Exposed seronegative: Cellular immune responses to SARS-CoV-2 in the absence of seroconversion

Abstract

The factors determining whether infection will occur following exposure to SARS-CoV-2 remain elusive. Certain SARS-CoV-2-exposed individuals mount a specific T-cell response but fail to seroconvert, representing a population that may provide further clarity on the nature of infection susceptibility and correlates of protection against SARS-CoV-2. Exposed seronegative individuals have been reported in patients exposed to the blood-borne pathogens Human Immunodeficiency virus and Hepatitis C virus and the sexually transmitted viruses Hepatitis B virus and Herpes Simplex virus. By comparing the quality of seronegative T-cell responses to SARS-CoV-2 with seronegative cellular immunity to these highly divergent viruses, common patterns emerge that offer insights on the role of cellular immunity against infection. For both SARS-CoV-2 and Hepatitis C, T-cell responses in exposed seronegatives are consistently higher than in unexposed individuals, but lower than in infected, seropositive patients. Durability of T-cell responses to Hepatitis C is dependent upon repeated exposure to antigen – single exposures do not generate long-lived memory T-cells. Finally, exposure to SARS-CoV-2 induces varying degrees of immune activation, suggesting that exposed seronegative individuals represent points on a spectrum rather than a discrete group. Together, these findings paint a complex landscape of the nature of infection but provide clues as to what may be protective early on in SARS-CoV-2 disease course. Further research on this phenomenon, particularly through cohort studies, is warranted.

Cytometry profiling of ex vivo recall responses to Coxiella burnetii in previously naturally exposed individuals reveals long-term changes in both adaptive and innate immune cellular compartments

“…Except for IFNγ, released cytokine levels in seronegative Group 2 individuals were indistinguishable from those in the control Group 1 ( Figure 1B ), and median IGRA responses in Group 2 were lower than in seropositive Group 3 and 5 individuals ( Table 1 ). These lower cellular responses in individuals that fail to show sero-conversion has previously already been described in a much larger cohort study in C. burnetii -exposed individuals ( 31 ) as well as in individuals exposed to HIV ( 35 – 37 ), HBV ( 38 ), HCV ( 39 ), HSV-2 ( 40 ) and SARS-CoV-2 ( 41 , 42 ).…”

Detection of SARS-CoV-2-Specific Secretory IgA and Neutralizing Antibodies in the Nasal Secretions of Exposed Seronegative Individuals

“…Household members of SARS-CoV-2-infected individuals encompass a unique population of individuals with continual virus exposure over short time periods [ 20 ]. While previous studies have mainly involved healthcare workers (HCWs) [ 21 , 22 , 23 ], our current characterization of individuals with extended SARS-CoV-2 exposure within households is more representative of viral transmission within the general population.…”

Evolution of protective SARS-CoV-2-specific B- and T-cell responses upon vaccination and Omicron breakthrough infection

“…Even long after breakthrough infection, we observed broad memory Tcell recognition against the three tested virus antigens S, M, and N, similar to what was observed in non-BTI Wuhan infection (15,32) and these -according to our model -possibly contributed to the high level of protection observed in our cohort after BTI. Indeed, pre-existing T cells, in particular those targeting the N protein, have been associated with protection from SARS-CoV-2 infection (13,14,33). Moreover, N-speci c T-cell responses are also associated with control of SARS-CoV-2 in the upper airways and reduced systemic in ammation (10).…”