Three years after COVID-19 upended their own lives and endangered the lives of their patients, researchers and physicians who specialize in protecting immune-compromised people from infectious diseases gathered in Seattle to assess the past and look ahead.
This 4th Symposium on Infectious Diseases in the Immunocompromised Host, organized by Fred Hutchinson Cancer Center, brought in participants from across the U.S. and around the world.
Drawing on their experiences, speaker after speaker stressed the need to include people with weakened immunity in clinical trials of new vaccines and treatments, so that they — comprising about 6% of the U.S. adult population — can benefit from scientific evidence to support their care.
Steven Pergam, MD, MPH, medical director of infection protection at Fred Hutch, described the medical status of immunocompromised patients as “incredibly diverse, incredibly complex.” While they may be the most vulnerable to infection, these individuals are often left out of clinical trials. Since the final goal of those expensive trials is to win marketing approval of a drug or vaccine candidate, funders are wary of enrolling people whose underlying health problems stray from the norm.
Pergam noted that he is immunocompromised. He is a cancer survivor and kidney transplant recipient with a personal stake in seeing more evidence-based medicine flow from clinical studies that include, rather than exclude, people with weakened immune systems.
Addressing researchers from pharmaceutical companies who were among those attending, he said, “Please, talk to us early, so we can get these vaccines into our patients who are often at highest risk.”
As envisioned by Michael Boeckh, MD, PhD, head of Fred Hutch’s Infectious Disease Sciences Program, the two-day symposium was both a scientific conference and an opportunity “to train the next generation of leaders, researchers and clinicians” in this specialized field.
Seventy-one promising, early career doctors and scientists attended with full travel grants. Senior researchers and physicians who spoke at the gathering served as mentors to the trainees throughout the event.
“We invited both leaders in the field, but also the rising stars to hear about their research and their interpretation of the science,” Boeckh said as he opened the Seattle event on May 1.
Although the catastrophe of COVID-19 was seldom out of mind, speakers noted that the field was once again turning to what passed for normal before the pandemic: acute concern about the panoply of other microbial threats to patients.
For cancer patients, and for those recovering from either bone marrow or solid organ transplantation, the list of potentially lethal microbes is a lengthy one, often including influenza and germs that pose little threat to people with healthy immune systems: cytomegalovirus, parainfluenza, human herpesvirus-6 (it causes roseola in infants), and rhinoviruses, which cause the common cold.
The broad sweep of the symposium included talks on fungal infections and the dearth of good drugs to treat them; a discussion about modifying communities of gut bacteria — the microbiome — to combat multidrug resistant organisms; the use of laboratory-grown (monoclonal) antibody drugs to protect patients recovering from transplant; and a report raising concerns that recipients of advanced CAR-T cell therapies to treat certain blood cancers may need extra protection from microbial infections.
Janet Englund, MD, director of pediatric transplant infectious diseases at Seattle Children’s Hospital, said one enduring lesson of the pandemic was that extra doses of vaccines seemed to increase protection for many members of this vulnerable population, without increased risks of side effects, according to recent studies.
“More doses are better,” she said. “This is really pretty simple: we want more doses. Two doses are not enough in our immunocompromised patients, three doses are not enough in our immunocompromised children for sure, and four doses are really quite good.”
Englund echoed the calls to include the immunocompromised population in clinical trials, citing 10 years of failed efforts to test better monoclonal antibodies against respiratory syncytial virus in children. Pediatric transplant surgeons would love to give such drugs to children as a precaution prior to their transplants.
“It’s only going to change by us investigators writing and clamoring and begging and being obnoxious to the pharmaceutical companies,” she said.
Englund recognized, however, that drugmakers are concerned that adding riskier patients to a trial can make winning Food and Drug Administration approval more difficult, should a participant die in a trial, and that regulators should understand this.
“Our government agencies don’t appreciate how much we need to do these trials,” Englund added.
Throughout the conference, several speakers cited a newly published study led by Fred Hutch researcher Joshua Hill, MD, who carried out precisely the kind of clinical trial the researchers there were talking about.
It followed 175 cancer patients who had received blood stem cell transplants at 22 different medical centers in the U.S. and compared their immune responses to COVID-19 vaccines given as early as three months after transplant with those who received vaccines later.
While transplant patients are extremely vulnerable to COVID-19, doctors were uncertain whether a recovering patient could generate enough protection with their newly grafted immune systems that early in their recovery.
In short, the study proved that they could.
“After transplant, we know we have to revaccinate our patients for everything, from scratch. The question has always been, when do you start?” Hill explained in an interview.
Unlike the massive, 30,000-participant trials used to prove the safety and effectiveness of COVID-19 vaccines, Hill’s unique and compact study did not look for outcomes such as whether vaccinated people were protected or not. Instead, it relied on biomarkers of effectiveness — so-called correlates of protection — which Fred Hutch researchers played a crucial role in finding.
“The antibody responses at 3 to 4 months after transplant looked just as good as waiting for six months,” Hill said. “And the T cell responses (measuring blood cells that attack infected cells) looked just as good. That’s why establishing those correlates are important — so we can use smaller studies to make the point more quickly in our immunocompromised patient population.”
— Dr. Joshua Schiffer, a Fred Hutch expert in mathematical modeling of infectious diseases
While the dramatic changes wrought by COVID-19 in the past three years appear to be behind us, the doctors are researchers who specialize in the immunocompromised population made it clear that SARS-CoV-2 is still very much with us and needs to be watched carefully.
University of Pittsburgh infectious disease specialist Ghady Haidar, MD, spoke about persistent, active infection by SARS-CoV-2, the virus that causes COVID-19, in immune compromised patients.
“The virus behaves very differently in people with immunodeficiencies,” he said. “… SARS-CoV-2 is still a problem in these individuals, with protracted viral shedding well beyond long COVID. The virus evolves, the virus can get resistance.”
Fred Hutch physician Joshua Schiffer, MD, MSc, commented that the delta and omicron variants of SARS-CoV-2, which changed the course of the pandemic, are thought to have evolved in immunocompromised patients with persistent infections, and the risk of new variants remains a concern.
“You could argue that this is the most important public health issue of our time. This is what keeps me up at night,” he said.
In a later interview, Schiffer said that because so much of the world’s population has now been exposed to COVID-19, the risk of an emergence of a deadly new variant is lower that it was earlier in the pandemic.
“Omicron turned out to be a more mild infection largely because the majority of people getting infected were vaccinated. Had omicron been the original variant, I think 2020 would have been worse that it was. It would have been a much worse pandemic,” Schiffer said.
He added that the current risk of a new variant could be further diminished if people with these persistent infections — even in asymptomatic patients — were followed up more rigorously and treated with existing drugs and new combination therapies in development, with a goal of eliminating the virus.
“To do so requires much better studies, with a focus on implementation,” or getting the advances developed by researchers to be available and accepted by the public. “This is a component of risk that is not well understood by society at large, and not well understood by policymakers. To act on it, therefore, is a real challenge.”
Sabin Russell is a staff writer at Fred Hutchinson Cancer Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT, and a freelance writer for the New York Times and Health Affairs. Reach him at firstname.lastname@example.org.
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