Plasma-based antigen persistence in the post-acute phase of SARS-CoV-2 infection

Abstract

BACKGROUND: Although RNA viruses like SARS-CoV-2 are generally thought to be transient, the persistence of viral components beyond the acute phase can be driven by a variety of virologic and immunologic factors. Recent studies have suggested that SARS-CoV-2 antigens may persist following COVID-19 but were limited by a lack of comparison to a large number of true negative control samples. METHODS: Using single molecule array (Simoa) assays for SARS-CoV-2 spike, S1, and nucleocapsid antigen in plasma from 171 pandemic-era individuals in the post-acute phase of SARS-CoV-2 infection and 250 pre-pandemic control samples, we compared prevalence of antigen detection. We used logistic regression models and prevalence ratios (PRs) to assess the relationship between demographic and disease factors and antigen persistence. RESULTS: Compared to the proportion of antigen positivity in the pre-pandemic controls (2%), detection of any SARS-CoV-2 antigen was more frequent across all post-acute COVID-19 time bins (3-6 months: 12.6%, p<0.001; 6-10 months, 10.7%, p=0.0002; 10-14 months, 7.5%, p=0.017). These differences were driven by spike protein for up to 14 months and nucleocapsid in the first 6 months after infection. The co-occurrence of multiple antigens at a single timepoint was uncommon. Hospitalization for acute COVID-19 (versus not hospitalized) and worse self-reported health during acute COVID-19 among those not hospitalized (versus more benign illness) were associated with higher prevalence of post-acute antigen detection (PR 1.86, p=0.03; PR 3.5, p=0.07, respectively) in the pandemic era. CONCLUSIONS: Our findings provide strong evidence that SARS-CoV-2 antigens can persist beyond the period of acute illness. The observation that more than 10% of plasma samples for over a year following initial SARS-CoV-2 infection contain detectable viral antigen, which are potentially immunogenic, has significant implications given the sheer number of people infected with SARS-CoV-2 to date. More work will be needed to determine whether these antigens have a causal role in post-acute sequelae of SARS-CoV-2 infection (PASC).

Restrained memory CD8+T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID

“…2a ). The S1 subunit of spike was detectable in fewer patients as previously observed in two other cohorts 18,19 ( Fig. 2b ), while the N antigen was detectable in 10/100 Long COVID cases, but only 1/50 convalescent controls ( Fig.…”

“…Numerous previous studies have reported the presence of SARS-CoV-2 viral particles or SARS-CoV-2 protein antigens, long after an initial infection 21 . Direct measurements of circulating SARS-CoV-2 spike proteins in the plasma of patients with Long COVID have also been reported 18,19 . Imaging studies have suggested persistent T cell activation and viral reservoirs in Long COVID 20 , and tissue biopsy studies have reported persistent viral proteins 21 months after SARS-CoV-2 infection, but these are not always associated with persistent symptoms 23 .…”

“…In women of reproductive age, efficient antiviral responses limit viral replication better than in males and could allow similar prioritization of limited resources for investments into reproduction, over antiviral T cell responses and systemic inflammation, leading to mild COVID-19 in most, but also an increased likelihood for viral persistence and higher incidence of Long COVID 15 . Viral persistence has been proposed to be the key unifying feature among these postinfectious conditions, as suggested by multiple reports involving plasma samples 17–19 , tissue imaging 20 , and tissue specimens from patients 21,22 , as well as indirect evidence of continued somatic hypermutation in SARS-CoV-2 specific B cells, months after initial infection 23 .…”

Association of nirmatrelvir for acute SARS‐CoV‐2 infection with subsequent Long COVID symptoms in an observational cohort study

“…3,4 Recent studies suggest viral persistence in a subset of individuals with PASC, including prolonged gastrointestinal shedding, ongoing Spike and Nucleocapsid antigen in neuronal and astrocytic exosomes, and evidence of persistent viral RNA or proteins in deep tissues and plasma. [5][6][7][8][9][10] Among high-risk, unvaccinated, nonhospitalized individuals with symptomatic COVID-19, nirmatrelvir, a novel orally-administered SARS-CoV-2 main protease (M pro ) inhibitor in combination with ritonavir reduces viral load and progression to severe disease. 11 Anecdotal reports suggest that nirmatrelvir may improve Long COVID symptoms.…”

“…Higher acute viral load or prolonged shedding may be associated with increased risk 3,4 . Recent studies suggest viral persistence in a subset of individuals with PASC, including prolonged gastrointestinal shedding, ongoing Spike and Nucleocapsid antigen in neuronal and astrocytic exosomes, and evidence of persistent viral RNA or proteins in deep tissues and plasma 5–10 …”