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Background A major goal of coronavirus disease 2019 (COVID-19) vaccination is to prevent severe outcomes (hospitalizations and deaths). We estimated the effectiveness of messenger RNA (mRNA) and ChAdOx1 COVID-19 vaccines against severe outcomes in 4 Canadian provinces between December 2020 and September 2021. Methods We conducted this multiprovincial, retrospective, test-negative study among community-dwelling adults aged ≥18 years in Ontario, Quebec, British Columbia, and Manitoba using linked provincial databases and a common study protocol. Multivariable logistic regression was used to estimate province-specific vaccine effectiveness against COVID-19 hospitalization and/or death. Estimates were pooled using random-effects models. Results We included 2 508 296 tested participants, with 31 776 COVID-19 hospitalizations and 5842 deaths. Vaccine effectiveness was 83% after a first dose and 98% after a second dose against both hospitalization and death (separately). Against severe outcomes, effectiveness was 87% (95% confidence interval [CI], 71%–94%) ≥84 days after a first dose of mRNA vaccine, increasing to 98% (95% CI, 96%–99%) ≥112 days after a second dose. Vaccine effectiveness against severe outcomes for ChAdOx1 was 88% (95% CI, 75%–94%) ≥56 days after a first dose, increasing to 97% (95% CI, 91%–99%) ≥56 days after a second dose. Lower 1-dose effectiveness was observed for adults aged ≥80 years and those with comorbidities, but effectiveness became comparable after a second dose. Two doses of vaccines provided very high protection for both homologous and heterologous schedules and against Alpha, Gamma, and Delta variants. Conclusions Two doses of mRNA or ChAdOx1 vaccine provide excellent protection against severe outcomes.

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Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; P < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; P < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; P = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ (P < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test–negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities.

Background Changes to pertussis vaccination programmes can have impacts on disease burden that should be estimated independently from factors such as age- and period-related trends. We used age-period-cohort (APC) models to explore pertussis incidence in Manitoba over a 25-year period (1992–2017). Methods We identified all laboratory-confirmed cases of pertussis from Manitoba’s Communicable Diseases Database and calculated age-standardized incidence rates. We used APC models to investigate trends in pertussis incidence. Results During the study period, 2479 cases were reported. Age-standardized rates were highest during a large outbreak in 1994 (55 cases/100 000 person-years), with much lower peaks in 1998, 2012 and 2016. We saw strong age and cohort effects in the APC models, with a steady decrease in incidence with increasing age and increased risk in the cohort born between 1980 and 1995. Conclusions The highest risk for pertussis was consistently in young children, regardless of birth cohort or time period. The 1981 programme change to an adsorbed whole-cell pertussis vaccine with low effectiveness resulted in reduced protection in the 1981–95 birth cohort and contributed to the largest outbreak of disease during the 25-year study period.

BackgroundA major goal of COVID-19 vaccination is to prevent severe outcomes (hospitalizations and deaths). We estimated the effectiveness of mRNA and ChAdOx1 COVID-19 vaccines against severe outcomes in four Canadian provinces between December 2020 and September 2021.MethodsWe conducted this multiprovincial retrospective test-negative study among community-dwelling adults aged ≥18 years in Ontario, Quebec, British Columbia, and Manitoba using linked provincial databases and a common study protocol. Multivariable logistic regression was used to estimate province-specific vaccine effectiveness against COVID-19 hospitalization and/or death. Estimates were pooled using random effects models.ResultsWe included 2,508,296 tested subjects, with 31,776 COVID-19 hospitalizations and 5,842 deaths. Vaccine effectiveness was 83% after a first dose, and 98% after a second dose, against both hospitalization and death (separately). Against severe outcomes (hospitalization or death), effectiveness was 87% (95%CI: 71%–94%) ≥84 days after a first dose of mRNA vaccine, increasing to 98% (95%CI: 96%–99%) ≥112 days after a second dose. Vaccine effectiveness against severe outcomes for ChAdOx1 was 88% (95%CI: 75%–94%) ≥56 days after a first dose, increasing to 97% (95%CI: 91%–99%) ≥56 days after a second dose. Lower one-dose effectiveness was observed for adults aged ≥80 years and those with comorbidities, but effectiveness became comparable after a second dose. Two doses of vaccines provided very high protection for both homologous and heterologous schedules, and against Alpha, Gamma, and Delta variants.ConclusionsTwo doses of mRNA or ChAdOx1 vaccines provide excellent protection against severe outcomes of hospitalization and death.

