Cross-reactive SARS-CoV-2 antibodies after exposure to avian coronavirus vaccine

By Dr. Liji Thomas, MDReviewed by Benedette Cuffari, M.Sc.Jul 28 2022

The coronavirus disease 2019 (COVID-19) pandemic, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), sparked scientific interest in developing a pan-coronavirus vaccine that is broadly protective against future pathogenic coronaviruses (CoVs) with pandemic potential.

One approach is to discover cross-reactive antibodies against SARS-CoV-2 in people exposed to other CoVs. A recent Allergy study reports the identification of such antibodies in poultry farm workers exposed to the avian infectious bronchitis virus (IBV).

Study: Exposure to Avian Coronavirus Vaccines Is Associated with Increased Levels of SARS-Cov-2-Cross-Reactive Antibodies. Image Credit: greenOlli / Shutterstock.com

Introduction

IBV caused the first known coronavirus pandemic in animals and has continued to be detected in farmed chickens, despite the administration of live attenuated IBV vaccines being administered.

During the vaccination process, vaccinators are exposed to the live attenuated virus through their respiratory tract and conjunctivae. This constant exposure lasts for the full duration of their work day.

Ordinary farm workers are also exposed constantly, but on a lower level, as they do not directly encounter the vaccine virus.

IBV has seven strains and multiple recombinants, with the S1 spike gene carrying the major antigenic determinants. Thus, neutralizing antibodies (nAbs) to the S1 protein may not protect against novel strains with S1 mutations. This may account for the persistence of IBV infection.

The spike protein mediates host cell binding and entry; therefore, nAbs primarily target this and the nucleocapsid (N) protein. The similarity between the epitopes of the S1 and N proteins of IBV and SARS-CoV-2 may be responsible for the presence of cross-reacting antibodies to either of these viruses following infection with the other.

Both the N and S2 spike nAbs may also be important for the development of cell-mediated immunity and viral neutralization outside the receptor binding domain (RBD) of the spike protein.

Thus, cross-reactive antibodies to IBV or other CoVs might protect against SARS-CoV-2 infection or at least prevent severe disease. Conversely, such antibodies that bind but do not neutralize the virus might cause increased severity of COVID-19 by enhancing SARS-CoV-2 entry into the host cells through a process known as antibody-dependent enhancement (ADE) of disease.

Study findings

SARS-CoV-2 antibodies

Immunoglobulin G (IgG) antibodies targeting SARS-CoV-2 S1, RBD, and N antigens in poultry farm workers were found at elevated levels as compared to pre-pandemic levels. However, these levels were much lower than those observed in COVID-19 patients, with the highest titers reported in hospitalized COVID-19 patients.

Among those who administered the IBV vaccine, ten had higher specific IgG to SARS-CoV-2 than pre-pandemic controls. Over a third of vaccinators exhibited elevated S1- and RBD-specific IgG levels as compared to 20% or less of other workers. Over 70% of other farm workers exhibited higher anti-S2 and N IgG levels.  

IBV antibodies

Detectable anti-IBV IgG levels were found in almost all vaccinators and poultry farm workers, with these levels particularly high among the vaccinators. Moreover, anti-IBV IgG levels were higher in pre-pandemic controls at comparable levels but not in COVID-19 patients. Antibodies to one IBV strain were higher in farm workers as well.

Non-hospitalized COVID-19 patients exhibited higher anti-IBV antibodies than hospitalized patients. Vaccinators had somewhat higher anti-IBV antibody titers than other farm workers.

Specific SARS-CoV-2 antibodies with epitopes homologous to those in IBV and endemic human seasonal coronaviruses (HCoVs) were higher in COVID-19 patients as compared to either poultry workers or pre-pandemic samples. These antibody levels in hospitalized COVID-19 patients were higher as compared to outpatients.

Anti-S IgG levels were higher in vaccinators than in poultry farm workers. Interestingly, vaccinators who had worked for over eight years in this field had higher IgG levels against SARS-CoV-2 S1, RBD, and IBV as compared to those with the least experience.

SARS-CoV-2 and IBV IgG antibodies were most closely correlated among poultry workers, with pre-pandemic controls showing moderate correlation. The presence of such a correlation may indicate cross-reactivity.

There was no, or only negative, correlation in COVID-19 patients. In this group, antibodies to SARS-CoV-2 antigens and peptides were well correlated. Conversely, in poultry workers, only SARS-CoV-2 N and N-peptide antibodies were correlated.

Neutralizing activity was also absent against SARS-CoV-2 except in the presence of SARS-CoV-2-specific IgG.

Conclusions

Earlier research has suggested that cross-reactive immune responses to SARS-CoV-2 are induced by prior exposure to HCoVs, primarily through the N and S proteins. This is similarly observed in the current study, with the S and N antigenic regions exhibiting about 30% homology between IBV and SARS-CoV-2. This level of homology is similar to that observed between SARS-CoV-2 and other HCoVs.

Despite this low level of homology, widespread exposure to HCoVs may induce cross-reactivity to other CoVs. This is due to the presence of IBV-specific IgG in most COVID-19 patients and pre-pandemic controls, who are unlikely to have been exposed to this avian virus.   

It remains unclear whether severe COVID-19 causes anti-IBV IgG levels to decline or whether these patients already had lower levels of these antibodies, especially as antibodies to rhinovirus A and human herpesvirus 4 were also reduced.

This could be due to reduced immune responses to other viruses induced by SARS-CoV-2, as observed with the measles virus. Both these viruses have been shown to infect T-cells, causing “immune amnesia”.

Independent of putative HCoV exposure, poultry farm workers showed a strong association between specific IgG to IBV and SARS-CoV-2 antigens as compared to COVID-19 patients and pre-pandemic controls, thereby indicating that cross-reactivity was induced by IBV exposure. With repeated exposure, as in vaccinators with over eight years of experience, higher levels of IBV- and SARS-CoV-2-specific IgG were observed.

The antibodies isolated from poultry workers did not neutralize SARS-CoV-2, unlike those obtained from COVID-19 patients. This may be due to lower affinity, low concentration, or non-binding to the RBD angiotensin-converting enzyme 2 (ACE2)-binding region. Importantly, the presence of other mechanisms of antibody-mediated protection was not explored in this study.

The current study is unique, and its findings may not be replicable, as mass COVID-19 vaccination has occurred worldwide, thereby obfuscating the SARS-CoV-2-specific antibody profile and resulting protection conferred by IBV vaccine exposure.