COVID-19 vaccination elicits an evolving, cross-reactive antibody response to epitopes conserved with endemic coronavirus spike proteins.

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Public Summary:
The first coronavirus vaccine was created during the pandemic against SARS-CoV-2. However, before this vaccine many people had come down with weaker, “common cold” coronaviruses. Those infections resulted in the formation of immune memory, stored in memory B cells (Bmems), that protected such recovered people from future infection by coronaviruses they had already encountered. Immune memory against SARS-CoV-2 is created in much the same way following vaccination, which acts as a more controlled stand-in for naturally-occurring infection. In both cases, Bmems which have learned to recognize SARS-CoV-2 or another specific virus cause antibodies against that virus to be mass-produced and released within the body, protecting the person from the virus. These processes were already understood; however, the possibility that existing natural immunity (i.e., against common cold coronaviruses) could interact with or alter the development of induced immunity (as from COVID-19 vaccines) had not yet been thoroughly investigated. To rectify that gap in our collective knowledge, Dr. Altin’s team collected blood samples from 21 volunteers. Each volunteer donated blood at four time points: once before and once after both their first and second doses of Moderna COVID-19 vaccine. By analyzing the antibodies contained in these blood samples, researchers were able to determine that pre-existing natural immunity against other coronaviruses did indeed influence the development of vaccine-induced immunity against SARS-CoV-2. Importantly, the team observed that pre-existing antibodies against weaker coronaviruses were sometimes also able to recognize SARS-CoV-2 and were stimulated further by vaccination. These results tell us that it may be possible to develop a future vaccine capable of inducing immune protection against not merely a single coronavirus, but against many coronaviruses at once. The CIRM-funded COH project in analysis of convalescent COVID plasma was useful as controls in this work.
Scientific Abstract:
The COVID-19 pandemic has triggered the first widespread vaccination campaign against a coronavirus. Many vaccinated subjects are previously naive to SARS-CoV-2; however, almost all have previously encountered other coronaviruses (CoVs), and the role of this immunity in shaping the vaccine response remains uncharacterized. Here, we use longitudinal samples and highly multiplexed serology to identify mRNA-1273 vaccine-induced antibody responses against a range of CoV Spike epitopes, in both phylogenetically conserved and non-conserved regions. Whereas reactivity to SARS-CoV-2 epitopes shows a delayed but progressive increase following vaccination, we observe distinct kinetics for the endemic CoV homologs at conserved sites in Spike S2: these become detectable sooner and decay at later time points. Using homolog-specific antibody depletion and alanine-substitution experiments, we show that these distinct trajectories reflect an evolving cross-reactive response that can distinguish rare, polymorphic residues within these epitopes. Our results reveal mechanisms for the formation of antibodies with broad reactivity against CoVs.