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In a cohort of essential workers in the United States previously infected with SARS-CoV-2, risk factors for reinfection included being unvaccinated, infrequent mask use, time since first infection, and being non-Hispanic Black. Protecting workers from reinfection requires a multipronged approach including up-to-date vaccination, mask use as recommended, and reduction in underlying health disparities.

Importance: Data on the epidemiology of mild to moderately severe COVID-19 are needed to inform public health guidance., Objective: To evaluate associations between 2 or 3 doses of mRNA COVID-19 vaccine and attenuation of symptoms and viral RNA load across SARS-CoV-2 viral lineages., Design, Setting, and Participants: A prospective cohort study of essential and frontline workers in Arizona, Florida, Minnesota, Oregon, Texas, and Utah with COVID-19 infection confirmed by reverse transcriptase-polymerase chain reaction testing and lineage classified by whole genome sequencing of specimens self-collected weekly and at COVID-19 illness symptom onset. This analysis was conducted among 1199 participants with SARS-CoV-2 from December 14, 2020, to April 19, 2022, with follow-up until May 9, 2022, reported., Exposures: SARS-CoV-2 lineage (origin strain, Delta variant, Omicron variant) and COVID-19 vaccination status., Main Outcomes and Measures: Clinical outcomes included presence of symptoms, specific symptoms (including fever or chills), illness duration, and medical care seeking. Virologic outcomes included viral load by quantitative reverse transcriptase-polymerase chain reaction testing along with viral viability., Results: Among 1199 participants with COVID-19 infection (714 [59.5%] women; median age, 41 years), 14.0% were infected with the origin strain, 24.0% with the Delta variant, and 62.0% with the Omicron variant. Participants vaccinated with the second vaccine dose 14 to 149 days before Delta infection were significantly less likely to be symptomatic compared with unvaccinated participants (21/27 [77.8%] vs 74/77 [96.1%]; OR, 0.13 [95% CI, 0-0.6]) and, when symptomatic, those vaccinated with the third dose 7 to 149 days before infection were significantly less likely to report fever or chills (5/13 [38.5%] vs 62/73 [84.9%]; OR, 0.07 [95% CI, 0.0-0.3]) and reported significantly fewer days of symptoms (10.2 vs 16.4; difference, -6.1 [95% CI, -11.8 to -0.4] days). Among those with Omicron infection, the risk of symptomatic infection did not differ significantly for the 2-dose vaccination status vs unvaccinated status and was significantly higher for the 3-dose recipients vs those who were unvaccinated (327/370 [88.4%] vs 85/107 [79.4%]; OR, 2.0 [95% CI, 1.1-3.5]). Among symptomatic Omicron infections, those vaccinated with the third dose 7 to 149 days before infection compared with those who were unvaccinated were significantly less likely to report fever or chills (160/311 [51.5%] vs 64/81 [79.0%]; OR, 0.25 [95% CI, 0.1-0.5]) or seek medical care (45/308 [14.6%] vs 20/81 [24.7%]; OR, 0.45 [95% CI, 0.2-0.9]). Participants with Delta and Omicron infections who received the second dose 14 to 149 days before infection had a significantly lower mean viral load compared with unvaccinated participants (3 vs 4.1 log10 copies/μL; difference, -1.0 [95% CI, -1.7 to -0.2] for Delta and 2.8 vs 3.5 log10 copies/μL, difference, -1.0 [95% CI, -1.7 to -0.3] for Omicron)., Conclusions and Relevance: In a cohort of US essential and frontline workers with SARS-CoV-2 infections, recent vaccination with 2 or 3 mRNA vaccine doses less than 150 days before infection with Delta or Omicron variants, compared with being unvaccinated, was associated with attenuated symptoms, duration of illness, medical care seeking, or viral load for some comparisons, although the precision and statistical significance of specific estimates varied.

