Comparison of measles IgG enzyme immunoassays (EIA) versus plaque reduction neutralization test (PRNT) for measuring measles serostatus: a systematic review of head-to-head analyses of measles IgG EIA and PRNT.

BACKGROUND: As countries move towards or achieve measles elimination status, serosurveillance is an important public health tool. However, a major challenge of serosurveillance is finding a feasible, accurate, cost-effective, and high throughput assay to measure measles antibody concentrations and estimate susceptibility in a population. We conducted a systematic review to assess, characterize, and - to the extent possible - quantify the performance of measles IgG enzyme-linked assays (EIAs) compared to the gold standard, plaque reduction neutralization tests (PRNT). METHODS: We followed the PRISMA statement for a systematic literature search and methods for conducting and reporting systematic reviews and meta-analyses recommended by the Cochrane Screening and Diagnostic Tests Methods Group. We identified studies through PubMed and Embase electronic databases and included serologic studies detecting measles virus IgG antibodies among participants of any age from the same source population that reported an index (any EIA or multiple bead-based assays, MBA) and reference test (PRNT) using sera, whole blood, or plasma. Measures of diagnostic accuracy with 95% confidence intervals (CI) were abstracted for each study result, where reported. RESULTS: We identified 550 unique publications and identified 36 eligible studies for analysis. We classified studies as high, medium, or low quality; results from high quality studies are reported. Because most high quality studies used the Siemens Enzygnost EIA kit, we generate individual and pooled diagnostic accuracy estimates for this assay separately. Median sensitivity of the Enzygnost EIA was 92.1% [IQR = 82.3, 95.7]; median specificity was 96.9 [93.0, 100.0]. Pooled sensitivity and specificity from studies using the Enzygnost kit were 91.6 (95%CI: 80.7,96.6) and 96.0 (95%CI: 90.9,98.3), respectively. The sensitivity of all other EIA kits across high quality studies ranged from 0% to 98.9% with median (IQR) = 90.6 [86.6, 95.2]; specificity ranged from 58.8% to 100.0% with median (IQR) = 100.0 [88.7, 100.0]. CONCLUSIONS: Evidence on the diagnostic accuracy of currently available measles IgG EIAs is variable, insufficient, and may not be fit for purpose for serosurveillance goals. Additional studies evaluating the diagnostic accuracy of measles EIAs, including MBAs, should be conducted among diverse populations and settings (e.g., vaccination status, elimination/endemic status, age groups).

In Elimination Settings, Measles Antibodies Wane After Vaccination but Not After Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: We conducted a systematic review to assess whether measles humoral immunity wanes in previously infected or vaccinated populations in measles elimination settings. METHODS: After screening 16 822 citations, we identified 9 articles from populations exposed to wild-type measles and 16 articles from vaccinated populations that met our inclusion criteria. RESULTS: Using linear regression, we found that geometric mean titers (GMTs) decreased significantly in individuals who received 2 doses of measles-containing vaccine (MCV) by 121.8 mIU/mL (95% confidence interval [CI], -212.4 to -31.1) per year since vaccination over 1 to 5 years, 53.7 mIU/mL (95% CI, -95.3 to -12.2) 5 to 10 years, 33.2 mIU/mL (95% CI, -62.6 to -3.9), 10 to 15 years, and 24.1 mIU/mL (95% CI, -51.5 to 3.3) 15 to 20 years since vaccination. Decreases in GMT over time were not significant after 1 dose of MCV or after infection. Decreases in the proportion of seropositive individuals over time were not significant after 1 or 2 doses of MCV or after infection. CONCLUSIONS: Measles antibody waning in vaccinated populations should be considered in planning for measles elimination.

SARS-CoV-2 Seroprevalence Survey Estimates Are Affected by Anti-Nucleocapsid Antibody Decline.

We analyzed 21 676 residual specimens from Ontario, Canada collected March-August 2020 to investigate the effect of antibody decline on SARS-CoV-2 seroprevalence estimates. Testing specimens orthogonally using Abbott (anti-nucleocapsid) and Ortho (anti-spike) assays, seroprevalence estimates were 0.4%-1.4%, despite ongoing disease activity. The geometric mean concentration (GMC) of antibody-positive specimens decreased over time (P = .015), and GMC of antibody-negative specimens increased over time (P = .0018). Association between the 2 tests decreased each month (P < .001), suggesting anti-nucleocapsid antibody decline. Lowering Abbott antibody index cutoff from 1.4 to 0.7 resulted in a 16% increase in positive specimens.

Assessment of population infection with SARS-CoV-2 in Ontario, Canada, March to June 2020.

