There is a growing evidence that cross-reactive immunity from common human coronaviruses (hCoVs) can shape the immunological response to SARS-CoV-2. Cross-reactive T cells appear to play a protective role against disease but there is no consensus on the role of cross-reactive antibodies, with some authors reporting protective effects/mechanisms and other authors reporting evidence of negative interference due to the generation of low-affinity antibodies in the context of an “original antigenic sin”. Reports of association of pre-existing immunity to hCoVs and milder clinical manifestations of COVID-19 conflict with other reports showing in COVID-19 patients a strong back-boosting of antibodies to hCoVs with very little if no neutralizing activity against SARS-CoV-2. However, SARS-CoV-2/hCoVs cross-reactive antibodies, more specifically those directed against the S2 subunit of the Spike protein, may be protective via Fc-mediated mechanisms that recruits NK cells (ADCC) or similar mechanisms. Since these antibodies do not neutralize or neutralize very poorly, SARS-CoV-2 in vitro, they have been only occasionally investigated and rarely considered in the search for correlates of protection. Alternatively, it should also be considered that protection against severe COVID-19 disease may be sustained by cross-reactive T cells with cross-reactive antibodies being only a proxy of protective T cell immunity.
Although pre-existing immunity to SARS-CoV-2 is more often linked hCoVs, other sources of cross-reactive immunity to SARS-CoV-2, including bacteria and vaccine antigens are also plausible and should be considered. In particular, it has been identified, first computationally and later experimentally, cross-reactive immunity to SARS-CoV-2 from combination tetanus-diptheria vaccines (DTaP, DTwP, TD and Tdap). Moreover, epidemiological studies have clearly shown that subjects vaccinated with tetanus-diptheria vaccines are less likely to suffer severe COVID-19. Cross-reactive immunity to SARS-CoV-2 from pediatric tetanus-Diptheria vaccines and seasonal exposures to hCoVs likely play an important role in protecting children from COVID-19. On the other hand, the elderly may fail to mount an effective primary response to SARS-CoV-2 following infection owing to the loss of cross-reactive memory B and T cells and their relative inability to recruit naive T and B cells.
Cross-reactive immunity has also important implications for the understanding of the immunological mechanisms behind the efficacy of current COVID-19 vaccines. Immunological profiling of immunologically naive individuals who received one or two doses of RNA vaccines showed that the response to the first dose is sustained by IgA responses specific to the Spike S2 subunit, whereas neutralizing antibodies targetting the S1 subunit appears only after the second dose, consistent with the initial recruitment of memory B cells which may be cross-reactive between hCoVs and SARS-CoV-2. It is not known to what extent the initial response to the cross-reactive epitopes contributes to protection.
The identification of cross-reactive epitopes capable of eliciting protective responses has important implications also for the design of pan-coronavirus vaccines capable of leveraging on structural similarities between coronaviruses. Dissecting the cross-reactive B and T cell responses elicited by SARS-CoV-2 and understanding their protective or pathogenetic role may help generate important insights on disease pathogenesis, age differences in the response to infection, hallmarks of vaccine efficacy, and, ultimately, potential correlates of protective immunity.
In this Research Topic, we welcome the submission of Original Research, Review, Mini Review, Opinion, and Perspective articles covering, but not limited to, the following subtopics:
1. Cross-reactive humoral immunity
2. Cross-reactive T cell immunity
3. Epidemiology of hCoVs
4. Spike structure and hCoVs regions of homology
5. Cross-reactive immunity following vaccination.
Topic Editor Dr. Alberto Beretta is currently a shareholder and scientific director of SoLongevity. Topic Editor Dr. Aristo Vojdani is a co-owner of Immunosciences Lab., Inc. The other Topic Editors declare no competing interests with regards to the Research Topic subject.
There is a growing evidence that cross-reactive immunity from common human coronaviruses (hCoVs) can shape the immunological response to SARS-CoV-2. Cross-reactive T cells appear to play a protective role against disease but there is no consensus on the role of cross-reactive antibodies, with some authors reporting protective effects/mechanisms and other authors reporting evidence of negative interference due to the generation of low-affinity antibodies in the context of an “original antigenic sin”. Reports of association of pre-existing immunity to hCoVs and milder clinical manifestations of COVID-19 conflict with other reports showing in COVID-19 patients a strong back-boosting of antibodies to hCoVs with very little if no neutralizing activity against SARS-CoV-2. However, SARS-CoV-2/hCoVs cross-reactive antibodies, more specifically those directed against the S2 subunit of the Spike protein, may be protective via Fc-mediated mechanisms that recruits NK cells (ADCC) or similar mechanisms. Since these antibodies do not neutralize or neutralize very poorly, SARS-CoV-2 in vitro, they have been only occasionally investigated and rarely considered in the search for correlates of protection. Alternatively, it should also be considered that protection against severe COVID-19 disease may be sustained by cross-reactive T cells with cross-reactive antibodies being only a proxy of protective T cell immunity.
Although pre-existing immunity to SARS-CoV-2 is more often linked hCoVs, other sources of cross-reactive immunity to SARS-CoV-2, including bacteria and vaccine antigens are also plausible and should be considered. In particular, it has been identified, first computationally and later experimentally, cross-reactive immunity to SARS-CoV-2 from combination tetanus-diptheria vaccines (DTaP, DTwP, TD and Tdap). Moreover, epidemiological studies have clearly shown that subjects vaccinated with tetanus-diptheria vaccines are less likely to suffer severe COVID-19. Cross-reactive immunity to SARS-CoV-2 from pediatric tetanus-Diptheria vaccines and seasonal exposures to hCoVs likely play an important role in protecting children from COVID-19. On the other hand, the elderly may fail to mount an effective primary response to SARS-CoV-2 following infection owing to the loss of cross-reactive memory B and T cells and their relative inability to recruit naive T and B cells.
Cross-reactive immunity has also important implications for the understanding of the immunological mechanisms behind the efficacy of current COVID-19 vaccines. Immunological profiling of immunologically naive individuals who received one or two doses of RNA vaccines showed that the response to the first dose is sustained by IgA responses specific to the Spike S2 subunit, whereas neutralizing antibodies targetting the S1 subunit appears only after the second dose, consistent with the initial recruitment of memory B cells which may be cross-reactive between hCoVs and SARS-CoV-2. It is not known to what extent the initial response to the cross-reactive epitopes contributes to protection.
The identification of cross-reactive epitopes capable of eliciting protective responses has important implications also for the design of pan-coronavirus vaccines capable of leveraging on structural similarities between coronaviruses. Dissecting the cross-reactive B and T cell responses elicited by SARS-CoV-2 and understanding their protective or pathogenetic role may help generate important insights on disease pathogenesis, age differences in the response to infection, hallmarks of vaccine efficacy, and, ultimately, potential correlates of protective immunity.
In this Research Topic, we welcome the submission of Original Research, Review, Mini Review, Opinion, and Perspective articles covering, but not limited to, the following subtopics:
1. Cross-reactive humoral immunity
2. Cross-reactive T cell immunity
3. Epidemiology of hCoVs
4. Spike structure and hCoVs regions of homology
5. Cross-reactive immunity following vaccination.
Topic Editor Dr. Alberto Beretta is currently a shareholder and scientific director of SoLongevity. Topic Editor Dr. Aristo Vojdani is a co-owner of Immunosciences Lab., Inc. The other Topic Editors declare no competing interests with regards to the Research Topic subject.