Background: Assessing the real-world effectiveness of COVID-19 vaccines and understanding the incidence and severity of SARS-CoV-2 illness in children are essential to inform policy and guide health care professionals in advising parents and caregivers of children who test positive for SARS-CoV-2., Objective: This report describes the objectives and methods for conducting the Pediatric Research Observing Trends and Exposures in COVID-19 Timelines (PROTECT) study. PROTECT is a longitudinal prospective pediatric cohort study designed to estimate SARS-CoV-2 incidence and COVID-19 vaccine effectiveness (VE) against infection among children aged 6 months to 17 years, as well as differences in SARS-CoV-2 infection and vaccine response between children and adolescents., Methods: The PROTECT multisite network was initiated in July 2021, which aims to enroll approximately 2305 children across four US locations and collect data over a 2-year surveillance period. The enrollment target was based on prospective power calculations and accounts for expected attrition and nonresponse. Study sites recruit parents and legal guardians of age-eligible children participating in the existing Arizona Healthcare, Emergency Response, and Other Essential Workers Surveillance (HEROES)-Research on the Epidemiology of SARS-CoV-2 in Essential Response Personnel (RECOVER) network as well as from surrounding communities. Child demographics, medical history, COVID-19 exposure, vaccination history, and parents/legal guardians' knowledge and attitudes about COVID-19 are collected at baseline and throughout the study. Mid-turbinate nasal specimens are self-collected or collected by parents/legal guardians weekly, regardless of symptoms, for SARS-CoV-2 and influenza testing via reverse transcription-polymerase chain reaction (RT-PCR) assay, and the presence of COVID-like illness (CLI) is reported. Children who test positive for SARS-CoV-2 or influenza, or report CLI are monitored weekly by online surveys to report exposure and medical utilization until no longer ill. Children, with permission of their parents/legal guardians, may elect to contribute blood at enrollment, following SARS-CoV-2 infection, following COVID-19 vaccination, and at the end of the study period. PROTECT uses electronic medical record (EMR) linkages where available, and verifies COVID-19 and influenza vaccinations through EMR or state vaccine registries., Results: Data collection began in July 2021 and is expected to continue through the spring of 2023. As of April 13, 2022, 2371 children are enrolled in PROTECT. Enrollment is ongoing at all study sites., Conclusions: As COVID-19 vaccine products are authorized for use in pediatric populations, PROTECT study data will provide real-world estimates of VE in preventing infection. In addition, this prospective cohort provides a unique opportunity to further understand SARS-CoV-2 incidence, clinical course, and key knowledge gaps that may inform public health., International Registered Report Identifier (irrid): RR1-10.2196/37929., (©Joy Burns, Patrick Rivers, Lindsay B LeClair, Krystal S Jovel, Ramona P Rai, Ashley A Lowe, Laura J Edwards, Sana M Khan, Clare Mathenge, Maria Ferraris, Jennifer L Kuntz, Julie Mayo Lamberte, Kurt T Hegmann, Marilyn J Odean, Hilary McLeland-Wieser, Shawn Beitel, Leah Odame-Bamfo, Natasha Schaefer Solle, Josephine Mak, Andrew L Phillips, Brian E Sokol, James Hollister, Jezahel S Ochoa, Lauren Grant, Matthew S Thiese, Keya B Jacoby, Karen Lutrick, Felipe A Pubillones, Young M Yoo, Danielle Rentz Hunt, Katherine Ellingson, Mark C Berry, Joe K Gerald, Joanna Lopez, Lynn B Gerald, Meredith G Wesley, Karl Krupp, Meghan K Herring, Purnima Madhivanan, Alberto J Caban-Martinez, Harmony L Tyner, Jennifer K Meece, Sarang K Yoon, Ashley L Fowlkes, Allison L Naleway, Lisa Gwynn, Jefferey L Burgess, Mark G Thompson, Lauren EW Olsho, Manjusha Gaglani. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 28.07.2022.)