Summary Background Seasonal influenza vaccine (SIV) uptake among US adults aged 65 years or older remains suboptimal and stagnant. Further, there is growing concern around racial and ethnic disparities in uptake. We aimed to assess racial and ethnic disparities in overall SIV and in high-dose vaccine (HDV) uptake among Medicare beneficiaries during the 2015–16 influenza season and sought to identify possible mediators for observed disparities. Methods We did a historical record-linkage cohort study using Medicare (a US national health insurance programme) databases, which included all older adults (≥65 years) enrolled in Medicare during the study period (July 1, 2015, to June 30, 2016). We excluded beneficiaries of Medicare Part C (managed care offered by private companies), and residents of long-term care facilities. The primary outcome was SIV receipt during the study period, classified into receipt of HDV and standard-dose vaccines (SDVs, representing all other SIVs). SIV uptake probabilities were estimated using competing-risk survival analysis methods. Mediation analyses were done to investigate potential mediators of the association between race and ethnicity and uptake. Findings During the study period, of 26·5 million beneficiaries in the study cohort, 47·4% received a SIV, 52·7% of whom received HDV. Compared with white beneficiaries (49·4%), Hispanic (29·1%), Black (32·6%), and Asian (47·6%) beneficiaries were less likely to be vaccinated and, when vaccinated, were less likely to receive HDV (37·8% for Hispanic people, 41·1% for Black people, and 40·3% for Asian people, compared with 53·8% of white people who received HDV). Among those vaccinated, after accounting for region, income, chronic conditions, and health-care use, minority groups were 26–32% less likely to receive HDV, relative to white people (odds ratio [OR] 0·68 [95% CI 0·68–0·69] for Black people; OR 0·71 [0·71–0·72] for Asian people; and OR 0·74 [0·73–0·74] for Hispanic people). Interpretation Substantial racial and ethnic disparities in SIV uptake among Medicare beneficiaries aged 65 years or older are evident. New legislative, fiscal, and educational strategies are urgently needed to address these inequities. Funding Sanofi Pasteur.

INTRODUCTION Vaccination is considered to be the most practical and effective preventative measure against influenza. It is highly recommended for population subgroups most at risk of developing complications, including pregnant women. However, seasonal influenza vaccine uptake remains suboptimal among pregnant women, even in jurisdictions with universal vaccination. We summarized the evidence on the determinants of seasonal influenza vaccine uptake during pregnancy to better understand factors that influence vaccine uptake among pregnant women. MATERIAL AND METHODS We systematically searched MEDLINE, Embase and CINAHL from January 2000 to February 2020 for publications in English reporting on sociodemographic and/or health-related determinants of seasonal influenza vaccine uptake during pregnancy. Two reviewers independently included studies. One reviewer extracted data and assessed study quality, and another reviewer checked extracted data and study quality assessments for errors. Disagreements were resolved through consensus, or a third reviewer. We meta-analyzed using the inverse variance, random-effects method, and reported the odds ratios (OR) and 95% confidence intervals (CI). RESULTS From 1663 retrieved citations, we included 36 studies. The following factors were associated with increased seasonal influenza vaccine uptake: Older age (20 studies: OR 1.13, 95% CI 1.07-1.20), being nulliparous (13 studies: OR 1.26, 95% CI 1.15-1.38), married (8 studies: OR 1.11, 95% CI 1.07-1.15), employed (4 studies: OR 1.13, 95% CI 1.02-1.24), a non-smoker (8 studies: OR 1.25, 95% CI 1.04-1.51) and having prenatal care (3 studies: OR 3.36, 95% CI 2.25-5.02), a chronic condition (6 studies: OR 1.30, 95% CI 1.17-1.44), been previously vaccinated (9 studies: OR 4.88, 95% CI 3.14-7.57) and living in a rural area (9 studies: OR 1.09, 95% CI 1.05-1.14). Compared with being black, being white was also associated with increased seasonal influenza vaccine uptake (11 studies: OR 1.30, 95% CI 1.20-1.41). CONCLUSIONS The evidence suggests that several sociodemographic and health-related factors may determine seasonal influenza vaccination in pregnancy, and that parity, history of influenza vaccination, prenatal care and comorbidity status may be influential.

Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; P < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; P < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; P = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ (P < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test–negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities.

We investigated the role of individual, community and vaccinator characteristics in mediating racial/ethnic disparities in the uptake of differentiated influenza vaccines (DIVs; including high-dose, adjuvanted, recombinant and cell-based vaccines). We included privately-insured (commercial and Medicare Advantage) ≥65 years-old community-dwelling health plan beneficiaries in the US with1 year of continuous coverage and who received ≥1 influenza vaccine during the study period (July 2014-June 2018). Of 2.8 million distinct vaccination claims, 60% were for DIVs; lower if received in physician offices (49%) compared to pharmacies/facilities (74%). Among those vaccinated in physician offices, non-whites had lower odds of receiving a DIV if they lived in a non-minority county (0.77;95%CI 0.75-0.80) and even lower odds if they lived in a minority county (0.62;0.60-0.63). Differences in education, household income, medical history, community and vaccinator characteristics did not fully explain the disparities. Similar patterns emerged for vaccinations in pharmacies/facilities, although disparities disappeared altogether after controlling for socio-economic and vaccinator characteristics. When vaccinated in physician offices, minority county residents were less likely to receive a DIV, especially for non-whites (0.72;0.67-0.78). These disparities disappeared for whites, but not for non-whites, after controlling for community and vaccinator characteristics. We found an alarming level of inequity in DIV vaccine uptake among fully insured older adults that could not be fully explained by differences in sociodemographic, medical, community, and vaccinator characteristics. New strategies are urgently needed to address these inequities.

