Hybrid immunity and SARS-CoV-2 antibodies: results of the HEROES-RECOVER prospective cohort study.

BACKGROUND: There are limited data on whether hybrid immunity differs by count and order of immunity-conferring events (SARS-CoV-2 infection or COVID-19 vaccination). From a cohort of health care personnel, first responders, and other frontline workers in six US states, we examined heterogeneity of the effect of hybrid immunity on SARS-CoV-2 antibody levels. METHODS: Exposures included event-count (sum of infections and vaccine doses) and event-order, categorized into seven permutations of vaccination and/or infection. Outcome was level of serum binding antibodies against receptor binding domain (RBD) of the ancestral SARS-CoV-2 spike protein (total RBD-binding Ig), measured by enzyme-linked immunosorbent assay. Mean antibody levels were examined up to 365 days after each of the 1st-7th events. RESULTS: Analysis included 5,793 participants measured from August 7, 2020 to April 15, 2023. Hybrid immunity from infection before one or two vaccine doses elicited modestly superior antibody responses after the 2nd and 3rd events (compared to infections or vaccine-doses alone). This superiority was not evident after the 4th and 5th events (additional doses). Among adults infected before vaccination, adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated-only) were 1.23 (1.14-1.33), 1.09 (1.03-1.14), 0.87 (0.81-0.94), and 0.99 (0.85-1.15) after the 2nd-5th events, respectively. Post-vaccination infections elicited superior responses: adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated-only) were: 0.93 (0.75-1.17), 1.11 (1.06-1.16), 1.17 (1.11-1.24), and 1.20 (1.07-1.34) after the 2nd-5th events, respectively. CONCLUSIONS AND RELEVANCE: Findings reflecting heterogeneity in antibody levels by permutations of infection and vaccination history could inform COVID-19 vaccination policy.

Redirecting antibody responses from egg-adapted epitopes following repeat vaccination with recombinant or cell culture-based versus egg-based influenza vaccines.

Repeat vaccination with egg-based influenza vaccines could preferentially boost antibodies targeting the egg-adapted epitopes and reduce immunogenicity to circulating viruses. In this randomized trial (Clinicaltrials.gov: NCT03722589), sera pre- and post-vaccination with quadrivalent inactivated egg-based (IIV4), cell culture-based (ccIIV4), and recombinant (RIV4) influenza vaccines were collected from healthcare personnel (18-64 years) in 2018-19 (N = 723) and 2019-20 (N = 684) influenza seasons. We performed an exploratory analysis. Vaccine egg-adapted changes had the most impact on A(H3N2) immunogenicity. In year 1, RIV4 induced higher neutralizing and total HA head binding antibodies to cell- A(H3N2) virus than ccIIV4 and IIV4. In year 2, among the 7 repeat vaccination arms (IIV4-IIV4, IIV4-ccIIV4, IIV4-RIV4, RIV4-ccIIV4, RIV4-RIV4, ccIIV4-ccIIV4 and ccIIV4-RIV4), repeat vaccination with either RIV4 or ccIIV4 further improved antibody responses to circulating viruses with decreased neutralizing antibody egg/cell ratio. RIV4 also had higher post-vaccination A(H1N1)pdm09 and A(H3N2) HA stalk antibodies in year 1, but there was no significant difference in HA stalk antibody fold rise among vaccine groups in either year 1 or year 2. Multiple seasons of non-egg-based vaccination may be needed to redirect antibody responses from immune memory to egg-adapted epitopes and re-focus the immune responses towards epitopes on the circulating viruses to improve vaccine effectiveness.

Immunogenicity of High-Dose Egg-Based, Recombinant, and Cell Culture-Based Influenza Vaccines Compared With Standard-Dose Egg-Based Influenza Vaccine Among Health Care Personnel Aged 18-65 Years in 2019-2020.

