Case-cohort design as an efficient approach to evaluating COVID-19 vaccine effectiveness, waning, heterologous immune effect and optimal dosing interval.

Though widely applied in other epidemiological fields, the case-cohort study design has seen little application in the field of vaccinology. Case-cohort studies use probabilistic sampling and reweighting to draw inferences about effects (in this case vaccine efficacy) at the population level in an efficient manner. The SARS-CoV-2 pandemic was met with high vaccine uptake, and high rates of population testing prior to the emergence of Omicron variants of concern, in Ontario, Canada, providing an ideal environment for application of case-cohort methodology. We combined a population-based case line list and vaccination database for the province of Ontario between December 2020 and October 2021. Risk of infection after vaccination was evaluated in all laboratory-confirmed vaccinated SARS-CoV-2 cases, and a 2 % sample of vaccinated controls, evaluated using survival analytic methods, including construction of Cox proportional hazards models. Vaccination status was treated as a time-varying covariate. First and second doses of SARS-CoV-2 vaccine markedly reduced risk of infection (first dose efficacy 68 %, 95 % CI 67 %-69 %; second dose efficacy 88 %, 95 % CI 87-88 %). In multivariable models, extended dosing intervals were associated with lowest risk of breakthrough infection (HR for redosing 0.64 (95 % CI 0.61-0.67) at 6-8 weeks). Heterologous vaccine schedules that mixed viral vector vaccine first doses with mRNA second doses were significantly more effective than mRNA only vaccines. Risk of infection largely vanished during the time period 4-6 months after the second vaccine dose, but rose markedly thereafter. We conclude that a case-cohort design provided an efficient means to identify strong protective effects associated with SARS-CoV-2 vaccination in real time, and also served to quantify the timing and magnitude of infection breakthrough risk in the same cohort. Heterologous vaccination and extended dosing intervals improved the durability of immune response.

Impact of immune evasion, waning and boosting on dynamics of population mixing between a vaccinated majority and unvaccinated minority.

BACKGROUND: We previously demonstrated that when vaccines prevent infection, the dynamics of mixing between vaccinated and unvaccinated sub-populations is such that use of imperfect vaccines markedly decreases risk for vaccinated people, and for the population overall. Risks to vaccinated people accrue disproportionately from contact with unvaccinated people. In the context of the emergence of Omicron SARS-CoV-2 and evolving understanding of SARS-CoV-2 epidemiology, we updated our analysis to evaluate whether our earlier conclusions remained valid. METHODS: We modified a previously published Susceptible-Infectious-Recovered (SIR) compartmental model of SARS-CoV-2 with two connected sub-populations: vaccinated and unvaccinated, with non-random mixing between groups. Our expanded model incorporates diminished vaccine efficacy for preventing infection with the emergence of Omicron SARS-CoV-2 variants, waning immunity, the impact of prior immune experience on infectivity, "hybrid" effects of infection in previously vaccinated individuals, and booster vaccination. We evaluated the dynamics of an epidemic within each subgroup and in the overall population over a 10-year time horizon. RESULTS: Even with vaccine efficacy as low as 20%, and in the presence of waning immunity, the incidence of COVID-19 in the vaccinated subpopulation was lower than that among the unvaccinated population across the full 10-year time horizon. The cumulative risk of infection was 3-4 fold higher among unvaccinated people than among vaccinated people, and unvaccinated people contributed to infection risk among vaccinated individuals at twice the rate that would have been expected based on the frequency of contacts. These findings were robust across a range of assumptions around the rate of waning immunity, the impact of "hybrid immunity", frequency of boosting, and the impact of prior infection on infectivity in unvaccinated people. INTERPRETATION: Although the emergence of the Omicron variants of SARS-CoV-2 has diminished the protective effects of vaccination against infection with SARS-CoV-2, updating our earlier model to incorporate loss of immunity, diminished vaccine efficacy and a longer time horizon, does not qualitatively change our earlier conclusions. Vaccination against SARS-CoV-2 continues to diminish the risk of infection among vaccinated people and in the population as a whole. By contrast, the risk of infection among vaccinated people accrues disproportionately from contact with unvaccinated people.

Impact of community mask mandates on SARS-CoV-2 transmission in Ontario after adjustment for differential testing by age and sex.

Mask use for prevention of respiratory infectious disease transmission is not new but has proven controversial during the SARS-CoV-2 pandemic. In Ontario, Canada, irregular regional introduction of community mask mandates in 2020 created a quasi-experiment useful for evaluating the impact of such mandates; however, Ontario SARS-CoV-2 case counts were likely biased by testing focused on long-term care facilities and healthcare workers. We developed a regression-based method that allowed us to adjust cases for under-testing by age and gender. We evaluated mask mandate effects using count-based regression models with either unadjusted cases, or testing-adjusted case counts, as dependent variables. Models were used to estimate mask mandate effectiveness, and the fraction of SARS-CoV-2 cases, severe outcomes, and costs, averted by mask mandates. Models using unadjusted cases as dependent variables identified modest protective effects of mask mandates (range 31-42%), with variable statistical significance. Mask mandate effectiveness in models predicting test-adjusted case counts was higher, ranging from 49% (95% CI 44-53%) to 76% (95% CI 57-86%). The prevented fraction associated with mask mandates was 46% (95% CI 41-51%), with 290,000 clinical cases, 3,008 deaths, and loss of 29,038 quality-adjusted life years averted from 2020 June to December, representing $CDN 610 million in economic wealth. Under-testing in younger individuals biases estimates of SARS-CoV-2 infection risk and obscures the impact of public health preventive measures. After adjustment for under-testing, mask mandates emerged as highly effective. Community masking saved substantial numbers of lives, and prevented economic costs, during the SARS-CoV-2 pandemic in Ontario, Canada.