BACKGROUND: Abnormal microbiota composition induced by prenatal exposure to antibiotics has been proposed as a potential contributor to the development of attention-deficit/hyperactivity disorder (ADHD). We examined the association between prenatal antibiotic exposure and risk of ADHD. METHODS: We conducted a population-based retrospective cohort study of children born in Manitoba, Canada, between 1998 and 2017 and their mothers. We defined exposure as the mother having filled 1 or more antibiotic prescriptions during pregnancy. The outcome was diagnosis of ADHD in the offspring, as identified in administrative databases. We estimated hazard ratios (HRs) using Cox proportional hazards regression in the overall cohort, in a separate cohort matched on high-dimensional propensity scores and in a sibling cohort. RESULTS: In the overall cohort, consisting of 187 605 children, prenatal antibiotic dispensation was associated with increased risk of ADHD (HR 1.22, 95% confidence interval [CI] 1.18–1.26). Similar results were observed in the matched cohort of 129 674 children (HR 1.20, 95% CI 1.15–1.24) but not in the sibling cohort (HR 1.06, 95% CI 0.99–1.13). Two negative-control analyses indicated a positive association with ADHD despite the lack of a reasonable biological mechanism, which suggested that the observed association between prenatal antibiotic dispensation and risk of ADHD was likely due to confounding. INTERPRETATION: In our study, prenatal antibiotic exposure was not associated with increased risk of ADHD in children. Although the risk was higher in the overall and matched cohorts, it was likely overestimated because of unmeasured confounding. Future studies are warranted to examine other factors affecting microbiota composition in association with risk of ADHD.

Background In children with epilepsy, fever and illness are known triggers for seizure; therefore, clinicians and parents could be concerned that immunization-induced inflammation and fever could also trigger seizures. We sought to estimate the risk of emergency department (ED) visit or hospitalization for epilepsy/seizure and all causes after immunization in children younger than 7 years of age with epilepsy. Methods We conducted a self-controlled case series of children diagnosed with epilepsy before their 7th birthday and immunized from 2005 to 2015 in Ontario (population 14.2 million) and Manitoba (population 1.3 million), Canada, using administrative healthcare data. We estimated the age- and season-adjusted relative incidence (aRI) of epilepsy/seizure-related and all-cause ED visits/hospitalizations during various risk periods 0-28 days after inactivated and live immunizations versus a control period 35-83 days postimmunization. Estimates from each province were analyzed separately and then combined in a random-effects meta-analysis. Results The combined risk of epilepsy/seizure-related hospitalization/ED visit was increased 0-2 days after inactivated vaccines (aRI = 1.5, 95% confidence interval: 1.1-1.9) and 7-10 days after live vaccines (aRI = 1.9, 1.4-2.7). For all-cause ED visit/hospitalization, the combined aRI estimate was 0.9 (0.8-1.2) 0-2 days after inactivated vaccines and 1.3 (1.1-1.5) 7-10 days after live vaccines. Conclusions The risk of epilepsy/seizure-related ED visit/hospitalization was modestly increased among children with epilepsy during peak periods of fever and inflammation following inactivated and live vaccines. These risks must be balanced against the risk of complications from vaccine-preventable diseases.

Introduction Despite improved understanding of the risks of influenza and better vaccines for older patients, influenza vaccination rates remain subpar, including in high-risk groups such as older adults, and demonstrate significant racial and ethnic disparities. Methods This study considers demographic, clinical, and geographic correlates of influenza vaccination among Medicare Fee-for-Service (FFS) beneficiaries in 2015–2016 and maps the data on a geographic information system (GIS) at the zip code level. Results Analyses confirm that only half of the senior beneficiaries evidenced a claim for receiving an inactivated influenza vaccine (IIV), with significant disparities observed among black, Hispanic, rural, and poorer beneficiaries. More extensive disparities were observed for the high-dose (HD) vaccine, with its added protection for older populations and confirmed economic benefit. Most white beneficiaries received HD; no non-white subgroup did so. Mapping of the data confirmed subpar vaccination in vulnerable populations with wide variations at the zip code level. Conclusion Urgent and targeted efforts are needed to equitably increase IIV rates, thus protecting the most vulnerable populations from the negative health impact of influenza as well as the tax-paying public from the Medicare costs from failing to do so. Electronic supplementary material The online version of this article (10.1007/s12325-020-01324-y) contains supplementary material, which is available to authorized users.

Background Adults 65 years and older (seniors) experience more complications following influenza infection than younger adults. We estimated the relative vaccine effectiveness (rVE) of a trivalent high dose (HD-IIV3) versus an adjuvanted trivalent influenza vaccine (aIIV3) in seniors for respiratory-related hospitalizations. Methods We conducted a retrospective cohort study using claims data from Optum’s Clinformatics® Data Mart to compare outcome rates between seniors who received HD-IIV3 versus aIIV3 during the 2016/17 and 2017/18, predominantly A/H3N2 respiratory seasons. Rates were adjusted for demographic characteristics, comorbid conditions, previous influenza vaccination, and geography. We used the previous event rate ratio (PERR) approach to address bias by time-fixed unmeasured confounders. Results We identified 842,282 HD-IIV3 and 34,157 aIIV3 recipients for the 2016/17 season and 1,058,638 HD-IIV3 and 189,636 aIIV3 recipients for the 2017/18 season. The pooled rVE of HD-IIV3 versus aIIV3 for respiratory-related hospitalizations over both seasons was 12% (95% confidence interval: 3.3%–20%); 13% (−6.4% to 32%) for the 2016/17 season and 12% (2.1%–21%) for the 2017/18 season. Conclusions Pooled over two predominantly A/H3N2 respiratory seasons, HD-IIV3 was associated with fewer respiratory hospital admissions than aIIV3 in senior members of large national managed health care company in the U.S.

