Immune genetics and previous common cold infections could help protect Japan against COVID-19

Schematic visualization of how the peptide VYIGDPAQL (“VYI”) can be presented by the MHC class I molecule HLA-A * 24:02 and how this can contribute to CCCoV-induced CD8 + T cell memory against SARS-CoV-2 . The map represents the geographical mainland of Japan. The imaged HLA-A * 24:02 structure is based on PDB enthronement 3I6L. Credit: Johannes M. Dijkstra

Protective immune memory – with B cells that make antibodies, and / or T cells that in the case of CD8+ T cells can kill virus-infected cells – they can be induced by identical but also by related viruses. In relation to the COVID-19 virus SARS-CoV-2, there are four common cold coronaviruses (CCCoVs) that together cause ~ 20% of common cold infections: OC43, HKU1, 229E and NL63. Most adults have been infected with CCCoVs several times in their lives. Whether or not there are significant CCCoV-induced anti-SARS-CoV-2 neutralizing antibodies remains debated. Meanwhile, the generation of T-cell memory must depend on the genetic makeup of the infected individual. Namely, immune recognition of T cells depends on the presentation of peptides (“epitopes”) of polymorphic major histocompatible complex (MHC) molecules, and different MHC alleles (variants between individuals) present different peptides of the same pathogen.

In their recent publication in F1000 Research, Dijkstra, Frenette, and Dixon provided the first systematic search for SARS-CoV-2 cell epitopic sequences that were experimentally determined in one or more of> 15 studies and are identical to at least one of the four CCCoV. They found that such epitopes were rare. The only such epitope repeatedly identified as immunogenic by independent research groups was the peptide VYIGDPAQL, which is also called “VYI” after its first three amino acids. This peptide is a fragment of the helicase virus and identical between SARS-CoV-2 and the CCCoVs OC43 and HKU1. The VYI peptide was found to bind an MLA-class HLA-A * 24:02 allele and effectively stimulate CD8.+ T cells from at least some – and sometimes most – of researched HLA-A * 24:02+ COVID-19 (convalescent) patients in each study that treated this issue. This finding has been confirmed in two recent studies that were not part of the Dijkstra et al. analysis.

To explain these findings, Dijkstra et al. conservatively assumed that infections with OC43 or HKU1 took precedence over the anti-VYI-T cells, which were then re-stimulated after infection with SARS-CoV-2. The authors also speculated that the surprisingly low frequency of COVID-19 in Japan can be partially explained by such anti-VYI-T-resistant memory, because in this country ~ 60% of individuals carry the HLA-A * allele 24:02 and in recent years there have been OC43 explosions. It is important to note, however, that at present this remains only a conjecture, as (i) experimental evidence for CCCoV-induced anti-VYI memory has yet to be provided, and (ii) immune memory does not necessarily mean immune protection. However at present the VYI / HLA-A * 24: 02 / Japan hypothesis presented by the authors is one of the most credible models to genetically explain differences in resistance to COVID-19 between populations. Right et al. described how even a small impact on virus reproduction levels can have a significant impact on the spread of the virus across a population. Their article is also an interesting read on the situation of COVID-19 in Japan.

Plue, Dijkstra et al. pointed out that the similarity between the spike (S) proteins of SARS-CoV-2 and CCCoVs is low, suggesting that the sequential conservation of this protein is relaxed. Therefore, the authors approve of the fear expressed by others that SARS-CoV-2 may mutate its S protein to escape the immune protection induced by the current generation of S-only vaccines. The inclusion in future vaccines of more conserved parts of the virus between SARS-CoV-2 and CCCoVs may decrease the risk of such escape. For populations in which HLA-A * 24:02 is prevalent, as in Japan, the peptide VYI is a major candidate for such inclusion.

Study shows vaccines can protect against new COVID-19 onions – and possibly the common cold

Additional information:
Johannes M. Dijkstra et al, Most Japanese individuals are genetically predisposed to recognize an immunogenic protein fragment shared between COVID-19 and common cold coronaviruses, F1000 Research (2021). DOI: 10.12688 / f1000research.51479.1

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