Background: Emerging data suggest that second-generation influenza vaccines with higher hemagglutinin (HA) antigen content and/or different production methods may induce stronger antibody responses to HA than standard-dose egg-based influenza vaccines in adults. We compared antibody responses to high-dose egg-based inactivated (HD-IIV3), recombinant (RIV4), and cell culture-based (ccIIV4) vs standard-dose egg-based inactivated influenza vaccine (SD-IIV4) among health care personnel (HCP) aged 18-65 years in 2 influenza seasons (2018-2019, 2019-2020). Methods: In the second trial season, newly and re-enrolled HCPs who received SD-IIV4 in season 1 were randomized to receive RIV4, ccIIV4, or SD-IIV4 or were enrolled in an off-label, nonrandomized arm to receive HD-IIV3. Prevaccination and 1-month-postvaccination sera were tested by hemagglutination inhibition (HI) assay against 4 cell culture propagated vaccine reference viruses. Primary outcomes, adjusted for study site and baseline HI titer, were seroconversion rate (SCR), geometric mean titers (GMTs), mean fold rise (MFR), and GMT ratios that compared vaccine groups to SD-IIV4. Results: Among 390 HCP in the per-protocol population, 79 received HD-IIV3, 103 RIV4, 106 ccIIV4, and 102 SD-IIV4. HD-IIV3 recipients had similar postvaccination antibody titers compared with SD-IIV4 recipients, whereas RIV4 recipients had significantly higher 1-month-postvaccination antibody titers against vaccine reference viruses for all outcomes. Conclusions: HD-IIV3 did not induce higher antibody responses than SD-IIV4, but, consistent with previous studies, RIV4 was associated with higher postvaccination antibody titers. These findings suggest that recombinant vaccines rather than vaccines with higher egg-based antigen doses may provide improved antibody responses in highly vaccinated populations.

SARS-CoV-2 Screening Testing Programs for Safe In-person Learning in K-12 Schools.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) screening testing is a recommended mitigation strategy for schools, although few descriptions of program implementation are available. METHODS: Kindergarten through 12th grade (K-12) students and staff practicing universal masking during the delta and omicron variant waves from five schools in Durham, North Carolina and eight schools in Kansas City, Missouri participated; Durham's program was structured as a public health initiative facilitated by school staff, and Kansas City's as a research study facilitated by a research team. Tests included school-based rapid antigen or polymerase chain reaction testing, at-home rapid antigen testing, and off-site nucleic acid amplification testing. RESULTS: We performed nearly 5700 screening tests on more than 1600 K-12 school students and staff members. The total cost for the Durham testing program in 5 public charter K-12 schools, each with 500-1000 students, was $246 587 and approximately 752 h per semester; cost per test was $70 and cost per positive result was $7076. The total cost for the Kansas City program in eight public K-12 schools was $292 591 and required approximately 537 h in personnel time for school-based testing; cost per test was $132 and cost per positive result was $4818. SARS-CoV-2 positivity rates were generally lower (0-16.16%) than rates in the community (2.7-36.47%) throughout all testing weeks. CONCLUSIONS AND RELEVANCE: Voluntary screening testing programs in K-12 schools are costly and rarely detect asymptomatic positive persons, particularly in universally masked settings. CLINICAL TRIAL REGISTRATION: NCT04831866.

Test-to-Stay After SARS-CoV-2 Exposure: A Mitigation Strategy for Optionally Masked K-12 Schools.

OBJECTIVES: We evaluated the impact of a test-to-stay (TTS) program on within-school transmission and missed school days in optionally masked kindergarten through 12th grade schools during a period of high community severe acute respiratory syndrome coronavirus 2 transmission. METHODS: Close contacts of those with confirmed severe acute respiratory syndrome coronavirus 2 infection were eligible for enrollment in the TTS program if exposure to a nonhousehold contact occurred between November 11, 2021 and January 28, 2022. Consented participants avoided school exclusion if they remained asymptomatic and rapid antigen testing at prespecified intervals remained negative. Primary outcomes included within-school tertiary attack rate (test positivity among close contacts of positive TTS participants) and school days saved among TTS participants. We estimated the number of additional school-acquired cases resulting from TTS and eliminating school exclusion. RESULTS: A total of 1675 participants tested positive or received at least 1 negative test between days 5 and 7 and completed follow-up; 92% were students and 91% were exposed to an unmasked primary case. We identified 201 positive cases. We observed a tertiary attack rate of 10% (95% confidence interval: 6%-19%), and 7272 (89%) of potentially missed days were saved through TTS implementation. We estimated 1 additional school-acquired case for every 21 TTS participants remaining in school buildings during the entire study period. CONCLUSIONS: Even in the setting of high community transmission, a TTS strategy resulted in substantial reduction in missed school days in optionally masked schools.

Effects of substance P on human cerebral microvascular endothelial cell line hCMEC/D3 are mediated exclusively through a truncated NK-1 receptor and depend on cell confluence.

