators are not fragmented, but the fragmentation in funding immunocompromised research has hurt our efforts,” said Fred Hutch President and Director Emeritus Larry Corey, MD, who directs the HIV Vaccine Trials Network, headquartered at Fred Hutch. “We need to unfragment it so we can actually do the studies — not just a 50- to 100-patient immunogenicity study, but a real efficacy study of 1,000 people.”
In presentations and panel discussions, participants addressed ways to incentivize inclusion of immunocompromised patients in industry trials, including regulatory incentives, risk reduction and different rubrics for assessing efficacy and adverse events. Patient advocates, including Karaffa, shared their experiences and interest in targeted treatments and trial participation for infection prevention.
Panelists discussed how a permanent trials infrastructure, funding source and body of experts could streamline trial design and analysis, participant recruitment and trial-site selection.
Filling the data gap will also help ACIP and the FDA to make more tailored recommendations for immunocompromised patients that will then be covered by insurance. And, attendees noted, a trials network could help facilitate the dissemination of trial results to the clinicians and patients who need them.
Panelists brainstormed strategies to produce fast, impactful preliminary results that could attract the funding and partners needed to build a robust and sustainable network. Every attendee highlighted the urgent need to make progress.
The impact of well-informed care for immunocompromised people extends far beyond each patient, as Pergam highlighted with a question to those assembled at the workshop:
“How many people in the room have someone in their household, a colleague or a friend, that’s immunocompromised?” he asked.
Every attendee raised their hand.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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Are you interested in reprinting or republishing this story? Be our guest! We want to help connect people with the information they need. We just ask that you link back to the original article, preserve the author’s byline and refrain from making edits that alter the original context. Questions? Email us at communications@fredhutch.org
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