Efficacy of Messenger RNA-1273 Against Severe Acute Respiratory Syndrome Coronavirus 2 Acquisition in Young Adults From March to December 2021.

Background: The efficacy of messenger RNA (mRNA)-1273 against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not well defined, particularly among young adults. Methods: Adults aged 18-29 years with no known history of SARS-CoV-2 infection or prior vaccination for coronavirus disease 2019 (COVID-19) were recruited from 44 US sites from 24 March to 13 September 2021 and randomized 1:1 to immediate vaccination (receipt of 2 doses of mRNA-1273 vaccine at months 0 and 1) or the standard of care (receipt of COVID-19 vaccine). Randomized participants were followed up for SARS-CoV-2 infection measured by nasal swab testing and symptomatic COVID-19 measured by nasal swab testing plus symptom assessment and assessed for the primary efficacy outcome. A vaccine-declined observational group was also recruited from 16 June to 8 November 2021 and followed up for SARS-CoV-2 infection as specified for the randomized participants. Results: The study enrolled 1149 in the randomized arms and 311 in the vaccine-declined group and collected >122 000 nasal swab samples. Based on randomized participants, the efficacy of 2 doses of mRNA-1273 vaccine against SARS-CoV-2 infection was 52.6% (95% confidence interval, -14.1% to 80.3%), with the majority of infections due to the Delta variant. Vaccine efficacy against symptomatic COVID-19 was 71.0% (95% confidence interval, -9.5% to 92.3%). Precision was limited owing to curtailed study enrollment and off-study vaccination censoring. The incidence of SARS-CoV-2 infection in the vaccine-declined group was 1.8 times higher than in the standard-of-care group. Conclusions: mRNA-1273 vaccination reduced the incidence of SARS-CoV-2 infection from March to September 2021, but vaccination was only one factor influencing risk. Clinical Trials Registration: NCT04811664.

Molecular Epidemiologic and Geo-Spatial Characterization of Staphylococcus aureus Cultured from Skin and Soft Tissue Infections from United States-Born and Immigrant Patients Living in New York City.

(1) Background: With increasing international travel and mass population displacement due to war, famine, climate change, and immigration, pathogens, such as Staphylococcus aureus (S. aureus), can also spread across borders. Methicillin-resistant S. aureus (MRSA) most commonly causes skin and soft tissue infections (SSTIs), as well as more invasive infections. One clonal strain, S. aureus USA300, originating in the United States, has spread worldwide. We hypothesized that S. aureus USA300 would still be the leading clonal strain among US-born compared to non-US-born residents, even though risk factors for SSTIs may be similar in these two populations (2) Methods: In this study, 421 participants presenting with SSTIs were enrolled from six community health centers (CHCs) in New York City. The prevalence, risk factors, and molecular characteristics for MRSA and specifically clonal strain USA300 were examined in relation to the patients' self-identified country of birth. (3) Results: Patients born in the US were more likely to have S. aureus SSTIs identified as MRSA USA300. While being male and sharing hygiene products with others were also significant risks for MRSA SSTI, we found exposure to animals, such as owning a pet or working at an animal facility, was specifically associated with risk for SSTIs caused by MRSA USA300. Latin American USA300 variant (LV USA300) was most common in participants born in Latin America. Spatial analysis showed that MRSA USA300 SSTI cases were more clustered together compared to other clonal types either from MRSA or methicillin-sensitive S. aureus (MSSA) SSTI cases. (4) Conclusions: Immigrants with S. aureus infections have unique risk factors and S. aureus molecular characteristics that may differ from US-born patients. Hence, it is important to identify birthplace in MRSA surveillance and monitoring. Spatial analysis may also capture additional information for surveillance that other methods do not.

Machine learning to predict risk for community-onset Staphylococcus aureus infections in children living in southeastern United States.

