Effects of Confounding Bias in Coronavirus Disease 2019 (COVID-19) and Influenza Vaccine Effectiveness Test-Negative Designs Due to Correlated Influenza and COVID-19 Vaccination Behaviors.

BACKGROUND: The test-negative design is commonly used to estimate influenza and coronavirus disease 2019 (COVID-19) vaccine effectiveness (VE). In these studies, correlated COVID-19 and influenza vaccine behaviors may introduce a confounding bias where controls are included with the other vaccine-preventable acute respiratory illness (ARI). We quantified the impact of this bias on VE estimates in studies where this bias is not addressed. METHODS: We simulated study populations under varying vaccination probabilities, COVID-19 VE, influenza VE, and proportions of controls included with the other vaccine-preventable ARI. Mean bias was calculated as the difference between estimated and true VE. Absolute mean bias in VE estimates was classified as low (<10%), moderate (10% to <20%), and high (≥20%). RESULTS: Where vaccination probabilities are positively correlated, COVID-19 and influenza VE test-negative studies with influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ARI controls, respectively, underestimate VE. For COVID-19 VE studies, mean bias was low for all scenarios where influenza represented ≤25% of controls. For influenza VE studies, mean bias was low for all scenarios where SARS-CoV-2 represented ≤10% of controls. Although bias was driven by the conditional probability of vaccination, low VE of the vaccine of interest and high VE of the confounding vaccine increase its magnitude. CONCLUSIONS: Where a low percentage of controls is included with the other vaccine-preventable ARI, bias in COVID-19 and influenza VE estimates is low. However, influenza VE estimates are likely more susceptible to bias. Researchers should consider potential bias and its implications in their respective study settings to make informed methodological decisions in test-negative VE studies.

Evaluation of Cell-Based and Surrogate SARS-CoV-2 Neutralization Assays.

Determinants of protective immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection require the development of well-standardized, reproducible antibody assays. This need has led to the emergence of a variety of neutralization assays. Head-to-head evaluation of different SARS-CoV-2 neutralization platforms could facilitate comparisons across studies and laboratories. Five neutralization assays were compared using 40 plasma samples from convalescent individuals with mild to moderate coronavirus disease 2019 (COVID-19): four cell-based systems using either live recombinant SARS-CoV-2 or pseudotyped viral particles created with lentivirus (LV) or vesicular stomatitis virus (VSV) packaging and one surrogate enzyme-linked immunosorbent assay (ELISA)-based test that measures inhibition of the spike protein receptor binding domain (RBD) binding its receptor human angiotensin converting enzyme 2 (hACE2). Vero cells, Vero E6 cells, HEK293T cells expressing hACE2, and TZM-bl cells expressing hACE2 and transmembrane serine protease 2 were tested. All cell-based assays showed 50% neutralizing dilution (ND50) geometric mean titers (GMTs) that were highly correlated (Pearson r = 0.81 to 0.89) and ranged within 3.4-fold. The live virus assay and LV pseudovirus assays with HEK293T/hACE2 cells showed very similar mean titers, 141 and 178, respectively. ND50 titers positively correlated with plasma IgG targeting SARS-CoV-2 spike protein and RBD (r = 0.63 to 0.89), but moderately correlated with nucleoprotein IgG (r = 0.46 to 0.73). ND80 GMTs mirrored ND50 data and showed similar correlation between assays and with IgG concentrations. The VSV pseudovirus assay and LV pseudovirus assay with HEK293T/hACE2 cells in low- and high-throughput versions were calibrated against the WHO SARS-CoV-2 IgG standard. High concordance between the outcomes of cell-based assays with live and pseudotyped virions enables valid cross-study comparison using these platforms.

Evaluation of the Impact of a Rotavirus Vaccine Program on Pediatric Acute Gastroenteritis Hospitalizations: Estimating the Overall Effect Attributable to the Program as a Whole and as a Per-Unit Change in Rotavirus Vaccine Coverage.