The neuropeptide substance P (SP) mediates pain transmission, immune modulation, vasodilation and neurogenic inflammation. Its role in the peripheral nervous system has been well characterised. However, its actions on the blood-brain barrier (BBB) are less clear and warrant further study. The aim of this study was to characterise the effect of SP on the brain microvascular endothelial cells using the immortalized human brain microvascular endothelial cell line hCMEC/D3. As part of our studies, we have evaluated changes in expression, at mRNA and protein levels, of genes involved in the function of the blood-brain barrier such as occludin, induced by exposure to SP. We show that the effect of SP is dependent on cell confluence status. Thus, at low confluence but not at full confluence, SP treatment reduced occludin expression. The expression of the SP receptor, neurokinin-1 receptor (NK-1R) (the truncated form of the receptor expressed exclusively in this cell line) was also modulated in a similar pattern. SP treatment stimulated extracellular signal-regulated kinase (Erk2) phosphorylation which was not associated to changes in Interleukin-6 (IL-6), Interleukin-8 (IL-8), or Intercellular Adhesion Molecule 1 (ICAM-1) protein expression. In addition, SP treatment effectively recovered nitric oxide production on cells exposed to tumour necrosis factor alpha (TNF-α). SP did not trigger intracellular calcium release in hCMEC/D3 cells. We conclude that hCMEC/D3 cells are partially responsive to SP, that the effects are mediated through the truncated form of the receptor and are dependent on the confluence status of these cells.

Pediatric Research Observing Trends and Exposures in COVID-19 Timelines (PROTECT): Protocol for a Multisite Longitudinal Cohort Study.

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.

Consistency of self-reported and documented historical influenza vaccination status of US healthcare workers.

BACKGROUND: Healthcare personnel (HCP) are a priority group for annual influenza vaccination. Few studies have assessed the validity of recall of prior influenza vaccination status among HCP, especially for more than one preceding season. METHODS: Using data from a randomized controlled trial of influenza vaccination among 947 HCP from two US healthcare systems, we assessed agreement between participant self-report and administrative record documentation of influenza vaccination status during the preceding five influenza seasons; kappa coefficients and sensitivity values were calculated. Administrative record documentation was considered the gold standard. Documented vaccination sources included electronic medical records, employee health records, outside immunization providers, and the state immunization information system. RESULTS: Among 683 HCP with prior influenza immunization information, 89.7% (95% CI: 87.2%, 91.9%) of HCP were able to self-report their vaccination status for the season preceding the survey. By the fifth preceding season, 82.6% (95% CI: 79.5%, 85.3%) of HCP were able to self-report. Among HCP who self-reported their vaccination status, agreement between self-report and documented vaccination status ranged from 81.9% (95% CI: 77.2%, 86.7%) for the fifth season to 90.5% (95% CI: 87.2%, 93.9%) for the season preceding interview. HCP who received vaccine for only some of the preceding five seasons (18.3%) more commonly had ≥2 errors in their recall compared with those vaccinated all five preceding seasons (55.7% vs. 4.3%). CONCLUSIONS: Self-reported vaccination status is a reliable source for historical influenza vaccination information among HCP who are consistently vaccinated but less reliable for those with a history of inconsistent vaccination.

Effectiveness of 2-Dose BNT162b2 (Pfizer BioNTech) mRNA Vaccine in Preventing SARS-CoV-2 Infection Among Children Aged 5-11 Years and Adolescents Aged 12-15 Years - PROTECT Cohort, July 2021-February 2022.

The BNT162b2 (Pfizer-BioNTech) mRNA COVID-19 vaccine was recommended by CDC's Advisory Committee on Immunization Practices for persons aged 12-15 years (referred to as adolescents in this report) on May 12, 2021, and for children aged 5-11 years on November 2, 2021 (1-4). Real-world data on vaccine effectiveness (VE) in these age groups are needed, especially because when the B.1.1.529 (Omicron) variant became predominant in the United States in December 2021, early investigations of VE demonstrated a decline in protection against symptomatic infection for adolescents aged 12-15 years and adults* (5). The PROTECT† prospective cohort of 1,364 children and adolescents aged 5-15 years was tested weekly for SARS-CoV-2, irrespective of symptoms, and upon COVID-19-associated illness during July 25, 2021-February 12, 2022. Among unvaccinated participants (i.e., those who had received no COVID-19 vaccine doses) with any laboratory-confirmed SARS-CoV-2 infection, those with B.1.617.2 (Delta) variant infections were more likely to report COVID-19 symptoms (66%) than were those with Omicron infections (49%). Among fully vaccinated children aged 5-11 years, VE against any symptomatic and asymptomatic Omicron infection 14-82 days (the longest interval after dose 2 in this age group) after receipt of dose 2 of the Pfizer-BioNTech vaccine was 31% (95% CI = 9%-48%), adjusted for sociodemographic characteristics, health information, frequency of social contact, mask use, location, and local virus circulation. Among adolescents aged 12-15 years, adjusted VE 14-149 days after dose 2 was 87% (95% CI = 49%-97%) against symptomatic and asymptomatic Delta infection and 59% (95% CI = 22%-79%) against Omicron infection. Fully vaccinated participants with Omicron infection spent an average of one half day less sick in bed than did unvaccinated participants with Omicron infection. All eligible children and adolescents should remain up to date with recommended COVID-19 vaccinations.

