Pre-existing immunity to other coronaviruses may be poor

By Dr. Ramya Dwivedi, Ph.D.Oct 13 2020

In severe coronavirus 2019 disease (COVID-19) cases, higher antibody titers against seasonal coronaviruses are found compared to low amounts in mild cases. The possibility of COVID-19 to be an immune-mediated disease can not be ruled out. Based on the observations on its infection history, and the resulting immunological background against seasonal coronaviruses (CoV), an insight into the type-specific and cross-reactive antigenicity are essential.

Brenda M. Westerhuis et al., in a recent medRxiv* preprint paper, investigate the antibody cross-reactivity - to explain the severe disease. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Severe COVID-19 patients display a back boost of seasonal coronavirus-specific antibodies. Image Credit: Corona Borealis Studio / Shutterstock

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

The researchers determine the kinetics, breadth, magnitude and level of cross-reactivity of IgG against SARS-CoV-2 and seasonal CoV nucleocapsid and spike from severe COVID-19 cases at the clonal level.

They find that in addition to a type-specific SARS-CoV-2 response, seasonal CoV dominated B cell clones are present that increase over a period.

Pre-existing immunity to related viruses with the same antigenicity generally determined the outcome of the infection. For example, in cases of influenza or dengue, the host exhibited dominance over subsequent infections due to the memory of the previous infection. This mechanism is termed "original antigenic sin" (OAS) - the propensity of adaptive immunity to fight pathogens based on memory recall preferentially. This may also affect the clones, primed to target a specific epitope, to dominate the response to target a new but slightly different cross-reactive epitope, thus causing poor immunity and neutralization of infection.

Now, structural homology between the ectodomain of SARS-CoV-2 Spike (S, SARS2-SECTO) or nucleocapsid protein (N, SARS2-N), is found with those of other endemic human seasonal CoV such as hCoV-229E, -NL63, -HKU1 and -OC43 or recent epidemic strains such as SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). This suggests that memory B-cells capable of expressing cross-reactive antibodies pre-exist in patients. High sequence homology is found towards SARS-CoV-2 in SARS-CoV infected individuals, while homology between SARS-CoV-2 and seasonal CoV is lower. Yet CoV is prevalent. Repeated exposure to seasonal CoV may lead to developing a SARS-CoV-2 response.

This study highlights the body's back boost of poorly protective coronavirus-specific antibodies in severe COVID-19 patients - this might impact the SARS-CoV-2 specific immune response. The detailed insights in kinetics and cross-reactivity patterns of N and S reactive IgG, in this study, helps to understand the humoral immune system response towards a novel CoV.

The cohort in this study included 17 patients with the severe COVID-19 disease, out of which six succumbed to, and five recovered from the SARS-CoV-2 infection.

While it is known that severe COVID-19 patients generate a strong SARS-CoV-2-specific IgG response, they also display an increasing IgG response towards other coronaviruses (seasonal CoV N and S antigens). The IgG responses against these viruses appear correlated by undefined mechanisms.

The supernatants of the in vitro stimulated B-cells also showed clonal IgG cross-reactivity patterns towards different coronavirus strains. B-cells were isolated from peripheral blood samples of a representative donor.

These observations in this study suggest that high antibody titers to seasonal CoV may be associated with poor disease outcome in COVID-19 patients. There was no IgG cross-reactivity observed towards SARS-CoV-2 in healthy controls.

Also, the further combined analysis of reactive clones from all the donors showed cross-reactivity patterns between human seasonal and emerging coronaviruses, reaffirming the previous observations.

Overall, this study suggests that cross-reactivity towards SARS-CoV-2 has a minor contribution to the outgrowth of clones targeting seasonal CoV.

It is shown that infection or vaccination induced a broad increase in titers towards preceding viruses. Based on the antigenic distance, it is calculated that the back boost extended beyond cross-reactivity.

The pre-existing CoV-specific B-cells and the presence of cross-neutralizing antibodies is a double-edged sword: it may aid in a quick viral clearance from memory recall compared to initiating a primary humoral response or it may also promote pathology.

This study expands the understanding of how the humoral immune system responds towards a novel CoV, specifically in the context of a CoV experienced immune system. This study emphasizes the importance of the immunological background of individuals - to assess the quality and quantity of a newly initiated response towards SARS-CoV-2. It may have strong implications for vaccine design and the response to infection.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources