Explore the vast range of titles available.

The dosing interval of a primary vaccination series can significantly impact on vaccine immunogenicity and efficacy. The current study compared 3 dosing intervals for the primary vaccination series of the BNT162b2 mRNA COVID-19 vaccine, on humoral immune response and durability against SARS-CoV-2 ancestral and Beta variants up to 9 months post immunization. Three groups of age- and sex-matched healthcare workers (HCW) who received 2 primary doses of BNT162b2 separated by 35-days, 35-42 days or >42-days were enrolled. Vaccine induced antibody titers at 3 weeks, 3 and 6-9 months post-second dose were assessed. There were 309 age- and sex-matched HCW (mean age 43 [sd 13], 58% females) enrolled. Anti-SARS-CoV-2 binding (IgG, IgM, IgA) and neutralizing antibody titers showed significant waning in levels beyond 35 days post first dose. The second dose induced a significant rise in antibody titers, which peaked at 3 weeks and then declined at variable rates across groups. The magnitude, consistency and durability of response was greater for anti-Spike than anti-RBD antibodies; and for IgG than IgA or IgM. Compared to the shorter schedules, a longer interval of >42 days offered the highest binding and neutralizing antibody titers against SARS-CoV-2 ancestral and Beta (B1.351) variants beyond 3 months post-vaccination. This is the first comprehensive study to compare 3 dosing intervals for the primary vaccination of BNT162b2 mRNA COVID-19 vaccine implemented in the real world. These findings suggest that delaying the second dose beyond 42 days can potentiate and prolong the humoral response against ancestral and Beta variants of SARS-CoV-2 up to 9 months post-vaccination.

Understanding the efficacy of SARS-CoV-2 vaccination in people on immunosuppressive drugs, including those with rheumatoid arthritis (RA), is critical for their protection. Vaccine induced protection requires antibodies, CD4 + T cells, and CD8 + T cells, but it is unclear if these are equally affected by immunomodulatory drugs. Here, we determined how humoral and cellular SARS-CoV-2 vaccination responses differed between people with RA and controls, and which drug classes impacted these responses. Blood was collected from participants with RA on immunomodulatory drugs and controls after their second, third, and fourth SARS-CoV-2 vaccinations. Receptor binding domain (RBD)-specific antibodies were quantified by ELISA. Spike-specific memory T cells were quantitated using flow cytometry. Linear mixed models assessed the impact of age, sex, and immunomodulatory drug classes on SARS-CoV-2 vaccination responses. Compared to non-RA controls (n = 35), participants with RA on immunomodulatory drugs (n = 62) had lower anti-RBD IgG and spike-specific CD4 + T cell levels, but no deficits in spike-specific CD8 + T cells, following SARS-CoV-2 vaccination. Use of costimulation inhibitors was associated with lower humoral responses. JAK inhibitors were associated with fewer spike-specific CD4 + T cells. Participants with RA on immunomodulatory drugs mounted weaker responses to SARS-CoV-2 vaccination, with different drug classes impacting the cellular and humoral compartments.

Coronavirus Disease 2019 (COVID-19) is a global pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While detection of SARS-CoV-2 by polymerase chain reaction with reverse transcription (RT-PCR) is currently used to diagnose acute COVID-19 infection, serological assays are needed to study the humoral immune response to SARS-CoV-2. Anti-SARS-CoV-2 immunoglobulin (Ig)G/A/M antibodies against spike (S) protein and its receptor-binding domain (RBD) were characterized in recovered subjects who were RT-PCR-positive (n = 153) and RT-PCR-negative (n = 55) using an enzyme-linked immunosorbent assay (ELISA). These antibodies were also further assessed for their ability to neutralize live SARS-CoV-2 virus. Anti-SARS-CoV-2 antibodies were detected in 90.9% of resolved subjects up to 180 days post-symptom onset. Anti-S protein and anti-RBD IgG titers correlated (r = 0.5157 and r = 0.6010, respectively) with viral neutralization. Of the RT-PCR-positive subjects, 22 (14.3%) did not have anti-SARS-CoV-2 antibodies; and of those, 17 had RT-PCR cycle threshold (Ct) values > 27. These high Ct values raise the possibility that these indeterminate results are from individuals who were not infected or had mild infection that failed to elicit an antibody response. This study highlights the importance of serological surveys to determine population-level immunity based on infection numbers as determined by RT-PCR.

