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.

Differences in mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech) SARS-CoV-2 vaccine immunogenicity among patients undergoing dialysis.

BACKGROUND: Differences in immunogenicity between mRNA SARS-CoV-2 vaccines have not been well characterized in patients undergoing dialysis. We compared the serologic response in patients undergoing maintenance hemodialysis after vaccination against SARS-CoV-2 with BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). METHODS: We conducted a prospective observational cohort study at 2 academic centres in Toronto, Canada, from Feb. 2, 2021, to July 20, 2021, which included 129 and 95 patients who received the BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines, respectively. We measured SARS-CoV-2 immunoglobulin G antibodies to the spike protein (anti-spike), receptor binding domain (anti-RBD) and nucleocapsid protein (anti-NP) at 6-7 and 12 weeks after the second dose of vaccine and compared those levels with the median convalescent serum antibody levels from 211 controls who were previously infected with SARS-CoV-2. RESULTS: At 6-7 weeks after 2-dose vaccination, we found that 51 of 70 patients (73%) who received BNT162b2 and 83 of 87 (95%) who received mRNA-1273 attained convalescent levels of anti-spike antibody (p < 0.001). In those who received BNT162b2, 35 of 70 (50%) reached the convalescent level for anti-RBD compared with 69 of 87 (79%) who received mRNA-1273 (p < 0.001). At 12 weeks after the second dose, anti-spike and anti-RBD levels were significantly lower in patients who received BNT162b2 than in those who received mRNA-1273. For anti-spike, 70 of 122 patients (57.4%) who received BNT162b2 maintained the convalescent level versus 68 of 71 (96%) of those who received mRNA-1273 (p < 0.001). For anti-RBD, 47 of 122 patients (38.5%) who received BNT162b2 maintained the anti-RBD convalescent level versus 45 of 71 (63%) of those who received mRNA-1273 (p = 0.002). INTERPRETATION: In patients undergoing hemodialysis, mRNA-1273 elicited a stronger humoral response than BNT162b2. Given the rapid decline in immunogenicity at 12 weeks in patients who received BNT162b2, a third dose is recommended in patients undergoing dialysis as a primary series, similar to recommendations for other vulnerable populations.

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.

A Call for Caution in Use of Pertussis Vaccine Effectiveness Studies to Estimate Waning Immunity: A Canadian Immunization Research Network Study.

BACKGROUND: Vaccine effectiveness (VE) studies provide essential evidence on waning vaccine-derived immunity, a major threat to pertussis control. We evaluated how study design affects estimates by comparing 2 case-control studies conducted in Ontario, Canada. METHODS: We compared results from a test-negative design (TND) with a frequency-matched design (FMD) case-control study using pertussis cases from 2005-2015. In the first study, we identified test-negative controls from the public health laboratory that diagnosed cases and, in the second, randomly selected controls from patients attending the same physicians that reported cases, frequency matched on age and year. We compared characteristics of cases and controls using standardized differences. RESULTS: In both designs, VE estimates for the early years postimmunization were consistent with clinical trials (TND, 84%; FMD, 89% at 1-3 years postvaccination) but diverged as time since last vaccination increased (TND, 41%; FMD, 74% by 8 years postvaccination). Overall, we observed lower VE and faster waning in the TND than the FMD. In the TND but not FMD, controls differed from cases in important confounders, being younger, having more comorbidities, and higher healthcare use. Differences between the controls of each design were greater than differences between cases. TND controls were more likely to be unvaccinated or incompletely vaccinated than FMD controls (P < .001). CONCLUSIONS: The FMD adjusted better for healthcare-seeking behavior than the TND. Duration of protection from pertussis vaccines is unclear because estimates vary by study design. Caution should be exercised by experts, researchers, and decision makers when evaluating evidence on optimal timing of boosters.

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.

What Is the Evidence to Support a Correlate of Protection for Measles? A Systematic Review.