Staphylococcus aureus (S. aureus) is known to cause human infections and since the late 1990s, community-onset antibiotic resistant infections (methicillin resistant S. aureus (MRSA)) continue to cause significant infections in the United States. Skin and soft tissue infections (SSTIs) still account for the majority of these in the outpatient setting. Machine learning can predict the location-based risks for community-level S. aureus infections. Multi-year (2002-2016) electronic health records of children <19 years old with S. aureus infections were queried for patient level data for demographic, clinical, and laboratory information. Area level data (Block group) was abstracted from U.S. Census data. A machine learning ecological niche model, maximum entropy (MaxEnt), was applied to assess model performance of specific place-based factors (determined a priori) associated with S. aureus infections; analyses were structured to compare methicillin resistant (MRSA) against methicillin sensitive S. aureus (MSSA) infections. Differences in rates of MRSA and MSSA infections were determined by comparing those which occurred in the early phase (2002-2005) and those in the later phase (2006-2016). Multi-level modeling was applied to identify risks factors for S. aureus infections. Among 16,124 unique patients with community-onset MRSA and MSSA, majority occurred in the most densely populated neighborhoods of Atlanta's metropolitan area. MaxEnt model performance showed the training AUC ranged from 0.771 to 0.824, while the testing AUC ranged from 0.769 to 0.839. Population density was the area variable which contributed the most in predicting S. aureus disease (stratified by CO-MRSA and CO-MSSA) across early and late periods. Race contributed more to CO-MRSA prediction models during the early and late periods than for CO-MSSA. Machine learning accurately predicts which densely populated areas are at highest and lowest risk for community-onset S. aureus infections over a 14-year time span.

Comparison of bivalent and monovalent SARS-CoV-2 variant vaccines: the phase 2 randomized open-label COVAIL trial.

Vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection wanes over time, requiring updated boosters. In a phase 2, open-label, randomized clinical trial with sequentially enrolled stages at 22 US sites, we assessed safety and immunogenicity of a second boost with monovalent or bivalent variant vaccines from mRNA and protein-based platforms targeting wild-type, Beta, Delta and Omicron BA.1 spike antigens. The primary outcome was pseudovirus neutralization titers at 50% inhibitory dilution (ID50 titers) with 95% confidence intervals against different SARS-CoV-2 strains. The secondary outcome assessed safety by solicited local and systemic adverse events (AEs), unsolicited AEs, serious AEs and AEs of special interest. Boosting with prototype/wild-type vaccines produced numerically lower ID50 titers than any variant-containing vaccine against all variants. Conversely, boosting with a variant vaccine excluding prototype was not associated with decreased neutralization against D614G. Omicron BA.1 or Beta monovalent vaccines were nearly equivalent to Omicron BA.1 + prototype or Beta + prototype bivalent vaccines for neutralization of Beta, Omicron BA.1 and Omicron BA.4/5, although they were lower for contemporaneous Omicron subvariants. Safety was similar across arms and stages and comparable to previous reports. Our study shows that updated vaccines targeting Beta or Omicron BA.1 provide broadly crossprotective neutralizing antibody responses against diverse SARS-CoV-2 variants without sacrificing immunity to the ancestral strain. ClinicalTrials.gov registration: NCT05289037 .

Immunogenicity of a 2-Dose Regimen of Moderna mRNA Beta/Omicron BA.1 Bivalent Variant Vaccine Boost in a Randomized Clinical Trial.

We compared the serologic responses of 1 dose versus 2 doses of a variant vaccine (Moderna mRNA-1273 Beta/Omicron BA.1 bivalent vaccine) in adults. A 2-dose boosting regimen with a variant vaccine did not increase the magnitude or the durability of the serological responses compared to a single variant vaccine boost.

Population-Level Disparities in Exposure to COVID-19 Mitigation Policies, April 2020-April 2021.

