Evidence antibodies targeting HCoV-OC43 are strongly enhanced in response to SARS-CoV-2 but not in response to vaccination.

A research team led by Dr. Margaret E. Ackerman is a cohort of spontaneously infected severe acute respiratory coronavirus 2 (SARS-CoV-2) with elevated cross-reactive antibodies to endemic coronavirus (CoV), especially β-CoVOC43. I observed. For simple control.

Existing antibodies against endemic CoV that cross-react with SARS-CoV-2 may affect the antibody response to SARS-CoV-2 vaccination and infection.The size of the cross-reactive antibody found in the current study published in medRxiv* The preprint server was well correlated with the response to SARS-CoV-2 peplomer and S2 subdomains.

study: Boost of cross-reactive antibodies against endemic coronavirus due to SARS-CoV-2 infection. However, we do not vaccinate with stable spikes. Image credit: P. Heitmann / Shutterstock.com

Do “antigenic sin” and “antibody-dependent enhancement” apply to SARS-CoV-2 exposure?

The human immune system tends to preferentially utilize immunological memory based on primary infection when encountering secondary and slightly different variants of the pathogen, thus resulting in a biased response to new strains. This phenomenon, also known as antigenic sin, Neutralizing antibody, Thereby weakening the effective clearance of new viruses.

This phenomenon has been established against influenza and dengue virus and has recently been suggested to be present against SARS-CoV-2 infection. This means that the low titers of neutralizing antibodies against SARS-CoV-2 may be due to the boost of existing cross-reactive viruses.

Another phenomenon that has been proposed to be present in SARS-CoV-2 infection is antibody-dependent enhancement (ADE). ADE is described as a case where cross-reactive antibodies induced by previous exposure to related pathogens promote infection of cell types with antibody Fc receptors and thus potentially increase morbidity and mortality. increase.

Observed In vitro There was no abundant evidence that ADE existed in the context of SARS-CoV-2 In vivo.. However, the establishment of ADE in the case of dengue has raised concerns about the enhancement of coronavirus disease 2019 (COVID-19).

About research

The unique CoV peplomer sequence was aligned with the SARS-CoV-2 peplomer sequence to compare sequence conservation across human CoV. Structural conservation was assessed by overlaying the SARS CoV-2 S1 and S2 domains with the best-conserved, widely circulating, endemic human CoV strain OC43.

Three diverse cohorts were included in the current study to evaluate the antibody profile of this observational study. The first small cohort consisted of COVID-19 convalescent individuals, with serum and mucosal samples available.

Second, the larger cohort Convalescent plasma Donors, acutely infected individuals, and pregnant women infected late in pregnancy. The third cohort consisted of subjects for whom pre- and post-infection samples were available. Included was a healthy adult cohort of individuals vaccinated with the SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine and pregnant women vaccinated late in pregnancy. All samples were analyzed with samples from naive and historical negative controls.

Investigation result

The N-terminal domain (NTD) of SARS-CoV-2, including the receptor binding domain (RBD), showed low sequence homology to the corresponding subdomain of the unique CoV compared to the S2 subdomain. .. However, superposition of the SARS CoV-2 S1 and S2 domains with the most well-conserved and widely circulating endemic human CoV OC43 shows high structural conservation in S2 and NTD and homology in RBD. Showed a complete lack of.

Based on both structural and sequence homology, the team found that existing antibodies produced against endemic human CoV target more conserved regions of SARS-CoV-2, such as S2. It was suggested that it was more likely to be done and less likely to recognize RBD.

Examination of the antibody response to human CoV in endemic diseases and pandemics in subjects 1 month after SARS-CoV-2 infection showed elevated OC43-specific antibody response during the recovery phase of SARS-CoV-2 compared to naive control. I found out that. The magnitude of these reactions correlated with the response to the SARS-CoV-2 peplomer and S2 subdomains.

The team also found OC43-specific immunoglobulin G (IgG), and mucosal IgA in both serum and mucosal samples of acutely infected subjects two weeks after COVID-19 diagnosis, but not IgM. .. This finding indicates that these elevated responses are real and not due to newly induced antibody strains with cross-reactivity with OC43. Testing of serum samples before and after SARS-CoV-2 infection strengthened the hypothesis that existing clonal families were boosted by SARS-CoV-2 infection.

Antibody response to SARS-CoV-2 and endemic CoV Spike protein Measured in a variety of cohorts. Antibodies to SARS-CoV-2 were induced in all isotypes, but only the IgA and IgG responses to endemic CoV were strongly boosted, only among naturally infected but unvaccinated individuals. It has occurred. These recalled cross-reactive responses to endemic CoV recognized and did not neutralize the S2 domain, which was primarily conserved. Other antiviral activities of widely cross-reactive S2-specific antibodies are not known, but the different antigenicity of vaccination with natural infections and stabilized pre-fusion spikes is with the breadth of protection provided by each. Potentially affect the level.

SARS-CoV-2S2 domain and total spike (S-2P) -specific antibodies isolated from convalescent sera were cross-reactive to OC43 spikes. However, RBD-specific antibodies were not. Similarly, antibodies isolated using OC43 cross-reacted with SARS-CoV-2 S-2P and S2, but not with RBD. This indicates that the cross-reactivity between these viral peplomer proteins is linked to the more conserved S2 domain. Both OC43S-specific and SARS-CoV-2S2-specific antibodies are non-neutralizing, consistent with the fact that neutralizing antibodies tend to target the SARS-CoV-2 RBD.

Immunogens were significantly contrasted compared to naturally infected and vaccinated subjects representing exposure to unstabilized and proline-stabilized S antigens, respectively. Immune responses generated from vaccination with SARS-CoV-2 peplomers stabilized in the pre-fusion conformation have very weak or no cross-reactivity profiles, resulting in spikes to the resulting humoral response. It suggests the crucial importance of the conformational state of proteins.

In addition, the high levels of neutralizing activity resulting from vaccination suggest a favorable antigenicity of the pre-fusion conformation of peplomers, and the cost of the original antigenic sin may be avoided by immunogen design. ..

“In summary, this study found that antibodies targeting OC43 were strongly boosted in response to SARS-CoV-2 infection, but not in response to stabilized S vaccination, and that the S2 sub of the peplomer protein. It provides evidence that the domain may be involved in triggering recalled IgG-. The dominant reaction. “

Our goal

Neutralization is not the only mechanism by which an antibody provides protection, as cross-reactive antibodies can also interact with receptors in the Fc region of the antibody on the surface of innate immune cells and promote protective effector function.

Therefore, researchers in the current study emphasize the need for further research aimed at characterizing the potential effector function of these antibodies. Future work will understand their role in vaccine-mediated protection to provide a more complete picture of the relative risks and benefits of this recall response in relation to vaccine design, especially in the context of viral variants of concern. You should focus on what you do.

*Important Notices

medRxiv Publish preliminary scientific reports that should not be considered definitive as they are not peer-reviewed, guide clinical practice / health-related behaviors, and should not be treated as established information.