BACKGROUND: Many studies assume that the serologic correlate of protection from measles disease is 120 mIU/mL. We systematically reviewed the literature to examine the evidence supporting this correlate of protection. METHODS: We searched peer-reviewed and gray literature for articles reporting a measles correlate of protection. We excluded studies focusing on special populations, infants aged <9 months, and those using animal models or nonstandard vaccines or administration routes. We extracted and synthesized data from full-text articles that met inclusion criteria. RESULTS: We screened 14 778 articles and included 5 studies in our review. The studies reported either preexposure antibody concentrations of individuals along with a description of symptoms postexposure, or the proportion of measles cases that had preexposure antibody concentrations above a threshold of immunity specified by the authors. Some studies also described secondary antibody responses upon exposure. The variation in laboratory methods between studies made comparisons difficult. Some of the studies that assumed 120 mIU/mL as a correlate of protection identified symptomatic individuals with preexposure titers exceeding this threshold. CONCLUSIONS: Our findings underscore the scant data upon which the commonly used 120 mIU/mL measles threshold of protection is based, suggesting that further work is required to characterize the measles immunity threshold.

Asymptomatic Infection and Transmission of Pertussis in Households: A Systematic Review.

We conducted a systematic review to describe the frequency of mild, atypical, and asymptomatic infection among household contacts of pertussis cases and to explore the published literature for evidence of asymptomatic transmission. We included studies that obtained and tested laboratory specimens from household contacts regardless of symptom presentation and reported the proportion of cases with typical, mild/atypical, or asymptomatic infection. After screening 6789 articles, we included 26 studies. Fourteen studies reported household contacts with mild/atypical pertussis. These comprised up to 46.2% of all contacts tested. Twenty-four studies reported asymptomatic contacts with laboratory-confirmed pertussis, comprising up to 55.6% of those tested. Seven studies presented evidence consistent with asymptomatic pertussis transmission between household contacts. Our results demonstrate a high prevalence of subclinical infection in household contacts of pertussis cases, which may play a substantial role in the ongoing transmission of disease. Our review reveals a gap in our understanding of pertussis transmission.

Calibration and Evaluation of Quantitative Antibody Titers for Varicella-Zoster Virus by Use of the BioPlex 2200.

Most commercially available enzyme immunoassay-based methods have limited sensitivity to detect antibody responses to varicella-zoster virus (VZV) in vaccinated individuals, who produce lower antibody levels than those with natural infection. However, more sensitive methods are either not commercially available or less amenable to high-throughput testing. The BioPlex 2200 measles, mumps, rubella, and varicella (MMRV) IgG assay (Bio-Rad Laboratories, Hercules, CA) is an automated high-throughput platform based on the microsphere Luminex technology that measures antibodies against measles, mumps, rubella, and varicella viruses simultaneously. Although it has U.S. Food and Drug Administration approval as a qualitative diagnostic test for measles, mumps, rubella, and varicella virus immunity, in this study, we have validated the assay to produce quantitative titers (off label) against the VaccZyme VZV glycoprotein (VZVgp) low-level IgG kit (The Binding Site Ltd., Birmingham, UK) using the World Health Organization international standard. Here, we show that the BioPlex 2200 MMRV IgG assay has sensitivity superior to that of the Zeus enzyme-linked immunosorbent assay (ELISA) VZV IgG assay (Zeus Diagnostics, Branchburg, NJ). Using receiver operating characteristic (ROC) analysis and adjusting the cutoff levels, we improved the sensitivity of the quantitative BioPlex 2200 MMRV IgG assay to 97.4%, while maintaining 100% specificity.

The evolving nature of Bordetella pertussis in Ontario, Canada, 2009-2017: strains with shifting genotypes and pertactin deficiency.

This study examined the evolving nature of Bordetella pertussis in Ontario, Canada, by characterizing isolates for their genotypes and expression of pertactin (PRN). From 2009 to 2017, 413 B. pertussis were cultured from pertussis cases at the Public Health Ontario Laboratory. Their genotypes were determined by partial gene sequence analysis of their virulence and (or) vaccine antigens: filamentous haemagglutinin, PRN, fimbriae 3, and pertussis toxin, including the promoter region. Expression of PRN was measured by Western immunoblot. Two predominant genotypes, ST-1 and ST-2, were found throughout the study and were responsible for 47.5% and 46.3% of all case isolates, respectively. The prevalence of ST-1 appeared to fluctuate from 80.3% in 2009 to 20.0% in 2014 and 58.5% in 2017, while the prevalence of ST-2 changed from 18.4% in 2009 to 80.0% in 2014 and 26.2% in 2017. A PRN-deficient strain was first noted in 2011 (16.7%), and its prevalence increased to 70.8% in 2016 but decreased to 46.2% in 2017. More ST-2 (46.6%) than ST-1 (16.8%) strains were associated with PRN deficiency. Newer ST-21 and ST-22 found in 2015-2017 were uniformly PRN deficient. The impact of the evolving nature of B. pertussis on disease epidemiology requires further longitudinal studies.