CONTEXT: Studies have found that COVID-19 stay-at-home orders (SHOs) and face mask policies (FMPs) were associated with reduced COVID-19 transmission and deaths. But it is unknown whether exposure to these policies varied by sociodemographic characteristics across the US population. OBJECTIVE: The goal of this study was to quantify and characterize the sociodemographic characteristics and geographic distribution of populations exposed to evidence-based COVID-19 mitigation policies. DESIGN: We obtained statewide SHOs and FMPs for all US counties from April 10, 2020, to April 10, 2021, calculated median policy lengths, and categorized counties into 4 groups based on length of policy exposure: low SHO-low FMP, high SHO-low FMP, low SHO-high FMP, and high SHO-high FMP. We described exposure groups by COVID-19 cumulative case/death and vaccination rates and county sociodemographic characteristics. SETTING: In total, 3142 counties from all 50 states and Washington, District of Columbia, were included in the analysis. MAIN OUTCOME MEASURES: County-level sociodemographic factors and county cumulative rates for COVID-19 cases, deaths, and vaccinations. RESULTS: The largest percentage of the US population lived in counties with high exposure to SHOs and FMPs. However, populations living in high SHO-high FMP counties had the lowest percent non-Hispanic Black (NHB) and highest percent non-Hispanic White (NHW) populations. Populations living in high SHO-low FMP counties had the highest percent NHB and Hispanic populations and the lowest percent NHW population. CONCLUSION: This study identified county-level racial, ethnic, and sociodemographic disparities in exposure to evidence-based statewide COVID-19 mitigation policies. POLICY IMPLICATIONS: Exposure to evidence-based policies is an important consideration for studies evaluating the root causes of health inequities.

Immunogenicity of a Two Dose Regimen of Moderna mRNA Beta/Omicron BA.1 Bivalent Variant Vaccine Boost in a Randomized Clinical Trial.

In this brief report, we compare the magnitude and durability of the serologic response of one versus two doses (separated by 56 days) of a variant vaccine (Moderna mRNA-1273 Beta/Omicron BA.1 bivalent vaccine) in adults.

Bivalent and Monovalent SARS-CoV-2 Variant Vaccine Boosters Improve coverage of the known Antigenic Landscape: Results of the COVID-19 Variant Immunologic Landscape (COVAIL) Trial.

Vaccine protection against COVID-19 wanes over time and has been impacted by the emergence of new variants with increasing escape of neutralization. The COVID-19 Variant Immunologic Landscape (COVAIL) randomized clinical trial (clinicaltrials.gov NCT05289037) compares the breadth, magnitude and durability of antibody responses induced by a second COVID-19 vaccine boost with mRNA (Moderna mRNA-1273 and Pfizer-BioNTech BNT162b2), or adjuvanted recombinant protein (Sanofi CoV2 preS DTM-AS03) monovalent or bivalent vaccine candidates targeting ancestral and variant SARS-CoV-2 spike antigens (Beta, Delta and Omicron BA.1). We found that boosting with a variant strain is not associated with loss in neutralization against the ancestral strain. However, while variant vaccines compared to the prototype/wildtype vaccines demonstrated higher neutralizing activity against Omicron BA.1 and BA.4/5 subvariants for up to 3 months after vaccination, neutralizing activity was lower for more recent Omicron subvariants. Our study, incorporating both antigenic distances and serologic landscapes, can provide a framework for objectively guiding decisions for future vaccine updates.

Influence of Mask Wearing during COVID-19 Surge and Non-Surge Time Periods in Two K-12 Public School Districts in Georgia, USA.

BACKGROUND: Into the third year of the COVID-19 pandemic and the second year of in-person learning for many K-12 schools in the United States, the benefits of mitigation strategies in this setting are still unclear. We compare COVID-19 cases in school-aged children and adolescents between a school district with a mandatory mask-wearing policy to one with an optional mask-wearing policy, during and after the peak period of the Delta variant wave of infection. METHODS: COVID-19 cases during the Delta variant wave (August 2021) and post the wave (October 2021) were obtained from public health records. Cases of K-12 students, stratified by grade level (elementary, middle, and high school) and school districts across two counties, were included in the statistical and spatial analyses. COVID-19 case rates were determined and spatially mapped. Regression was performed adjusting for specific covariates. RESULTS: Mask-wearing was associated with lower COVID-19 cases during the peak Delta variant period; overall, regardless of the Delta variant period, higher COVID-19 rates were seen in older aged students. CONCLUSION: This study highlights the need for more layered prevention strategies and policies that take into consideration local community transmission levels, age of students, and vaccination coverage to ensure that students remain safe at school while optimizing their learning environment.

Immunogenicity of the BA.1 and BA.4/BA.5 SARS-CoV-2 Bivalent Boosts: Preliminary Results from the COVAIL Randomized Clinical Trial.

