Introduction

Severe Acute Respiratory Syndrome (SARS-CoV-2) has caused more than 6.5 million deaths globally [1]. Safe and effective vaccines to prevent SARS-CoV-2 infection and severe outcomes have been approved since late 2020 for adults [2]. With the emergence of viral variants B.1.617.2 (Delta) in May 2021 and B.1.1.529 (Omicron) in late November 2021, decreased vaccine effectiveness against infection was observed [3–6]. Given that the goal of vaccination is to prevent death, severe disease, and overall disease burden, it is important to consider how well vaccines achieve these goals among individuals infected with SARS-CoV-2 [7].

Four recent studies focused on quantifying the real-world effectiveness of SARS-CoV-2 vaccination against hospitalization among adolescent or pediatric populations [8–11]. All the studies used uninfected controls, and resulting vaccine effectiveness estimates reflect the joint risk of SARS-CoV-2 infection and the risk of hospitalization conditional on infection [12]. Olson et al. [8] showed that BNT162b2 was 94% effective against hospitalization among adolescents infected with the Delta variant (B.1.617.2). After the emergence of the Omicron variant (B.1.1.529), two dose vaccine effectiveness against hospitalization was estimated to be 73% among adolescents ages 12 to 17 and 48% among pediatric patients ages 5 to 11 [9]. In a recent Morbidity and Mortality Weekly Report (MMWR), two dose vaccine effectiveness against hospitalization was between 73% and 94% among adolescent and pediatric populations [10]. In a study among hospitalized patients, two dose vaccine effectiveness against SARS-CoV-2 hospitalization was 93% during the Delta-dominant period and 40% during the Omicron-dominant period among adolescents, and 68% during the Omicron-dominant period among pediatric patients [11]. In contrast to the approach used in these studies, we conditioned upon SARS-CoV-2 infection in our analysis to estimate the direct association between vaccination and hospitalization risk among pediatric and adolescent SARS-CoV-2 cases [13].

The Canadian province of Ontario is a large (population 14.6 million) and diverse jurisdiction with high levels of SARS-CoV-2 vaccine coverage [14]. Approximately 87% of Ontario residents ages 12 to 17 and 53% of Ontario residents ages 5 to 11 received at least one SARS-CoV-2 dose as of January 2022 [15]. Most individuals ages 12–17 were eligible to receive the BNT162b2 (Pfizer-BioNTech, Comirnaty) vaccine beginning on May 28, 2021 [16], followed by ages 5 to 11 on November 28, 2021 [17]. Health Canada authorized Moderna Spikevax on August 27, 2021 for ages 12 to 17, but it was not authorized for ages 6 to 11 until after our study period [18]. We calculated one dose and two dose mRNA vaccine effectiveness against hospitalization among adolescent and pediatric SARS-CoV-2 cases to examine if vaccines prevent hospitalization when they fail to prevent SARS-CoV-2 infection.

Methods

Results

In total, 62 hospitalized SARS-CoV-2 cases and 27,674 non-hospitalized SARS-CoV-2 cases were included (Fig 1; Table 1). In the full cohort across both age groups and the two time periods, individuals hospitalized with SARS-CoV-2 were more likely to be unvaccinated, immunocompromised, have an asthma diagnosis, live in the West or North health regions, and have an earlier case onset date (Table 1). We were unable to present frequencies, percentages, means, and standard deviations for the cohort stratified by age group and time period due to small cell sizes, however the relationships were quantified using standardized differences and statistical tests (S1 Table).

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Fig 1. Flow diagram for creation of cohort.

https://doi.org/10.1371/journal.pone.0283715.g001

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Table 1. Description of adolescent and pediatric SARS-CoV-2 cases by hospitalization status (n = 27,736).

https://doi.org/10.1371/journal.pone.0283715.t001

In the pre-Omicron period after adjustment for sex, asthma, immunocompromising condition, age, health region, and case onset date, we observed that one and two SARS-CoV-2 vaccine doses were not significantly associated (adjusted OR (aOR) one dose = 3.09 [95% CI: 0.31, 16.84], p = 0.26; aOR two doses = 0.90 [95% CI: 0.22, 2.86), p = 0.15) with additional protection against hospitalization among adolescent SARS-CoV-2 cases (Table 2). In the Omicron period after adjustment for sex, asthma, immunocompromising condition, age, health region, and case onset date, one SARS-CoV-2 dose was not significantly associated (aOR = 0.90 [95% CI: 0.05, 5.83], p = 0.93) with additional protection against hospitalization, but two SARS-CoV-2 doses were associated with an 85% (aOR = 0.15, [95% CI: 0.04, 0.53], p<0.01) lower likelihood of hospitalization among adolescent SARS-CoV-2 cases. After adjustment for sex, asthma, immunocompromising condition, age, health region, and case onset date, one SARS-CoV-2 vaccine dose was associated with a 79% (aOR = 0.21, [95% CI: 0.03, 0.77], p<0.05) lower likelihood of hospitalization among pediatric SARS-CoV-2 cases (ages 4–11) in the Omicron period (Table 2).