Incidence of SARS-CoV-2 infection among COVID-19 vaccinated and unvaccinated healthcare personnel, first responders, and other essential and frontline workers: Eight US locations, January-September 2021.

BACKGROUND: We sought to evaluate the impact of changes in estimates of COVID-19 vaccine effectiveness on the incidence of laboratory-confirmed infection among frontline workers at high risk for SARS-CoV-2. METHODS: We analyzed data from a prospective frontline worker cohort to estimate the incidence of COVID-19 by month as well as the association of COVID-19 vaccination, occupation, demographics, physical distancing, and mask use with infection risk. Participants completed baseline and quarterly surveys, and each week self-collected mid-turbinate nasal swabs and reported symptoms. RESULTS: Among 1018 unvaccinated and 3531 fully vaccinated workers, the monthly incidence of laboratory-confirmed SARS-CoV-2 infection in January 2021 was 13.9 (95% confidence interval [CI]: 10.4-17.4), declining to 0.5 (95% CI -0.4-1.4) per 1000 person-weeks in June. By September 2021, when the Delta variant predominated, incidence had once again risen to 13.6 (95% CI 7.8-19.4) per 1000 person-weeks. In contrast, there was no reportable incidence among fully vaccinated participants at the end of January 2021, and incidence remained low until September 2021 when it rose modestly to 4.1 (95% CI 1.9-3.8) per 1000. Below average facemask use was associated with a higher risk of infection for unvaccinated participants during exposure to persons who may have COVID-19 and vaccinated participants during hours in the community. CONCLUSIONS: COVID-19 vaccination was significantly associated with a lower risk of SARS-CoV-2 infection despite Delta variant predominance. Our data demonstrate the added protective benefit of facemask use among both unvaccinated and vaccinated frontline workers.

Neutralizing Antibody Response to Pseudotype Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Differs Between mRNA-1273 and BNT162b2 Coronavirus Disease 2019 (COVID-19) Vaccines and by History of SARS-CoV-2 Infection.

BACKGROUND: Data on the development of neutralizing antibodies (nAbs) against SARS-CoV-2 after SARS-CoV-2 infection and after vaccination with mRNA COVID-19 vaccines are limited. METHODS: From a prospective cohort of 3975 adult essential and frontline workers tested weekly from August 2020 to March 2021 for SARS-CoV-2 infection by reverse transcription-polymerase chain reaction assay irrespective of symptoms, 497 participants had sera drawn after infection (170), vaccination (327), and after both infection and vaccination (50 from the infection population). Serum was collected after infection and each vaccine dose. Serum-neutralizing antibody titers against USA-WA1/2020-spike pseudotype virus were determined by the 50% inhibitory dilution. Geometric mean titers (GMTs) and corresponding fold increases were calculated using t tests and linear mixed-effects models. RESULTS: Among 170 unvaccinated participants with SARS-CoV-2 infection, 158 (93%) developed nAbs with a GMT of 1003 (95% confidence interval, 766-1315). Among 139 previously uninfected participants, 138 (99%) developed nAbs after mRNA vaccine dose 2 with a GMT of 3257 (2596-4052). GMT was higher among those receiving mRNA-1273 vaccine (GMT, 4698; 3186-6926) compared with BNT162b2 vaccine (GMT, 2309; 1825-2919). Among 32 participants with prior SARS-CoV-2 infection, GMT was 21 655 (14 766-31 756) after mRNA vaccine dose 1, without further increase after dose 2. CONCLUSIONS: A single dose of mRNA vaccine after SARS-CoV-2 infection resulted in the highest observed nAb response. Two doses of mRNA vaccine in previously uninfected participants resulted in higher nAbs to SARS-CoV-2 than after 1 dose of vaccine or SARS-CoV-2 infection alone. nAb response also differed by mRNA vaccine product.

