ABSTRACT
Background: There is mounting evidence regarding the frequency and spectrum of post-acute sequelae of SARS-CoV-2 infection (PASC), but a search for causes has been elusive. Recently, a plasma-based assay for SARS-CoV-2 antigen has been developed, which in initial use revealed that a high fraction of severely affected patients with PASC had circulating antigen. It is unknown whether detectable SARS-CoV-2 antigen is specific for PASC or how the assay performs in a broader clinical spectrum of patients with PASC. Method(s): We evaluated a cohort of patients with RNA-confirmed SARS-CoV-2 infection enrolled >=3 weeks following initial symptoms. Participants, both with and without PASC at enrollment, were identified via facility- and communitybased advertising and examined every 4 months. An interviewer-administered questionnaire ascertained presence of 30 different symptoms (new or worse compared to pre-COVID) in the prior 2 days at each exam. Using the single molecule array (Simoa) assay, we measured spike, S1, and nucleocapsid SARSCoV- 2 antigens in plasma collected at time of symptom assessment. Result(s): We examined 172 participants (50% men, 46% non-white, median age 46 years) who contributed 667 timepoints from 0.7 to 15.4 months following infection, at which 66% featured report of >=1 symptom. Sixty-one of 667 timepoints (9.1%) representing 24% of persons had >=1 detectable SARSCoV- 2 antigen. Among the 437 timepoints at which >=1 symptom was present, 9.8% had >=1 detectable antigen;this compares to 7.8% of timepoints at which symptoms were absent. In comparison to those without symptoms, individuals with several specific symptom complexes (gastrointestinal, musculoskeletal, and central neurologic) more commonly had detectable antigen (Figure). Hospitalization during acute COVID-19 was strongly related to antigen detection. Conclusion(s): Among a diverse group of SARS-CoV-2-infected persons in the post-acute phase of infection, SARS-CoV-2 antigen is detectable in plasma in both those with and without symptoms but more commonly in those with gastrointestinal, musculoskeletal, and central neurologic complaints. The findings indicate that antigen persists in at least some persons and suggest (but do not prove) that antigen is causally related to symptoms. That antigen is found in only a fraction of those with PASC indicates either that not all symptoms are driven by antigen, current plasma antigen detection is insensitive relative to tissue, or nominal PASC symptoms are sometimes unrelated to SARS-CoV-2. (Figure Presented).
ABSTRACT
Background. mRNA vaccines for coronavirus disease 2019 (COVID-19) illicit strong humoral and cellular responses and have high efficacy for preventing and reducing the risk of severe illness from COVID-19. Since solid organ transplant (SOT) recipients were excluded from the phase 3 trials, the efficacy of the COVID-19 vaccine remains unknown. Understanding the serological responses to COVID vaccines among SOT recipients is essential to better understand vaccine protection for this vulnerable population. Methods. In this prospective cohort study, a subset of SOT recipients who were part of our center's larger antibody study were enrolled prior to receipt of two doses of the BNT162b2 (Pfizer, Inc) vaccine for high resolution immunophenotyping. To date, plasma has been collected for 10 participants on the day of their first dose (baseline), day of their second dose, and 28 days post second dose. 23 healthy participants planning to receive either BNT162b2 or mRNA-1273 (ModernaTX, Inc) were also enrolled, providing plasma at the same timepoints. Ultrasensitive single-molecule array (Simoa) assays were used to detect SARS-CoV-2 Spike (S), S1, receptor-binding domain (RBD) and Nucleocapsid (N) IgG antibodies. Results. Participant demographics and SOT recipient characteristics are summarized in Table 1. Low titers of anti-N IgG at all timepoints indicate no natural infection with COVID-19 during the study (Fig 1A). There were significantly lower magnitudes for anti-S (p< 0.0001), anti-S1 (p< 0.0001), and anti-RBD (p< 0.0001) IgG titers on the day of dose 2 and day 28 post second dose for SOT recipients compared to healthy controls (Fig 1B,C,D). Using the internally validated threshold of anti-S IgG >1.07 based on pre-pandemic controls, only 50% of the SOT sub-cohort responded to vaccine after series completion (Fig 2). There was a positive trend between months from transplant and anti-S IgG titer (Fig 3). Black error bars denote median and 95% CI. The dotted line on panel B denotes an internally validated cutoff of 1.07;anti-S IgG titers greater than 1.07 denote a positive response. SOT recipients further out from transplant tend to have a higher anti-S IgG response. The dotted line denotes an internally validated cutoff, with anti-S IgG titers greater than 1.07 indicating a positive response. Conclusion. SOT recipients had a significantly decreased humoral response to mRNA COVID-19 vaccines compared to the healthy cohort, with those further out from transplant more likely to respond. Further research is needed to evaluate T-cell responses and clinical efficacy to maximize the SARS-CoV-2 vaccine response among SOT recipients.