Background: Workers critical to emergency response and continuity of essential services during the COVID-19 pandemic are at a disproportionally high risk of SARS-CoV-2 infection. Prospective cohort studies are needed for enhancing the understanding of the incidence of symptomatic and asymptomatic SARS-CoV-2 infections, identifying risk factors, assessing clinical outcomes, and determining the effectiveness of vaccination., Objective: The Research on the Epidemiology of SARS-CoV-2 in Essential Response Personnel (RECOVER) prospective cohort study was designed to estimate the incidence of symptomatic and asymptomatic SARS-CoV-2 infections, examine the risk factors for infection and clinical spectrum of illness, and assess the effectiveness of vaccination among essential workers., Methods: The RECOVER multisite network was initiated in August 2020 and aims to enroll 3000 health care personnel (HCP), first responders, and other essential and frontline workers (EFWs) at 6 US locations. Data on participant demographics, medical history, and vaccination history are collected at baseline and throughout the study. Active surveillance for the symptoms of COVID-19-like illness (CLI), access of medical care, and symptom duration is performed by text messages, emails, and direct participant or medical record reports. Participants self-collect a mid-turbinate nasal swab weekly, regardless of symptoms, and 2 additional respiratory specimens at the onset of CLI. Blood is collected upon enrollment, every 3 months, approximately 28 days after a reverse transcription polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infection, and 14 to 28 days after a dose of any COVID-19 vaccine. From February 2021, household members of RT-PCR-confirmed participants are self-collecting mid-turbinate nasal swabs daily for 10 days., Results: The study observation period began in August 2020 and is expected to continue through spring 2022. There are 2623 actively enrolled RECOVER participants, including 280 participants who have been found to be positive for SARS-CoV-2 by RT-PCR. Enrollment is ongoing at 3 of the 6 study sites., Conclusions: Data collected through the cohort are expected to provide important public health information for essential workers at high risk for occupational exposure to SARS-CoV-2 and allow early evaluation of COVID-19 vaccine effectiveness., International Registered Report Identifier (irrid): DERR1-10.2196/31574., (©Laura J Edwards, Ashley L Fowlkes, Meredith G Wesley, Jennifer L Kuntz, Marilyn J Odean, Alberto J Caban-Martinez, Kayan Dunnigan, Andrew L Phillips, Lauren Grant, Meghan K Herring, Holly C Groom, Karley Respet, Shawn Beitel, Tnelda Zunie, Kurt T Hegmann, Archana Kumar, Gregory Joseph, Brandon Poe, Paola Louzado-Feliciano, Michael E Smith, Matthew S Thiese, Natasha Schaefer-Solle, Young M Yoo, Carlos A Silvera, Julie Mayo Lamberte, Josephine Mak, L Clifford McDonald, Matthew J Stuckey, Preeta Kutty, Melissa L Arvay, Sarang K Yoon, Harmony L Tyner, Jefferey L Burgess, Danielle Rentz Hunt, Jennifer Meece, Manjusha Gaglani, Allison L Naleway, Mark G Thompson. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 03.12.2021.)

Background: Information is limited regarding the effectiveness of the two-dose messenger RNA (mRNA) vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) in preventing infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and in attenuating coronavirus disease 2019 (Covid-19) when administered in real-world conditions., Methods: We conducted a prospective cohort study involving 3975 health care personnel, first responders, and other essential and frontline workers. From December 14, 2020, to April 10, 2021, the participants completed weekly SARS-CoV-2 testing by providing mid-turbinate nasal swabs for qualitative and quantitative reverse-transcriptase-polymerase-chain-reaction (RT-PCR) analysis. The formula for calculating vaccine effectiveness was 100% × (1 - hazard ratio for SARS-CoV-2 infection in vaccinated vs. unvaccinated participants), with adjustments for the propensity to be vaccinated, study site, occupation, and local viral circulation., Results: SARS-CoV-2 was detected in 204 participants (5%), of whom 5 were fully vaccinated (≥14 days after dose 2), 11 partially vaccinated (≥14 days after dose 1 and <14 days after dose 2), and 156 unvaccinated; the 32 participants with indeterminate vaccination status (<14 days after dose 1) were excluded. Adjusted vaccine effectiveness was 91% (95% confidence interval [CI], 76 to 97) with full vaccination and 81% (95% CI, 64 to 90) with partial vaccination. Among participants with SARS-CoV-2 infection, the mean viral RNA load was 40% lower (95% CI, 16 to 57) in partially or fully vaccinated participants than in unvaccinated participants. In addition, the risk of febrile symptoms was 58% lower (relative risk, 0.42; 95% CI, 0.18 to 0.98) and the duration of illness was shorter, with 2.3 fewer days spent sick in bed (95% CI, 0.8 to 3.7)., Conclusions: Authorized mRNA vaccines were highly effective among working-age adults in preventing SARS-CoV-2 infection when administered in real-world conditions, and the vaccines attenuated the viral RNA load, risk of febrile symptoms, and duration of illness among those who had breakthrough infection despite vaccination. (Funded by the National Center for Immunization and Respiratory Diseases and the Centers for Disease Control and Prevention.)., (Copyright © 2021 Massachusetts Medical Society.)

