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

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

Canada's National Advisory Committee on immunization: Adaptations and challenges during the COVID-19 pandemic.

The COVID-19 pandemic has challenged traditional vaccine guidance infrastructure and frameworks, and added urgency and complexity to the operation of National Immunization Technical Advisory Groups (NITAGs). Canada's National Advisory Committee on Immunization (NACI) provides immunization guidance to the Public Health Agency of Canada (PHAC) who publicly shares expert and evidence-informed guidance with Canadian provinces and territories. Throughout the pandemic, NACI and PHAC implemented many adaptations to meet urgent needs for pandemic vaccine guidance. In this paper, we describe: structural adaptations in response to the accelerated pace and amount of work required to issue recommendations that were timed around product authorizations and dynamic epidemiology; technical adaptations in response to rapidly evolving evidence of variable quality which required close monitoring, and which promoted reliance on basic vaccine principles due to incomplete direct evidence; the need to provide nimble advice (e.g., off-label recommendations, preferential recommendations); communications adaptations (e.g. identify sustainable spokespeople for the committee, receive stakeholder feedback, and ensure urgent nuanced advice was communicated to a diverse audience); and research adaptations focussing on solutions to constrained supply (e.g. prioritisation, extended intervals, and heterologous schedules). The early pandemic vaccine experience has created a roadmap of lessons and adaptations that should be leveraged in future pandemic vaccine programs, and has highlighted the essential role of NITAGs to complement regulatory structures during pandemics to ensure timely, impactful, and evidence-informed public health vaccine guidance.

Use of existing systematic reviews for the development of evidence-based vaccination recommendations: Guidance from the SYSVAC expert panel.

National immunization technical advisory groups (NITAGs) develop immunization-related recommendations and assist policy-makers in making evidence informed decisions. Systematic reviews (SRs) that summarize the available evidence on a specific topic are a valuable source of evidence in the development of such recommendations. However, conducting SRs requires significant human, time, and financial resources, which many NITAGs lack. Given that SRs already exist for many immunization-related topics, and to prevent duplication and overlap of reviews, a more practical approach may be for NITAGs to use existing SRs. Nevertheless, it can be challenging to identify relevant SRs, to select one SR from among multiple SRs, or to critically assess and effectively use them. To support NITAGs, the London School of Hygiene and Tropical Medicine, Robert Koch Institute and collaborators developed the SYSVAC project, which consists of an online registry of systematic reviews on immunization-related topics and an e-learning course, that supports the use of them (both freely accessible at https://www.nitag-resource.org/sysvac-systematic-reviews). Drawing from the e-learning course and recommendations from an expert panel, this paper outlines methods for using existing systematic reviews when making immunization-related recommendations. With specific examples and reference to the SYSVAC registry and other resources, it offers guidance on locating existing systematic reviews; assessing their relevance to a research question, up-to-dateness, and methodological quality and/or risk of bias; and considering the transferability and applicability of their findings to other populations or settings.

Quantifying the economic gains associated with COVID-19 vaccination in the Canadian population: A cost-benefit analysis.

Background: Vaccination has been a key part of Canada's coronavirus disease 2019 (COVID-19) pandemic response. Although the clinical benefits of vaccination are clear, an understanding of the population-level benefits of vaccination relative to the programmatic costs is of value. The objective of this article is to quantify the economic impact of COVID-19 vaccination in the Canadian population between December 2020 and March 2022. Methods: We conducted a model-based cost-benefit analysis of Canada's COVID-19 vaccination program. We used an epidemiological model to estimate the number of COVID-19 symptomatic cases, hospitalizations, post-COVID condition (PCC) cases, and deaths in the presence and absence of vaccination. Median, lower and upper 95% credible interval (95% CrI) outcome values from 100 model simulations were used to estimate the direct and indirect costs of illness, including the value of health. We used a societal perspective and a 1.5% discount rate. Results: We estimated that the costs of the vaccination program were far outweighed by the savings associated with averted infections and associated downstream consequences. Vaccination increased the net benefit by CAD $298.1 billion (95% CrI: 27.2-494.6) compared to the no vaccination counterfactual. The largest benefits were due to averted premature mortality, resulting in an estimated $222.0 billion (95% CrI: 31.2-379.0) benefit. Conclusion: Our model-based economic evaluation provides a retrospective assessment of COVID-19 vaccination during the first 16 months of the program in Canada and suggests that it was welfare-improving, considering the decreased hospitalizations and use of healthcare resources, deaths averted and lower morbidity from conditions such as PCC.

Impact of industry sponsorship on the quality of systematic reviews of vaccines: a cross-sectional analysis of studies published from 2016 to 2019.

BACKGROUND: Systematic reviews (SRs) provide the highest level of evidence and inform evidence-based decision making in health care. Earlier studies found association with industry to be negatively associated with methodological quality of SRs. However, this has not been investigated in SRs on vaccines. METHODS: We performed a systematic literature search using MEDLINE and EMBASE in March 2020. The results were restricted to those published between 2016 and 2019 with no language restrictions. Study characteristics were extracted by one person and checked by an experienced reviewer. The methodological quality of the SRs was assessed with the AMSTAR 2 tool by multiple reviewers after a calibration exercise was performed. A summary score for each SR was calculated. The Mann-Whitney U test and Fisher's exact test were performed to compare both groups. RESULTS: Out of 185 SRs that met all inclusion criteria, 27 SRs were industry funded. Those were matched with 30 non-industry funded SRs resulting in a total sample size of 57. The mean AMSTAR 2 summary score across all SRs was 0.49. Overall, the median AMSTAR 2 summary score was higher for the non-industry funded SRs than for the industry-funded SRs (0.62 vs. 0.36; p < .00001). Lower ratings for industry funded SRs were consistent across all but one AMSTAR 2 item, though significantly lower only for three specific items. CONCLUSION: The methodological quality of SRs in vaccination is comparable to SRs in other fields, while it is still suboptimal. We are not able to provide a satisfactory explanation why industry funded SRs had a lower methodological quality than non-industry funded SRs over recent years. Industry funding is an important indicator of methodological quality for vaccine SRs and should be carefully considered when appraising SR quality.

The Efficacy of a Brief, Altruism-Eliciting Video Intervention in Enhancing COVID-19 Vaccination Intentions Among a Population-Based Sample of Younger Adults: Randomized Controlled Trial.

BACKGROUND: High COVID-19 vaccine uptake is crucial to containing the pandemic and reducing hospitalizations and deaths. Younger adults (aged 20-39 years) have demonstrated lower levels of vaccine uptake compared to older adults, while being more likely to transmit the virus due to a higher number of social contacts. Consequently, this age group has been identified by public health authorities as a key target for vaccine uptake. Previous research has demonstrated that altruistic messaging and motivation is associated with vaccine acceptance. OBJECTIVE: This study had 2 objectives: (1) to evaluate the within-group efficacy of an altruism-eliciting short, animated video intervention in increasing COVID-19 vaccination intentions amongst unvaccinated Canadian younger adults and (2) to examine the video's efficacy compared to a text-based intervention focused exclusively on non-vaccine-related COVID-19 preventive health measures. METHODS: Using a web-based survey in a pre-post randomized control trial (RCT) design, we recruited Canadians aged 20-39 years who were not yet vaccinated against COVID-19 and randomized them in a 1:1 ratio to receive either the video intervention or an active text control. The video intervention was developed by our team in collaboration with a digital media company. The measurement of COVID-19 vaccination intentions before and after completing their assigned intervention was informed by the multistage Precaution Adoption Process Model (PAPM). The McNemar chi-square test was performed to evaluate within-group changes of vaccine intentions. Exact tests of symmetry using pairwise McNemar tests were applied to evaluate changes in multistaged intentions. Between-group vaccine intentions were assessed using the Pearson chi-square test postintervention. RESULTS: Analyses were performed on 1373 participants (n=686, 50%, in the video arm, n=687, 50%, in the text arm). Within-group results for the video intervention arm showed that there was a significant change in the intention to receive the vaccine (χ21=20.55, P<.001). The between-group difference in postintervention intentions (χ23=1.70, P=.64) was not significant. When administered the video intervention, we found that participants who had not thought about or were undecided about receiving a COVID-19 vaccine were more amenable to change than participants who had already decided not to vaccinate. CONCLUSIONS: Although the video intervention was limited in its effect on those who had firmly decided not to vaccinate, our study demonstrates that prosocial and altruistic messages could increase COVID-19 vaccine uptake, especially when targeted to younger adults who are undecided or unengaged regarding vaccination. This might indicate that altruistic messaging provides a "push" for those who are tentative toward, or removed from, the decision to receive the vaccine. The results of our study could also be applied to more current COVID-19 vaccination recommendations (eg, booster shots) and for other vaccine-preventable diseases. TRIAL REGISTRATION: ClinicalTrials.gov NCT04960228; https://clinicaltrials.gov/ct2/show/NCT04960228.

Burden of illness in infants and young children hospitalized for respiratory syncytial virus: A rapid review.

Respiratory syncytial virus (RSV) infections are common among young children and represent a significant burden to patients, their families and the Canadian health system. Here we conduct a rapid review of the burden of RSV illness in children 24 months of age or younger. Four databases (Medline, Embase, Cochrane Database of Clinical Trials, ClinicalTrials.gov from 2014 to 2018), grey literature and reference lists were reviewed for studies on the following: children with or without a risk factor, without prophylaxis and with lab-confirmed RSV infection. Of 29 studies identified, 10 provided within-study comparisons and few examined clinical conditions besides prematurity. For infants of 33-36 weeks gestation (wGA) versus term infants, there was low-to-moderate certainty evidence for an increase in RSV-hospitalizations (n=599,535 infants; RR 2.05 [95% CI 1.89-2.22]; 1.3 more per 100 [1.1-1.5 more]) and hospital length of stay (n=7,597 infants; mean difference 1.00 day [95% CI 0.88-1.12]). There was low-to-moderate certainty evidence of little-to-no difference for infants born at 29-32 versus 33-36 wGA for hospitalization (n=12,812 infants; RR 1.20 [95% CI 0.92-1.56]). There was low certainty evidence of increased mechanical ventilation for hospitalized infants born at 29-32 versus 33-35 wGA (n=212 infants; RR 1.58, 95% CI 0.94-2.65). Among infants born at 32-35 wGA, hospitalization for RSV in infancy may be associated with increased wheeze and asthma-medication use across six-year follow-up (RR range 1.3-1.7). Children with versus without Down syndrome may have increased hospital length of stay (n=7,206 children; mean difference 3.00 days, 95% CI 1.95-4.05; low certainty). Evidence for other within-study comparisons was of very low certainty. In summary, prematurity is associated with greater risk for RSV-hospitalization and longer hospital length of stay, and Down syndrome may be associated with longer hospital stay for RSV. Respiratory syncytial virus-hospitalization in infancy may be associated with greater wheeze and asthma-medication use in early childhood. Lack of a comparison group was a major limitation for many studies.

Ranking the relative importance of COVID-19 vaccination strategies in Canada: a priority-setting exercise.

BACKGROUND: When vaccine supplies are anticipated to be limited, necessitating the vaccination of certain groups earlier than others, the assessment of values and preferences of stakeholders is an important component of an ethically sound vaccine prioritization framework. The objective of this study was to conduct a priority-setting exercise to establish an expert stakeholder perspective on the relative importance of COVID-19 vaccination strategies in Canada. METHODS: The priority-setting exercise included a survey of stakeholders that was conducted from July 22 to Aug. 14, 2020. Stakeholders included clinical and public health expert groups, provincial and territorial committees and national Indigenous groups, patient and community advocacy representatives and experts, health professional associations and federal government departments. Survey results were analyzed to identify trends. RESULTS: Of 155 stakeholders contacted, 76 surveys were received for a participation rate of 49%. During a period of anticipated initial vaccine scarcity for all pandemic scenarios, stakeholders generally considered the most important vaccination strategy to be protecting those who are most vulnerable to severe illness and death from COVID-19. This was followed in importance by strategies to protect health care capacity, minimize transmission of SARS-CoV-2 and protect critical infrastructure. INTERPRETATION: This priority-setting exercise established that there is general alignment in the values and preferences across stakeholder groups: the most important vaccination strategy at the time of limited initial vaccine availability is to protect those who are most vulnerable. The findings of this priority-setting exercise provided a timely expert perspective to guide early public health planning for COVID-19 vaccines.

Continuity of routine immunization programs in Canada during the COVID-19 pandemic.

INTRODUCTION: In Canada, the COVID-19 pandemic has interrupted many routine health services, placed additional strain on the health care system, and resulted in many Canadians being either unable or unwilling to attend routine immunization appointments. We sought to capture and synthesize information about changes to routine immunization programs in response to the pandemic and plans to catch-up any missed immunizations. METHODS: Provincial/territorial (P/T) public health leaders were interviewed via teleconference between August-October 2020 to collect information on the following topics: how routine immunization delivery was affected during and after initial lockdown periods, plans to catch-up missed doses, and major challenges and achievements in continuing routine immunization programs. Data were coded and categorized according to common responses and descriptive analysis was performed. RESULTS: Interviews occurred with participants from 11 of 13 P/Ts. School immunization programs were reported to be most negatively affected by the pandemic (n = 9). In the early pandemic period, infant, preschool, and maternal/prenatal programs were prioritized, with most P/Ts continuing these services with adaptations for COVID-19. After the initial lockdown period, all routine programs were continuing with adaptations in most P/Ts. Infant, preschool, and school programs were most often targeted for catch-up through measures such as appointment rebooking and making additional clinics and/or providers available. Major challenges included resource limitations (e.g., staff shortages, PPE shortages, limited infrastructure) (n = 11), public health restrictions (n = 8), and public hesitancy to attend appointments (n = 5). CONCLUSIONS: Canadian routine immunization programs faced some disruptions due to the COVID-19 pandemic, particularly the school, adult, and older adult programs. Further research is needed to determine the measurable impact of the pandemic on routine vaccine coverage levels.

Demonstrating the capacity of the National Advisory Committee on Immunization for timely responses to post-market vaccine monitoring signals: Canada's experience with the live-attenuated influenza vaccine.

Over the last several years, the recommended use of the live-attenuated influenza vaccine (LAIV) for children has evolved in the United States (US) in response to evidence of a potential decrease in LAIV effectiveness based on post-market monitoring. These issues were not observed in Canada or elsewhere; consequently, recommendations from Canada's National Advisory Committee on Immunization (NACI) and the US Advisory Committee on Immunization Practices (ACIP) on whether to use LAIV differed for two influenza seasons (2016-2017 and 2017-2018). This retrospective describes how NACI arrived at its recommendations in response to post-market signals of reduced LAIV performance from the US in 2013-2014 and again in 2015-2016. NACI's experience with LAIV marks the first time in Canada where a preferential recommendation on the use of an influenza vaccine in a routine immunization program was reversed. This experience highlights the importance of ongoing post-market monitoring of vaccines, international collaboration and careful consideration of local context to inform vaccine recommendations. NACI's capacity for timely responses to post-market vaccine performance signals will facilitate responsiveness to similar post-market monitoring signals from the coronavirus disease 2019 (COVID-19) vaccines.

Health inequities related to vaccination: An evidence map of potentially influential factors and systematic review of interventions.

