NEW ORLEANS — A couple months before the pandemic started, Joseph Ford started experiencing a rash of pinpoint polka dots around his lips, ankles, and lower legs. They were itchy, inflamed, painful, and, for him, the first signs of non-Hodgkin lymphoma. “Petechiae,” he explained. Just as he was starting to deal with that, Covid-19 changed the world.
“Go home and stay there,” Ford, a 77-year-old retired librarian in Tumwater, Wash., recalled a physician telling him as Covid hollowed out society. “You won’t survive a Covid infection.”
That advice has largely remained unchanged over the last two years for the millions who, like Ford, are immunocompromised and haven’t produced adequate — or any — antibodies from the Covid-19 vaccines. But researchers at the University Hospital Tübingen are designing a vaccine to elicit a deeper T cell response than the currently approved vaccines by targeting several key points on viral proteins — epitopes — that are good at stirring up immune T cells.
The researchers, who presented Phase 1/2 clinical data at the American Association for Cancer Research conference on Tuesday, said they hoped their approach would protect immunocompromised patients from Covid, even if they still cannot make antibodies. Other experts said it was an intriguing idea, though whether it’ll actually protect against Covid has yet to be shown.
Vaccines work in at least two main ways to protect individuals against infection or severe disease. One is by teaching T cells to recognize and kill the pathogen. The other is to trigger the body to produce neutralizing antibodies, immune molecules that can seize onto a key piece of the virus and arrest its function. The current Covid-19 vaccines target the coronavirus’ spike protein, which the virus uses to enter and infect human cells.
But antibodies are made by the immune B cells, and many cancer patients have depleted B cell populations. Certain cancer therapies can damage B cells, as does having a blood cancer like lymphoma, leukemia, or myeloma. Some patients can lose their B cells altogether. Joseph Ford is one of them.
“Last time I was tested, I had no B cells whatsoever — it appears that B cells that are malignant have malignant implications,” he said dryly.
When the first Covid-19 vaccines were approved, Ford was ecstatic. Finally, he thought, he and his wife, Mary, could leave the house and see their families for the first time in months. They both got the shots as soon as they could. “We relaxed our guard just a little bit,” he said. “But it was only a little false spring.”
When his doctor at Seattle Cancer Care Alliance tested his blood for antibodies a few weeks after receiving his second shot, there was no trace of any neutralizing antibodies to Covid-19 in his blood. It was as if Ford hadn’t even gotten the shots. As a result, for about 19 months, Ford estimated he made only three commercial outings.
“One to a bicycle shop,” he said. “One to REI. And one to a hardware store. Mary helped me isolate, quarantine, even if that’s a burden on her. A vaccine that would interact with what remains of my immune system — such as this work being done in University of Tübingen — would be wonderful.”
To create this vaccine, the investigators first scoured the coronavirus genome using an algorithm that would highlight any viral protein fragments or peptides that would cause a T cell to perk up, said Juliane Walz, the medical director of translational immunology at the University Hospital Tübingen and the lead author of the study.
“I’m a hematologist and oncologist by training, and we realized very early on in the pandemic that our patients are at severe risk of Covid, and we knew that they wouldn’t make a sufficient antibody response,” Walz said. “So we decided to develop a peptide vaccine to induce a T cell response to patients.”
To test the peptides their algorithm underscored, the lab made synthetic versions of the peptides and then tested them on T cells from healthy patients who had already recovered from Covid. Then, they looked to see which peptides seemed to elicit the greatest immune response from the T cells and included them in the vaccine’s recipe. Those turned out to be proteins from many different parts of the virus.
“This particular vaccine has peptides from the spike protein, nucleic acid, membrane envelope, along with agents to basically hype up the immune system,” Walz said.
In their Phase 1/2 clinical trial, the team tested the vaccine in 14 people with B cell deficiencies, 12 of whom had leukemia or lymphoma. More than half of them had received approved Covid-19 vaccines that did not elicit an antibody response, but 93% of them in this trial had a measurable T cell response 28 days after this vaccine.
But that response varied widely. “There’s a really large range,” Walz said. “We test T cell response based on these spot counts, and some people had only 10 spot counts and some had 2,000. We still don’t know if there’s any predictors to who will have a stronger or less strong response.”
For many participants, Walz said their T cell responses exceeded those of healthy patients who received the mRNA vaccines or the Johnson & Johnson vaccine. It was also comparable to the T cell response of healthy individuals who recovered from Covid and only had a T cell response to their infection. Importantly, Walz added, all of these T cell responses were measured in the team’s lab at Tübingen.
“Conceptually, it’s better” for B-cell-deficient patients, Lee Greenberger, an immunologist and chief scientific officer of the Leukemia and Lymphoma Society who did not work on this vaccine, said of the approach. One potential benefit might be longer-lasting protection, Greenberger speculated, since the coronavirus is unlikely to mutate every protein epitope included in this vaccine.
But questions abound. For instance, there’s a subset of blood cancer patients who had neither a T cell nor an antibody response to currently approved vaccines. It’s unclear if this vaccine would still be able to elicit a T cell response in many of them. “And we don’t know which of these T cell responses are the most potent in avoiding infection and hospitalization,” he said.
Scientists also don’t know what level of T cell response is needed to fend off infection or severe disease, and it’s also difficult to infer what a sufficient response size might be. Ana Maria Lopez, a medical oncology professor at the Kimmel Cancer Center who did not work on the trial, said this vaccine “would be supportive of the immune response to Covid,” but added: “Whether it would be sufficient has yet to be investigated. It is a novel way to get an immune response, though, so it merits more study.”
Those questions can only be answered in a larger, Phase 3 clinical trial designed to test the vaccine’s efficacy — specifically in patients who are immunocompromised. Walz and her colleagues at the University Hospital Tübingen have just wrapped up a Phase 2 clinical trial and, she added, and they’re working on finding either corporate partners to move the vaccine into Phase 3 and onward to approval — or starting their own company with venture capital funding.
If this vaccine makes it through to approval, the Leukemia and Lymphoma Society’s Greenberger said he doesn’t think it would replace the currently approved vaccines. “That’s hard to imagine. We know the efficacy of those, and we know many people do make sufficient antibodies, even for those with hematological malignancies,” he said. “But it’d be good to have an alternative.”
Especially since, he said, current alternatives like the anti-coronavirus monoclonal antibodies in Evusheld are not foolproof against the continued evolution of the coronavirus. That continues to be a source of worry for Ford and other blood cancer patients. Although, he added, he is starting to go out and see friends and family more now that he has Evusheld and two boosters of the mRNA vaccines — albeit still with masks and distance.
“I’m pleased to have been vaccinated and to have Evusheld,” Ford said. “But none of them have guarantees against new variants like BA.2 or Omicron. The probability of them completely preventing me from being infected seems low. I’m still susceptible.”
But, he added, that’s why work from scientists developing vaccines for patients like him is so important. Along with University Hospital Tübingen, City of Hope is also working on a separate Covid-19 vaccine designed to elicit T cell responses in immunocompromised individuals.
“It is research that focuses on the needs of a relatively small part of the population that is relatively defenseless,” he said. “I very much appreciate hearing about Tübingen. When they’re looking for North American patients, put my name on the list.”
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