SARS-CoV-2 antigen detected in body 14 months after infection

A substantial number of plasma samples from immunocompetent people who had SARS-CoV-2 infection more than a year ago appears to contain detectable viral antigens.

Data from a study presented at CROI 2024 showed that the frequency of detecting any SARS-CoV-2 antigen (spike, S1, or nucleocapsid) was greater for plasma samples collected across different time points ranging from 3 to 14 months postinfection than for plasma samples from collected before the pandemic (3-6 months: 12.6 percent vs 2.0 percent, p<0.001; 6-10 months: 10.7 percent vs 2.0 percent, p=0.0002; 10-14 months: 7.5 percent vs 2.0 percent, p=0.017). [CROI 2024, abstract 138]

“These differences were driven by spike for up to 14 months and nucleocapsid in the first 6 months after infection,” reported lead study author Dr Michael Peluso of the University of California San Francisco School of Medicine, San Francisco, California, US.

Peluso also noted that the 2 percent false-positive rate observed for SARS-CoV-2 antigen detection in prepandemic samples analysed by single molecule array meant that the assay was 98-percent specific.

Several interesting observations could lend biological plausibility to the finding, he said. First, people who were sick enough to be hospitalized with COVID-19 were twice as likely as those who were not hospitalized to have antigen persistence (p=0.03). Second, among people who were not hospitalized, those who self-reported their overall health to be the lowest during their acute infection were three times as likely to have antigen persistence compared with those who said they had mild COVID-19 (p=0.14).

Finally, hospitalization for acute COVID-19 was associated with detectable antigen in the postacute infection phase (odds ratio [OR], 2.27; p=0.054) and with detectable N antigen (OR, 11.82; p=0.001).

The prepandemic cohort consisted of 250 individuals (median age 48 years, 23 percent women, 20 percent HIV positive), while the post-COVID cohort comprised 172 individuals (median age 46 years, 50 percent women, 15 percent HIV positive), of which 19 percent had been hospitalized and 32 percent had full recovery. Notably, the plasma samples collected from 77 percent of individuals in the post-COVID cohort were collected before the development of the COVID-19 vaccines. There were no documented reinfections in the post-COVID cohort.

Possibly immunogenic

Peluso and his team performed flexible sigmoidoscopy in five individuals between 90 and 676 days post-COVID (without reinfection) to obtain rectal tissue samples. These samples were assessed for the presence of SARS-CoV-2 spike RNA in situ via RNAscope, with additional H&E and immunohistochemical visualization of CD3 and CD68 to localize viral RNA signals within tissue regions and immune cell types.

Results showed evidence of SARS-CoV-2 spike RNA in four of the five patients, mostly in the connective tissue layer, where there is increased immune cell activity. Furthermore, samples from a subset of patients had double-stranded RNAs, which, according to Peluso, should only be present if the virus is undergoing active replication.

Peluso stated that the genetic material may not just be some “fossilized inert remnant virus that isn’t doing anything” but reflect a potential reservoir of SARS-CoV-2.

“Our findings provide strong evidence that SARS-CoV-2 antigens can persist beyond the period of acute illness,” which goes against the framework for SARS-CoV-2 as transient pathogens that come and go, he added. “[This] has significant implications given the sheer number of people infected with SARS-CoV-2 to date.”

What is unclear, according to Peluso, is whether this postacute infection antigen persistence is responsible for symptoms of long COVID or discrete medical events such as myocardial infarction. He stated that the study data can serve as a basis for mechanistic studies that can provide important new insights.