ABSTRACT
Background. Allogeneic stem cell transplant (SCT) recipients are at an increased risk of poor outcomes from COVID-19. While the mRNA-1273 (Moderna) and BNT162b2 (Pfizer) COVID-19 mRNA vaccines are highly immunogenic in the general population, the immune response in SCT recipients is poorly understood. We characterized the immunogenicity and reactogenicity of COVID-19 mRNA vaccines in a cohort of SCT patients. Methods. We performed a prospective cohort study of 16 allogeneic SCT patients and 23 healthy controls. Blood samples for both cohorts were collected prior to first vaccination (baseline), at the time of second vaccination, and approximately 28 days post-second vaccination. Anti-Spike (S), anti-S1, anti-receptor binding domain (RBD), and anti-Nucleocapsid (N) IgG levels were measured quantitatively from plasma using a multiplexed single molecule array (Simoa) immunoassay. Reactogenicity was captured for the SCT cohort via a self-reported post-vaccination diary for 7 days after each dose. Results. Demographics and SCT recipients' characteristics are shown in Table 1. In the SCT cohort, we observed a significantly lower anti-S (p< 0.0001), S1 (p< 0.0001), and RBD (p< 0.0001) IgG responses as compared to healthy controls, both at the time of dose 2 and 28 days post-vaccine series (Fig 1). Overall, 62.5% of SCT recipients were responders after vaccine series completion, as compared to 100% of healthy controls (Fig 2). While no patients had a reported history of COVID-19 diagnosis, 2 patients in the SCT cohort had elevated anti-S IgG levels and 1 showed elevated anti-N at baseline. 10/16 participants in the SCT cohort completed at least one post-vaccination diary. Local and systemic reactions were reported by 67% and 22% of participants, respectively, after dose 1, and 63% and 50% after dose 2 (Figure 3). All reported events were mild. Anti-Spike (A), anti-S1 (B), anti-RBD (C), and anti-nucleocapsid (D) IgG titers were measured at baseline, time of second dose, and approximately 28 days after second vaccination. IgG levels were measured quantitatively using multiplexed single molecule array (Simoa) immunoassays, and are reported as Normalized Average Enzymes per Bead (AEB). Allogeneic stem cell transplant recipients (mauve) showed significantly lower anti-S, S1, and RBD IgG responses as compared to healthy controls (mint). Low titers of anti-N IgG demonstrates no history of COVID-19 natural infection during the course of the study. 10 allogeneic stem cell transplant recipients completed at least one diary for 7 days after vaccination. Reactions after dose 1 are shown in light blue, and reactions after dose 2 are shown in dark blue. Local reactions (A) were reported by 67% (6/9) of participants after dose 1, and 63% (5/8) after dose 2. Systemic reactions (B) were reported by 22% (2/9) of participants after dose 1, and 50% (4/8) after dose 2. All reported events were mild (Grade 1). Conclusion. Among SCT recipients, mRNA COVID-19 vaccines were well-tolerated but less immunogenic than in healthy controls. Further study is warranted to better understand heterogeneous characteristics that may affect the immune response in order to optimize COVID-19 vaccination strategies for SCT recipients. Figure 2: Response Rate to COVID-19 Vaccination An internally validated threshold for responders was established using pre-pandemic sera from healthy adults. A positive antibody response was was defined as individuals with anti-Spike IgG levels above the 1.07 Normalized AEB threshold.