BackgroundSerosurveys for SARS-CoV-2 aim to estimate the proportion of the population that has been infected.AimThis observational study assesses the seroprevalence of SARS-CoV-2 antibodies in Ontario, Canada during the first pandemic wave.MethodsUsing an orthogonal approach, we tested 8,902 residual specimens from the Public Health Ontario laboratory over three time periods during March-June 2020 and stratified results by age group, sex and region. We adjusted for antibody test sensitivity/specificity and compared with reported PCR-confirmed COVID-19 cases.ResultsAdjusted seroprevalence was 0.5% (95% confidence interval (CI): 0.1-1.5) from 27 March-30 April, 1.5% (95% CI: 0.7-2.2) from 26-31 May, and 1.1% (95% CI: 0.8-1.3) from 5-30 June 2020. Adjusted estimates were highest in individuals aged ≥ 60 years in March-April (1.3%; 95% CI: 0.2-4.6), in those aged 20-59 years in May (2.1%; 95% CI: 0.8-3.4) and in those aged ≥ 60 years in June (1.6%; 95% CI: 1.1-2.1). Regional seroprevalence varied, and was highest for Toronto in March-April (0.9%; 95% CI: 0.1-3.1), for Toronto in May (3.2%; 95% CI: 1.0-5.3) and for Toronto (1.5%; 95% CI: 0.9-2.1) and Central East in June (1.5%; 95% CI: 1.0-2.0). We estimate that COVID-19 cases detected by PCR in Ontario underestimated SARS-CoV-2 infections by a factor of 4.9.ConclusionsOur results indicate low population seroprevalence in Ontario, suggesting that public health measures were effective at limiting the spread of SARS-CoV-2 during the first pandemic wave.

Parallel reorganization of protein function in the spindle checkpoint pathway through evolutionary paths in the fitness landscape that appear neutral in laboratory experiments.

Regulatory networks often increase in complexity during evolution through gene duplication and divergence of component proteins. Two models that explain this increase in complexity are: 1) adaptive changes after gene duplication, such as resolution of adaptive conflicts, and 2) non-adaptive processes such as duplication, degeneration and complementation. Both of these models predict complementary changes in the retained duplicates, but they can be distinguished by direct fitness measurements in organisms with short generation times. Previously, it has been observed that repeated duplication of an essential protein in the spindle checkpoint pathway has occurred multiple times over the eukaryotic tree of life, leading to convergent protein domain organization in its duplicates. Here, we replace the paralog pair in S. cerevisiae with a single-copy protein from a species that did not undergo gene duplication. Surprisingly, using quantitative fitness measurements in laboratory conditions stressful for the spindle-checkpoint pathway, we find no evidence that reorganization of protein function after gene duplication is beneficial. We then reconstruct several evolutionary intermediates from the inferred ancestral network to the extant one, and find that, at the resolution of our assay, there exist stepwise mutational paths from the single protein to the divergent pair of extant proteins with no apparent fitness defects. Parallel evolution has been taken as strong evidence for natural selection, but our results suggest that even in these cases, reorganization of protein function after gene duplication may be explained by neutral processes.

Autism spectrum disorders in adult outpatients with obsessive compulsive disorder in the UK.

OBJECTIVES: Patients with obsessive compulsive disorder (OCD) frequently show traits of autism spectrum disorders (ASD). This is one of the first studies to explore the clinical impact of the overlap between OCD and ASD as a categorical diagnosis. METHODS: A cross-sectional survey in 73 adult outpatients with DSM-IV OCD. Autistic traits were measured using the Autism-Spectrum Quotient (AQ). A clinical estimate ASD diagnosis was made by interview using DSM-IV-TR criteria. OCD patients with and without autistic traits or ASD were compared on demographic and clinical parameters and level of OCD treatment-resistance based on treatment history. RESULTS: Thirty-four (47%) patients scored above the clinical threshold on the AQ (≥26) and 21 (27.8%) met diagnostic criteria for ASD. These diagnoses had not been made before. Patients with autistic traits showed a borderline significant increase in OCD symptom-severity (Yale-Brown Obsessive Compulsive Scale (Y-BOCS); p = .054) and significantly increased impairment of insight (Brown Assessment of Beliefs Scale; p = .01). There was a positive correlation between AQ and Y-BOCS scores (p = .04), but not with OCD treatment resistance. CONCLUSION: There is a high prevalence of previously undiagnosed ASD in patients with OCD. ASD traits are associated with greater OCD symptom-severity and poor insight.

Population immunity to varicella in Canada: A Canadian Immunization Research Network (CIRN) study.

