Editorial: Cross-reactive immunity and COVID-19

SARS-CoV-2 and COVID-19 impacted the world like a modern plague, stretching icy fingers across the globe. Humanity was even more horrified upon finding that this new plague came with variants, and surviving one version of the virus did not automatically grant immunity to all variants. But as has happened with previous pandemics, the deadliness and reach of COVID-19 has subsided into a slightly worrisome status quo due to the advancements of medical science and the virus' own evolution into less harmful forms. The intense scrutiny that SARS-CoV-2 and COVID-19 received during the height of their deadly assault on the world has revealed things that are now used to combat this pandemic.We now know that, unlike us, our immune system was not so surprised by SARS-CoV-2 since crossreactive immunity to SARS-CoV-2 existed prior to the COVID-19 pandemic. Cross-reactive immunity is mediated by antibodies and memory B and T cells elicited by a specific pathogen or antigen that can also react to other pathogens or antigens (1) Cross-reactivity is a main feature of adaptive immunity, which is highly favored by the recognition of small portions within protein antigens (epitopes) (2) and the poly-specificity of cognate B and T cell receptors (3,4). Human common cold coronaviruses (hCoVs) have received major attention as potential sources of crossreactive immunity to SARS-CoV-2 (5). However, immune cross-reactivity has also been reported between SARS-CoV-2 and unrelated viruses (6), bacteria (7), vaccines (8,9) and even food antigens (9). Activation of cross-reactive immunity is not always protective and can also produce immunopathology (10). Moreover, immune cross-reactivity is a two-way road and SARS-CoV-2 infection as well as COVID-19 vaccines can also induce cross-reactive immunity. Indeed, immune cross-reactivity between SARS-CoV-2 and COVID-19 vaccines with human tissues has been shown, raising the possibility that autoimmune reactivity can result from SARS-CoV-2 infection and COVID-19 vaccines (11).Clearly, pre-existing cross-reactive immunity must have a major impact in shaping the immune response to the virus and to COVID-19 vaccines, but to what extent and its contribution to protection is still undetermined. Likewise, SARS-CoV-2 and COVID-vaccines can have profound crossreactive immunological consequences that need to be investigated. In this special issue of Frontiers in Immunology about "Cross-Reactive Immunity and COVID-19," editors Aristo Vojdani, Pedro Reche, Alberto Beretta and Ahmed Yaqinuddin have gathered an impressive collection of articles investigating sources of immune cross-reactivity with SARS-CoV-2, contribution to protection, COVID-19 course and its ancillary condition, long COVID.On the face of it, it would seem that cross-reactive immunity would be a welcome weapon to wield against COVID-19. Pedro Reche, one of the editors of this collection, published an article in 2020 (8) in which he concluded, "Overall, our results clearly support that cross-reactive immunity from DTP vaccines can be protecting children against SARS-CoV-2 and could protect the general population." In 2022, Fonte et al. looked at the lower susceptibility of children to SARS-CoV-2 infection and concluded that the lower incidence and severity of the disease in children could be due to nonspecific resistance to SARS-CoV-2 generated by the childhood vaccines received by the subjects (12). ). These authors report that broadly neutralizing ability is critical for developing the next generation SARS-CoV-2 vaccine. They found that a specific homologous vaccine was insufficient for dealing with the Omicron virus variant, which had very different antigenic characteristics from the original. They also found that anti-ACE2 autoantibodies were significantly increased in all vaccinated test groups.The Omicron variant also proved problematic for Li M et al.'s study in this collection (INSERT LINK TO Article #18: Li M, Weng S, Wang Q, Yang Z, Wang X, Yin Y et al. Reduced binding activity of vaccine serum to Omicron receptor-binding domain. Front Immunol, 2022, 13: 960195, doi: 10.3389/fimmu.2022.960195). They found that vaccination contributes significantly in limiting the spread of SARS-CoV-2. However, they also found that this vaccine protection is not efficient against the Omicron variant. This was evidenced by the reduction in the binding of SARS-CoV-2 antibody-positive human sera to Omicron RBDs compared to its homogenous recombinant RBDs. We have already mentioned that the emergence of SARS-CoV-2 variants prevents acquiring general immunity to the disease. Thompson et al. investigated the impact of cross-reactive immunity on the emergence of these variants (INSERT LINK TO Article #13: Thompson RN., Southali E, Daon Y, Lovell-Read FA, Iwami S, Thompson CP, Obolski U. The impact of cross-reactive immunity on the emergence of SARS-CoV-2 variants. Front Immunol, 2023, 13: 1049458, doi: 10.3389/fimmu.2022.1049458). They found that if cross-reactivity immunity is complete, that the antigenically related novel variant must be more transmissible than the previous virus in order to invade the