In a randomized clinical trial, we compare early neutralizing antibody responses after boosting with bivalent SARS-CoV-2 mRNA vaccines based on either BA.1 or BA.4/BA.5 Omicron spike protein combined with wildtype spike. Responses against SARS-CoV-2 variants exhibited the greatest reduction in titers against currently circulating Omicron subvariants for both bivalent vaccines.

Immunogenicity of the BA.1 and BA.4/BA.5 Severe Acute Respiratory Syndrome Coronavirus 2 Bivalent Boosts: Preliminary Results From the COVAIL Randomized Clinical Trial.

In a randomized clinical trial, we compare early neutralizing antibody responses after boosting with bivalent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines based on either BA.1 or BA.4/BA.5 Omicron spike protein combined with wild-type spike. Responses against SARS-CoV-2 variants exhibited the greatest reduction in titers against currently circulating Omicron subvariants for both bivalent vaccines.

Interpersonal Primary Care Continuity for Chronic Conditions Is Associated with Fewer Hospitalizations and Emergency Department Visits Among Medicaid Enrollees.

BACKGROUND: Interpersonal primary care continuity or chronic condition continuity (CCC) is associated with improved health outcomes. Ambulatory care-sensitive conditions (ACSC) are best managed in a primary care setting, and chronic ACSC (CACSC) require management over time. However, current measures do not measure continuity for specific conditions or the impact of continuity for chronic conditions on health outcomes. The purpose of this study was to design a novel measure of CCC for CACSC in primary care and determine its association with health care utilization. METHODS: We conducted a cross-sectional analysis of continuously enrolled, nondual eligible adult Medicaid enrollees with a diagnosis of a CACSC using 2009 Medicaid Analytic eXtract files from 26 states. We conducted adjusted and unadjusted logistic regression models of the relationship between patient continuity status and emergency department (ED) visits and hospitalizations. Models were adjusted for age, sex, race/ethnicity, comorbidity, and rurality. We defined CCC for CACSC as at least 2 outpatient visits with any primary care physician for a CACSC in the year, and (2) more than 50% of outpatient CACSC visits with a single PCP. RESULTS: There were 2,674,587 enrollees with CACSC and 36.3% had CCC for CACSC visits. In fully adjusted models, enrollees with CCC were 28% less likely to have ED visits compared with those without CCC (aOR = 0.71, 95% CI = 0.71 - 0.72) and were 67% less likely to have hospitalization than those without CCC (aOR = 0.33, 95% CI = 0.32-0.33). CONCLUSIONS: CCC for CACSCs was associated with fewer ED visits and hospitalizations in a nationally representative sample of Medicaid enrollees.

Predicting Low-Level Childhood Lead Exposure in Metro Atlanta Using Ensemble Machine Learning of High-Resolution Raster Cells.

Low-level lead exposure in children is a major public health issue. Higher-resolution spatial targeting would significantly improve county and state-wide policies and programs for lead exposure prevention that generally intervene across large geographic areas. We use stack-ensemble machine learning, including an elastic net generalized linear model, gradient-boosted machine, and deep neural network, to predict the number of children with venous blood lead levels (BLLs) ≥2 to <5 µg/dL and ≥5 µg/dL in ~1 km2 raster cells in the metro Atlanta region using a sample of 92,792 children ≤5 years old screened between 2010 and 2018. Permutation-based predictor importance and partial dependence plots were used for interpretation. Maps of predicted vs. observed values were generated to compare model performance. According to the EPA Toxic Release Inventory for air-based toxic release facility density, the percentage of the population below the poverty threshold, crime, and road network density was positively associated with the number of children with low-level lead exposure, whereas the percentage of the white population was inversely associated. While predictions generally matched observed values, cells with high counts of lead exposure were underestimated. High-resolution geographic prediction of lead-exposed children using ensemble machine learning is a promising approach to enhance lead prevention efforts.

Space-time trends of community-onset Staphylococcus aureus infections in children: a group-based trajectory modeling approach.