INTRODUCTION: The National Advisory Committee on Immunization (NACI) makes recommendations for vaccines in Canada. To inform considerations for equity when making recommendations, the NACI Secretariat developed a matrix of factors that may influence vaccine equity. To inform the matrix we mapped the evidence for P2ROGRESS And Other factors potentially associated with unequal levels of illness or death from vaccine-preventable diseases (VPDs) and systematically reviewed the evidence for interventions aimed at reducing inequities. METHODS: In October 2019 we searched Medline, Embase, and CINAHL. Two reviewers agreed on the included studies. Our primary outcomes were VPD-related hospitalizations and deaths. Secondary outcomes were differential vaccine access, and exposure, susceptibility, severity, and consequences of VPDs. Two reviewers appraised the certainty of evidence. We mapped the evidence for P2ROGRESS And Other factors and summarized the findings descriptively. We summarized the interventions narratively. RESULTS: We identified 413 studies reporting on P2ROGRESS And Other factors. The most commonly investigated factors included age (n = 374, 89%), pre-existing conditions (n = 179, 42%), and gender identity or sex (n = 144, 34%). We identified 2 trials investigating the effects of interventions. One (n = 1249) provided very low certainty evidence that staff vaccination policies may reduce hospitalizations and deaths from influenza among private care home residents. The other (n not reported) provided very low certainty evidence that universal vaccination by nurses in clinics may reduce hospitalizations for rotavirus gastroenteritis compared with vaccination by physicians or no intervention. CONCLUSIONS: There is a large body of studies reporting on hospitalizations and deaths from VPDs stratified by P2ROGRESS And Other factors. We found only two trials examining the effects of interventions on hospitalization for or mortality from VPDs. This review has been helpful to NACI and will be helpful to similar organizations aiming to systematically identify and target health inequities through the development of vaccine program recommendations.

Using existing systematic reviews for developing vaccination recommendations: Results of an international expert workshop.

National immunization technical advisory groups (NITAGs) develop immunization-related recommendations. Systematic reviews are recommended to be used in this process, but conducting them requires significant resources, which many NITAGs lack. Using existing systematic reviews could help address this problem. The Robert Koch Institute and collaborators set up the SYSVAC2 project to facilitate the retrieval of existing systematic reviews and offer guidance on using them. This will include an online registry of systematic reviews relevant to immunization policy and an online course on how to use existing reviews. This report describes an international expert workshop held in December 2019 to develop consensus on methods for using existing reviews and other relevant factors for the registry and course. Members from NITAGs representing different regions of the world presented their experiences of using systematic reviews and reflected on challenges inhibiting use. Three methodologists considered different aspects of using systematic reviews. Interactive sessions followed, where implications for SYSVAC2 were discussed. Participants supported having critical appraisal ratings, plain language summaries, keyword search, and data visualization functions in the registry. They suggested tailoring course content to different audiences and including overviews of reviews as a topic and examples of how NITAGs have used or could use existing reviews. Participants agreed that whether a review is out-of-date should be decided by those using the review rather than registry staff. The registry could help by highlighting the date of literature search or included primary studies. Participants recommended a visualization function to highlight overlap across reviews and guidance on handling challenges to using reviews, ideally, involving a practical element. No consensus was reached on which critical appraisal tool to use for reviews in the registry, but a majority of participants wanted registry staff to perform appraisals. Formative research is planned before the registry and online course are launched in 2020.

Effect of early measles vaccination on long-term protection: A systematic review.

BACKGROUND: In North America, the first dose of a measles-containing vaccine (MCV1) is administered at ≥12 months of age. However, MCV1 may be given to infants <12 months living in highly endemic areas or traveling to these areas. Although an early dose of MCV1 leads to immediate protection, it remains unclear how this impacts long-term immunity. METHODS: This systematic review and meta-analysis evaluates the impact of MCV1 given at <12 months vs. ≥12 months of age on long-term immunogenicity and vaccine effectiveness, with long-term defined as at least one-year post-vaccination. PubMed, EMBASE, Global Health, Web of Science and Scopus were searched on October 31st, 2019. Studies were included if they included a cohort of infants vaccinated <12 months of age and evaluated long-term immunogenicity, vaccine efficacy, or effectiveness. RESULTS: A total of 51 texts were identified: 23 reported outcomes related to vaccine effectiveness and 30 to immunogenicity. Infants vaccinated with MCV1 < 12 months of age showed an overall higher risk of measles compared to ≥12 months of age (RR = 3.16, 95% CI: 2.00, 5.01; OR = 2.46, 95% CI: 1.40, 4.32). Risk of measles decreased with increasing age at first vaccination, with those vaccinated with one dose ≥15 months at a lesser risk compared to 12-14 months or <12 months. Measles seroconversion and seropositivity was not affected by age at first vaccination, but antibody levels were significantly lower in the MCV1 < 12-month group (MD = -0.40, 95% CI: -0.71, -0.09). CONCLUSION: Long-term measles seroconversion and seropositivity did not appear to be affected by age at MCV1, while vaccine effectiveness decreased with younger age. There was not enough evidence to look at the effect of age at MCV1 on immune blunting.

