Why Researchers Are Exploring Antibodies From Recovered Patients For Possible Treatment And Prevention Of COVID-19

(Posted on Monday, April 6, 2020)

Is there a Covid-19 treatment that can treat critically ill, hospitalized patients, on the one hand, and protect healthcare workers on the other? Passive immune therapy has the potential to do both—immediately, and with major improvements over time. Broadly speaking, it involves giving antibodies, in this case specific to Covid-19 virus SARS-CoV-2, to people who need them.

The first stage is sera from convalescents. The second is purified antibody fractions that are safer and more potent, but also achievable—hopefully by summer. The third is monoclonal antibodies, which will take more time but is already on the fast track. Each approach mobilizes antibodies against SARS-CoV-2 in unique ways, with varying degrees of safety, speed, and efficacy—and all three must be explored.

A primer on antibodies

When the body is under attack, the immune system’s B cells produce antibodies specific to the invading organism that fit its viral proteins with utmost precision. This hand-and-glove binding mechanism either marks the target for destruction via other white blood cells, inhibits basic biological activity, or targets the invading organism for clearance from the body.

Some virus-specific antibodies linger on in the body long after infection has cleared. While immunoglobulin M (IgM) antibodies, the largest and first to be produced, disappear shortly after their role as the initial line of defense has been fulfilled, immunoglobulin G (IgG) antibodies remain in abundance in all bodily fluids, ready to leap into action should the virus ever return. If a patient makes a full recovery from Covid-19, the IgG antibodies their immune system weaponized to fight the virus will retain a memory of the disease at least for many months.

Shortest term solution: convalescent sera

In the event of an infectious disease outbreak for which neither a cure nor a vaccine yet exists, such as the current pandemic, medical practitioners can transfer the antibody-rich blood plasma of recently recovered patients to those critically ill. Collected at least a few weeks after the donor has been discharged, this convalescent plasma, also known as convalescent sera, still contains antibodies against the virus that can treat patients in critical condition. Treatment, not protection, is the purpose of convalescent sera, which buys enough time for some to stabilize and recover.

Use of convalescent sera dates back to the 1900s but has more contemporary precedents that suggest its viability as a somewhat reliable stopgap measure against emerging infectious diseases. From H1N1 influenza to Ebola to COVID-19’s foremost predecessor, SARS, medical practitioners have repeatedly turned to this basic form of passive immune therapy and, in several cases, reported back promising reductions in mortality and viral load. Combined with small studies recently conducted with COVID-19 patients, the evidence is favorable enough that convalescent sera transfers, as of March 24, are FDA approved for emergency cases in the United States.

That said, there are many valid reasons why convalescent sera therapy is still considered experimental and reserved for emergencies only. Although modern blood banking technology does a fine job of filtering rogue substances out of plasma donations, the principle worry is infection from hepatitis and other viruses. Patients with certain immunodeficiencies or lung-related comorbidities, among the most vulnerable to COVID-19, may be ineligible. With so many lives on the line, and so few options in the way of treatment, these risks may be worth it—but there are safer alternatives worth pursuing.

Shorter term solution: hyperimmune globulins

In New York City, the new epicenter of the pandemic, the New York Blood Center has already started to collect blood plasma donations from convalescent COVID-19 patients for therapeutic use. The ultimate distribution of donors and donations will be determined by patterns in caseload and recovery, with convalescent sera moving between hospitals accordingly. As both the number of recovered patients and the number of infected patients continue to rise, a good portion of incoming donations received by the 380 licensed plasma collection centers across the country should be pooled for the creation of a cleaner, more concentrated, and more effective passive immune therapy: hyperimmune globulins.

Unlike convalescent sera, which is processed and circulated through a network of hospitals and clearinghouses, the preparation of hyperimmune globulins—especially at a commercial scale—requires proper manufacturing infrastructure. First, in designated labs and manufacturing plants, samples of collected plasma are assessed for their potency. The goal is to locate and quantify highly neutralizing antibodies, those most adept at fighting the virus, and concentrate them into a clinical grade solution.

