Determining the Optimal SARS-CoV-2 mRNA Vaccine Dosing Interval for Maximum Immunogenicity.

OBJECTIVE: Emerging evidence indicates that longer SARS-CoV-2 vaccine dosing intervals results in an enhanced immune response. However, the optimal vaccine dosing interval for achieving maximum immunogenicity is unclear. METHODS: This study included samples from adult paramedics in Canada who received two doses of either BNT162b2 or mRNA-1273 vaccines and provided blood samples six months (170 to 190 days) after the first vaccine dose. The main exposure variable was vaccine dosing interval (days), categorized as "short" (first quartile), "moderate" (second quartile), "long" (third quartile), and "longest" interval (fourth quartile). The primary outcome was total spike antibody concentrations, measured using the Elecsys SARS-CoV-2 total antibody assay. Secondary outcomes included spike and receptor-binding domain (RBD) immunoglobulin G (IgG) antibody concentrations, and inhibition of angiotensin-converting enzyme 2 (ACE-2) binding to wild-type spike protein and several different Delta variant spike proteins. We fit a multiple log-linear regression model to investigate the association between vaccine dosing intervals and the antibody concentrations. RESULTS: A total of 564 adult paramedics (mean age 40 years, SD=10) were included. Compared to "short interval" (≤30 days), vaccine dosing intervals of the long (39-73 days) group (ß= 0.31, 95% Confidence interval (CI): 0.10-0.52) and the longest (≥74 days) group (ß = 0.82. 95% CI: 0.36-1.28) were associated with increased spike total antibody concentration. Compared to the short interval, the longest interval quartile was associated with higher spike IgG antibodies, while the long and longest intervals were associated with higher RBD IgG antibody concentrations. Similarly, the longest dosing intervals increased inhibition of ACE-2 binding to viral spike protein. CONCLUSION: Increased mRNA vaccine dosing intervals longer than 38 days result in higher levels of anti-spike antibodies and ACE-2 inhibition when assessed six months after the first COVID-19 vaccine.

Post-tuberculosis airway disease: A population-based cohort study of people immigrating to British Columbia, Canada, 1985-2015.

BACKGROUND: Current epidemiological evidence of post-TB airway disease is largely cross-sectional and derived from high-TB-incidence settings. We present the first cohort study of post-TB airway disease in a low-TB-incidence setting. AIMS: (1) analyze the risk of airway disease by respiratory TB, (2) assess potential unmeasured confounding between TB and airway disease, and (3) investigate TB effect measure modification. METHODS: A population-based cohort study using healthcare claims data for immigrants to British Columbia (BC), Canada, 1985-2015. Airway disease included chronic airway obstruction, asthma, bronchitis, bronchiolitis, and emphysema. Respiratory TB was defined from TB registry data. Cox proportional hazards (PH) regressions were used to analyze time-to-airway disease by respiratory TB. Sensitivity analyses included varying definitions of TB and airway disease. Potential unmeasured confounding by smoking was evaluated by E-value and hybrid least absolute shrinkage and selection operator (LASSO)-high-dimensional propensity score (hdPS). FINDINGS: In our cohort (N = 1 005 328; nTB=1141) there were 116 840 incident cases of airway disease during our 30-year study period (10.43 per 1,000 person-years of follow-up), with cumulative incidence of 42·5% among respiratory TB patients compared with 11·6% among non-TB controls. The covariate-adjusted hazard ratio (aHR) for airway disease by respiratory TB was 2·08 (95% CI: 1·91-2·28) with E-value=3·58. The LASSO-hdPS analysis produced aHR=2·26 (95% CI: 2·07-2·47). INTERPRETATION: A twofold higher risk of airway disease was observed among immigrants diagnosed with respiratory TB, compared with non-TB controls, in a low-TB-incidence setting. Unmeasured confounding is unlikely to explain this relationship. Models of post-TB care are needed. FUNDING: Canadian Institutes of Health Research.

Association between human papillomavirus vaccine status and sexually transmitted infection outcomes among females aged 18-35 with a history of sexual activity in the United States: A population survey-based cross-sectional analysis.