Navigating inequities: a roadmap out of the pandemic.

The COVID-19 pandemic has exposed social inequities that rival biological inequities in disease exposure and severity. Merely identifying some inequities without understanding all of them can lead to harmful misrepresentations and deepening disparities. Applying an 'equity lens' to bring inequities into focus without a vision to extinguish them is short-sighted. Interventions to address inequities should be as diverse as the pluralistic populations experiencing them. We present the first validated equity framework applied to COVID-19 that sheds light on the full spectrum of health inequities, navigates their sources and intersections, and directs ethically just interventions. The Equity Matrix also provides a comprehensive map to guide surveillance and research in order to unveil epidemiological uncertainties of novel diseases like COVID-19, recognising that inequities may exist where evidence is currently insufficient. Successfully applied to vaccines in recent years, this tool has resulted in the development of clear, timely and transparent guidance with positive stakeholder feedback on its comprehensiveness, relevance and appropriateness. Informed by evidence and experience from other vaccine-preventable diseases, this Equity Matrix could be valuable to countries across the social gradient to slow the spread of SARS-CoV-2 by abating the spread of inequities. In the race to SARS-CoV-2 vaccines, this urgently needed roadmap can effectively and efficiently steer global leadership towards equitable allocation with diverse strategies for diverse inequities. Such a roadmap has been absent from discussions on managing the COVID-19 pandemic, and is critical for our passage out of it.

A systematic review of factors that influence the acceptability of vaccines among Canadians.

BACKGROUND: Canada's National Advisory Committee on Immunization (NACI) provides guidance on the use of vaccines in Canada. To support the expansion of its mandate to include considerations for vaccine acceptability when making recommendations, the NACI Secretariat developed a matrix of factors that influence acceptability. To inform and validate the matrix, we systematically reviewed evidence for factors that influence vaccine acceptability, and for interventions aimed at improving acceptability. METHODS: On 10-11 October 2018 we searched four bibliographic databases, the Theses Canada Portal, and ClinicalTrials.gov. Two reviewers agreed on the included studies. From each study, we extracted information about the participants, intervention or exposure, comparator, and relevant outcomes. Due to heterogeneity in the reported factors and acceptability indicators we synthesized the findings narratively. We appraised the certainty of evidence using GRADE. For each vaccine-preventable disease we populated a matrix of factors for which there was evidence of an influence on acceptability. RESULTS: One hundred studies (>1 million participants) contributed data relevant to the public, 16 (6191 participants) to healthcare providers, and three (84 participants) to policymakers. There were 43 intervention studies (~2 million participants). Across vaccines, we identified low certainty evidence for 70 factors relevant to the general population, 56 to high-risk groups, and 30 to healthcare providers. The perceived safety and importance of the vaccine, vaccination history, and receiving a recommendation from a healthcare provider were common influential factors. We found low certainty evidence that reminders for childhood vaccines and policies or delivery models for rotavirus vaccines could improve uptake and coverage. Evidence for other interventions was of very low certainty. CONCLUSIONS: The NACI vaccine acceptability matrix is useful for categorizing acceptability factors for the general public. Reminder systems may improve the uptake of childhood vaccines. Policies that make the rotavirus vaccine universally available and easily accessible may improve coverage. FUNDING: This systematic review was completed under contract to the Public Health Agency of Canada, Contract #4600001536.