Background Unmeasured confounders are commonplace in observational studies conducted using real-world data. Prior event rate ratio (PERR) adjustment is a technique shown to perform well in addressing such confounding. However, it has been demonstrated that, in some circumstances, the PERR method actually increases rather than decreases bias. In this work, we seek to better understand the robustness of PERR adjustment. Methods We begin with a Bayesian network representation of a generalized observational study, which is subject to unmeasured confounding. Previous work evaluating PERR performance used Monte Carlo simulation to calculate joint probabilities of interest within the study population. Here, we instead use a Bayesian networks framework. Results Using this streamlined analytic approach, we are able to conduct probabilistic bias analysis (PBA) using large numbers of combinations of parameters and thus obtain a comprehensive picture of PERR performance. We apply our methodology to a recent study that used the PERR in evaluating elderly-specific high-dose (HD) influenza vaccine in the US Veterans Affairs population. That study obtained an HD relative effectiveness of 25% (95% CI: 2%-43%) against influenza- and pneumonia-associated hospitalization, relative to standard-dose influenza vaccine. In this instance, we find that the PERR-adjusted result is more like to underestimate rather than to overestimate the relative effectiveness of the intervention. Conclusions Although the PERR is a powerful tool for mitigating the effects of unmeasured confounders, it is not infallible. Here, we develop some general guidance for when a PERR approach is appropriate and when PBA is a safer option.

Background Pertussis persists in Manitoba despite the universal availability of pertussis vaccines. Recent cases have included previously vaccinated individuals, raising concerns about declining vaccine effectiveness (VE). We measured pertussis VE and duration of protection using Manitoba’s provincial immunization and communicable disease registries. Methods Using a nested case-control design, individuals with laboratory-confirmed pertussis in Manitoba diagnosed between April 1, 1992, and March 31, 2015, were matched to up to five population-based controls on age, gender, geography, and case physician or number of physician visits. Conditional logistic regression was used to estimate VE against pertussis for both the whole-cell (wP) and acellular (aP) pertussis vaccines. Duration of protection was assessed using time since last dose. Results Data on 534 eligible cases and 2614 controls were available for analysis. The adjusted VE estimate for aP-containing vaccines was 85% (95%CI: 74–91%); VE was 89% (66–96%) one to three years after the last vaccination. The adjusted VE of wP-containing vaccines was –15% (–91–31%) during a large outbreak in 1994 and 1995 compared to 35% (–26–66%) during non-outbreak years. Conclusions Our estimates suggest that the aP vaccine was effective in preventing pertussis since its introduction in Manitoba. VE was lower during a large outbreak, highlighting the importance of separately analyzing outbreak periods when estimating pertussis VE over time.

Better CLL patient survival has been reported for specialized CLL clinics/hematologists (compared to other CLL patients). It is possible that improved survival is driven by a better prognosis of referred patients.We used logistic regression to calculate the odds ratios (ORs) and 95 % confidence intervals 95 %CIs) of the association between patient characteristics and CLL referral of all persons diagnosed in 2005-2016 with a pathologically-confirmed CLL or SLL.Two-thirds of 1293 patients were referred to the CLL clinic. Referred patients were younger (16 % vs 44 % were 80 +) and in better health (47 % vs 56 % with a chronic diseases) than non-referred patients. Referral increased over time: in 2005-2010, about 60 % of patients were referred; in 2011-2016, this increased to 76 %. Gender did not affect referral (the OR for females is 1.0, 95 %CI 0.8-1.2), but age played a major role; CLL patients diagnosed at age 80 + were less likely to be referred than patients diagnosed 60, 0.2 (0.1-0.3).Because referral to Manitoba's specialized CLL clinic is associated with age and the patient's overall health before referral, one should be careful in interpreting differences in outcomes between CLL patients based on referral status alone.

Two influenza vaccines are licensed in the U.S. exclusively for the 65 years and older population: a trivalent inactivated high-dose influenza vaccine (HD-IIV3) and a trivalent inactivated adjuvanted influenza vaccine (aIIV3). In a recent publication, we estimated a relative vaccine effectiveness (rVE) of HD-IIV3 vs. aIIV3 of 12% (95% CI: 3.3–20%) for influenza-related hospitalizations using a retrospective study design, but did not report the number of prevented hospitalizations nor the associated avoided cost. In this paper we report estimations for both. Methods: Leveraging the rVE of a cohort study over two influenza seasons (2016/17 and 2017/18), we collected cost data for healthcare provided to the same study population. Vaccine costs were obtained from the Medicare pricing schedule. Our economic assessment compared cost of vaccination and hospital care for patients experiencing acute respiratory or cardiovascular illness. Results: We analyzed 1.9 million HD-IIV3 and 223,793 aIIV3 recipients. Average vaccine list prices were $46.23 for HD-IIV3 and $48.26 for aIIV3. The hospitalization rates for respiratory disease in HD-IIV3 and aIIV3 recipients were 187 (95% CI: 185–189) and 212 (195–231) per 10,000 persons-years, respectively. Attributing the average cost per hospitalization of $12,652 ($12,214–$13,090) to the difference in hospitalization rates, we estimate net savings of HD-IIV3 to be $34 ($10–$62) per recipient. Conclusion: Pooled over two predominantly A/H3N2 respiratory seasons, vaccination with HD-IIV3 was associated with lower hospitalization rates and associated costs compared to aIIV3 in senior members of a large national managed health care company in the U.S. Reduced hospitalizations affect healthcare utilization overall, and therefore other costly health outcomes.