INTRODUCTION: The incidence of varicella in Canada has decreased by almost 99% since vaccination was introduced. However, variation in the timing and eligibility of vaccination programs across the country has resulted in some cohorts being under-vaccinated and therefore potentially susceptible to infection. METHODS: We used nationally representative specimens from the Biobank of Statistics Canada's Canadian Health Measures Survey (CHMS) as well as residual specimens from Ontario collected between 2009-2014 to estimate population immunity across age-groups and geography, and identify any groups at increased risk of varicella infection. RESULTS: The weighted proportion of specimens with antibody levels above the threshold of protection was 93.6% (95% CI: 92.4, 95.0). Protection was lowest among those aged 3-5 years (54.3%; 95% CI: 47.3, 61.4), but increased with age. Individuals born outside Canada had more than twice the odds of varicella susceptibility than those born in Canada (aOR: 2.7; 95% CI: 1.4, 5.0; p = 0.004). There were no differences by sex or geography within Canada, and there were no statistically significant differences when Ontario CHMS sera were compared to Ontario residual sera, apart from in participants aged 12-19 year age-group, for whom the CHMS estimate (91.2%; 95% CI: 86.7, 95.7) was significantly higher (p = 0.03) than that from residual specimens (85.9%, 95% CI: 81.1, 90.8). DISCUSSION: Varicella immunity in Canada is changing. Children appear to have low population immunity, placing them at greater risk of infection and at increased risk of severe disease as they age. Our results underscore the importance of performing periodic serosurveys to monitor further population immunity changes as the proportion of vaccine-eligible birth-cohorts increases, and to continually assess the risk of outbreaks.

Immunity of Canadians and risk of epidemics workshop - Conference report.

On November 18-19, 2019, the Immunity of Canadians and Risk of Epidemics (iCARE) Network convened a workshop in Toronto, Ontario, Canada. The objectives of the workshop were to raise the profile of sero-epidemiology in Canada, discuss best practice and methodological innovations, and strategize on the future direction of sero-epidemiology work in Canada. In this conference report, we describe the presentations and discussions from the workshop, and comment on the impact of the COVID-19 pandemic on serosurveillance initiatives, both in Canada and abroad.

Uptake of pertussis immunization in pregnancy and determinants of vaccination in Toronto, Canada.

INTRODUCTION: Pertussis causes significant morbidity and mortality in infants aged <6 months. Maternal pertussis vaccination during pregnancy has been recommended in Canada since 2018 to reduce these negative outcomes. In the absence of routine immunization coverage data, our objective was to evaluate uptake in Toronto, Canada. METHODS: We recruited mother-infant pairs at The Hospital for Sick Children, Toronto, between 2018 and 2020. We performed logistic regression to examine associations between demographics and self-reported pertussis vaccination. RESULTS: 76/243 mothers (31.3 %) reported receiving pertussis vaccination during their most recent pregnancy. Odds of receiving vaccination more than doubled with each 1-year increase in year of pregnancy (aOR: 2.2; 95 % CI: 1.3, 3.6; p < 0.01) and among those born in Canada as compared to those not (aOR: 2.0; 95 % CI: 1.1, 3.6; p = 0.02) CONCLUSION: Uptake of pertussis vaccination during pregnancy in Ontario has increased in recent years, however coverage remains lower than desirable.

Maternal varicella antibodies in children aged less than one year: Assessment of antibody decay.

OBJECTIVES: To investigate maternal antibody levels to varicella in infants <12 months of age in Ontario, Canada. STUDY DESIGN: In this study, we included specimens from infants <12 months of age, born at ≥37 weeks gestational age, who had sera collected at The Hospital for Sick Children (Toronto, Canada) between 2014-2016. We tested sera using a glycoprotein-based enzyme-linked immunosorbent assay (gpELISA). We measured varicella susceptibility (antibody concentration <150mIU/mL) and mean varicella antibody concentration, and assessed the probability of susceptibility and concentration between one and 11 months of age using multivariable logistic regression and Poisson regression. RESULTS: We found that 32% of 196 included specimens represented infants susceptible to varicella at one month of age, increasing to nearly 80% at three months of age. At six months of age, all infants were susceptible to varicella and the predicted mean varicella antibody concentration declined to 62 mIU/mL (95% confidence interval 40, 84), well below the threshold of protection. CONCLUSIONS: We found that varicella maternal antibody levels wane rapidly in infants, leaving most infants susceptible by four months of age. Our findings have implications for the timing of first dose of varicella-containing vaccine, infection control measures, and infant post-exposure prophylaxis recommendations.

Does a humoral correlate of protection exist for SARS-CoV-2? A systematic review.

