Antibody Therapy of COVID-19
Author: Ivana Mišová, PhD.
Published at: 05/11/2021
Vaccines aspire to teach the body's immune system to safely recognize and block the virus that causes COVID-19. They are a preventative treatment, and it takes some time for the immune system to be ready to fight against SARS-CoV-2 infection. Nowadays, several antibody-based therapies have emergency use authorization by the FDA. These therapies do not require our immune system to create antibodies against the virus but directly supply the SARS-CoV-2 antibodies. This type of strategy has great potential for those already infected with SARS-CoV-2 - a vaccine administered at that time would not help; however, a direct infusion with SARS-CoV-2 specific antibodies could make the difference.
Convalescent plasma was the first antibody-based product to receive emergency use authorization in August 20201. It was authorized for the treatment of hospitalized patients with COVID-19. COVID-19 convalescent plasma is human plasma collected from individuals whose plasma contains anti-SARS-CoV-2 antibodies2.
What is convalescent plasma, and how does it help? Convalescent plasma therapy uses blood from people who have recovered from an illness to help others recover. Blood donated from people that have recovered from COVID-19 contains antibodies against the SARS-CoV-2. This donated blood is processed to remove blood cells. The remaining plasma (the liquid part of the blood) with a high concentration of SARS-CoV-2 antibodies can be given to people with COVID-19 to boost their ability to fight the virus3. It is stored frozen at -18°C or colder, and once thawed and refrigerated, it must be used within five days for patient transfusion2.
What are the possible benefits of getting COVID-19 convalescent plasma? It might improve the patient's likelihood of recovering from COVID-19, based on the supporting evidence and clinical trials related to COVID-19. To be effective, COVID-19 convalescent plasma therapy needs to be high titer (high concentration of SARS-CoV-2 antibodies) and used early in the course of the disease - it is not beneficial for the hospitalized patients following respiratory failure that requires intubation and mechanical ventilation. However, for the immunosuppressed or immunodeficient patients, the potential therapeutic window seems to be longer than for other (immunocompetent) patients4.
On the other hand, there are risks related to transfusion, and it might not work for everyone5. Further limitations are that it is based on blood donations - you cannot simply manufacture more without the donors - and also the issue of the number of antibodies present in the blood - not all people having recovered from COVID-19 have enough antibodies. Nevertheless, it is a therapy previously used for other diseases, with the potential to help many people with COVID-19.
In November 2020, another antibody-based product received emergency use authorization from the FDA6. The combination of two monoclonal antibodies, casirivimab and imdevimab, administered together as REGEN-COV, was authorized for emergency use to treat mild to moderate COVID-19. It is meant for patients 12 years old and older (weighing at least 40 kg) who are positive for SARS-CoV-2 and are at high risk for progressing to severe COVID-19 and hospitalization.
What are monoclonal antibodies, and how do they help? They are lab-made proteins that mimic the immune system's ability to fight off harmful pathogens. Casirivimab and imdevimab are monoclonal antibodies specifically directed against the spike protein of SARS-CoV-2, designed to block the virus's attachment and entry into human cells. Casirivimab and imdevimab must be administered together by intravenous (IV) infusion7. Unlike convalescent plasma therapy, REGEN-COV is not authorized for patients hospitalized due to COVID-19 and similarly does not help once the patient requires oxygen therapy.
This medical product is also famous for successfully treating former USA President Donald Trump in 2020, even before receiving the EUA by the FDA. In March 2021, the manufacturer - Regeneron Pharmaceuticals, Inc. announced positive topline results from the largest trial to date assessing a COVID-19 treatment in infected non-hospitalized patients. The Phase 3 trial shows that the REGEN-COV antibody cocktail reduced hospitalization or death by 70%8.
Could REGEN-COV be used also for preventing COVID-19? The manufacturer thinks so, as they are seeking FDA authorization as a preventative treatment9. This is backed up by the results of the phase three clinical trial, which found that the drug reduced the risk of symptomatic infections in individuals by 81%, and those that were symptomatic and treated with the drug resolved their symptoms on average two weeks faster than those who received a placebo.
Bamlanivimab and Etesevimab
So far, the latest antibody-based treatment for COVID-19 to receive emergency use authorization by the FDA is the combination of monoclonal antibodies bamlanivimab and etesevimab. It was authorized in February 2021 to treat mild to moderate COVID-19 in adults and pediatric patients (12 years of age or older weighing at least 40 kilograms) who test positive for SARS-CoV-2 and who are at high risk for progressing to severe COVID-1910.
Just like casirivimab and imdevimab, bamlanivimab and etesevimab are monoclonal antibodies that work on the same principle. In a clinical trial, an IV infusion of bamlanivimab and etesevimab administered together has significantly reduced COVID-19-related hospitalization and death during 29 days of follow-up compared to placebo. However, the timing is once again critical, as the treatment is not authorized for hospitalized patients or those that require oxygen therapy due to COVID-19.
Initially, bamlanivimab as a single infusion was issued an emergency use authorization in November 2021 but was later revoked11. While both bamlanivimab on its own and in combination with etesevimab are expected to benefit patients at high risk of disease progression, the combination of the two antibodies presents a lower risk of resistant viruses developing during treatment than bamlanivimab alone.
How Do These Therapies Fare Faced With SARS-Cov-2 Variants?
The emergence of novel virus variants with mutations in critical parts of the virus is indeed a threat to any developed vaccine or antibody therapy (read more). In the case of COVID-19 convalescent plasma therapy, the antibodies present in the plasma vary based on the variant of SARS-CoV-2 the donor had been infected with. Lab-made monoclonal antibodies have constant characteristics, and their efficacy against the mutant variants has been addressed in various in vitro tests. The combination of casirivimab and imdevimab retained neutralization activity against pseudovirus expressing any of the tested spike protein substitutions (N501Y present in the UK variant B.1.1.7, K417N, E484K, and N501Y present in the South African variant B.1.351, L452R present in the B.1.427/B.1.429 variant of California origin and E484K present in the B.1.526 variant of New York origin)12. On the other hand, the combination of bamlanivimab and etesevimab retained unchanged neutralization activity only against the N501Y mutation present in the UK variant. The rest of the tested variants showed a significant reduction in their susceptibility13. However, it is unclear how these pseudovirus data correlate with clinical outcomes.
Antibodies as a Possible Treatment for All?
So far, the available antibody treatments are authorized for people with mild COVID-19 who are at high risk for progressing to severe COVID-19, and they could also be effective as a preventative treatment. Does this mean that we finally have a cure for all? Unfortunately, no. Antibody-based therapy is not effective for patients in severe and critical conditions who desperately need an effective treatment strategy. So, what about all the people waiting for a vaccine? Could this be a solid strategy for those? In theory, it would help - however, there are three main limitations. The first is the limited capacity for manufacturing, which is a well-known problem also for vaccines. The second is the price of the therapy, which is over a thousand dollars per dose14. Lastly, antibodies have a limited lifespan - unlike vaccination, which aspires for long-term cellular immunity, antibody therapy has a shorter therapeutic window.
Overall, antibody-based therapy of COVID-19 is a valuable treatment strategy in the fight against the pandemic, though relatively expensive and very time-sensitive. With the vaccination plans taking longer due to limited vaccine production capacities, we are in serious need of helping those that are already infected. While antibody therapy is not for everyone, people with mild COVID-19 who are at risk for progressing to severe disease can significantly benefit from it. Vaccination against COVID-19 is the only way to stop the pandemic truly; nevertheless, as far as taking care of those infected right now, antibody therapy is a solid strategy.