Although pertussis vaccines have been widely used for many decades, a burden of illness persists. Resurgences in Ontario, Canada, have not been substantial in the past decade, but an outbreak of pertussis occurred in Toronto between 1 October 2005 and 31 March 2006. Previous Ontario studies found high vaccine effectiveness (VE) in the initial years post-immunization. In order to explore the impact of outbreaks and external factors on VE, we investigated pertussis VE during the period 2006-2008.We assessed pertussis VE using a frequency-matched case-control study for the period 1 March 2006 to 31 December 2008. We used logistic regression to estimate VE by age, time since last vaccination, and vaccination status according to the Ontario recommended schedule. We compared analyses including and excluding cases from Toronto, and to two recent Ontario pertussis VE studies.We included 1797 confirmed cases and 7188 matched controls. Most cases were under 4 years of age during the study period. Pertussis VE was 3.8% (95% CI: - 21.0, 24.0) in the period 15-364 days following the last pertussis vaccine dose, and increased with increasing time since vaccination. Pertussis VE in the first 15-364 days excluding Toronto increased to 57.1% (95% CI: 26.0, 75.1), but the trend of increasing VE with time since vaccination persisted. Although VE was higher in older (6-11 years) than younger (0-5 years) children, it was lower at 12-13 years than after 14 years.VE was lower in comparison with other studies conducted in Ontario, particularly in younger children. Various factors occurring during the study period may have influenced the results, including clinical testing of asymptomatic contacts, laboratory testing and methods and reporting practice, and a sensitive case definition. Further studies are needed to optimize methods for measuring VE to inform pertussis vaccine policy.RéSUMé: OBJECTIFS: Bien que les vaccins anticoquelucheux soient couramment utilisés depuis des dizaines d’années, la charge de morbidité de la coqueluche persiste. Sa réapparition en Ontario, au Canada, a été modérée au cours des 10 dernières années, mais une éclosion de coqueluche s’est produite à Toronto entre le 1

Objective To estimate the effectiveness of mRNA covid-19 vaccines against symptomatic infection and severe outcomes (hospital admission or death). Design Test negative design study. Setting Ontario, Canada between 14 December 2020 and 19 April 2021. Participants 324 033 community dwelling people aged ≥16 years who had symptoms of covid-19 and were tested for SARS-CoV-2. Interventions BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine. Main outcome measures Laboratory confirmed SARS-CoV-2 by reverse transcription polymerase chain reaction (RT-PCR) and hospital admissions and deaths associated with SARS-CoV-2 infection. Multivariable logistic regression was adjusted for personal and clinical characteristics associated with SARS-CoV-2 and vaccine receipt to estimate vaccine effectiveness against symptomatic infection and severe outcomes. Results Of 324 033 people with symptoms, 53 270 (16.4%) were positive for SARS-CoV-2 and 21 272 (6.6%) received at least one dose of vaccine. Among participants who tested positive, 2479 (4.7%) were admitted to hospital or died. Vaccine effectiveness against symptomatic infection observed ≥14 days after one dose was 60% (95% confidence interval 57% to 64%), increasing from 48% (41% to 54%) at 14-20 days after one dose to 71% (63% to 78%) at 35-41 days. Vaccine effectiveness observed ≥7 days after two doses was 91% (89% to 93%). Vaccine effectiveness against hospital admission or death observed ≥14 days after one dose was 70% (60% to 77%), increasing from 62% (44% to 75%) at 14-20 days to 91% (73% to 97%) at ≥35 days, whereas vaccine effectiveness observed ≥7 days after two doses was 98% (88% to 100%). For adults aged ≥70 years, vaccine effectiveness estimates were observed to be lower for intervals shortly after one dose but were comparable to those for younger people for all intervals after 28 days. After two doses, high vaccine effectiveness was observed against variants with the E484K mutation. Conclusions Two doses of mRNA covid-19 vaccines were observed to be highly effective against symptomatic infection and severe outcomes. Vaccine effectiveness of one dose was observed to be lower, particularly for older adults shortly after the first dose.

ObjectivesTo estimate the effectiveness of mRNA COVID-19 vaccines against symptomatic infection and severe outcomes.DesignWe applied a test-negative design study to linked laboratory, vaccination, and health administrative databases, and used multivariable logistic regression adjusting for demographic and clinical characteristics associated with SARS-CoV-2 and vaccine receipt to estimate vaccine effectiveness (VE) against symptomatic infection and severe outcomes.SettingOntario, Canada between 14 December 2020 and 19 April 2021.ParticipantsCommunity-dwelling adults aged ≥16 years who had COVID-19 symptoms and were tested for SARS-CoV-2.InterventionsPfizer-BioNTech’s BNT162b2 or Moderna’s mRNA-1273 vaccine.Main outcome measuresLaboratory-confirmed SARS-CoV-2 by RT-PCR; hospitalization/death associated with SARS-CoV-2 infection.ResultsAmong 324,033 symptomatic individuals, 53,270 (16.4%) were positive for SARS-CoV-2 and 21,272 (6.6%) received ≥1 vaccine dose. Among test-positive cases, 2,479 (4.7%) had a severe outcome. VE against symptomatic infection ≥14 days after receiving only 1 dose was 60% (95%CI, 57 to 64%), increasing from 48% (95%CI, 41 to 54%) at 14–20 days after the first dose to 71% (95%CI, 63 to 78%) at 35–41 days. VE ≥7 days after 2 doses was 91% (95%CI, 89 to 93%). Against severe outcomes, VE ≥14 days after 1 dose was 70% (95%CI, 60 to 77%), increasing from 62% (95%CI, 44 to 75%) at 14–20 days to 91% (95%CI, 73 to 97%) at ≥35 days, whereas VE ≥7 days after 2 doses was 98% (95%CI, 88 to 100%). For adults aged ≥70 years, VE estimates were lower for intervals shortly after receiving 1 dose, but were comparable to younger adults for all intervals after 28 days. After 2 doses, we observed high VE against E484K-positive variants.ConclusionsTwo doses of mRNA COVID-19 vaccines are highly effective against symptomatic infection and severe outcomes. Single-dose effectiveness is lower, particularly for older adults shortly after the first dose.