Estimation of the overall effect of a vaccine program is essential, but the effect is typically estimated for a whole program. We estimated the overall effect of the Quebec rotavirus vaccine program, launched in November 2011, and the effect for each 10% increase in rotavirus vaccine coverage on pediatric hospitalizations for all-cause acute gastroenteritis. We implemented negative binomial regressions adjusted for seasonality, long-term trends, and infection dynamics, to estimate the effect of the vaccine program as: 1) a dichotomous variable, representing program presence/absence, and linear term to account for changes in trend in the period after the program began; and 2) a continuous variable, representing rotavirus vaccine coverage. Using exposure 1, the vaccine program was associated with a 51.2% (95% confidence interval (CI): 28.5, 66.7) relative decline in adjusted weekly hospitalization rates for all-cause acute gastroenteritis as of December 28, 2014. Using exposure 2, a 10% increase in rotavirus ≥1-dose coverage was associated with a 7.1% (95% CI: 3.5, 10.5) relative decline in adjusted weekly rates, with maximum coverage of 87.0% associated with a 47.2% (95% CI: 26.9, 61.9) relative decline. Estimation of the overall effect attributable to a change in vaccine coverage might be a useful addition to standard measurement of the overall effect.

Two Birds With One Stone: Estimating Population Vaccination Coverage From a Test-negative Vaccine Effectiveness Case-control Study.

Vaccination program evaluation includes assessment of vaccine uptake and direct vaccine effectiveness (VE). Often examined separately, we propose a design to estimate rotavirus vaccination coverage using controls from a rotavirus VE test-negative case-control study and to examine coverage following implementation of the Quebec, Canada, rotavirus vaccination program. We present our assumptions for using these data as a proxy for coverage in the general population, explore effects of diagnostic accuracy on coverage estimates via simulations, and validate estimates with an external source. We found 79.0% (95% confidence interval, 74.3%, 83.0%) ≥2-dose rotavirus coverage among participants eligible for publicly funded vaccination. No differences were detected between study and external coverage estimates. Simulations revealed minimal bias in estimates with high diagnostic sensitivity and specificity. We conclude that controls from a VE case-control study may be a valuable resource of coverage information when reasonable assumptions can be made for estimate generalizability; high rotavirus coverage demonstrates success of the Quebec program.

Mumps outbreak in Orthodox Jewish communities in the United States.

BACKGROUND: By 2005, vaccination had reduced the annual incidence of mumps in the United States by more than 99%, with few outbreaks reported. However, in 2006, a large outbreak occurred among highly vaccinated populations in the United States, and similar outbreaks have been reported worldwide. The outbreak described in this report occurred among U.S. Orthodox Jewish communities during 2009 and 2010. METHODS: Cases of salivary-gland swelling and other symptoms clinically compatible with mumps were investigated, and demographic, clinical, laboratory, and vaccination data were evaluated. RESULTS: From June 28, 2009, through June 27, 2010, a total of 3502 outbreak-related cases of mumps were reported in New York City, two upstate New York counties, and one New Jersey county. Of the 1648 cases for which clinical specimens were available, 50% were laboratory-confirmed. Orthodox Jewish persons accounted for 97% of case patients. Adolescents 13 to 17 years of age (27% of all patients) and males (78% of patients in that age group) were disproportionately affected. Among case patients 13 to 17 years of age with documented vaccination status, 89% had previously received two doses of a mumps-containing vaccine, and 8% had received one dose. Transmission was focused within Jewish schools for boys, where students spend many hours daily in intense, face-to-face interaction. Orchitis was the most common complication (120 cases, 7% of male patients ≥12 years of age), with rates significantly higher among unvaccinated persons than among persons who had received two doses of vaccine. CONCLUSIONS: The epidemiologic features of this outbreak suggest that intense exposures, particularly among boys in schools, facilitated transmission and overcame vaccine-induced protection in these patients. High rates of two-dose coverage reduced the severity of the disease and the transmission to persons in settings of less intense exposure.

An evaluation of voluntary 2-dose varicella vaccination coverage in New York City public schools.

OBJECTIVES: We assessed coverage for 2-dose varicella vaccination, which is not required for school entry, among New York City public school students and examined characteristics associated with receipt of 2 doses. METHODS: We measured receipt of either at least 1 or 2 doses of varicella vaccine among students aged 4 years and older in a sample of 336 public schools (n = 223 864 students) during the 2010 to 2011 school year. Data came from merged student vaccination records from 2 administrative data systems. We conducted multivariable regression to assess associations of age, gender, race/ethnicity, and school location with 2-dose prevalence. RESULTS: Coverage with at least 1 varicella dose was 96.2% (95% confidence interval [CI] = 96.2%, 96.3%); coverage with at least 2 doses was 64.8% (95% CI = 64.6%, 64.9%). Increasing student age, non-Hispanic White race/ethnicity, and attendance at school in Staten Island were associated with lower 2-dose coverage. CONCLUSIONS: A 2-dose varicella vaccine requirement for school entry would likely improve 2-dose coverage, eliminate coverage disparities, and prevent disease.

