Blood plasma — the yellowish, cell-free portion that remains after red and white blood cells have been filtered out by a machine and returned to the plasma donor — is rich with antibodies. Plasma from recovered COVID-19 patients might prove useful in preventing infection as well as in treatment, scientists say.
Harvested Antibodies Now Being Tested As A Prevention Tool …
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein produced mainly by plasma cells that is used by the immune system to neutralize pathogens such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen, via the fragment antigen-binding (Fab) variable region. Each tip of the “Y” of an antibody contains a paratope (analogous to a lock) that is specific for one particular epitope (analogous to a key) on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize its target directly (for example, by inhibiting a part of a microbe that is essential for its invasion and survival). Depending on the antigen, the binding may impede the biological process causing the disease or may activate macrophages to destroy the foreign substance. The ability of an antibody to communicate with the other components of the immune system is mediated via its Fc region (located at the base of the “Y”), which contains a conserved glycosylation site involved in these interactions. The production of antibodies is the main function of the humoral immune system.Antibodies are secreted by B cells of the adaptive immune system, mostly by differentiated B cells called plasma cells. Antibodies can occur in two physical forms, a soluble form that is secreted from the cell to be free in the blood plasma, and a membrane-bound form that is attached to the surface of a B cell and is referred to as the B-cell receptor (BCR). The BCR is found only on the surface of B cells and facilitates the activation of these cells and their subsequent differentiation into either antibody factories called plasma cells or memory B cells that will survive in the body and remember that same antigen so the B cells can respond faster upon future exposure. In most cases, interaction of the B cell with a T helper cell is necessary to produce full activation of the B cell and, therefore, antibody generation following antigen binding. Soluble antibodies are released into the blood and tissue fluids, as well as many secretions to continue to survey for invading microorganisms.
Antibodies are glycoproteins belonging to the immunoglobulin superfamily. They constitute most of the gamma globulin fraction of the blood proteins. They are typically made of basic structural units—each with two large heavy chains and two small light chains. There are several different types of antibody heavy chains that define the five different types of crystallisable fragments (Fc) that may be attached to the antigen-binding fragments (Fab). The five different types of Fc regions allow antibodies to be grouped into five isotypes. Each Fc region of a particular antibody isotype is able to bind to its specific Fc Receptor (FcR), except for IgD, which is essentially the BCR, thus allowing the antigen-antibody complex to mediate different roles depending on which FcR it binds. The ability of an antibody to bind to its corresponding FcR is further modulated by the structure of the glycan(s) present at conserved sites within its Fc region. The ability of antibodies to bind to FcRs helps to direct the appropriate immune response for each different type of foreign object they encounter. For example, IgE is responsible for an allergic response consisting of mast cell degranulation and histamine release. IgE’s Fab paratope binds to allergic antigen, for example house dust mite particles, while its Fc region binds to Fc receptor ε. The allergen-IgE-FcRε interaction mediates allergic signal transduction to induce conditions such as asthma.Though the general structure of all antibodies is very similar, a small region at the tip of the protein is extremely variable, allowing millions of antibodies with slightly different tip structures, or antigen-binding sites, to exist. This region is known as the hypervariable region. Each of these variants can bind to a different antigen. This enormous diversity of antibody paratopes on the antigen-binding fragments allows the immune system to recognize an equally wide variety of antigens. The large and diverse population of antibody paratope is generated by random recombination events of a set of gene segments that encode different antigen-binding sites (or paratopes), followed by random mutations in this area of the antibody gene, which create further diversity. This recombinational process that produces clonal antibody paratope diversity is called V(D)J or VJ recombination. The antibody paratope is polygenic, made up of three genes, V, D, and J. Each paratope locus is also polymorphic, such that during antibody production, one allele of V, one of D, and one of J is chosen. These gene segments are then joined together using random genetic recombination to produce the paratope. The regions where the genes are randomly recombined together is the hypervariable region used to recognise different antigens on a clonal basis.
Antibody genes also re-organize in a process called class switching that changes the one type of heavy chain Fc fragment to another, creating a different isotype of the antibody that retains the antigen-specific variable region. This allows a single antibody to be used by different types of Fc receptors, expressed on different parts of the immune system.
If you’re bitten or scratched by an animal with rabies, your doctor can give you a shot to prevent the virus from taking hold in you and causing an infection. The same concept is now being put to the test for the coronavirus.
Most people who get sick with COVID-19 produce antibodies in their blood that seem to protect them from reinfection. A study is now underway to see whether an infusion of those antibodies can protect someone who has been exposed to the virus and is at high risk of infection.