Several epidemiological studies have found an association between maternal antibiotics use during pregnancy and increased risk of certain cancer types, although conclusions differ between studies. We examined this association in a cohort study including 262 116 mother‐child pairs of Manitoba births between 1996 and 2013. Maternal antibiotics use during prepregnancy (6 months prior to pregnancy) and pregnancy periods was assessed. Children's cancer incidence was tracked up to the end of the follow‐up period (December 2015). We calculated incidence rate and used Cox regression to estimate adjusted hazard ratios (HRs). Antibiotics use during pregnancy was not associated with overall cancer (HR = 1.1, 95% confidence interval 0.9‐1.4), leukemias (1.3, 0.9‐1.8), or acute lymphocytic leukemia (1.1, 0.7‐1.6). The association between antibiotics use and overall cancer risk differed by trimester: 1.5 (1.1‐1.9) in the first, 0.8 (0.6‐1.0) in the second, and 1.1 (0.8‐1.5) in the third trimester. Further research is necessary to confirm the association between first‐trimester exposure and cancer risk after a better controlling of confounding factors.

To better understand the relationship between baseline immunoglobulin measurements and subsequent clinical outcomes in chronic lymphocytic leukemia (CLL), we performed a retrospective analysis on 660 patients with CLL (72%), monoclonal B-cell lymphocytosis (MBL) (13%), and small lymphocytic lymphoma (SLL) (14%), diagnosed between 2005 and 2014 at CancerCare Manitoba. Of 511 patients who had their first immunoglobulin level determined within 3 months of diagnosis, abnormal (either increased or decreased) immunoglobulin M (IgM), IgG, and IgA values were observed in 58% of patients with CLL, 27% of patients with MBL, and 20% of patients with SLL. Immunoglobulin deviances were similar for MBL and CLL Rai stage 0 and for SLL and Rai stages I and II; for CLL, IgG and IgA abnormalities occurred with increasing frequency with advancing Rai stage. In contrast, the frequency of IgM abnormalities was similar in all patient groups. IgA abnormalities significantly correlated with high β2-microglobulin (B2M) expression, whereas abnormal IgG and IgA levels were associated with the use of IGHV1-69, 3-21, and 3-49 subtypes. Increases in IgG or IgM were commonly associated with the presence of a CLL-type M-band, whereas oligoclonal bands were frequently observed with increased IgA levels. Although abnormal levels of IgG and IgA at diagnosis were independent predictors for future immunoglobulin replacement, only abnormal IgA levels were associated with shorter time to first treatment and overall survival. These findings indicate that both reduced and elevated levels of IgG and IgA at diagnosis are important and independent prognostic markers for infection in CLL, with IgA being more relevant as a marker of disease progression and survival.

Objective To compare the economic impact of high-dose trivalent (HD) versus standard-dose trivalent (SD) influenza vaccination on direct medical costs for cardio-respiratory hospitalizations in adults aged 65 years or older enrolled in the United States (US) Veteran’s Health Administration (VHA). Methods Leveraging a relative vaccine effectiveness study of HD versus SD over five respiratory seasons (2010/11 through 2014/15), we collected cost data for healthcare provided to the same study population both at VHA and through Medicare services. Our economic assessment compared the costs of vaccination and hospital care for patients experiencing acute cardio-vascular or respiratory illness. Results We analyzed 3.5 million SD and 158,636 HD person-seasons. The average cost of HD and SD vaccination was $23.48 (95% CI: $21.29 - $25.85) and $12.21 (95% CI: $11.49 - $13.00) per recipient, respectively, while the hospitalization rates for cardio-respiratory disease in HD and SD recipients were 0.114 (95% CI: 0.108–0.121) and 0.132 (95% CI: 0.132–0.133) per person-season, respectively. Attributing the average cost per hospitalization of $11,796 (95% CI: $11,685 - $11,907) to the difference in hospitalization rates, we estimated savings attributable to HD to be $202 (95% CI: $115 – $280) per vaccinated recipient. Conclusions For the five-season period of 2010/11 through 2014/15, HD influenza vaccination was associated with net cost savings due to fewer hospitalizations, and therefore lower direct medical costs, for cardio-respiratory disease as compared to SD influenza vaccination in the senior US VHA population.