Outbreak of measles among persons with prior evidence of immunity, New York City, 2011.

BACKGROUND: Measles was eliminated in the United States through high vaccination coverage and a public health system able to rapidly respond to measles. Measles may occur among vaccinated individuals, but secondary transmission from such individuals has not been documented. METHODS: Suspected patients and contacts exposed during a measles outbreak in New York City in 2011 were investigated. Medical histories and immunization records were obtained. Cases were confirmed by detection of measles-specific immunoglobulin M and/or RNA. Tests for measles immunoglobulin G (IgG), IgG avidity, measurement of measles neutralizing antibody titers, and genotyping were performed to characterize the cases. RESULTS: The index patient had 2 doses of measles-containing vaccine; of 88 contacts, 4 secondary patients were confirmed who had either 2 doses of measles-containing vaccine or a past positive measles IgG antibody. All patients had laboratory confirmation of measles infection, clinical symptoms consistent with measles, and high-avidity IgG antibody characteristic of a secondary immune response. Neutralizing antibody titers of secondary patients reached >80 000 mIU/mL 3-4 days after rash onset and that of the index was <500 mIU/mL 9 days after rash onset. No additional cases of measles occurred among 231 contacts of secondary patients. CONCLUSIONS: This is the first report of measles transmission from a twice-vaccinated individual with documented secondary vaccine failure. The clinical presentation and laboratory data of the index patient were typical of measles in a naive individual. Secondary patients had robust anamnestic antibody responses. No tertiary cases occurred despite numerous contacts. This outbreak underscores the need for thorough epidemiologic and laboratory investigation of suspected cases of measles regardless of vaccination status.

School Vaccine Coverage and Medical Exemption Uptake After the New York State Repeal of Nonmedical Vaccination Exemptions.

Importance: Although New York State (NYS) recently adopted legislation eliminating nonmedical vaccination exemption options from school-entry requirements, the implications of the law for school vaccine coverage and medical vaccine exemption uptake have not been examined. Objective: To evaluate the implications of the repeal of school-entry nonmedical vaccination exemptions for vaccine coverage and medical exemption uptake at NYS schools outside of New York City (NYC). Design, Setting, and Participants: This cohort study had an interrupted time-series design and used generalized estimating equation models to examine longitudinal school immunization compliance data from the 2012 to 2013 through 2021 to 2022 school years. The cohort comprised NYS public and nonpublic schools, excluding NYC schools, with any students enrolled in kindergarten to 12th grade. Eligible schools had enrollment and immunization data before and after the implementation of the Senate Bill 2994A legislation. Data analyses were conducted in July 2023. Exposure: Senate Bill 2994A was passed in June 2019, eliminating school-entry nonmedical vaccination exemptions. Since compliance with the law was evaluated for most students during the next school year, the 2019 to 2020 school year was considered to be the law's effective date. Main Outcomes and Measures: The primary outcomes were school vaccine coverage (defined as the percentage of students at each school who completed grade-appropriate requirements for all required vaccines) and medical exemption uptake (defined as the percentage of students at each school who received a medical exemption). Results: Among the 3821 eligible schools, 3632 (95.1%) were included in the analysis, representing 2794 (96.9% of eligible) public schools and 838 (89.2% of eligible) nonpublic schools. The implementation of Senate Bill 2994A was associated with absolute increases in mean vaccine coverage of 5.5% (95% CI, 4.5%-6.6%) among nonpublic schools and 0.9% (95% CI, 0.7%-1.1%) among public schools, with additional annual increases in vaccine coverage observed through the 2021 to 2022 school year. The law's implementation was also associated with a 0.1% (95% CI, 0.0%-0.1%) mean absolute decrease in medical vaccination exemption uptake at both public and nonpublic schools, and small but significant mean annual decreases in medical vaccination exemptions (0.02%; 95% CI, 0.01%-0.03%) through the end of the study period. Conclusions and Relevance: Results of this cohort study suggested that repeal of school-entry nonmedical vaccination exemptions was associated with increased vaccine coverage at NYS schools outside of NYC. Coverage gains were not replaced by increases in medical vaccination exemptions.

