Post by Nadica (She/Her) on Aug 8, 2024 22:01:51 GMT
Plasma-based antigen persistence in the post-acute phase of COVID-19 - Published April 8, 2024
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Persistent symptoms among some individuals who develop COVID-19 have led to the hypothesis that SARS-CoV-2 might, in some form or location, persist for long periods following acute infection.1, 2 Studies on SARS-CoV-2 persistence to date, however, have been limited by small and non-representative study populations, short durations since acute infection, unclear documentation of vaccination and reinfection histories, and the absence of a true negative comparator group to assess assay specificity (appendix p 2). To address these limitations, we evaluated the presence of SARS-CoV-2 antigens in once-thawed plasma from a well characterised group of 171 adults (appendix pp 3, 9) at several timepoints in the 14 months following RNA-confirmed SARS-CoV-2 infection, most of whom were studied before vaccination or reinfection (so-called pandemic-era participants).3 To understand the specificity of our findings, we compared them to 250 adults (appendix pp 3, 9) whose plasma was collected before 2020, who, by definition, were not infected with SARS-CoV-2 (pre-pandemic era). We used the Simoa (Quanterix) single molecule array detection platform to measure SARS-CoV-2 spike, S1, and nucleocapsid antigens (appendix p 4).4, 5
Of 660 pandemic-era specimens tested, 61 (9·2%) specimens from 42 participants (25% of the group), had one or more detectable SARS-CoV-2 antigens (figure A). The most commonly detected antigen was spike (n=33, 5·0%), followed by S1 (n=15, 2·3%) and N (n=15, 2·3%). Compared with the pre-pandemic era participants who had 2% assay positivity, detection of any SARS-CoV-2 antigen was significantly more frequent among the pandemic-era participants at all three timepoints in the post-acute phase of infection (figure B–E). The absolute difference in SARS-CoV-2 plasma antigen prevalence was +10·6% (95% CI +5·0 to +16·2) at 3·0–6·0 months post-onset of COVID-19; +8·7% (+3·1 to +14·3) at 6·1–10·0 months; and +5·4% (+0·42 to +10·3) at 10·1–14·1 months (appendix p 11).
Compared with those not hospitalised, participants who required hospitalisation for acute COVID-19 were nearly twice as likely to have SARS-CoV-2 antigens detected (prevalence ratio 1·97, 95% CI 1·11 to 3·48), an absolute difference of +18·4% (95% CI +0·3 to +36·5). Among participants not hospitalised, those with worse self-reported health during acute COVID-19 had greater post-acute antigen detection (appendix pp 7, 10). These findings suggest the influence of the acute phase of infection in establishing a persistent SARS-CoV-2 reservoir. Coupled with a 2024 study of replication-competent virus in blood during acute infection,6 our findings suggest that SARS-CoV-2 might seed distal sites through the bloodstream and establish protected reservoirs in some sites. Alternatively, more severe acute infection could be a marker of higher inoculum in sites of primary infection, which then have a greater chance of evading immune clearance.
Because our measurement of SARS-CoV-2 is via immunoreactivity, it cannot be assumed that every signal is specific for SARS-CoV-2 antigen. Antigens from related pathogens or the host can theoretically cross-react, differing from the detection of nucleic acid for which specificity is typically complete and direct analyte evaluation by sequencing is possible. Therefore, understanding the specificity of any immune-based assay purporting to detect SARS-CoV-2 antigens is crucial and requires a large true negative group to precisely estimate false positivity. The 98% specificity that we documented for our Simoa assay is high but imperfect, so caution is needed if interpreting individual-level results.
To mitigate concerns that vaccination against SARS-CoV-2 or recent reinfections could affect interpretation of positive results,1 we studied specimens largely collected before these occurrences. Most samples were collected before the emergence of the Delta and Omicron SARS-CoV-2 variants, when reinfections became common.7
Although not without limitations (appendix p 14), our data provide strong evidence that SARS-CoV-2, in some form or location, persists for up to 14 months following acute SARS-CoV-2 infection (appendix p 13). This persistence is influenced by the events of acute infection. These findings motivate an urgent research agenda regarding the clinical manifestations of SARS-CoV-2 persistence, specifically whether it is causally related to either post-acute chronic symptoms (eg, fatigue, pain, and cognitive difficulty) or discrete incident complications (eg, cardiovascular events).
MJP reports consulting for Gilead Sciences and AstraZeneca and reports research support from Aerium Therapeutics outside the submitted work. SGD reports consulting for Enanta Pharmaceuticals and Pfizer and reports research support from Aerium Therapeutics outside the submitted work. DRW has a financial interest in Quanterix Corporation, a company that develops an ultra-sensitive digital immunoassay platform and is an inventor of the Simoa technology, reports being a founder of Quanterix Corporation, and also serves on its Board of Directors. DRW's interests were reviewed and are managed by Mass General Brigham and Harvard University in accordance with their conflict of interest policies. All other authors declare no competing interests. This work was supported with funding from the PolyBio Research Foundation for the LIINC Clinical Core and was supported by NIH/NIAID 3R01AI141003–03S1, NIH/NIAID R01AI158013, NIH/NIAID K23AI134327, and NINDS 1R01NS136197-01.