Background: Recent studies have reported reduced risk of chronic lymphocytic leukemia (CLL) among statin users. However, the possibility that the effect of statins may differ by their chemical or pharmacodynamic properties has not been investigated. Methods: In this nested case-control study, all Manitobans aged ≥ 40 years when diagnosed with CLL (as a first cancer) from 1999 to 2014 (n=1,385) were matched (on gender, age, residence, and duration of insurance coverage) to cancer-free controls (n=6,841). Using conditional logistic regression, statin use was analyzed by individual statins and groups: hydrophilic, low-potency lipophilic (fluvastatin and lovastatin) and high-potency lipophilic statins. Results: Statin users constituted 27% and 28% of the CLL cases and controls. After adjusting for potential confounding by indication, patterns of healthcare utilization and use of other drugs, CLL incidence was not associated with use of hydrophilic (odds ratio: 1.08; 95% confidence interval: 0.86-1.34) or high-potency lipophilic statins (0.94; 0.79-1.11). Low-potency lipophilic statins were associated with a lower risk of CLL (0.64; 0.45-0.92), with stronger association (0.44; 0.22-0.88) observed with more regular use (half to full standard dose on average). Conclusions: We found an association between low-potency lipophilic statin use and reduced CLL risk, with a possible dose-response effect. Impact: While requiring replication in future studies, our findings suggest that the effect of statins on CLL risk may depend on their specific chemical or pharmacodynamic properties.

Background Resurgences of pertussis have occurred in several high-income countries, often linked to waning of immunity from acellular pertussis vaccines. The degree of waning observed has varied by study design and setting. In Ontario, pertussis has not shown a substantial resurgence in the past decade. The routine immunization schedule comprises three priming doses in infancy, toddler and pre-school doses, and an adolescent dose at 14–16 years of age. Methods We estimated pertussis vaccine effectiveness (VE) through a case-control study of 1335 cases statutorily reported to public health in Ontario and occurring between January 1, 2009 and March 31, 2015, compared with 5340 randomly selected population controls, frequency-matched by age, primary-care provider and year of diagnosis. Pertussis cases met provincial confirmed or probable case definitions. We used multivariable logistic regression to estimate crude and adjusted odds ratios (aOR). Results VE against pertussis was sustained between 92% (95% confidence interval (95%CI) 88–95%) in 2–3 year olds and 90% (95%CI: 80–95%) in 8–9 year olds, but fell rapidly to 49% (95%CI: 2–73%) in children 12–13 years of age. VE following the teenage booster given at 14–16 years in Ontario reached 76% (95%CI: 52–88%) in 14–16 year olds and 78% (95%CI: −31 to 96%) in those 16–22 years old. For children who were up-to-date with the immunization schedule, VE declined from 87% (95%CI: 84–90%) during the first year to 74% (95%CI: 63–82%) after 8 or more years following their last dose of immunization. Conclusions VE is high during the first decade of life but then falls rapidly. Protection is not fully restored by the teenage booster. Our findings are consistent with the localized outbreaks we observe in high school children and underline the importance of additional policies to protect infants.

OBJECTIVES: Autism spectrum disorders (ASD) are among the leading causes of disabilities in children. We examined the annual prevalence and incidence rate of ASD between 2004 and 2015 in children aged 1 to 5 years residing in Manitoba. METHODS: A population-based study was conducted using the Manitoba Population Research Data Repository. The study included children aged 1 to 5 years residing in Manitoba between 2004 and 2015. Standard identification algorithm was used to identify ASD cases from hospital abstracts and medical claims. Annual prevalence and incidence rates were calculated for the overall population and then stratified according to sex, region, and socio-economic status (SES). Multivariable negative binomial regression models, adjusted for sex, region, and SES, were used to examine changes in prevalence and incidence over study years. RESULTS: Among children aged 1 to 5 years, 1685 ASD cases were diagnosed between 2004 and 2015. The crude ASD prevalence increased from 0.46% in 2004 to 0.97% in 2015 (p = 0.002). The crude incidence rate increased from 0.16% in 2004 to 0.39% in 2015 (p = 0.002). The increase in ASD prevalence and incidence was observed in all subgroups based on sex, region, and SES. The adjusted negative binomial model showed an annual relative risk increase, since 2004, for both prevalence and incidence of 1.69 (95% CI 1.56–1.83) and 1.84 (95% CI 1.62–2.09), respectively. CONCLUSION: During the period from 2004 to 2015, both prevalence and incidence rates of diagnosed ASD in preschoolers and toddlers residing in Manitoba increased significantly. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.17269/s41997-019-00181-9) contains supplementary material, which is available to authorized users.

The effectiveness of a vaccination program is influenced by its design and implementation details and by the target population characteristics. Using routinely collected population-based individual-level data, we assessed the effectiveness (against cervical dysplasia) of Manitoba's quadrivalent human papillomavirus (qHPV) routine school-based vaccination program and a short-lived campaign that targeted women at high-risk of developing cervical cancer. Females ≥9 years old who received the qHPV vaccine in Manitoba (Canada) between September 1, 2006, and March 31, 2013 (N = 31,442) were matched on age and area of residence to up to three unvaccinated females. Cox proportional hazards models were used to estimate qHPV VE against high-grade (HSILs) and low-grade squamous intraepithelial lesions (LSILs) and atypical squamous cells of undetermined significance (ASCUS). Among 14-17-year-old participants who had Pap cytology after enrollment, the adjusted qHPV VE estimates were 30% (17-58%) and 36% (21-48%) against the detection of HSILs and LSILs, respectively. There was, however, no evidence of program effectiveness among females vaccinated at ≥18 years of age and among those with a history of abnormal cytology, who were mostly vaccinated as part of the high-risk program. Estimates of VE for females vaccinated in the school-based program are consistent with the expected benefits from qHPV vaccination. No similar benefits were detected among women vaccinated at an older age, and those with abnormal cytology, who were targeted by the high-risk program. Further efforts should be targeted at achieving higher vaccine coverage among preadolescents, prior to the initiation of sexual activity.