Exploring the impact of the New York State repeal of nonmedical vaccination exemptions on student enrollment, absenteeism, and school workload: Perspectives from a survey of school administrators.

In June 2019, New York State (NYS) adopted Senate Bill 2994A eliminating nonmedical vaccine exemptions from school entry laws. Since student noncompliance with the law required school exclusion, we sought to evaluate the law's effects on student enrollment and absenteeism, and school workloads related to its implementation. In November 2019, we sent an electronic survey to NYS (excluding New York City) schools. Due to the COVID-19 pandemic, outreach was curtailed in March 2020 with 525 (14%) of 3,759 eligible schools responding. To account for non-response, results were analyzed using inverse probability weighting. After weighting, 39% (95% CI: 34%, 44%) of schools reported enrollment changes and 31% (95% CI: 26%, 36%) of schools reported absenteeism related to the law. In addition, 95% (95% CI: 93%, 98%) of schools reported holding meetings and/or preparing correspondence about the law, spending a mean of 14 (95% CI: 11, 18) hours on these communication efforts. Schools in the highest pre-mandate nonmedical exemption tertile (vs. lowest) were more likely to report enrollment and absenteeism changes, and higher workloads. While our results should be interpreted with caution, changes in student enrollment, absenteeism, and school workloads may represent important considerations for policymakers planning similar legislation.

Acute and Postacute COVID-19 Outcomes Among Immunologically Naive Adults During Delta vs Omicron Waves.

Importance: The US arrival of the Omicron variant led to a rapid increase in SARS-CoV-2 infections. While numerous studies report characteristics of Omicron infections among vaccinated individuals or persons with previous infection, comprehensive data describing infections among adults who are immunologically naive are lacking. Objectives: To examine COVID-19 acute and postacute clinical outcomes among a well-characterized cohort of unvaccinated and previously uninfected adults who contracted SARS-CoV-2 during the Omicron (BA.1/BA.2) surge, and to compare outcomes with infections that occurred during the Delta wave. Design, Setting, and Participants: This prospective multisite cohort study included community-dwelling adults undergoing high-resolution symptom and virologic monitoring in 8 US states between June 2021 and September 2022. Unvaccinated adults aged 30 to less than 65 years without an immunological history of SARS-CoV-2 who were at high risk of infection were recruited. Participants were followed for up to 48 weeks, submitting regular COVID-19 symptom surveys and nasal swabs for SARS-CoV-2 polymerase chain reaction (PCR) testing. Data were analyzed from May to October 2022. Exposures: Omicron (BA.1/BA.2 lineages) vs Delta SARS-CoV-2 infection, defined as a positive PCR test result that occurred during a period when the variant represented at least 50% of circulating SARS-CoV-2 variants in the participant's geographic region. Main Outcomes and Measure(s): The main outcomes examined were the prevalence and severity of acute (≤28 days after onset) and postacute (≥5 weeks after onset) symptoms. Results: Among 274 participants who were immunologically naive (mean [SD] age, 49 [9.7] years; 186 [68%] female; 19 [7%] Hispanic participants; 242 [88%] White participants), 166 (61%) contracted SARS-CoV-2. Of these, 137 infections (83%) occurred during the Omicron-predominant period and 29 infections (17%) occurred during the Delta-predominant period. Asymptomatic infections occurred among 7% (95% CI, 3%-12%) of Omicron-wave infections and 0% (95% CI, 0%-12%) of Delta-wave infections. Health care use among individuals with Omicron-wave infections was 79% (95% CI, 43%-92%) lower relative to individuals with Delta-wave infections (P = .001). Compared with individuals infected during the Delta wave, individuals infected during the Omicron wave also experienced a 56% (95% CI, 26%-74%, P = .004) relative reduction in the risk of postacute symptoms and a 79% (95% CI, 54%-91%, P < .001) relative reduction in the rate of postacute symptoms. Conclusions and Relevance: These findings suggest that among adults who were previously immunologically naive, few Omicron-wave (BA.1/BA.2) and Delta-wave infections were asymptomatic. Compared with individuals with Delta-wave infections, individuals with Omicron-wave infections were less likely to seek health care and experience postacute symptoms.

Short-Term Mortality Associated with Outpatient Vascular Access Restoration Procedures.

This study confirms the safety of endovascular interventions for thrombosis of hemodialysis access in outpatient and office-based settings.Risk of death in the week after vascular access procedure was not associated with hemodialysis access type (fistula versus graft).