Evaluation of the ability of standardized supports to improve public health response to syndromic surveillance for respiratory diseases in Canada.

BACKGROUND: Despite widespread implementation of syndromic surveillance systems within public health agencies, previous studies of the implementation and use of these systems have indicated that the functions and responses taken in response to syndromic surveillance data vary widely according to local context and preferences. The objective of the Syndromic Surveillance Evaluation Study was to develop and implement standardized supports in local public health agencies in Ontario, Canada, and evaluate the ability of these supports to affect actions taken as part of public health communicable disease control programs. METHODS: Local public health agencies (LPHA) in Ontario, which used syndromic surveillance based on emergency department visits for respiratory disease, were recruited and randomly allocated to the study intervention or control group. The intervention group health agencies received standardized supports in terms of a standardized aberrant event detection algorithm and a response protocol dictating steps to investigate and assess the public health significance of syndromic surveillance alerts. The control group continued with their pre-existing syndromic surveillance infrastructure and processes. Outcomes were assessed using logbooks, which collected quantitative and qualitative information about alerts received, investigation steps taken, and public health responses. The study was conducted prospectively for 15 months (October 2013 to February 2015). RESULTS: Fifteen LPHAs participated in the study (n = 9 intervention group, n = 6 control group). A total of 1,969 syndromic surveillance alerts were received by all LPHAs. Variations in the types and amount of responses varied by LPHA, in particularly differences were noted by the size of the health unit. Smaller health units had more challenges to both detect and mount a response to any alerts. LPHAs in the control group were more likely to declare alerts to have public health significance and to initiate any action. Regression models using repeated measures showed an interaction between the year (Year 1 versus Year 2) and the intervention as well as an interaction between year and sustained nature of the alert. Both of these were linked to the control health units reporting more "watchful waiting". CONCLUSIONS: This study raises questions about the effectiveness of using standardized protocols to improve the performance of syndromic surveillance in a decentralized public health system. Despite efforts to create standardized protocols and engage public health agencies in the process, no significant differences in the effective use of syndromic alerts were observed beyond year 1. It also raises questions about the minimum capacity of the agency and minimum population size that are required for an effective response.

Effectiveness of pertussis vaccination and duration of immunity.

BACKGROUND: A resurgence of pertussis cases among both vaccinated and unvaccinated people raises questions about vaccine effectiveness over time. Our objective was to study the effectiveness of the pertussis vaccine and characterize the effect of waning immunity and whole-cell vaccine priming. METHODS: We used the test-negative design, a nested case-control study with test-negative individuals as controls. We constructed multivariable logistic regression models to estimate odds ratios (ORs). Vaccine effectiveness was calculated as (1 - OR) × 100. We assessed waning immunity by calculating the odds of developing pertussis per year since last vaccination and evaluated the relative effectiveness of priming with acellular versus whole-cell vaccine. RESULTS: Between Dec. 7, 2009, and Mar. 31, 2013, data on 5867 individuals (486 test-positive cases and 5381 test-negative controls) were available for analysis. Adjusted vaccine effectiveness was 80% (95% confidence interval [CI] 71% to 86%) at 15-364 days, 84% (95% CI 77% to 89%) at 1-3 years, 62% (95% CI 42% to 75%) at 4-7 years and 41% (95% CI 0% to 66%) at 8 or more years since last vaccination. We observed waning immunity with the acellular vaccine, with an adjusted OR for pertussis infection of 1.27 (95% CI 1.20 to 1.34) per year since last vaccination. Acellular, versus whole-cell, vaccine priming was associated with an increased odds of pertussis (adjusted OR 2.15, 95% CI 1.30 to 3.57). INTERPRETATION: We observed high early effectiveness of the pertussis vaccine that rapidly declined as time since last vaccination surpassed 4 years, particularly with acellular vaccine priming. Considering whole-cell vaccine priming and/or boosters in pregnancy to optimize pertussis control may be prudent.

Global travel patterns and risk of measles in Ontario and Quebec, Canada: 2007-2011.