Interim Estimate of Vaccine Effectiveness of BNT162b2 (Pfizer-BioNTech) Vaccine in Preventing SARS-CoV-2 Infection Among Adolescents Aged 12-17 Years - Arizona, July-December 2021.

The BNT162b2 (Pfizer-BioNTech) mRNA COVID-19 vaccine has demonstrated high efficacy in preventing infection with SARS-CoV-2 (the virus that causes COVID-19) in randomized placebo-controlled Phase III trials in persons aged 12-17 years (referred to as adolescents in this report) (1); however, data on real-word vaccine effectiveness (VE) among adolescents are limited (1-3). As of December 2021, the Pfizer-BioNTech vaccine is approved by the Food and Drug Administration (FDA) for adolescents aged 16-17 years and under FDA emergency use authorization for those aged 12-15 years. In a prospective cohort in Arizona, 243 adolescents aged 12-17 years were tested for SARS-CoV-2 by reverse transcription-polymerase chain reaction (RT-PCR) each week, irrespective of symptoms, and upon onset of COVID-19-like illness during July 25-December 4, 2021; the SARS-CoV-2 B.1.617.2 (Delta) variant was the predominant strain during this study period. During the study, 190 adolescents contributed fully vaccinated person-time (≥14 days after receiving 2 doses of Pfizer-BioNTech vaccine), 30 contributed partially vaccinated person-time (receipt of 1 dose or receipt of 2 doses but with the second dose completed <14 days earlier), and 66 contributed unvaccinated person-time. Using the Cox proportional-hazards model, the estimated VE of full Pfizer-BioNTech vaccination for preventing SARS-CoV-2 infection was 92% (95% CI = 79%-97%), adjusted for sociodemographic characteristics, health information, frequency of social contact, mask use, location, and local virus circulation. These findings from a real-world setting indicate that 2 doses of Pfizer-BioNTech vaccine are highly effective in preventing SARS-CoV-2 infection among Arizona adolescents. CDC recommends COVID-19 vaccination for all eligible persons in the United States, including persons aged 12-17 years.

Research on the Epidemiology of SARS-CoV-2 in Essential Response Personnel (RECOVER): Protocol for a Multisite Longitudinal Cohort Study.

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.

Prevention and Attenuation of Covid-19 with the BNT162b2 and mRNA-1273 Vaccines.

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.).

Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health Care Personnel, First Responders, and Other Essential and Frontline Workers - Eight U.S. Locations, December 2020-March 2021.

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.

PAF-R on activated T cells: Role in the IL-23/Th17 pathway and relevance to multiple sclerosis.

IL-23 is a potent stimulus for Th17 cells. These cells have a distinct developmental pathway from Th1 cells induced by IL-12 and are implicated in autoimmune and inflammatory disorders including multiple sclerosis (MS). TGF-ß, IL-6, and IL-1, the transcriptional regulator RORγt (RORC) and IL-23 are implicated in Th17 development and maintenance. In human polyclonally activated T cells, IL-23 enhances IL-17 production. The aims of our study were: 1). To validate microarray results showing preferential expression of platelet activating factor receptor (PAF-R) on IL-23 stimulated T cells. 2). To determine whether PAF-R on activated T cells is functional, whether it is co-regulated with Th17-associated molecules, and whether it is implicated in Th17 function. 3). To determine PAF-R expression in MS. We show that PAF-R is expressed on activated T cells, and is inducible by IL-23 and IL-17, which in turn are induced by PAF binding to PAF-R. PAF-R is co-expressed with IL-17 and regulated similarly with Th17 markers IL-17A, IL-17F, IL-22 and RORC. PAF-R is upregulated on PBMC and T cells of MS patients, and levels correlate with IL-17 and with MS disability scores. Our results show that PAF-R on T cells is associated with the Th17 phenotype and function. Clinical Implications Targeting PAF-R may interfere with Th17 function and offer therapeutic intervention in Th17-associated conditions, including MS.

Intent to obtain pediatric influenza vaccine among mothers in four middle income countries.