Acute and Post-Acute COVID-19 Outcomes Among Immunologically Naïve Adults During Delta Versus Omicron Waves.

Importance: The U.S. arrival of the Omicron variant led to a rapid increase in SARS-CoV-2 infections. While numerous studies report characteristics of Omicron infections among vaccinated individuals and/or persons with a prior history of infection, comprehensive data describing infections among immunologically naïve adults is lacking. Objective: To examine COVID-19 acute and post-acute clinical outcomes among a well-characterized cohort of unvaccinated and previously uninfected adults who contracted SARS-CoV-2 during the Omicron (BA.1/BA.2) surge, and to compare outcomes with infections that occurred during the Delta wave. Design: A prospective cohort undergoing high-resolution symptom and virologic monitoring between June 2021 and September 2022. Setting: Multisite recruitment of community-dwelling adults in 8 U.S. states. Participants: Healthy, unvaccinated adults between 30 to 64 years of age without an immunological history of SARS-CoV-2 who were at high-risk of infection were recruited. Participants were followed for up to 48 weeks, submitting regular COVID-19 symptom surveys and nasal swabs for SARS-CoV-2 PCR testing. Exposures: Omicron (BA.1/BA.2 lineages) versus Delta SARS-CoV-2 infection, defined as a positive PCR that occurred during a period when the variant represented ≥50% of circulating SARS-CoV-2 variants in the participant's geographic region. Main Outcomes and Measures: The main outcomes examined were the prevalence and severity of acute (≤28 days post-onset) and post-acute (≥5 weeks post-onset) symptoms. Results: Among 274 immunologically naïve participants, 166 (61%) contracted SARS-CoV-2. Of these, 137 (83%) and 29 (17%) infections occurred during the Omicron- and Delta-predominant periods, respectively. Asymptomatic infections occurred among 6.7% (95% CI: 3.1%, 12.3%) of Omicron cases and 0.0% (95% CI: 0.0%, 11.9%) of Delta cases. Healthcare utilization among Omicron cases was 79% (95% CI: 43%, 92%, P =0.001) lower relative to Delta cases. Relative to Delta, Omicron infections also experienced a 56% (95% CI: 26%, 74%, P =0.004) and 79% (95% CI: 54%, 91%, P <0.001) reduction in the risk and rate of post-acute symptoms, respectively. Conclusions and Relevance: These findings suggest that among previously immunologically naïve adults, few Omicron (BA.1/BA.2) and Delta infections are asymptomatic, and relative to Delta, Omicron infections were less likely to seek healthcare and experience post-acute symptoms.

Revisiting the 2014-15 Disneyland measles outbreak and its influence on pediatric vaccinations.

The 2014-15 Disneyland measles outbreak that began at the California theme park in December 2014 sparked an international conversation regarding measles, vaccine hesitancy, and vaccine policies. The outbreak capped a year with the highest number of measles cases reported in two decades and came amidst increasing trends in nonmedical vaccine exemptions in California and elsewhere. Because of its sensational story line and spread among unvaccinated populations, the outbreak received a high level of media coverage that focused on vaccine hesitancy as a primary driver of the outbreak. This media coverage and the ostensible public support for vaccines that followed led some to hypothesize that the outbreak might have a "Disneyland effect," or a positive influence on the uptake of pediatric measles vaccine. This article reviews the facts of the outbreak and its context, and explores the evidence for the Disneyland outbreak causing an influence on U.S. pediatric vaccine-related beliefs and behaviors.

Trends in the uptake of pediatric measles-containing vaccine in the United States: A Disneyland effect?