Messenger RNA (mRNA) BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccines have been shown to be effective in preventing symptomatic COVID-19 in randomized placebo-controlled Phase III trials (1,2); however, the benefits of these vaccines for preventing asymptomatic and symptomatic SARS-CoV-2 (the virus that causes COVID-19) infection, particularly when administered in real-world conditions, is less well understood. Using prospective cohorts of health care personnel, first responders, and other essential and frontline workers* in eight U.S. locations during December 14, 2020-March 13, 2021, CDC routinely tested for SARS-CoV-2 infections every week regardless of symptom status and at the onset of symptoms consistent with COVID-19-associated illness. Among 3,950 participants with no previous laboratory documentation of SARS-CoV-2 infection, 2,479 (62.8%) received both recommended mRNA doses and 477 (12.1%) received only one dose of mRNA vaccine. † Among unvaccinated participants, 1.38 SARS-CoV-2 infections were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) per 1,000 person-days. § In contrast, among fully immunized (≥14 days after second dose) persons, 0.04 infections per 1,000 person-days were reported, and among partially immunized (≥14 days after first dose and before second dose) persons, 0.19 infections per 1,000 person-days were reported. Estimated mRNA vaccine effectiveness for prevention of infection, adjusted for study site, was 90% for full immunization and 80% for partial immunization. These findings indicate that authorized mRNA COVID-19 vaccines are effective for preventing SARS-CoV-2 infection, regardless of symptom status, among working-age adults in real-world conditions. COVID-19 vaccination is recommended for all eligible persons., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Allison L. Naleway reported funding from Pfizer for a meningococcal B vaccine study unrelated to the submitted work. Kurt T. Hegmann serves at the Editor of the American College of Occupational and Environmental Medicine’s evidence-based practice guidelines. Matthew S. Thiese reported grants and personal fees from Reed Group and the American College of Occupational and Environmental Medicine, outside the submitted work. No other potential conflicts of interest were disclosed.

Objective: To examine the association of symptoms with vitamin D deficiency and symptom response to cholecalciferol treatment in a randomized, double-blind, placebo-controlled trial., Methods: Adult primary care patients in Duluth, Minnesota, were screened for vitamin D deficiency in February 2007. Participants completed questionnaires pertaining to a variety of symptoms, vitamin D intake, and selected medical conditions. Patients with mild to moderate vitamin D deficiency (25-hydroxyvitamin D [25(OH)D], 10-25 ng/mL) participated in a randomized controlled trial (RCT) of vitamin D replacement and its effect on symptoms. Participants were randomly assigned to receive 50 000 units of cholecalciferol (vitamin D3) weekly or placebo for 8 weeks. Patients with severe vitamin D deficiency (25[OH]D <10 ng/mL) were treated in an unblinded fashion, and symptoms were reevaluated post treatment., Results: A total of 610 patients underwent initial screening, and 100 patients with mild to moderate vitamin D deficiency participated in the RCT. Thirty-eight severely deficient patients were treated in an unblinded fashion. On initial screening, 46.2% of participants were deficient in vitamin D. Self-reported vitamin D supplementation, milk intake, celiac disease, gastric bypass, and chronic pancreatitis were predictive of vitamin D status. Severely deficient participants reported increased musculoskeletal symptoms, depression (including seasonal), and higher (worse) scores on a fibromyalgia assessment questionnaire. In the RCT, the treated group showed significant improvement in fibromyalgia assessment scores (P = 0.03), whereas the placebo-treated participants did not. Severely deficient patients did not show symptom improvement over the 8-week trial period or when followed up 1 year later., Conclusions: Compared with participants in the placebo group, patients in the treatment group showed mild short-term improvement in the overall fibromyalgia impact score, but did not show significant improvement in most musculoskeletal symptoms or in activities of daily living.

Monophosphoryl lipid A and a synthetic, nontoxic monosaccharide analog of lipid A, termed GLA 60, both strongly suppressed antibody production when administered 1 to 2 days prior to antigen. Evidence is presented that this suppression was mediated by two cytokines, prostaglandin E and transforming growth factor beta, because it was reversed by multiple injections of the cyclooxygenase inhibitor indomethacin and by in vitro addition of antibody to transforming growth factor beta.

The ability of spleen cells from poly A:poly U-treated mice to inhibit murine cytomegalovirus (MCMV) replication in confluent monolayer cells of secondary mouse embryo fibroblasts (MEFs) cultured at 37 and 40 degrees C was investigated. When spleen cells from BALB/c mice injected 48 h earlier with poly A:poly U were added to MEFs infected 2 h previously with MCMV, 37% less plaques were observed than in cultures containing control cells. Of interest, the poly A:poly U-induced antiviral activity at the elevated temperature (40 degrees C) resulted in a further drop to 61% in MCMV-induced plaques compared to those of the normothermic (37 degrees C) cultures. The antiviral function of spleen cells induced by poly A:poly U was evident in the supernatant fluid when cultured for 48 h at 37 degrees C. MCMV-induced plaques were reduced to 52 and 5% of controls in the plaque assays performed at 37 and 40 degrees C, respectively. Supernatant fluids generated at 40 degrees C, however, inhibited MCMV replication only when incubated at 40 degrees C. No direct inhibitory effect of the supernatant fluids on MCMV was evident; rather, inhibition was effected directly on the MEFs. The NK cell fraction of spleen cells from poly A:poly U-treated mice alone showed only a slight inhibitory effect at 40 degrees C. However, in the presence of the supernatant fluid from poly A:poly U-exposed spleen cells, the antiviral activity of NK cells was significantly increased both at 37 and 40 degrees C. The cellular source of the culture fluid showing poly A:poly U-induced antiviral activity appeared to be in the T-cell population. It was completely neutralized by monoclonal anti-IFN gamma antibody but not by anti-IFN beta, anti-IL4, anti-transforming growth factor, or anti-prostaglandin E2. In conclusion, these data document the ability of spleen cells from poly A:poly U-treated mice to inhibit MCMV replication and this activity is potentiated by hyperthermic conditions. The antiviral function of poly A:poly U-treated spleen cells appeared to be due mainly to the action of IFN gamma produced by T cells. The enhanced antiviral activity by hyperthermia appeared to be related to the action of IFN gamma rather than its production.