Survivors of severe SARS-CoV-2 infections frequently suffer from a range of post-infection sequelae. Whether survivors of mild or asymptomatic infections can expect any long-term health consequences is not yet known. Herein we investigated lasting changes to soluble inflammatory factors and cellular immune phenotype and function in individuals who had recovered from mild SARS-CoV-2 infections (n = 22), compared to those that had recovered from other mild respiratory infections (n = 11). Individuals who had experienced mild SARS-CoV-2 infections had elevated levels of C-reactive protein 1–3 months after symptom onset, and changes in phenotype and function of circulating T-cells that were not apparent in individuals 6–9 months post-symptom onset. Markers of monocyte activation, and expression of adherence and chemokine receptors indicative of altered migratory capacity, were also higher at 1–3 months post-infection in individuals who had mild SARS-CoV-2, but these were no longer elevated by 6–9 months post-infection. Perhaps most surprisingly, significantly more T-cells could be activated by polyclonal stimulation in individuals who had recently experienced a mild SARS-CoV-2, infection compared to individuals with other recent respiratory infections. These data are indicative of prolonged immune activation and systemic inflammation that persists for at least three months after mild or asymptomatic SARS-CoV-2 infections.

Nucleic acids are potential pathogen‐associated or danger‐associated molecular patterns that modulate immune responses and the development of autoimmune disorders. Class A scavenger receptors (SR‐As) are a diverse group of pattern recognition receptors that recognize a variety of polyanionic ligands including nucleic acids. While SR‐As are important for the recognition and internalization of extracellular dsRNA, little is known about extracellular DNA, despite its association with chronic infections and autoimmune disorders. In this study, we investigated the specificity of and requirement for SR‐As in binding and internalizing different species, sequences and lengths of nucleic acids. We purified recombinant coiled‐coil/collagenous and scavenger receptor cysteine‐rich (SRCR) domains that have been implicated as potential ligand‐binding domains. We detected a direct interaction of RNA and DNA species with the coiled‐coil/collagenous domain, but not the SRCR domain. Despite the presence of additional surface receptors that bind nucleic acids, SR‐As were found to be sufficient for nucleic acid binding and uptake in A549 human lung epithelial cells. Moreover, these findings suggest that the coiled‐coil/collagenous domain of SR‐As is sufficient to bind nucleic acids independent of species, sequence or length. Class A scavenger receptors have been implicated in the binding and uptake of circulating nucleic acids. Here, we show that the collagenous domain of class A scavenger receptors is sufficient to directly bind RNA and DNA species of different length, sequence and size. Furthermore, scavenger receptors are sufficient to mediate the binding and uptake of circulating RNA and DNA species.

Vaccine-induced immune thrombotic thrombocytopaenia (VITT) is a rare adverse effect of COVID-19 adenoviral vector vaccines 1 – 3 . VITT resembles heparin-induced thrombocytopaenia (HIT) in that it is associated with platelet-activating antibodies against platelet factor 4 (PF4) 4 ; however, patients with VITT develop thrombocytopaenia and thrombosis without exposure to heparin. Here we sought to determine the binding site on PF4 of antibodies from patients with VITT. Using alanine-scanning mutagenesis 5 , we found that the binding of anti-PF4 antibodies from patients with VITT ( n  = 5) was restricted to eight surface amino acids on PF4, all of which were located within the heparin-binding site, and that the binding was inhibited by heparin. By contrast, antibodies from patients with HIT ( n  = 10) bound to amino acids that corresponded to two different sites on PF4. Biolayer interferometry experiments also revealed that VITT anti-PF4 antibodies had a stronger binding response to PF4 and PF4–heparin complexes than did HIT anti-PF4 antibodies, albeit with similar dissociation rates. Our data indicate that VITT antibodies can mimic the effect of heparin by binding to a similar site on PF4; this allows PF4 tetramers to cluster and form immune complexes, which in turn causes Fcγ receptor IIa (FcγRIIa; also known as CD32a)-dependent platelet activation. These results provide an explanation for VITT-antibody-induced platelet activation that could contribute to thrombosis. Alanine-scanning mutagenesis is used to identify the PF4 epitope that is recognized by anti-PF4 antibodies in patients with vaccine-induced immune thrombotic thrombocytopaenia, revealing that the epitope corresponds to the heparin-binding site on PF4.