BACKGROUND: Current human papillomavirus (HPV) vaccine coverage in the United States (in 2019, 66-70%), remains below the Healthy People 2020 coverage goal of 80%. HPV vaccine misinformation, including parental concerns of sexual risk-compensation influence vaccine uptake. We examined the association between HPV vaccination and sexually transmitted infection (STI) outcomes. METHODS: Of the 20,146 participants from 2013 to 2014 and 2015-2016 cycles of the National Health and Nutrition Examination Survey, 1050 females aged 18-35 with a history of sexual activity had complete case data. Roa-Scott Chi-squared and F-tests assessed survey-weighted socio-demographic differences between vaccinated and unvaccinated participants. Weighted logistic regression assessed crude and adjusted associations between self-reported HPV vaccination (none vs. ≥ 1dose) and lab-confirmed STIs (trichomonas and chlamydia) and vaccine-type HPV (6/11/16/18). As a sensitivity analysis, we conducted weighted-propensity score (PS) models and inverse probability weighting by vaccination status. PS and logistic regression were estimated through survey-weighted logistic regression on variables including race, education, income, marital status, US citizenship, cycle year and age. RESULTS: Overall, 325 (31.8%) females with a history of sexual activity were HPV vaccinated, of which 22 (6.1%) received the vaccine at the routine-recommended ages of 11-12, 65.7% were vaccinated after their self-reported sexual debut, 3.8% had a lab-confirmed STI and 3.5% had vaccine-type HPV. There was no association between HPV vaccination and any STIs (adjusted odds ratio [aOR] 0.67, 95%CI:0.38-1.20), and vaccinated participants had 61% reduced odds of vaccine-type HPV (vs. unvaccinated; aOR 0.39, 95%CI:0.19-0.83). Results from the PS sensitivity analysis were similar to the main findings. CONCLUSION: Among females who reported a history of sexual activity, HPV vaccination status was protective against vaccine-type HPV and not associated with lab-based STI outcomes. Although findings may be susceptible to reporting bias, results indicating low vaccine uptake at routine-recommended ages requires additional efforts promoting HPV vaccination before sexual-debut.

Role of Nonsteroidal Antiinflammatory Drugs in the Association Between Osteoarthritis and Cardiovascular Diseases: A Longitudinal Study.

OBJECTIVE: To elucidate the role of nonsteroidal antiinflammatory drugs (NSAIDs) in the increased risk of cardiovascular disease (CVD) among osteoarthritis (OA) patients. METHODS: This longitudinal study was based on linked health administrative data from British Columbia, Canada. From a population-based cohort of 720,055 British Columbians, we selected 7,743 OA patients and 23,229 age- and sex-matched non-OA controls. We used multivariable Cox proportional hazards models to estimate the risk of developing incident CVD (primary outcome) as well as ischemic heart disease, congestive heart failure, and stroke (secondary outcomes). To estimate the mediating effect of NSAIDs, defined as current use of an NSAID according to linked PharmaNet data, in the OA-CVD relationship, we implemented a marginal structural model. RESULTS: OA patients had a higher risk of developing CVD than controls without OA. After adjusting for socioeconomic status, body mass index, hypertension, diabetes, hyperlipidemia, chronic obstructive pulmonary disease, and Romano comorbidity score, the adjusted hazard ratio (HR) was 1.23 (95% confidence interval [95% CI] 1.17-1.28). The adjusted HRs for congestive heart failure, ischemic heart disease, and stroke were 1.42 (95% CI 1.33-1.51), 1.17 (95% CI 1.10-1.26), and 1.14 (95% CI 1.07-1.22), respectively. Approximately 41% of the total effect of OA on increased CVD risk was mediated through NSAIDs. For the secondary outcomes, the proportion mediated through NSAIDs was 23%, 56%, and 64% for congestive heart failure, ischemic heart disease, and stroke, respectively. CONCLUSION: The findings of this first study to evaluate the mediating role of NSAIDs in the relationship between OA and CVD suggest that NSAID use contributes substantially to the OA-CVD association.

Determinants of Antibiotic Tailoring in Pediatric Intensive Care: A National Survey.

OBJECTIVES: To describe the criteria that currently guide empiric antibiotic treatment in children admitted to Canadian PICUs. DESIGN: Cross-sectional survey. SETTING: Canadian PICUs. SUBJECTS: Pediatric intensivists and pediatric infectious diseases specialists. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used focus groups and literature review to design the survey questions and its four clinical scenarios (sepsis, pneumonia, meningitis, and intra-abdominal infections). We analyzed our results using descriptive statistics and multivariate linear regression. Our response rate was 60% for pediatric intensivists (62/103) and 36% for pediatric infectious diseases specialists (37/103). Variables related to patient characteristics, disease severity, pathogens, and clinical, laboratory, and radiologic infection markers were associated with longer courses of antibiotics, with median increment ranging from 1.75 to 7.75 days. The presence of positive viral polymerase chain reaction result was the only variable constantly associated with a reduction in antibiotic use (median decrease from, -3.25 to -8.25 d). Importantly, 67-92% of respondents would still use a full course of antibiotics despite positive viral polymerase chain reaction result and marked clinical improvement for patients with suspected sepsis, pneumonia, and intra-abdominal infection. Clinical experience was associated with shorter courses of antibiotics for meningitis and sepsis (-1.3 d [95% CI, -2.4 to -0.2] and -1.8 d [95% CI, -2.8 to -0.7] per 10 extra years of clinical experience, respectively). Finally, site and specialty also influenced antibiotic practices. CONCLUSIONS: Decisions about antibiotic management for PICU patients are complex and involve the assessment of several different variables. With the exception of a positive viral polymerase chain reaction, our findings suggest that physicians rarely consider reducing the duration of antibiotics despite clinical improvement. In contrast, they will prolong the duration when faced with a nonreassuring characteristic. The development of objective and evidence-based criteria to guide antibiotic therapy in critically ill children is crucial to ensure the rational use of these agents in PICUs.