PURPOSE: Staphylococcus aureus (S. aureus) remains a serious cause of infections in the United States and worldwide. In the United States, methicillin-resistant S. aureus (MRSA) is the leading cause of skin and soft tissue infections. This study identifies 'best' to 'worst' infection trends from 2002 to 2016, using group-based trajectory modeling approach. METHODS: Electronic health records of children living in the southeastern United States with S. aureus infections from 2002 to 2016 were retrospectively studied, by applying a group-based trajectory model to estimate infection trends (low, high, very high), and then assess spatial significance of these trends at the census tract level; we focused on community-onset infections and not those considered healthcare acquired. RESULTS: Three methicillin-susceptible S. aureus (MSSA) infection trends (low, high, very high) and three MRSA trends (low, high, very high) were identified from 2002 to 2016. Among census tracts with community-onset S. aureus cases, 29% of tracts belonged to the best trend (low infection) for both methicillin-resistant S. aureus and methicillin-susceptible S. aureus; higher proportions occurring in the less densely populated areas. Race disparities were seen with the worst methicillin-resistant S. aureus infection trends and were more often in urban areas. CONCLUSIONS: Group-based trajectory modeling identified unique trends of S. aureus infection rates over time and space, giving insight into the associated population characteristics which reflect these trends of community-onset infection.

SARS-CoV-2 Variant Vaccine Boosters Trial: Preliminary Analyses.

Background: Protection from SARS-CoV-2 vaccines wanes over time and is compounded by emerging variants including Omicron subvariants. This study evaluated safety and immunogenicity of SARS-CoV-2 variant vaccines. Methods: This phase 2 open-label, randomized trial enrolled healthy adults previously vaccinated with a SARS-CoV-2 primary series and a single boost. Eligible participants were randomized to one of six Moderna COVID19 mRNA vaccine arms (50µg dose): Prototype (mRNA-1273), Omicron BA.1+Beta (1 or 2 doses), Omicron BA.1+Delta, Omicron BA.1 monovalent, and Omicron BA.1+Prototype. Neutralization antibody titers (ID 50 ) were assessed for D614G, Delta, Beta and Omicron BA.1 variants and Omicron BA.2.12.1 and BA.4/BA.5 subvariants 15 days after vaccination. Results: From March 30 to May 6, 2022, 597 participants were randomized and vaccinated. Median age was 53 years, and 20% had a prior SARS-CoV-2 infection. All vaccines were safe and well-tolerated. Day 15 geometric mean titers (GMT) against D614G were similar across arms and ages, and higher with prior infection. For uninfected participants, Day 15 Omicron BA.1 GMTs were similar across Omicron-containing vaccine arms (3724-4561) and higher than Prototype (1,997 [95%CI:1,482-2,692]). The Omicron BA.1 monovalent and Omicron BA.1+Prototype vaccines induced a geometric mean ratio (GMR) to Prototype for Omicron BA.1 of 2.03 (97.5%CI:1.37-3.00) and 1.56 (97.5%CI:1.06-2.31), respectively. A subset of samples from uninfected participants in four arms were also tested in a different laboratory at Day 15 for neutralizing antibody titers to D614G and Omicron subvariants BA.1, BA.2.12.2 and BA.4/BA.5. Omicron BA.4/BA.5 GMTs were approximately one third BA.1 GMTs (Prototype 517 [95%CI:324-826] vs. 1503 [95%CI:949-2381]; Omicron BA.1+Beta 628 [95%CI:367-1,074] vs. 2125 [95%CI:1139-3965]; Omicron BA.1+Delta 765 [95%CI:443-1,322] vs. 2242 [95%CI:1218-4128] and Omicron BA.1+Prototype 635 [95%CI:447-903] vs. 1972 [95%CI:1337-2907). Conclusions: Higher Omicron BA.1 titers were observed with Omicron-containing vaccines compared to Prototype vaccine and titers against Omicron BA.4/BA.5 were lower than against BA.1 for all candidate vaccines. Clinicaltrialsgov: NCT05289037.

Shift Work Predicts Increases in Lipopolysaccharide-Binding Protein, Interleukin-10, and Leukocyte Counts in a Cross-Sectional Study of Healthy Volunteers Carrying Low-Grade Systemic Inflammation.