Introduction During the COVID pandemic, at the San Francisco VA Healthcare System (VASFHS), positive airway pressure (PAP) set-up visits transitioned from in person to a mix of in person and telehealth for patients newly diagnosed sleep apnea. As part of a larger study examining the clinical outcomes resulting from telehealth versus in-person PAP initiation, we performed a cost analysis of these two treatment pathways within VASFHS. Methods The telehealth pathway included mailing of PAP machines to patients (initially from VASFHS and later through a centralized national distributor), with follow-up video/phone education by respiratory therapists (RTs) and registered sleep technicians (RSTs). We used a bottom-up analysis to examine the total variable direct cost of telehealth versus in-person PAP initiation at various points through the COVID pandemic for patients newly diagnosed with sleep apnea at VASFHS. Results The total variable direct cost of telehealth PAP initiation was $49.66 per patient mid-pandemic (Feb-Dec 2020) compared to $31.02 per patient post-pandemic (Oct-Dec 2022). The total variable direct cost of in-person PAP initiation was $16.76 per patient pre-pandemic (Jan-Dec 2019) compared to $22.71 per patient post-pandemic. The reduction in costs (37.5%) for telehealth PAP initiation mid- to post-pandemic was due to 25% less RT/RST time required and elimination of PAP shipping costs as PAP distribution became nationally centralized. The increase in costs (35.5%) for in-person PAP initiation pre- to post-pandemic was largely due to elimination of group PAP initiation sessions (33.3% more RT/RST time required for individual PAP initiation). Post-pandemic, telehealth PAP initiation cost was 36.6% more than in-person due to 25% more RT/RST time required and five times as much troubleshooting help required for the telehealth pathway. Conclusion With integration of telehealth for PAP initiation, as RT/RSTs gained more expertise with this interface through the pandemic and as distribution of PAP machines/supplies became centralized, costs were significantly reduced, making telehealth a financially sustainable workflow. Future cost analysis can evaluate if group rather than individual telehealth PAP initiation would yield additional cost savings, placing it on par with the cost of in-person PAP initiation. Support (if any) VA OCC FY21 RFA, VAGLAHS GRECC, K24HL143055

The dosing interval of a primary vaccination series can significantly impact on vaccine immunogenicity and efficacy. The current study compared 3 dosing intervals for the primary vaccination series of the BNT162b2 mRNA COVID-19 vaccine, on humoral immune response and durability against SARS-CoV-2 ancestral and Beta variants up to 9 months post immunization. Three groups of age- and sex-matched healthcare workers (HCW) who received 2 primary doses of BNT162b2 separated by 35-days, 35-42 days or >42-days were enrolled. Vaccine induced antibody titers at 3 weeks, 3 and 6-9 months post-second dose were assessed. There were 309 age- and sex-matched HCW (mean age 43 [sd 13], 58% females) enrolled. Anti-SARS-CoV-2 binding (IgG, IgM, IgA) and neutralizing antibody titers showed significant waning in levels beyond 35 days post first dose. The second dose induced a significant rise in antibody titers, which peaked at 3 weeks and then declined at variable rates across groups. The magnitude, consistency and durability of response was greater for anti-Spike than anti-RBD antibodies; and for IgG than IgA or IgM. Compared to the shorter schedules, a longer interval of >42 days offered the highest binding and neutralizing antibody titers against SARS-CoV-2 ancestral and Beta (B1.351) variants beyond 3 months post-vaccination. This is the first comprehensive study to compare 3 dosing intervals for the primary vaccination of BNT162b2 mRNA COVID-19 vaccine implemented in the real world. These findings suggest that delaying the second dose beyond 42 days can potentiate and prolong the humoral response against ancestral and Beta variants of SARS-CoV-2 up to 9 months post-vaccination.

Macrophage receptor with collagenous structure (MARCO) is a class A scavenger receptor (cA‐SR) that recognizes and phagocytoses a wide variety of pathogens. Most cA‐SRs that contain a C‐terminal scavenger receptor cysteine‐rich (SRCR) domain use the proximal collagenous domain to bind ligands. In contrast, the role of the SRCR domain of MARCO in phagocytosis, adhesion and pro‐inflammatory signaling is less clear. The discovery of a naturally occurring transcript variant lacking the SRCR domain, MARCOII, provided the opportunity to study the role of the SRCR domain of MARCO. We tested whether the SRCR domain is required for ligand binding, promoting downstream signaling and enhancing cellular adhesion. Unlike cells expressing full‐length MARCO, ligand binding was abolished in MARCOII‐expressing cells. Furthermore, co‐expression of MARCO and MARCOII impaired phagocytic function, indicating that MARCOII acts as a dominant‐negative variant. Unlike MARCO, expression of MARCOII did not enhance Toll‐like receptor 2 (TLR2)‐mediated pro‐inflammatory signaling in response to bacterial stimulation. MARCO‐expressing cells were more adherent and exhibited a dendritic‐like phenotype, whereas MARCOII‐expressing cells were less adherent and did not exhibit changes in morphology. These data suggest the SRCR domain of MARCO is the key domain in modulating ligand binding, enhancing downstream pro‐inflammatory signaling and MARCO‐mediated cellular adhesion.