BACKGROUND: Despite a large burden of influenza in middle income countries, pediatric vaccination coverage remains low. The aims of this study were to (1) describe mothers' knowledge and attitudes about influenza illnesses and vaccination, and (2) identify characteristics associated with mothers' intent to vaccinate their child. METHODS: From 2015 to 2017, infants 0-11 months old in Nicaragua, Philippines, Jordan, and Albania were enrolled from community settings and hospitals. Interviewers administered a questionnaire to their mothers. Mothers of infants aged 6-11 months rated their intention (small-to-moderate vs. large chance) to accept pediatric vaccination if it was offered at no-cost. The importance of knowledge, attitudes, and sociodemographic characteristics in predicting influenza vaccination intention was measured as the mean decrease in Gini index when that factor was excluded from 1000 decision trees in a random forest analysis. RESULTS: In total, 1,308 mothers were enrolled from the community setting and 3,286 from the hospital setting. Prevalence of at least some knowledge of influenza illness ranged from 34% in Philippines to 88% in Albania (in the community sample), and between 23% in Philippines to 88% in Jordan (in the hospital sample). In the community sample, most mothers in Albania (69%) and Philippines (58%) would accept the influenza vaccine, and these proportions were higher in the hospital sample for all countries except Albania (48%) (P < 0.0001). Perceived vaccine safety (mean decrease in Gini index = 61) and effectiveness (55), and perceived knowledge of influenza vaccine (45) were the most important predictors of influenza vaccination intention in models that also included country and community versus hospital sample. CONCLUSION: Intent to vaccinate infants aged 6-11 months in four middle income countries was tied primarily to knowledge of the vaccine and perceptions of vaccine safety and effectiveness. These findings were noted among mothers interviewed in the community and mothers of recently hospitalized infants.

An Outbreak of Paralytic Shellfish Poisoning in Tasmania.

Paralytic shellfish poisoning (PSP) is a rare illness caused by eating shellfish containing paralytic shellfish toxins (PST). Toxins are produced during harmful algal blooms, which occur most years on the east coast of Tasmania. Contaminated seafood looks and tastes normal and toxins are not destroyed by cooking or freezing. Commercial shellfish farms are monitored for harmful algae and shellfish toxins, but wild shellfish are not and pose a potential public health risk. A case of PSP was documented in Tasmania in 2011, and we are aware of anecdotal reports of cases in the 1980s and 1990s. We are not aware of cases elsewhere in Australia but harmful algal blooms have been detected in Victoria, South Australia and New South Wales. Routine monitoring of commercial shellfish in 2015 detected a large bloom of Alexandrium tamarense on the east coast of Tasmania, which can cause PSP. Between 2 and 12 October 2015, four cases of PSP were identified. All were adults who ate wild mussels from the east coast of Tasmania and had onset of numbness or tingling of the face and muscle weakness from 30 minutes to 12 hours later. Two cases were briefly hospitalised, both recovered. Since the outbreak, permanent signage at locations where shellfish are frequently recreationally foraged has been erected. Additional alerts are released during high risk periods based on surveillance of commercial sites by the Tasmanian Shellfish Quality Assurance Program. Several states in Australia are at risk of cases of PSP. We recommend active surveillance and multi-jurisdictional collaboration to manage this risk.

MiR-126 and miR-126* regulate shear-resistant firm leukocyte adhesion to human brain endothelium.

Leukocyte adhesion to brain endothelial cells, the blood-brain barrier main component, is a critical step in the pathogenesis of neuroinflammatory diseases such as multiple sclerosis (MS). Leukocyte adhesion is mediated mainly by selectins, cell adhesion molecules and chemokines induced by pro-inflammatory cytokines such as TNFα and IFNγ, but the regulation of this process is not fully clear. This study investigated the regulation of firm leukocyte adhesion to human brain endothelium by two different brain endothelial microRNAs (miRs), miR-126 and miR-126*, that are downregulated by TNFα and IFNγ in a human brain endothelial cell line, hCMEC/D3. Using a leukocyte adhesion in vitro assay under shear forces mimicking blood flow, we observed that reduction of endothelial miR-126 and miR-126* enhanced firm monocyte and T cell adhesion to hCMEC/D3 cells, whereas their increased expression partially prevented THP1, Jurkat and primary MS patient-derived PBMC firm adhesion. Furthermore, we observed that miR-126* and miR-126 downregulation increased E-selectin and VCAM1, respectively, while miR-126 overexpression reduced VCAM1 and CCL2 expression by hCMEC/D3 cells, suggesting that these miRs regulate leukocyte adhesion by modulating the expression of adhesion-associated endothelial mRNA targets. Hence, human brain endothelial miR-126 and miR-126* could be used as a therapeutic tool to reduce leukocyte adhesion and thus reduce neuroinflammation.