After almost three years of the pandemic, many of us have antibodies against the virus, thanks to a few infections, doses of the mRNA vaccine, or a course of monoclonal antibody therapy. However, not all immune responses are the same, and the nature of our body’s response to SARS-CoV-2 may depend on how our antibodies were initially produced.
A recent study demonstrates the distinct immune response that those who received monoclonal antibodies prior to receiving two doses of an mRNA vaccination produced. The study, which was published in Nature, examines a process called antibody feedback inhibition, which is known to change the body’s immune responses to some infections while enhancing its antibody repertoire against a number of others. The results imply that feedback inhibition enhances COVID vaccine coverage in individuals who have previously received monoclonal antibodies.
According to Michel C. Nussenzweig, who co-led the work with collaborators Theodora Hatziioannou, Paul Bieniasz, and Marina Caskey, “Depending on the virus, feedback inhibition can either improve immunity or block it.” Our findings imply that pre-existing SARS-CoV-2 antibodies can diversify the antibody response, potentially expanding the range of mRNA vaccines.
Of guinea pigs and antibodies
Theobald Smith, a pioneering epidemiologist, first identified antibody feedback inhibition at the turn of the century when he showed that too many antibodies might suppress the immunological response to diphtheria in guinea pigs. It struck me as odd that the same chemical that presumably protects the animal from illness would periodically shut down the immune system.
We now understand that viruses have a variety of epitopes, which are distinct pieces of antigen that antibodies utilize to recognize and attach to the virus. The immune system moves on and diversifies, producing antibodies that attach to other sections of the virus instead after the body has created potent antibodies for one epitope. The goal is to broaden the immune response; for instance, if a virus changes and loses the ability to identify one epitope, antibodies against other epitopes may still be able to kill it.
According to Nussenzweig, “antibody feedback can be a really good thing.” You develop a collection of beneficial neutralizing antibodies against numerous distinct sections of the virus.
Antibody feedback can, however, occasionally be more detrimental than beneficial. A perfect storm might happen if one of the few available epitopes for HIV or influenza fails to produce antibodies that are particularly potent. The body will stop producing that line of antibodies when it notices a surplus of weakly protective antibodies, unintentionally preventing the development of antibodies of a similar type that may have performed better.
According to Nussenzweig, the HIV virus only has a few locations worth targeting, and if the initial reaction blocks those epitopes, we won’t have a broadly neutralizing reaction.
Antibody feedback in COVID
Nussenzweig and colleagues monitored volunteers who received a single dose of monoclonal antibody therapy and later two doses of an mRNA vaccine to learn more about how antibody feedback affects COVID immunity. They discovered that these participants’ immunological reactions were noticeably different from those of others who had just received the mRNA vaccinations.
After two doses of an mRNA COVID vaccination, memory B cells often predominate and express antibodies that are specific to one of three essential regions of the spike protein’s receptor-binding domain, which the coronavirus needs to infect a cell. As predicted, Nussenzweig and associates discovered that over 50% of the antibodies isolated from people who only got vaccinations targeted so-called Class 1, 2, or 3 epitopes.
However, only 20% of the volunteers’ antibodies, who had received monoclonal antibodies prior to the vaccination, were directed against one of these three epitopes. Instead, almost 80% of their antibodies focused on a different set of epitopes or a different portion of the receptor-binding domain. The authors came to the conclusion that feedback inhibition was at play since the body ceased generating antibodies against Class 1, 2, or 3 epitopes following monoclonal antibody therapy and switched to targeting other epitopes following vaccination. In this instance, the effects are favorable.
According to Nussenzweig, “their immune response is different, but definitely not worse.” In actuality, those who received monoclonal antibodies had excellent protection.
According to the research, monoclonal antibodies may aid in diversifying the immune response to COVID by broadening the range of mRNA vaccines. There might also be crucial lessons for improving. According to Nussenzweig, “antibody feedback is highly useful since there are several sites on the receptor-binding domain that can kill the virus.”
And whether monoclonal antibodies or extra vaccination boosters are responsible for the antibody surplus generating that feedback, he asserts that “antibody feedback is really excellent for COVID.”
