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Scientists Look to Convalescent Plasma, Antibody Cloning as Possible COVID Cures

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Since early in the pandemic, scientists have said antibodies that the immune system makes to fight the coronavirus could be crucial in finding a cure for COVID-19.

UCSF expects results from a placebo-controlled trial using COVID-19 convalescent plasma by the end of 2020. (Dr. Ashok Nambiar/UCSF)

The FDA recently authorized one of these treatments — convalescent plasma, in which the antibody-rich portion of blood donated by recovered COVID-19 patients is given to people hospitalized with the disease. But the approval, which came soon after President Donald Trump accused the agency of moving too slowly on the treatment for political reasons, has prompted pushback from some in the scientific community, who say more research is needed to determine if and how plasma can be effective against COVID-19. Meanwhile, research on another therapy, involving antibodies cloned in the lab, is just getting underway in human subjects.

‘Liquid Gold’

Plasma, sometimes called “liquid gold” by doctors for its yellow hue and potential therapeutic value, is made by spinning blood to separate antibodies and other proteins from red blood cells.

The use of convalescent plasma in medicine dates back more than a hundred years.

“We’ve used it in infectious diseases from polio to influenza, ebola, etc.,” said UCSF professor of medicine Dr. Peter Chin-Hong.

Chin-Hong, whose team is running a COVID-19 convalescent plasma trial, says that while the treatment is considered relatively low-risk, the FDA’s authorization is too hasty.

“The main reason why it’s the wrong time is that we just don’t have enough data yet to say if it works,” he said.

Early results from a Mayo Clinic study suggest convalescent plasma may reduce COVID-19 mortality rates. But the study, which is available as a non-peer-reviewed preprint, wasn’t placebo-controlled, and Chin-Hong says results from rigorous clinical trials with COVID-19 convalescent plasma have yet to be published.

I think plasma is a great potential intervention,” he said. “I just don’t know where it works best.

The FDA’s authorization limits plasma treatment to hospitalized patients, and much of the early application for research purposes has focused on the most severe cases. But Chin-Hong says convelescent plasma may work better early on, before the disease has a chance to progress and patients get seriously ill.

Dr. James Zehnder, director of clinical pathology at Stanford, agrees that the jury is still out on whether plasma can treat the sickest COVID-19 patients. In looking at the natural patterns of how infected patients make antibodies, he says, researchers have seen the most robust antibody response from those who have severe, potentially life-threatening inflammation. In contrast, those who have milder illness tend to have a weaker antibody response.

So one question is that if the really sick patients are already making really high levels of antibodies,” Zehnder said, “how does infusing more antibodies help?

Results from placebo-controlled trials, Zehnder says, are the gold standard for clinical research, and they will be key in answering questions surrounding COVID-19 convalescent plasma therapy.

Dr. Stuart Cohen, chief of infectious diseases at UC Davis, worries that a broad rollout of the treatment in the wake of the FDA authorization could jeopardize that research by stifling enrollment.

“If I tell you, you can be on this clinical trial where you could get a placebo and then they say, ‘Well, I saw that this is available already, why don’t you just give it to me?’” Cohen said, “that sort of finishes off any real ability to determine whether this really works or not.”

While he acknowledges doctors are desperate for more tools to try to fight COVID-19, Cohen cautions that the supply of convalescent plasma, which has mostly kept up with the demand for research studies, could be depleted as a result of the FDA authorization.

If doctors all of sudden begin prescribing the drug liberally, Chin-Hong adds, “it may mean that the patients who need it the most may not get it.”


Cloning Antibodies in the Lab

Convalescent plasma isn’t the only way researchers are using antibodies from the blood of recovered patients to develop COVID-19 treatments. Scientists are also working to manufacture antibodies in the lab.

“What you can do is you can go into that person who’s a survivor and find the most potent antibody in that person, clone it and then give it to millions of people,” said Dr. Phil Pang, chief medical officer at San Francisco-based Vir Biotechnology.

These “monoclonal antibodies,” Pang says, are made by cloning the powerful, neutralizing antibodies that prevent the coronavirus from invading healthy cells.

The FDA first approved this type of treatment in the 1980s. Doctors have used them mainly to help treat cancer patients and people with autoimmune conditions.

Unlike convalescent plasma, Pang says, the supply of monoclonal antibodies isn’t dependent on blood donations and can be scaled up to potentially reach more people. The proteins are typically replicated in the lab using cell lines from hamsters or mice.

“The antibody manufacturing process is now a very well-defined process,” Pang said. “I would say it’s akin to the way in which we can go about manufacturing cars.”

Pang says one of the antibodies Vir has cloned has been shown to neutralize SARS-CoV-2 in a lab. The finding was supported by an article published in Nature in May. The company recently launched a randomized trial to see if giving a single injection to newly diagnosed COVID-19 patients can help stop the illness from progressing.

The treatment may eventually be able to prevent infection in front-line workers and other at-risk populations exposed to the coronavirus, acting like a short-term vaccine, Pang says.

“A vaccine works by giving a person to, say, a fragment of a viral protein and hoping that their immune system creates antibodies,” Pang said. “In this case, what we’re saying is let’s just give them the immune response we know or believe will be protective.

The NIH and a host of drug companies, including Regeneron Pharmaceuticals and Eli Lilly, are testing their own COVID-19 monoclonal antibody candidates.

Preliminary results from both Vir’s monoclonal antibody study and UCSF’s convalescent plasma research are expected by the end of 2020.


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