BACKGROUND: A correlate of protection (CoP) is an immunological marker associated with protection against infection. Despite an urgent need, a CoP for SARS-CoV-2 is currently undefined. OBJECTIVES: Our objective was to review the evidence for a humoral correlate of protection for SARS-CoV-2, including variants of concern. METHODS: We searched OVID MEDLINE, EMBASE, Global Health, Biosis Previews and Scopus to January 4, 2022 and pre-prints (using NIH iSearch COVID-19 portfolio) to December 31, 2021, for studies describing SARS-CoV-2 re-infection or breakthrough infection with associated antibody measures. Two reviewers independently extracted study data and performed quality assessment. RESULTS: Twenty-five studies were included in our systematic review. Two studies examined the correlation of antibody levels to VE, and reported values from 48.5% to 94.2%. Similarly, several studies found an inverse relationship between antibody levels and infection incidence, risk, or viral load, suggesting that both humoral immunity and other immune components contribute to protection. However, individual level data suggest infection can still occur in the presence of high levels of antibodies. Two studies estimated a quantitative CoP: for Ancestral SARS-CoV-2, these included 154 (95% confidence interval (CI) 42, 559) anti-S binding antibody units/mL (BAU/mL), and 28.6% (95% CI 19.2, 29.2%) of the mean convalescent antibody level following infection. One study reported a CoP for the Alpha (B.1.1.7) variant of concern of 171 (95% CI 57, 519) BAU/mL. No studies have yet reported an Omicron-specific CoP. CONCLUSIONS: Our review suggests that a SARS-CoV-2 CoP is likely relative, where higher antibody levels decrease the risk of infection, but do not eliminate it completely. More work is urgently needed in this area to establish a SARS-CoV-2 CoP and guide policy as the pandemic continues.

Population immunity to measles in Canada using Canadian Health Measures survey data - A Canadian Immunization Research Network (CIRN) study.

We aimed to determine population immunity to measles in Canada, and to assess the risk of future outbreaks. We tested 11,176 sera from Cycles 2 (2009-2011) and 3 (2011-2013) cohorts from the biobank of Statistics Canada's Canadian Health Measures Survey (CHMS) using the BioPlex 2220 MMRV IgG assay. We then tested all BioPlex negative and equivocal samples using a more sensitive Plaque Reduction Neutralization Test (PRNT). We determined the weighted proportion of positive, equivocal, and negative samples by age, sex, region and whether individuals were born in Canada. We found that 90.0% (95% confidence interval (CI): 88.2, 91.9) of samples were positive, 4.5% (95% CI: 3.4, 5.5) were equivocal and 5.5% (95% CI: 4.3, 6.7) were negative. Individuals in the 12-19 year age band had the lowest proportion positive at 78.7% (95% CI: 74.2, 83.2) and the highest proportion of positive samples was found in those 60-79 years (99.6%, 95% CI: 99.3, 99.9). Seropositivity was consistently <90% across a broad range of pediatric and adult age bands (6-39 years). We found that a slightly higher proportion of females were positive (91.9%, 95% CI: 90.1, 93.6) compared to males (88.3%, 95% CI: 85.8, 90.7). When taking into account interaction between age and born in Canada status, we found individuals born in Canada aged 19 and under were less susceptible (OR = 0.6 (95% CI: 0.4, 0.95)) compared to those born outside Canada whereas, those aged 20 and over were more susceptible (OR = 1.7 (95% CI: 1.1, 2.8)). Our findings indicate that measles immunity in Canada is below the 95% immunity threshold required to sustain measles elimination, underscoring the importance of maintaining high vaccine coverage to prevent future measles outbreaks and sustain Canada's elimination status.

The Association between Risk Factors and Chronic Obstructive Pulmonary Disease in Canada: A Cross-sectional Study Using the 2014 Canadian Community Health Survey.

BACKGROUND: The global prevalence of chronic obstructive pulmonary disease (COPD) is expected to increase and the disease is projected to be the third leading cause of death by the year 2020. The purpose of this study was to measure the prevalence and determine the risk factors for COPD in Canada. METHODS: This is a cross-sectional study that uses data from a nationally generalizable survey, the Canadian Community Health Survey, 2014. There were 46,924 respondents aged 35 years or older. Uni- and multi-variate logistic regression analyses were conducted to determine the risk factors associated with COPD. RESULTS: The overall prevalence of COPD in the surveyed population was 5.69%. Results from multivariate logistic regression showed that COPD was significantly higher among individuals who were 65 years or older (odds ratio [OR] =4.43; 95% confidence interval [CI]: 3.69-5.33), current smokers (OR = 5.13; 95% CI: 4.43-5.95), underweight or obese by body mass index ([OR = 1.81; 95% CI: 1.38-2.38] and [OR = 1.58; 95% CI: 1.41-1.77], respectively), with a total personal income of <$20,000 (OR = 3.67; 95% CI: 2.95-4.57,), and some postsecondary education (OR = 1.42; 95% CI: 1.14-1.76). Immigrants were less likely to have COPD compared to Canadian-born respondents (OR = 0.67; 95% CI: 0.57-0.79). CONCLUSIONS: COPD is a growing and serious public health issue in Canada. The risk factors identified in this study provide useful targets to health promotion and education initiatives, health-care providers, and public health organizations to decrease the prevalence of COPD.