BACKGROUND: In 2011 the largest measles outbreak in North America in a decade occurred in Quebec, Canada with over 700 cases. In contrast, measles activity in neighbouring province Ontario remained low (8 cases). Our objective was to determine the extent to which the difference could be explained by differing travel patterns. METHODS: We explored the relationship between measles cases over 2007-2011, by importation classification, in Quebec and Ontario in relation to global travel patterns to each province using an ecological approach. Global measles exposure was estimated by multiplying the monthly traveler volume for each country of origin into Quebec or Ontario by the yearly measles incidence rate for the corresponding country. Visual inspection of temporal figures and calculation of Pearson correlation coefficients were performed. RESULTS: Global measles exposure was similar in Ontario and Quebec. In Quebec, there was a nearly perfectly linear relationship between annual measles cases and its global measles exposure index over 2007-2011 (r = 0.99, p = 0.001). In contrast, there was a non-significant association in Ontario. The 2011 rise in Quebec's index was largely driven by a dramatic increase in measles activity in France the same year. CONCLUSIONS: Global measles activity was associated with measles epidemiology in Quebec. Global measles exposure risk is higher in Ontario than Quebec. Differences in measles epidemiology between Ontario and Quebec from 2007-2011 are not explained by greater exposure in Quebec. A combination of alternative factors may be responsible, including differences in population susceptibility.

Cross-Canada Variability in Blood Donor SARS-CoV-2 Seroprevalence by Social Determinants of Health.

We compared the seroprevalence of SARS-CoV-2 anti-nucleocapsid antibodies in blood donors across Canadian regions in 2021. The seroprevalence was the highest in Alberta and the Prairies, and it was so low in Atlantic Canada that few correlates were observed. Being male and of young age were predictive of seropositivity. Racialization was associated with higher seroprevalence in British Columbia and Ontario but not in Alberta and the Prairies. Living in a materially deprived neighborhood predicted higher seroprevalence, but it was more linear across quintiles in Alberta and the Prairies, whereas in British Columbia and Ontario, the most affluent 60% were similarly low and the most deprived 40% similarly elevated. Living in a more socially deprived neighborhood (more single individuals and one parent families) was associated with lower seroprevalence in British Columbia and Ontario but not in Alberta and the Prairies. These data show striking variability in SARS-CoV-2 seroprevalence across regions by social determinants of health. IMPORTANCE Canadian blood donors are a healthy adult population that shows clear disparities associated with racialization and material deprivation. This underscores the pervasiveness of the socioeconomic gradient on SARS-CoV-2 infections in Canada. We identify regional differences in the relationship between SARS-CoV-2 seroprevalence and social determinants of health. Cross-Canada studies, such as ours, are rare because health information is under provincial jurisdiction and is not available in sufficient detail in national data sets, whereas other national seroprevalence studies have insufficient sample sizes for regional comparisons. Ours is the largest seroprevalence study in Canada. An important strength of our study is the interpretation input from a public health team that represented multiple Canadian provinces. Our blood donor seroprevalence study has informed Canadian public health policy at national and provincial levels since the start of the SARS-CoV-2 pandemic.

Hepatitis B Blood Donor Screening Data: An Under-Recognized Resource for Canadian Public Health Surveillance.

Hepatitis B surveillance is essential to achieving Canada's goal of eliminating hepatitis B by 2030. Hepatitis B rates, association of infection with vaccine age-eligibility, and risk factors were analyzed among 1,401,603 first-time Canadian blood donors from 2005 to 2020. Donors were classified as having likely chronic or likely resolved/occult infections based on hepatitis B surface antigen, anti-hepatitis B core antigen, and hepatitis B nucleic acid test results. Likely chronically infected and control donors (ratio 1:4) participated in risk-factor interviews. The 2019 rate of likely chronic infection was 61.9 per 100,000 (95% CI 46.5-80.86) and 1449.5 per 100,000 for likely resolved/occult infections (95% CI 1370.7-1531.7). Likely chronic infections were higher in males (OR 3.2; 95% CI 2.7-3.7) and the vaccine-ineligible birth cohort (OR 1.9; 95% CI 1.6-2.2). The main risk factors were living with someone who had hepatitis (OR 12.5; 95% CI 5.2-30.0) and ethnic origin from a high-prevalence country (OR 8.4; 95% CI 5.9-11.9). Undiagnosed chronic hepatitis B may be more prevalent in Canada than currently determined by traditional passive hepatitis B reporting. Blood donor data can be useful in informing hepatitis B rates and evaluating vaccination programs in Canada.