Once identified, the highly neutralizing antibodies are pooled, purified, and incubated in large batches over the course of several weeks. If all goes well, the resulting hyperimmune globulin preparations should be safer and less variable than a dose of convalescent sera. They can be administered to critically ill patients as treatment and healthcare workers as protection. Hyperimmune globulins have already been produced for diseases like cytomegalovirus, H1N1, and hepatitis. They were even prepared for SARS, though these, like so many other potential coronavirus therapies, never left the lab.

The process of industrial purification may be more labor intensive and time consuming, but with enough resources and facilities mobilized, it can also be accelerated. At this point, the coronavirus pandemic is so widespread that recruiting enough plasma donors for rapid manufacturing—usually one of the most significant challenges in yielding high volumes of hyperimmune globulins—will only grow in feasibility.

Another technique that has demonstrated success in the past is the collection and refinement of equine plasma. Groups of horses would be immunized with a killed version of SARS-CoV-2, the COVID-19 virus, and develop antibodies in response. Because horses are larger animals, they produce more plasma than humans that can, in turn, be purified just as we purify that of convalescents. Either way, hyperimmune globulins would take longer to prepare than convalescent sera, but not nearly as much time as vaccines or antiviral drugs—meaning they’re well worth the effort.

Long term solution: Monoclonal antibodies

The final, most advanced, and most specific of the passive immune therapies being explored for COVID-19 are monoclonal antibody drugs. These treatments are engineered using a single cell that produces a single, highly neutralizing antibody, one that is replicated over and over again at a large scale. Monoclonal antibodies have the purity and consistency of a synthetically generated product but remain wholly human and potentially very effective. To date, more than 80 pharmaceutical products that use this technology to treat cancer, infectious diseases like Ebola, and other health conditions have received FDA approval.

The main downside to monoclonal antibody drugs is that they’re difficult and expensive to make. Luckily, research was conducted on monoclonal antibodies against SARS and MERS that were never brought to market, but are now of use to scientists developing drugs for COVID-19. In the case of SARS and MERS, the considerable investment of time, money, and labor needed to produce monoclonal antibody drugs exceeded any conceivable benefits. Today, with initiatives like Bill Gates’ Covid-19 therapeutics accelerator pouring funds into multiple avenues of immunotherapy discovery, prospects may still be uncertain, but they’re also more promising than they’ve ever been.

Meanwhile, as we await the verdict on more ambitious therapies, here are five steps we can take to get what is already at our disposal—and what could be, within weeks—into the hands of healthcare workers, extremely ill patients, and any other high priority groups in dire need of protective immunity.

First, find convalescents eligible for plasma donation. This should be a nationwide effort.

Second, identify the plasma that contains the highest concentration of neutralizing antibodies that can either be administered in emergencies as convalescent sera, or pooled for the production of hyperimmune globulins.

Third, purify these potent antibody fractions into hyperimmune globulins.

Fourth, after testing for safety and efficacy, ramp up production.

And last but not least, give the finished product to the patients who need it most and the healthcare workers who need it to continue their efforts.

To recap, the broader strategy would be to use convalescent sera today to treat critically ill patients. Then, to use hyperimmune globulins to both treat critically ill patients and to protect healthcare workers. Lastly, to use monoclonal antibodies both as treatment and as prevention for increasingly broad segments of the population. The first monoclonal antibodies are likely to be protective for three to four weeks. It is possible, through genetic engineering, to extend that period for up to four months.

Once passive immune therapies have been administered, we don’t know how many weeks we can expect the antibodies to persist. At the end of the day, we can only buy time—for the COVID-19 patients in acute condition, and the healthcare workers putting themselves on the line to save them. But until more long term solutions emerge as viable, we’ll need every minute and every hour we can get.

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Originally published on Forbes (April 6, 2020)