Synthetic acylated glucosamine monosaccharides, representative of the non-reducing subunit of lipid A, were compared for their ability to induce non-specific suppression of antibody forming cells. Five of nine analogs were found to be functional in this respect, indicating that these compounds, carrying a phosphate at C4 and acyl substituents at C2 and C3 are the smallest synthetic analogs of lipid A capable of eliciting non-specific immunosuppression. A comparison of the analogs inducing suppression with those testing negative revealed that (i) a single 3-hydroxymyristoyl group at C2 is common to 4/5 analogs inducing suppression; (ii) addition of an oxytetradecanoyl group to the 3-hyroxymyristoyl group at either C2 or C3 negated suppression; and (iii) extreme specificity was exhibited in suppression induction such that substitution of either lauric (C12) or palmitic (C16) for myristic acid (C14) at C2 voided transmission of the suppressive signal.

Synthetic polyribonucleotide complexes, which have been shown to be potent adjuvants to the immune response of animals and humans were tested for their capacity to activate cells involved in suppressing antibody synthesis. Poly A:poly U and poly I:poly C inhibited murine antibody forming spleen cells when given 1-6 days before antigenic stimulus. To determine the cellular and molecular mediators of this suppression, individual cell populations were isolated or deleted and the resulting cell populations tested for induction of suppression. When the natural killer (NK) cell population was rendered non-functional with anti-asialo GM1 antiserum no diminution in suppressive activity was observed. Further experiments implicated adherent cells as the population responsible for mediating suppression. Supernatants from poly A:poly U-treated adherent cells were found both to contain increased levels of prostaglandin E (PGE) and to induce a significant decrease in antibody production when added to in vitro spleen cell cultures. In addition, indomethacin, an inhibitor of the cyclo-oxygenase pathway of the arachidonic acid cascade was found to reverse the suppression of antibody induced by poly A:poly U. Thus, the polyribonucleotide complexes appear to suppress antibody synthesis by inducing macrophages to secrete PGE, a known immune suppressant.

In a previous study the adjuvant action of a monophosphoryl lipid A, a nontoxic derivative of endotoxic lipopolysaccharide (LPS), was found to be negated by a monoclonal anti-gamma interferon (anti-IFN-gamma) antibody. The present investigation centered on three other adjuvants of diverse microbial origins, testing for their capacity to affect the release of IFN-gamma as an explanation for their antibody-enhancing action. The adjuvant action of each of the three, a wild-type LPS, synthetic poly(A)-poly(U) complexes, and a synthetic muramyl dipeptide, n-acetylmuramyl-L-alanyl-D-glutaminyl-n-butyl ester (murabutide), was transferable by adjuvant-stimulated T cells to normal spleen cells on coculture. Supernatant fluids from these T cells contained increased levels of IFN-gamma. Addition of a monoclonal anti-IFN-gamma antibody to adjuvant-stimulated spleen cell cultures reduced the adjuvant action by approximately one-half. Removal of natural killer cells from spleen cell populations prior to culture with antigen had no effect on the enhancement induced by LPS and monophosphoryl lipid A. It was concluded that the enhancement induced by the adjuvants LPS, poly(A)-poly(U), and murabutide is mediated in part by their action on T cells resulting in release of IFN-gamma suggesting activation of a common transmembrane signal.

Sera from mice which have been injected iv with either poly(A) X poly(U) or poly(I) X poly(C) 1 1/2 hr prior to bleeding were found to suppress the mixed lymphocyte reaction. This effect was reduced considerably by 18 hr. Characterization of the suppressive sera revealed it (a) was stable to heating at 56 degrees C for 1 hr and freezing at -20 degrees C for 1 month; (b) had a molecular weight greater than 30,000; (c) could be induced in sera from athymic nude mice; and (d) was present to a lower degree in sera from aging mice.