Nearly three years into the pandemic, many of us now carry antibodies against the virus — due to an infection or two, a few doses of mRNA vaccine, or a round of monoclonal-antibody treatment. But not all immune responses are created equal, and how we first developed our antibodies may influence the character of our body’s response to SARS-CoV-2.

Now, a new study describes the unique immune response elicited in individuals who received monoclonal antibodies before taking two doses of an mRNA vaccine. The research, published in Nature, explores a phenomenon known as antibody feedback inhibition, known to alter immune responses to some pathogens while beneficially diversifying the body’s antibody repertoire against several others. The findings suggest that feedback inhibition increases the coverage provided by COVID vaccines in people who previously received monoclonal antibodies.

“Depending on the virus, feedback inhibition can either enhance immunity or inhibit it,” says Michel C. Nussenzweig, who co-led the study with colleagues Theodora Hatziioannou, Paul Bieniasz, and Marina Caskey. “Our results suggest that pre-existing SARS-CoV-2 antibodies can diversify the antibody response, which may increase the breadth of mRNA vaccines.”

Of guinea pigs and antibodies

Antibody feedback inhibition was first discovered at the turn of the century by pioneering epidemiologist Theobald Smith, who demonstrated that excess antibodies could inhibit the immune response to diphtheria in guinea pigs. It seemed like a curious twist — why would the same molecule that supposedly protects the animal from disease occasionally shut the immune system down?

We now know that viruses have multiple epitopes — stand-out bits of antigen that antibodies use to identify the virus and latch on to it. Once the body has produced strong antibodies for one epitope, the immune system moves on and diversifies, instead making antibodies that attach to other parts of the virus. Ideally, this increases the breadth of the immune response — if a virus mutates so that one epitope can no longer be recognized, for example, it might still be vulnerable to antibodies targeting other epitopes.

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