Cost-effectiveness of RSVpreF vaccine and nirsevimab for the prevention of respiratory syncytial virus disease in Canadian infants.

BACKGROUND: Health Canada recently authorized the RSVpreF pregnancy vaccine and nirsevimab to protect infants against respiratory syncytial virus (RSV) disease. OBJECTIVE: Assess the cost-effectiveness of RSVpreF and nirsevimab programs in preventing RSV disease in infants, compared to a palivizumab program. METHODS: We used a static cohort model of a Canadian birth cohort during their first RSV season to estimate sequential incremental cost-effectiveness ratios (ICERs) in 2023 Canadian dollars per quality-adjusted life year (QALY) for nine strategies implemented over a one-year time period, from the health system and societal perspectives. Sensitivity and scenario analyses were conducted to explore the impact of uncertainties on the results. RESULTS: All-infants nirsevimab programs averted more RSV-related outcomes than year-round RSVpreF programs, with the most RSV cases averted in a seasonal nirsevimab program with catch-up. Assuming list prices for these immunizing agents, all-infants nirsevimab and year-round RSVpreF programs were never cost-effective, with ICERs far exceeding commonly used cost-effectiveness thresholds. Seasonal nirsevimab with catch-up for infants born outside the RSV season was a cost-effective program if prioritized for infants at moderate/high-risk (ICER <$28,000 per QALY) or those living in settings with higher RSV burden and healthcare costs, such as remote communities where transport would be complex (ICER of $5700 per QALY). Using a $50,000 per QALY threshold, an all-infants nirsevimab program could be optimal if nirsevimab is priced at <$110-190 per dose. A year-round RSVpreF for all pregnant women and pregnant people plus nirsevimab for infants at high-risk was optimal if nirsevimab is priced at >$110-190 per dose and RSVpreF priced at <$60-125 per dose. INTERPRETATION: Prophylactic interventions can substantially reduce RSV disease in infants, and more focused nirsevimab programs are the most cost-effective option at current product prices.

Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis.

The success of checkpoint inhibitors (CPIs) for cancer has been tempered by immune-related adverse effects including colitis. CPI-induced colitis is hallmarked by expansion of resident mucosal IFNγ cytotoxic CD8+ T cells, but how these arise is unclear. Here, we track CPI-bound T cells in intestinal tissue using multimodal single-cell and subcellular spatial transcriptomics (ST). Target occupancy was increased in inflamed tissue, with drug-bound T cells located in distinct microdomains distinguished by specific intercellular signaling and transcriptional gradients. CPI-bound cells were largely CD4+ T cells, including enrichment in CPI-bound peripheral helper, follicular helper, and regulatory T cells. IFNγ CD8+ T cells emerged from both tissue-resident memory (TRM) and peripheral populations, displayed more restricted target occupancy profiles, and co-localized with damaged epithelial microdomains lacking effective regulatory cues. Our multimodal analysis identifies causal pathways and constitutes a resource to inform novel preventive strategies.

Relative pandemic severity in Canada and four peer nations during the SARS-CoV-2 pandemic.

Background: National responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic have been highly variable. We sought to explore the effectiveness of the Canadian pandemic response up to May 2022 relative to responses in four peer countries with similar political, economic and health systems, and with close historical and cultural ties to Canada. Methods: We used reported age-specific mortality data to generate estimates of pandemic mortality standardized to the Canadian population. Age-specific case fatality, hospitalization, and intensive care admission probabilities for the Canadian province of Ontario were applied to estimated deaths, to calculate hospitalizations and intensive care admissions averted by the Canadian response. Health impacts were valued in both monetary terms, and in terms of lost quality-adjusted life years. Results: We estimated that the Canadian pandemic response averted 94,492, 64,306 and 13,641 deaths relative to the responses of the United States, United Kingdom and France, respectively, and more than 480,000 hospitalizations relative to the United States. The United States pandemic response, if applied to Canada, would have resulted in more than $40 billion in economic losses due to healthcare expenditures and lost quality-adjusted life years. In contrast, an Australian pandemic response applied to Canada would have averted over 28,000 additional deaths and averted nearly $9 billion in costs. Conclusion: Canada outperformed several peer countries that aimed for mitigation rather than elimination of SARS-CoV-2 in the first two years of the pandemic, with substantial numbers of lives saved and economic costs averted. However, a comparison with Australia demonstrated that an elimination focus would have saved Canada tens of thousands of lives as well as substantial economic costs.