BACKGROUND: The measles outbreak that began in December 2014 at the California Disneyland theme park in the United States (U.S.) received a high amount of media attention. Media attention can influence health-related behaviors. We investigated the effect of the Disneyland outbreak on measles-containing vaccine (MCV) uptake among U.S. children. METHODS: We used 2012-2017 National Immunization Survey-Child (NIS-Child) data to examine MCV uptake among U.S. children by 19 months of age. We classified MCV coverage among birth cohorts as exposed based on age at the time of the outbreak. A difference-in-differences design with adjustment for categorical birth cohort was implemented in base models to estimate the exposure effect on the outcomes, ≥1-dose MCV coverage or age at first MCV dose, with pneumococcal conjugate vaccination as a control. Primary analyses included this model adjusted for geographic region, maternal education, race/ethnicity, household income, and insurance status, and an exposure-interaction term with maternal education. All analyses included sampling weights. RESULTS: The study population represented 34,471,357 children. In base models, the Disneyland outbreak was associated with a 1.0% (95% CI: 0.2%, 1.8%) increase in ≥1-dose MCV coverage and a 6.6 (95% CI: 4.8, 8.5)-day decrease in MCV administration age. In primary analyses, the outbreak was associated with a 3.9% (95% CI: 3.1%, 4.8%) increase in ≥1-dose MCV coverage among children of college-educated mothers, and a 3.2% (95% CI: 0.6%, 5.9%) decrease among children of mothers earning less than a high school degree. Decreases in MCV administration age ranging from 5.9 (95% CI: 3.3, 8.5) to 9.1 (95% CI: 6.8, 11.4) days were observed across maternal education categories. CONCLUSIONS: The Disneyland outbreak was associated with differential effects on MCV coverage by maternal education and decreases in MCV administration age among U.S. children. These findings may provide useful insights to inform methods to address pediatric MCV undervaccination.

High Community SARS-CoV-2 Antibody Seroprevalence in a Ski Resort Community, Blaine County, Idaho, US. Preliminary Results.

Community-level seroprevalence surveys are needed to determine the proportion of the population with previous SARS-CoV-2 infection, a necessary component of COVID-19 disease surveillance. In May, 2020, we conducted a cross-sectional seroprevalence study of IgG antibodies for nucleocapsid of SARS-CoV-2 among the residents of Blaine County, Idaho, a ski resort community with high COVID-19 attack rates in late March and Early April (2.9% for ages 18 and older). Participants were selected from volunteers who registered via a secure web link, using prestratification weighting to the population distribution by age and gender within each ZIP Code. Participants completed a survey reporting their demographics and symptoms; 88% of volunteers who were invited to participate completed data collection survey and had 10 ml of blood drawn. Serology was completed via the Abbott Architect SARS-CoV-2 IgG immunoassay. Primary analyses estimated seroprevalence and 95% credible intervals (CI) using a hierarchical Bayesian framework to account for diagnostic uncertainty. Stratified models were run by age, sex, ZIP Code, ethnicity, employment status, and a priori participant-reported COVID-19 status. Sensitivity analyses to estimate seroprevalence included base models with post-stratification for ethnicity, age, and sex, with or without adjustment for multi-participant households. IgG antibodies to the virus that causes COVID-19 were found among 22.7% (95% CI: 20.1%, 25.5%) of residents of Blaine County. Higher levels of antibodies were found among residents of the City of Ketchum 34.8% (95% CI 29.3%, 40.5%), compared to Hailey 16.8% (95%CI 13.7%, 20.3%) and Sun Valley 19.4% (95% 11.8%, 28.4%). People who self-identified as not believing they had COVID-19 had the lowest prevalence 4.8% (95% CI 2.3%, 8.2%). The range of seroprevalence after correction for potential selection bias was 21.9% to 24.2%. This study suggests more than 80% of SARS-CoV-2 infections were not reported. Although Blaine County had high levels of SARS-CoV-2 infection, the community is not yet near the herd immunity threshold.

Evaluation of SARS-CoV-2 neutralization assays for antibody monitoring in natural infection and vaccine trials.

Determinants of protective immunity against SARS-CoV-2 infection require the development of well-standardized, reproducible antibody assays to be utilized in concert with clinical trials to establish correlates of risk and protection. This need has led to the appearance of a variety of neutralization assays used by different laboratories and companies. Using plasma samples from COVID-19 convalescent individuals with mild-to-moderate disease from a localized outbreak in a single region of the western US, we compared three platforms for SARS-CoV-2 neutralization: assay with live SARS-CoV-2, pseudovirus assay utilizing lentiviral (LV) and vesicular stomatitis virus (VSV) packaging, and a surrogate ELISA test. Vero, Vero E6, HEK293T cells expressing human angiotensin converting enzyme 2 (hACE2), and TZM-bl cells expressing hACE2 and transmembrane serine protease 2 (TMPRSS2) were evaluated. Live-virus and LV-pseudovirus assay with HEK293T cells showed similar geometric mean titers (GMTs) ranging 141-178, but VSV-pseudovirus assay yielded significantly higher GMT (310 95%CI 211-454; p < 0.001). Fifty percent neutralizing dilution (ND50) titers from live-virus and all pseudovirus assay readouts were highly correlated (Pearson r = 0.81-0.89). ND50 titers positively correlated with plasma concentration of IgG against SARS-CoV-2 spike and receptor binding domain (RBD) ( r = 0.63-0.89), but moderately correlated with nucleoprotein IgG ( r = 0.46-0.73). There was a moderate positive correlation between age and spike (Spearman's rho=0.37, p=0.02), RBD (rho=0.39, p=0.013) and nucleoprotein IgG (rho=0.45, p=0.003). ND80 showed stronger correlation with age than ND50 (ND80 rho=0.51 (p=0.001), ND50 rho=0.28 (p=0.075)). Our data demonstrate high concordance between cell-based assays with live and pseudotyped virions.

