A recent study published in Science by Shrock et al.
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examined how responses to COVID-19 severity differed amongst patients with different
prior viral exposure history, finding notable correlations between both. Such serological
profiling provides a window into differential viral responses amongst patients with
diverse outcomes, potentially mediating improved therapeutics and vaccines for SARS-CoV-2.
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The ongoing global coronavirus disease-2019 (COVID-19) pandemic caused by the novel
respiratory coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),
underlies widespread global morbidity, but particularly rapidly overwhelmed medical
facilities of Europe and North America. Indeed, only 9% of deaths have occurred in
Asia where the outbreak originated, while Europe and North America account for 75%
of case fatalities.
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Shrock et al.
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examined the antibody profiles of 232 COVID-19 patients and 190 pre-COVID-19 era controls,
identifying several antibody epitopes shared between other coronaviruses (CoVs) and
SARS-CoV-2. COVID-19 patients requiring hospitalization. Such patients were also observed
to exhibit stronger and broader antibody responses to SARS-CoV-2, but weaker responses
to past infections compared with those who did not need hospitalization.
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This perhaps suggests that patients who did not need hospitalization had exhibited
a stronger response to previous infections.
Perhaps the stronger the exposure/response to previous CoV infections, the lower the
chances that hospitalization was required upon SARS-CoV-2 infection. Indeed, a significantly
lower level of antibodies targeting common viruses including rhinoviruses, enteroviruses,
and influenza was observed in COVID-19 patients requiring hospitalization compared
to those who did not.
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However, this could also just be indicative of a lower immune capacity as opposed
to acquired immunity through multiple infections. Astoundingly though, in the same
study, Shrock et al.
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also observed that COVID-19 patients requiring hospitalization exhibited a higher
seroprevalence rate for cytomegalovirus (CMV) and herpes simplex virus 1 (HSV-1),
indicating that even though exposure to non-CoVs mounted an adequate immune response,
this was unable to prevent hospitalization following SARS-CoV-2 infection. Conversely,
the hospitalized group of COVID-19 patients exhibited a lower response to CMV and
HSV-1 peptides, suggesting a reduced immune capacity.
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Seven CoVs have been associated with human disease, mostly amounting to mild respiratory
illness, perhaps underlying 15–30% of global common colds. Previous CoV outbreaks
have included severe respiratory syndrome (SARS) caused by SARS-CoV, and Middle East
respiratory syndrome (MERS) caused by MERS-CoV. Significantly, SARS-CoV, MERS-CoV,
and SARS-CoV-2 share significant sequence homology and antigenic epitopes capable
of inducing an adaptive immune response.
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All CoVs consist of transmembrane trimeric spike (S) glycoproteins, membrane (M) glycoproteins,
and transmembrane envelope (E) proteins. The RNA of CoV is bound to nucleocapsid (N)
proteins resembling string-on-beads. Due to high levels of homology between these
proteins in SARS-CoV, MERS-CoV, and SARS-CoV-2, perhaps prior exposure to one virus
could confer partial immunity to another. Thus, perhaps an ‘adaptive immune response’
due to repeated/increased CoV exposure in Asian/Middle Eastern populations underlies
low morbidity seen in those regions.
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Shrock et al.
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indicated that peptides corresponding to the S and N proteins were most reactive in
COVID-19 patient sera, but significantly lower in pre-COVID era controls. However,
the third most frequently recognized peptide in COVID-19 patient sera was the replicase
polyprotein ORF1, recognized to a similar degree in pre-COVID era control sera as
well. This was posited to be likely due to cross-reactivity between antibodies elicited
by previous CoVs exposure, suggesting that such patterns represented a pre-existing
cross-reactive response.
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Indeed, mapping highly conserved regions of the S protein between SARS-CoV-2 and other
common CoVs, as well as specific regions mapping to individual CoVs, indicated cross-reactivity
with SARS-CoV, MERS-CoV, and seasonal CoVs to varying degrees. This phenomenon, perhaps,
could potentially be attributed to antibody production induced by other pathogens.
Collectively, such data seems to suggest that responses to seasonal CoVs may be able
to influence the immune response to SARS-CoV-2.
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Taken collectively, the findings of Shrock et al., and increasing numbers of other
groups seem to strongly suggest that perhaps previous CoV infection infers an ‘immune
response memory’, which could be an explanation as to why locations around the world
with a history of CoV infections have yielded a lower morbidity rate.
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Indeed, prior viral exposure could provide some protection if cross-reactive neutralizing
antibodies or T cell responses are stimulated upon exposure to SARS-CoV-2
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(Fig. 1).
Fig. 1
Representative indicators of the findings by Shrock et al.,
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suggesting significant overlap between SARS-CoV-2 proteins with other coronaviruses
in human patients. a Box plots illustrating the number of peptide hits from the indicated
coronaviruses in confirmed COVID-19 patients and pre-COVID-19 era controls (negative
for SARS-CoV-2). Cross-reactivity toward SARS-CoV-2 peptides was observed in pre-COVID-19
era samples, while COVID-19 patients also exhibited cross-reactivity with other common
hCoVs, SARS-CoV, and MERS-CoV. b Bar graphs depicting the average number of peptides
derived from SARS-CoV-2, SARS-CoV, and each of the four most common hCoVs significantly
enriched per sample following IgG immunoprecipitation in the experiments of Shrock
et al.
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The ORF1 region of SARS-CoV-2 exhibited greatest comparative matches between patients
diagnosed with COVID-19 versus those that tested negative, indicating a potentially
large degree of overlap between previous CoV and SARS-CoV-2 infection, whereby previous
CoV perhaps reduced the severity of SARS-CoV-2 infection. Figure adapted from Shrock
et al.,
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with permission
Such potential mechanisms whereby patients are rendered with levels of ‘antibody memory’
against various prior viral infections could thus be utilized in both therapeutic
and vaccinology applications. One such demonstrative example is that of intravenous
immunoglobulin (IVIG) administration, which through formation of antigen–antibody
complexes and their neutralization, mitigating autoimmune responses.
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Indeed, IVIG has been demonstrated to benefit treatment of severe COVID-19.
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It is not too much of a stretch of the imagination to infer that a similar principle
may be at play in the results indicated by Shrock et al.
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A further therapeutic application can also be observed in the apparent advantageous
non-specific effects (NSEs) of live attenuated vaccines such as the Bacilli-Calmette-Guerin
(BCG) and Polio (OPV) vaccines.
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The thought is that such vaccines broadly stimulate the innate immune system to confer
non-specific protection against diseases other than the intended target of that vaccine,
in essence ‘training’ components of the innate immune system.
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While the exact measurement of such protection provided remains unclear, numerous
data suggest that at least some level of immunity is provided, with quantifiable reductions
in mortality. Perhaps in such cases, a similar mechanism of prior ‘molecular immunity
training’ is at play as observed by Shrock et al.
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Regardless, serological profiling has provided a window into viral responses amongst
patients with diverse outcomes. In particular, we are only just beginning to understand
how prior viral exposures may influence current/future responses. Of course, demographic
and socioeconomic factors make it difficult to draw strong conclusions, and it will
be some time before a suitable patient population can be examined to definitively
obtain such answers. However, studies such as the one performed by Shrock et al. provide
significant stepping-stones in understanding and isolating the molecular mechanisms
of SARS-CoV-2 and COVID-19. Collectively, such milestones will potentially enable
us to inform the production of improved diagnostics, therapeutics, and even vaccinations
for SARS-CoV-2.
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Supplementary information
Permission to use modified figure