BACKGROUND. Varicella-zoster virus (VZV) is under consideration as a promising recombinant viral vector to deliver foreign antigens including HIV. However, new vectors have come under increased scrutiny, since trials with adenovirus serotype 5–vectored (Ad5-vectored) HIV vaccine demonstrated increased HIV risk in individuals with pre-immunity to the vector that was thought to be associated with mucosal immune activation (IA). Therefore, given the prospect of developing an HIV/VZV chimeric vaccine, it is particularly important to define the impact of VZV vaccination on IA. METHODS. Healthy VZV-seropositive Kenyan women (n = 44) were immunized with high-dose live attenuated VZV vaccine, and we assessed the expression on CD4((+)) T cells isolated from blood, cervix, and rectum of IA markers including CD38 and HLA-DR and of markers of cell migration and tissue retention, as well as the concentration of genital and intestinal cytokines. A delayed-start group (n = 22) was used to control for natural variations in these parameters. RESULTS. Although immunogenic, VZV vaccination did not result in significant difference in the frequency of cervical activated (HLA-DR((+))CD38((+))) CD4((+)) T cells (median 1.61%, IQR 0.93%–2.76%) at 12 weeks after vaccination when compared with baseline (median 1.58%, IQR 0.75%–3.04%), the primary outcome for this study. VZV vaccination also had no measurable effect on any of the IA parameters at 4, 8, and 12 weeks after vaccination. CONCLUSION. This study provides the first evidence to our knowledge about the effects of VZV vaccination on human mucosal IA status and supports further evaluation of VZV as a potential vector for an HIV vaccine. TRIAL REGISTRATION. ClinicalTrials.gov NCT02514018. FUNDING. Primary support from the Canadian Institutes for Health Research (CIHR). For other sources, see Acknowledgments.

Background Although children have historically been excluded from clinical trials (CTs), many require medicines tested and approved in CTs, forcing health care providers to treat their pediatric patients based on extrapolated data. Unfortunately, traditional randomized CTs can be slow and resource-intensive, and they often require multi-center collaboration. However, an adaptive design (AD) framework for CTs could be used to increase the efficiency of pediatric CTs by incorporating prospectively planned modifications to CT methods without undermining the integrity or validity of the study. There are many possible adaptations, but each will have ethical, logistical, and statistical implications. It remains unclear which adaptations (or combinations thereof) will lead to real-world improvements in pediatric CT efficiency. This study will identify, evaluate, and synthesize the various regulatory, ethical, logistical, and statistical considerations and emerging issues of AD in CTs that could be used to evaluate the use of drugs in children. Methods/design Following the development of a peer-reviewed search strategy, a systematic review on AD in CTs will be conducted. Data on regulatory, ethical, logistic, and statistical considerations as well as population and trial design characteristics will be synthesized. A mixed-methods study including surveys and focus groups with regulators, research ethics board members, biostatisticians, clinicians, and scientists, as well as representatives from patient groups and the public will evaluate the opportunities and challenges in applying AD in trials enrolling children and propose recommendations on best practices. Discussion This study will deliver practical recommendations on the use of AD in pediatric CTs. Collaboration and consultation with national and global partners will ensure that our results meet the needs of researchers, regulators, and patients, both locally and globally, and that they remain current and relevant by engaging a wide variety of stakeholders. Overall, this research will enrich the knowledge base regarding if, how, and when AD can be used to answer research questions with fewer resources while still meeting the highest ethical standards and regulatory requirements for CTs. In turn, this will result in increased high-quality clinical research needed by health care providers so they have access to appropriate, population-specific evidence regarding the safe and effective use of medicines in children.

Background Seasonal influenza vaccination (SIV) rates remain suboptimal in many populations, even in those with universal SIV. Objective To summarize the evidence on interventions on health care providers (physicians/nurses/pharmacists) to increase SIV rates. Methods We systematically searched/selected full-text English publications from January 2000 to July 2019 (PROSPERO-CRD42019147199). Our outcome was the difference in SIV rates between patients in intervention and non-intervention groups. We calculated pooled difference using an inverse variance, random-effects model. Results We included 39 studies from 8370 retrieved citations. Compared with no intervention, team-based training/education of physicians significantly increased SIV rates in adult patients: 20.1% [7.5–32.7%; I2 = 0%; two randomized controlled trials (RCTs)] and 13.4% [8.6–18.1%; I2 = 0%; two non-randomized intervention studies (NRS)]. A smaller increase was observed in paediatric patients: 7% (0.1–14%; I2 = 0%; two NRS), and in adult patients with team-based training/education of physicians and nurses together: 0.9% (0.2–1.5%; I2 = 30.6%; four NRS). One-off provision of guidelines/information to physicians, and to both physicians and nurses, increased SIV rates in adult patients: 23.8% (15.7–31.8%; I2 = 45.8%; three NRS) and paediatric patients: 24% (8.1–39.9%; I2 = 0%; two NRS), respectively. Use of reminders (prompts) by physicians and nurses slightly increased SIV rates in paediatric patients: 2.3% (0.5–4.2%; I2 = 0%; two RCTs). A larger increase was observed in adult patients: 18.5% (14.8–22.1%; I2 = 0%; two NRS). Evidence from both RCTs and NRS showed significant increases in SIV rates with varied combinations of interventions. Conclusions Limited evidence suggests various forms of physicians’ and nurses’ education and use of reminders may be effective for increasing SIV rates among patients.