Determinants of under-immunization and cumulative time spent under-immunized in a Quebec cohort.

BACKGROUND: Under-immunization refers to a state of sub-optimal protection against vaccine preventable diseases. Vaccine coverage for age may not capture intentional or non-intentional spacing of vaccines in the recommended provincial immunization guidelines. We aimed to identify factors associated with coverage and under-immunization and to determine the number of days during which children were under-immunized during their first 24months of life. METHODS: Secondary analysis of children ≤3years recruited through active surveillance for gastroenteritis from three Quebec pediatric emergency departments from 2012 to 2014. Vaccination status for children at least 24months of age was determined using provincial immunization guidelines. Cumulative days under-immunized were calculated for DTaP-VPI-Hib, PCV, MMR, and Men-C-C. Factors associated with up-to-date (UTD) status at 24months of life and for under-immunization ≥6months were analyzed using logistic regression. RESULTS: Of 246 eligible children, 180 (73%) were UTD by 24months of life. The mean cumulative days under-immunized for MMR was 107days, for PCV 209days, for Men-C-C 145days, and for DTaP-VPI-Hib 227days. Overall, 149 children (60%) experienced delay for at least 1 vaccine. Factors associated with both an UTD status at 24months and concurrently associated with being under-immunization ≥6months, included timely initiation of immunization (OR=5.85; 95% CI: 2.80-12.22) and (OR=0.13; 95% CI: 0.07-0.24), failure to co-administer 18-month vaccines (OR=0.15; 95% CI: 0.10-0.21) and (OR=3.29; 95% CI: 2.47-4.39), and having a household with ≥3 children under 18years ((OR=0.50; 0.28-0.86) and (OR=2.99; 1.45-6.22), respectively. CONCLUSION: Paired with an unexpected low level of coverage at 24months of life, the majority of our cohort also experienced a state of under-immunization for a least one vaccine. Estimates of coverage do not capture intentional or non-intentional gaps in protection from vaccine preventable illnesses. Timely preventive care should be prioritized.

Temporal Changes in Pediatric Gastroenteritis after Rotavirus Vaccination in Quebec.

BACKGROUND: Rotavirus and norovirus are among the leading causes of pediatric gastroenteritis. We examined the relative burden of pediatric gastroenteritis by etiology and compared the clinical severity of rotavirus and norovirus cases after the November 2011 implementation of publicly funded rotavirus vaccination program in Quebec. METHODS: Prospective, active surveillance for acute gastroenteritis among children aged 8 weeks to less than 3 years of age was implemented at 3 hospitals. Participant demographics, clinical histories and stools were collected; stools were tested for rotavirus, norovirus and sapovirus. Risk and absolute differences of several clinical severity outcomes were compared by etiology with adjustment for patient age. RESULTS: From February 2012 to May 2014, 734 eligible active surveillance patients were recruited, and stools from 705 (96.0%) were tested and included in study analyses. Of these, 20.4% [95% confidence interval (CI): 16.5-24.3%] were rotavirus positive and 25.5% (95% CI: 21.3-29.8%) were norovirus positive, representing a difference of 5.1% (95% CI: 0.1-10.1%). When stratified by year, rotavirus and norovirus prevalence were similar from June 2012 to May 2013, but rotavirus prevalence was 21.4% (95% CI: 14.3-28.5%) lower than norovirus from June 2013 to May 2014. On average, rotavirus patients were more likely to be febrile, dehydrated, hospitalized and report more diarrheal episodes at the height of illness in comparison with norovirus patients of the same age. CONCLUSIONS: Norovirus infections were more prevalent than rotavirus infections among pediatric gastroenteritis cases hospitalized or seeking emergency care. Rotavirus cases were, on average, more clinically severe than norovirus cases among participants of the same age.