Follow the link for tables and references!
Persistent symptoms among some individuals who develop COVID-19 have led to the hypothesis that SARS-CoV-2 might, in some form or location, persist for long periods following acute infection.1, 2 Studies on SARS-CoV-2 persistence to date, however, have been limited by small and non-representative study populations, short durations since acute infection, unclear documentation of vaccination and reinfection histories, and the absence of a true negative comparator group to assess assay specificity (appendix p 2). To address these limitations, we evaluated the presence of SARS-CoV-2 antigens in once-thawed plasma from a well characterised group of 171 adults (appendix pp 3, 9) at several timepoints in the 14 months following RNA-confirmed SARS-CoV-2 infection, most of whom were studied before vaccination or reinfection (so-called pandemic-era participants).3 To understand the specificity of our findings, we compared them to 250 adults (appendix pp 3, 9) whose plasma was collected before 2020, who, by definition, were not infected with SARS-CoV-2 (pre-pandemic era). We used the Simoa (Quanterix) single molecule array detection platform to measure SARS-CoV-2 spike, S1, and nucleocapsid antigens (appendix p 4).4, 5
Of 660 pandemic-era specimens tested, 61 (9·2%) specimens from 42 participants (25% of the group), had one or more detectable SARS-CoV-2 antigens (figure A). The most commonly detected antigen was spike (n=33, 5·0%), followed by S1 (n=15, 2·3%) and N (n=15, 2·3%). Compared with the pre-pandemic era participants who had 2% assay positivity, detection of any SARS-CoV-2 antigen was significantly more frequent among the pandemic-era participants at all three timepoints in the post-acute phase of infection (figure B–E). The absolute difference in SARS-CoV-2 plasma antigen prevalence was +10·6% (95% CI +5·0 to +16·2) at 3·0–6·0 months post-onset of COVID-19; +8·7% (+3·1 to +14·3) at 6·1–10·0 months; and +5·4% (+0·42 to +10·3) at 10·1–14·1 months (appendix p 11).
Compared with those not hospitalised, participants who required hospitalisation for acute COVID-19 were nearly twice as likely to have SARS-CoV-2 antigens detected (prevalence ratio 1·97, 95% CI 1·11 to 3·48), an absolute difference of +18·4% (95% CI +0·3 to +36·5). Among participants not hospitalised, those with worse self-reported health during acute COVID-19 had greater post-acute antigen detection (appendix pp 7, 10). These findings suggest the influence of the acute phase of infection in establishing a persistent SARS-CoV-2 reservoir. Coupled with a 2024 study of replication-competent virus in blood during acute infection,6 our findings suggest that SARS-CoV-2 might seed distal sites through the bloodstream and establish protected reservoirs in some sites. Alternatively, more severe acute infection could be a marker of higher inoculum in sites of primary infection, which then have a greater chance of evading immune clearance.
Because our measurement of SARS-CoV-2 is via immunoreactivity, it cannot be assumed that every signal is specific for SARS-CoV-2 antigen. Antigens from related pathogens or the host can theoretically cross-react, differing from the detection of nucleic acid for which specificity is typically complete and direct analyte evaluation by sequencing is possible. Therefore, understanding the specificity of any immune-based assay purporting to detect SARS-CoV-2 antigens is crucial and requires a large true negative group to precisely estimate false positivity. The 98% specificity that we documented for our Simoa assay is high but imperfect, so caution is needed if interpreting individual-level results.
To mitigate concerns that vaccination against SARS-CoV-2 or recent reinfections could affect interpretation of positive results,1 we studied specimens largely collected before these occurrences. Most samples were collected before the emergence of the Delta and Omicron SARS-CoV-2 variants, when reinfections became common.7
Although not without limitations (appendix p 14), our data provide strong evidence that SARS-CoV-2, in some form or location, persists for up to 14 months following acute SARS-CoV-2 infection (appendix p 13). This persistence is influenced by the events of acute infection. These findings motivate an urgent research agenda regarding the clinical manifestations of SARS-CoV-2 persistence, specifically whether it is causally related to either post-acute chronic symptoms (eg, fatigue, pain, and cognitive difficulty) or discrete incident complications (eg, cardiovascular events).
MJP reports consulting for Gilead Sciences and AstraZeneca and reports research support from Aerium Therapeutics outside the submitted work. SGD reports consulting for Enanta Pharmaceuticals and Pfizer and reports research support from Aerium Therapeutics outside the submitted work. DRW has a financial interest in Quanterix Corporation, a company that develops an ultra-sensitive digital immunoassay platform and is an inventor of the Simoa technology, reports being a founder of Quanterix Corporation, and also serves on its Board of Directors. DRW's interests were reviewed and are managed by Mass General Brigham and Harvard University in accordance with their conflict of interest policies. All other authors declare no competing interests. This work was supported with funding from the PolyBio Research Foundation for the LIINC Clinical Core and was supported by NIH/NIAID 3R01AI141003–03S1, NIH/NIAID R01AI158013, NIH/NIAID K23AI134327, and NINDS 1R01NS136197-01.