Harvested Antibodies Now Being Tested As A Prevention Tool …
One of the first volunteers for this study is a physician who treats transplant patients at the Johns Hopkins University School of Medicine. Jonathan Orens had a close brush with the coronavirus involving not his work, but his family.
His daughter from Los Angeles wanted to come home to be near her sister, who was about to give birth to her first baby. Orens says the traveling daughter was careful about protecting her health in Los Angeles and did everything she could think of to stay safe on her flight to Baltimore.
“She wore a mask, she wore gloves, she had sanitizer, she had wipes,” he says. “The load on the plane was relatively small.” They chose the Fourth of July as a travel day, knowing that even fewer people were likely to be traveling that day. “We actually bought the two seats in the row to keep her away from everybody else.”
She wore masks through the airports and in the car ride back to her parents’ house. Once there, she kept her distance from them.
Just to be sure, about a week after she arrived, she and her parents went for coronavirus testing.
Though she had no symptoms, “she was positive,” Orens says. “And fortunately my wife and I were negative.” But they were still at high risk of contracting the disease, given the close contact with their daughter.
As luck would have it, one of Orens’ colleagues at Hopkins was just starting a study to see if purified blood serum from people who have recovered from COVID-19 — called convalescent plasma — could prevent the disease in someone else. Orens and his wife, who are in their early 60s, are entering an age group at higher risk of serious disease if infected with the coronavirus. They signed up for the experimental treatment.
Half the people in this clinical trial get an intravenous infusion of convalescent plasma, while the other half get an infusion of blood serum that had been donated before the pandemic emerged (so it lacked protective antibodies). Neither the participants nor the doctors treating them know who’s getting what.
The infusion took about an hour, Orens says. “I didn’t feel anything except for the pinprick from the IV, and we went on our merry way.”
He now returns to the clinic for regular blood tests.
“We’ll follow him along to see if he develops symptoms and if he turns positive,” says Dr. Shmuel Shoham, who is directing the study. Shoham says he plans to enroll up to 500 patients — though, in the best-case scenario, if the treatment is highly effective he won’t need to study that many people.
In addition to recruiting patients in Baltimore, “right now we have sites in Houston, sites in Alabama,” Shoham says. “We’re opening up additional sites in Dallas and Arizona. We have sites all over Southern California.”
He’s also involved in a second study that looks at whether plasma will prevent serious illness in people who are infected but not sick. He says if both of these strategies work, they could help a lot of people, even in the absence of a vaccine.
“That would give people a lot of confidence, I think, to go back to school, go back to work,” he says, “because if somebody gets sick it’s not a tragedy –because we can protect them and protect those around them.”
These studies are among a growing number of experiments involving convalescent plasma, both as preventive measures and as treatments for COVID-19.
Dr. Jessica Justman at Columbia University’s Mailman School of Public Health in New York tried to launch a similar study this spring. Good news for New York — but a complication for her study — was that the disease had largely abated in the city, and she didn’t have luck recruiting people to participate.
“Compared to March and April, people have become less worried, less scared of COVID and perhaps a little bit less inclined to go for a preventive treatment,” Justman says.
That situation could turn around if the disease roars back in her area. And Justman says the idea is well worth pursuing. A similar strategy works against other diseases — not just rabies, but hepatitis B, botulism and a potentially serious viral infection in babies called respiratory syncytial virus. In fact, this general strategy dates back more than a century. Shohan was involved in a study that attempted to use convalescent serum to treat the flu, and it was not successful — so it isn’t a cure-all.
Piggybacking on this strategy, drug companies are gearing up to manufacture antibodies, instead of collecting blood from recovered patients. But those products — monoclonal antibodies — wouldn’t be cheap.
“What I like about the convalescent plasma idea is that if it worked, I see it as something that could really be scalable in resource-limited settings,” Justman says, referring to developing countries where expensive pharmaceuticals are frequently out of reach. “And I think that’s where convalescent plasma has this really great potential.”
As for the Orens family, nobody fell ill — whether that was due to in part to treatment or luck, nobody knows. Their quarantine period ended just in time for a quick trip to New York after the baby’s birth to see the new mom.
“The plan is to drive up after she is out of the hospital. Hopefully, everything will go well, and we will all be outside,” Orens says. “We will see the baby from a distance. I’ve already been informed by my daughter that I am not allowed to get anywhere near the baby. And then we will turn around and come back to Baltimore.”
It’s hardly the way he was hoping to greet his first grandchild, he says, “however it’s the price we have to pay to bring this pandemic under control.”
The researchers in Baltimore hope to know by mid-September whether the convalescent plasma will in fact inoculate people from COVID-19.
You can contact NPR science correspondent Richard Harris at [email protected].