The disruption of inflammatory responses is a potential mechanism behind the harmful effects of shift work and is associated with increased risk of hypertension, stroke, obesity, diabetes, and cancer. These responses are linked to the proliferation of leukocytes in shift workers, suggesting a systemic signal as a potential mediator. The purpose of this study was to assess the relationship between systemic inflammation, leukocyte counts, and systemic endotoxemia in samples from a diverse cohort of day workers and shift workers. Participants (normothermic and normotensive) were healthy volunteers, non-smoking, and drug- and medication-free. The following outcomes were measured: C-reactive protein, TNF-α, IL-6, IL-1ß, IL-10, leukocyte counts (monocytes, lymphocytes, and neutrophils), and lipopolysaccharide-binding protein (LBP). Risk factors that increase systemic inflammation, such as blood pressure, sleep loss, and cortisol, were also assessed. The results indicated that shift workers slept significantly less than day workers and had significantly increased concentrations of all of the cytokines measured as well as plasma cortisol. Regression models found that after controlling for covariates, shift-work exposure predicted the significant increase observed in IL-10, leukocyte counts, and LBP. Our results suggest that acute increases in low-grade systemic endotoxemia are unresolved during chronic shift-work exposure. This ongoing immune challenge may underlie the disrupted inflammatory responses characteristic of shift-work-related pathologies. Systemic endotoxemia may represent a novel target to investigate the early effects of exposure to shift-work schedules.

Increased Risk of Sub-Clinical Blood Lead Levels in the 20-County Metro Atlanta, Georgia Area-A Laboratory Surveillance-Based Study.

Lead (Pb) is a naturally occurring, highly toxic metal that has adverse effects on children across a range of exposure levels. Limited screening programs leave many children at risk for chronic low-level lead exposure and there is little understanding of what factors may be used to identify children at risk. We characterize the distribution of blood lead levels (BLLs) in children aged 0-72 months and their associations with sociodemographic and area-level variables. Data from the Georgia Department of Public Health's Healthy Homes for Lead Prevention Program surveillance database was used to describe the distribution of BLLs in children living in the metro Atlanta area from 2010 to 2018. Residential addresses were geocoded, and "Hotspot" analyses were performed to determine if BLLs were spatially clustered. Multilevel regression models were used to identify factors associated with clinical BBLs (≥5 µg/dL) and sub-clinical BLLs (2 to <5 µg/dL). From 2010 to 2018, geographically defined hotspots for both clinical and sub-clinical BLLs diffused from the city-central area of Atlanta into suburban areas. Multilevel regression analysis revealed non-Medicaid insurance, the proportion of renters in a given geographical area, and proportion of individuals with a GED/high school diploma as predictors that distinguish children with BLLs 2 to <5 µg/dL from those with lower (<2 µg/dL) or higher (≥5 µg/dL) BLLs. Over half of the study children had BLLs between 2 and 5 µg/dL, a range that does not currently trigger public health measures but that could result in adverse developmental outcomes if ignored.

Shift work influences the outcomes of Chlamydia infection and pathogenesis.

Shift work, performed by approximately 21 million Americans, is irregular or unusual work schedule hours occurring after 6:00 pm. Shift work has been shown to disrupt circadian rhythms and is associated with several adverse health outcomes and chronic diseases such as cancer, gastrointestinal and psychiatric diseases and disorders. It is unclear if shift work influences the complications associated with certain infectious agents, such as pelvic inflammatory disease, ectopic pregnancy and tubal factor infertility resulting from genital chlamydial infection. We used an Environmental circadian disruption (ECD) model mimicking circadian disruption occurring during shift work, where mice had a 6-h advance in the normal light/dark cycle (LD) every week for a month. Control group mice were housed under normal 12/12 LD cycle. Our hypothesis was that compared to controls, mice that had their circadian rhythms disrupted in this ECD model will have a higher Chlamydia load, more pathology and decreased fertility rate following Chlamydia infection. Results showed that, compared to controls, mice that had their circadian rhythms disrupted (ECD) had higher Chlamydia loads, more tissue alterations or lesions, and lower fertility rate associated with chlamydial infection. Also, infected ECD mice elicited higher proinflammatory cytokines compared to mice under normal 12/12 LD cycle. These results imply that there might be an association between shift work and the increased likelihood of developing more severe disease from Chlamydia infection.