population. They highlighted that a fast assessment of the level of cross-reactive immunity conferred by related viruses against novel SAR-CoV-2 variants is essential to assessing the risk posed by those variants.The more we know about SARS-CoV-2 variants, then, the better it is for understanding the virus, its diseases, and how to deal with them. Kuthning et al. (INSERT LINK TO Article #1: Kuthning E, Raafat D, Holtfreter S, Gramenz J, Wittmann N, Bröker BM, Meyer-Bahlburg A. Variant-specific antibody profiling for tracking SARS-CoV-2 variant infections in children and adolescents. Front Immunol, 2024, 15: 1434291, doi: 10.3389/fimmu.2024.1434291) monitored SARS-CoV-2 specific antibodies in children and adolescents to determine whether the S1-specific antibody response can identify the infecting variant of concern (VoC), estimate the prevalence of silent infections, and test whether vaccination or infection with SARS-CoV-2 induces hCoV cross-reactive antibodies. They concluded that the antibody response to the S1 domain of the SARS-CoV-2 spike protein is highly specific, providing important information about the infecting VoC and revealing clinically silent infections. ) report that anti-RBD IgG antibodies from endemic hCoVs do not protect against the acquisition of SARS-CoV-2 infection among exposed uninfected individuals. In line with this result, Lin et al. reports that pre-existing humoral immunity to hCoVs negatively impacts the protective SARS-CoV-2 antibody response (14). Additionally, in one of the articles published in this collection, Li N et al. looked at whether preexisting antibodies induced by low pathogenic human coronaviruses (LPH-CoVs) in children can cross-react with SARS-CoV-2 (INSERT LINK TO Article #14: Li N, Li XY, Wu J, Zhang S, Zhu L, Chen Q. Pre-existing humoral immunity to low pathogenic human coronaviruses exhibits limited cross-reactive antibodies response against SARS-CoV-2 in children. Front Immunol, 2022, 13: 042406, doi: 10.3389/fimmu.2022.1042406). They found that the seroprevalence of four analyzed LPH-CoVs reached 75.84%, and about 24.64% of the seropositive samples had cross-reactive IgG antibodies against the nucleocapsid S and against the receptor binding domain (RBD) antigens of SARS-CoV-2. These data suggest that children's pre-existing antibodies to LPH-CoVs have limited cross-reactive neutralizing antibodies against SARS-CoV-2.In (15).Unlike cross-reactive humoral immunity, which may enhance disease severity (16), there is mounting evidence of the protective role of SARS-CoV-2 cross-reactive T cells (17) 2024) 15:1343716.: 10.3389/fimmu.2024.1343716. eCollection 1342024) support a protective role for alpha-hCoVspecific memory T cells cross-reactive with SARS-CoV-2. However, hCoV cannot account for all pre-existing SARS-CoV-2 cross-reactive T cells (18), and it is still unproven that hCoV can prime T cells cross-reactive with SARS-CoV-2. Interestingly, such a proof is provided in this research topic for tetanus-diphtheria vaccine. Thus, Fernandez et al. ( INSERT LINK TO Article #2: Fernandez SA, Pelaez-Prestel HF, Fiyouzi T, Gomez-Perosanz M, Reine J, Reche PA. Tetanus-diphtheria vaccine can prime SARS-CoV-2 cross-reactive T cells. Front Immunol, 2024, 15: 1425374, doi: 10.3389/fimmu.2024.1425374) showed that antigen-inexperienced naive T cells primed with tetanusdiphtheria vaccine recognized SARS-CoV-2-specific CD8 T cell epitopes, as anticipated by Reche in a seminal in silico study (8). Given that children received several immunizations with vaccines containing tetanus-dihptheria antigens, the results by Fernandez et al support that tetanus-diphtheria vaccine likely had a major contribution shaping exiting SARS-CoV-2 T cell responses. However, pre-existing cross-reative T cells may not always be protective. Thus ) observed that a significant percentage of SARS-CoV-2-infected individuals develop long COVID which overlaps with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). They identified alterations in metabolic pathways, including the elevation of plasma pro-inflammatory cytokines with a reduction in ATP in long COVID patients. These metabolic abnormalities not only help in better understanding the pathophysiology of long COVID but also in finding supplements with potential therapeutic implications which were suggested by the researchers.Taken all together, the 19 articles in this special topic collection examine cross-reactive immunity concerning SARS-CoV-2 and COVID-19. They highlight the intricate interplay between prior immune responses and the evolving viral landscape. The information obtained implies that response to antibodies and immune cells are likely to be critical in both the risk of infection and the response to vaccines. Although there are encouraging signs that pre-existing immunity may provide a degree of protection, the heterogeneity in responses-particularly against new variations such as Omicronsuggests that this phenomenon is not universally effective. As the pandemic evolved, it became evident that understanding of mechanisms involved in cross-reactive immunity will be essential for developing strategies to fight against COVID-19 and its variants.