Researchers find evidence of negative repercussions of immune history in SARS-CoV-2 infection

In a recent article posted to PLoS ONE, researchers found proof of negative repercussions of immune history in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Study: Evidence for deleterious effects of immunological history in SARS-CoV-2. Image Credit: Naeblys/Shutterstock
Study: Evidence for deleterious effects of immunological history in SARS-CoV-2. Image Credit: Naeblys/Shutterstock


According to a recent study, the antibodies adhering to the Ep9 epitope from the SARS-CoV-2 nucleocapsid (N) protein strongly correlate with the severity of the coronavirus disease 2019 (COVID-19) illness.

When the immune reaction attacks a similar but distinct pathogen rather than the primary infection it was designed for, antigenic interference (AIN) occurs. COVID-19 patients harboring anti-Ep9 antibodies (Abs) exhibited characteristics of AIN, such as early immunoglobulin G (IgG) activation and cytokine-linked injury. Hence, it was likely that the immune memory of a past infection influences inadequate anti-Ep9 Abs development in severe COVID-19 cases.

About the study

In the current study, the researchers explored the epitope similarity landscape and cross-reactivity of αEp9 Ab to possibly discover a major antigen triggering an Ab-based immune reaction in αEp9-positive COVID-19 patients. Assays assessed the concentrations of αEp9 IgMs and IgGs in αEp9-positive patients whose plasma was taken at various points post-symptom onset (PSO).

Further, the team used the pBLAST and VAST databases to look for Ep9 structural homologs and sequences. The putative AIN epitope areas were subcloned to phagemids that encoded the sequences as hybrids to the P8 coat protein of the M13 bacteriophage to speed up the adhesion assessments in subsequent assays.

To reduce anomaly concentrations and accurately represent the median Ab population among patients, samples from different patients were combined for the preliminary assays. Initially, cross-reactivity against various potential epitopes was screened utilizing the pooled sample information. In addition, Ep9 homolog binding to αEp9 Abs was examined using phage enzyme-linked immunosorbent assays (ELISAs).

Next, the selectivity of αEp9 Abs adhering to neuraminidase (NA) from various viral strains was investigated. Furthermore, the authors examined if EpNeu from the H3N2 influenza A sequence and Ep9 epitopes attach to the same Abs.


The study results indicated that αEp9 IgG titers of a patient appeared to increase as early as one day PSO, which was commensurate with the characteristics of AIN following a previous infection. Comparable IgG concentrations were seen in the patient group for more than four weeks; as a result, αEp9 IgG titers spiked and stayed high. Likewise, αEp9 IgM levels among patients at different PSO periods were comparable. Compared to similar Ep9 IgG levels, the indications for Ep9 IgM titers were much lower; this discrepancy may be due to reduced IgM quantity, affinity, or both.

Further, the finding that both IgM and IgG antibodies target the Ep9 epitope implies that numerous antibodies with comparable binding characteristics may exist across COVID-19 patients. As a result, the scientists pointed out the anti-Ep9 paratopes as a part of an Abs population in sera.

SARS-CoV-2 Ep9 and a corresponding SARS-CoV-1 epitope having 90% similarity bind solely to plasma from Ep9-positive COVID-19 patients, corroborating earlier reported results. Due to the limited distribution of SARS-CoV-1 in the United States (US), the αEp9 Ab preference for SARS-CoV-1 was unlikely to induce SARS-CoV-2 AIN.

A putative epitope from the H3N2 influenza A strain NA protein circulated during 2014, named EpNeu by the authors, was identified from the possible epitope panel. EpNeu was bound by plasma from three separate pools of αEp9-positive SARS-CoV-2 patients but not by plasma from αEp9-negative subjects or healthy people. Despite the 38% amino acid sequence homology between EpNeu and Ep9, other potential epitope sites with noticeably higher homology did not bind to αEp9-positive plasma.

No EpNeu homologs were linked to Abs from αEp9-positive patients, despite having just one residue variation or a 92.3% similarity to EpNeu. One EpNeu amino acid change, K142N in an H1N2 swine flu strain from 2016, significantly reduced binding preference to Abs from patients who were αEp9-positive. A 2010 H9N4 avian influenza A virus epitope that lacked S141 residue but still had conserved K142 significantly decreased adherence to Abs from αEp9-positive patients. Thus, the team suggested that S141 and K142 were essential for αEp9 Ab binding.

The investigators stated that αEp9 Abs also bind to the EpNeu epitope. Moreover, they predicted that the mean number of Abs in each pool, namely αEp9 and EpNeu, would be comparable, negating the need for further optimization.


The team discovered a potential primary antigen that could promote the generation of cross-reactive, anti-Ep9 Abs. Direct cross-reactivity among Abs adhering to Ep9 and just one bioinformatics-derived similar presumptive antigen, a sequence generated from the H3N2 influenza A virus NA protein, was demonstrated by binding experiments using patient blood samples.

This cross-reactive attachment was very strain-specific for the influenza virus and susceptible to even single amino acid alterations in the epitope sequence. The researchers mentioned that the influenza vaccine did not harbor the NA protein, and the extensive influenza infection during 2014 perhaps resulted in anti-Ep9 Abs.

The authors concluded that some cases of COVID-19 disease severity linked to αEp9 Abs might be caused by AIN from a prior H3N2 influenza A virus infection. While several factors may contribute to illness severity during COVID-19, the study findings imply that a subgroup of COVID-19 patients' dependence on elevated titers of imprinted influenza Abs could indicate a less functional immune reaction and, as a result, more severe illness outcomes.

The scientists added that future research should look at the relationship between the prevalence of the H3N2 2014 influenza virus and severe SARS-CoV-2 infection in the US. Additionally, they noted that this association could be analyzed via health networks recording influenza infections.

Besides, the prediction of AIN-based immune reactions and illness outcomes in upcoming infections may be possible by examining Ab cross-reactivity and epitope conservation. Further, recognizing benign, beneficial, or detrimental AIN routes could also inform vaccine design.

Journal reference:
Shanet Susan Alex

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.


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