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Table 2. Adjusted odds ratios of the association between vaccination status and hospitalization among adolescent and pediatric SARS-CoV-2 cases (n = 27,736).

https://doi.org/10.1371/journal.pone.0283715.t002

The E-value for the adjusted association between vaccination with two doses and the risk of hospitalization in our primary analysis among the adolescent population in the Omicron period (i.e., aOR = 0.15) was 12.8 [29]. An unmeasured confounder would need to be independently associated with vaccination and hospitalization by a 12.8-fold risk ratio to result in a null association, after adjusting for sex, asthma, immunocompromising condition, age, health region, and case onset date. Similarly, the E-value for the upper 95% CI bound (i.e., 95% CI upper bound = 0.53) is 3.2. A set of unmeasured confounders would need to be independently associated with vaccination and hospitalization by a 3.2-fold risk ratio for the 95% CI to encompass the null value after controlling sex, asthma, immunocompromising condition, age, health region, and case onset date. The E-value for the adjusted association between vaccination with one dose and the risk of hospitalization among the pediatric population (i.e., aOR = 0.21) was 9.0 and the E-value for the upper 95% CI bound (i.e., 95% CI upper bound = 0.77) was 1.9.

Our vaccine effectiveness estimates did not substantially change when we matched on specimen collection date, when we only included symptomatic cases, and when we included income and visible minority status at the census subdivision level (S2 Table). In our sensitivity analysis where only cases with onset dates prior to January 5, 2022 were included, the association between one vaccine dose and hospitalization among pediatric Omicron SARS-CoV-2 cases was invalid (due to too few hospitalizations in the time period), but the association among adolescent Omicron SARS-CoV-2 cases remained unchanged compared to our main analysis (S2 Table).

Discussion

In this population-based analysis from the Canadian province of Ontario, we find evidence that mRNA vaccines against SARS-CoV-2 prevent hospitalization when adolescents receive a full two dose series and children received one dose in the context of an epidemic dominated by the immune-evasive Omicron variants. Among adolescent SARS-CoV-2 cases one vaccine dose was not significantly associated with a lower likelihood of protection against hospitalization in the pre-Omicron and Omicron periods, and two doses were not significantly protective in the pre-Omicron period. Our vaccine effectiveness estimates demonstrate robustness to unmeasured confounding, as evidenced by the high E-values for the estimates. As all subjects in this study had SARS-CoV-2 infection, the protection afforded by vaccination against hospitalization relates to attenuation of disease and is independent of protection provided against infection. This may in part explain our finding that vaccination was ineffective at preventing hospitalization in adolescents conditional upon infection with the Delta variant. SARS-CoV-2 infection with the Delta variant was less common among vaccinated individuals, and our study cohort during the Delta time period likely had a higher proportion of high risk population members compared to during the Omicron period [33].

The studies that have focused on SARS-CoV-2 vaccine effectiveness against hospitalization in adolescent and pediatric populations are not directly comparable to ours due to differences in control selection. Our estimated vaccine effectiveness estimates against hospitalization are lower than most estimates from studies using negative controls in the United States [8–10], likely because we isolated the impact of vaccination of hospitalization risk, independent of susceptibility to SARS-CoV-2 infection. In a case-control study conducted between May and October 2021 (i.e., prior to widespread infection with Omicron) with test-negative and syndrome-negative controls, vaccine effectiveness against hospitalization was 94% among those with two doses and 97% among those with one dose [8]. A study with 164 hospitals in the United States from April 2021 to January 2022 found that two dose vaccine effectiveness against hospitalization was 74% among children ages 5–11 years and between 73% and 94% among adolescents [10].

In contrast, two dose vaccine effectiveness was calculated to be 40% against hospitalization among adolescents during the circulation of Omicron in a study including 31 hospitals across the United States [11]. This lower estimate but may be due to earlier adolescent vaccination dates in the United States compared to in Ontario, as well as the impact of vaccine waning [11]. Unlike prior studies, our control group consisted of non-hospitalized SARS-CoV-2 cases, not uninfected individuals. This allowed for the isolation of the effectiveness of vaccination against hospitalization independent of infection risk, which explains our lower vaccine effectiveness estimates against hospitalization compared to the majority of prior studies [12].

Our study has several notable strengths. Due to Ontario’s high quality public health surveillance data, we isolated the impact of vaccination on hospitalization risk with control for individual level demographic and health related factors. Our study includes the population of a diverse region with publicly funded healthcare [34, 35]. We used a quantitative bias analysis to quantify the susceptibility of our results to unmeasured confounding [29]. Our study also had a few limitations. First, we did not consider time since vaccination in our analysis. In a recent study in the United States, time since vaccination was not shown to significantly impact SARS-CoV-2 vaccine effectiveness estimates against hospitalization in younger individuals [10]. We were unable to assess two dose effectiveness against hospitalization specifically among cases ages 4–11 years due to few hospitalizations among two-dose vaccinated individuals. Additionally, with only 62 total hospitalizations included in our study, we were likely underpowered to detect all true vaccine effects. Vaccination may be protective where our study showed a lack of statistical significance (i.e., Type II error), and a larger study over a longer period is needed. Some individuals aged four in our study were ineligible for vaccination. If they had a higher incidence of hospitalization, our vaccine effectiveness estimates would be biased away from the null. The availability of testing, and the propensity to get tested may have differed between vaccinated and unvaccinated individuals, and the comorbidities may have been more completely ascertained among hospitalized SARS-CoV-2 cases. Finally, comorbidities (i.e., asthma and immunocompromising conditions) in the CCM did not have a standardized definition which leads to residual confounding.

With the continued emergence of variants that may further decrease SARS-CoV-2 vaccine effectiveness against infection, it is vital to consider how effective these vaccines are at preventing severe outcomes [36]. Future studies should examine the impact of subsequent vaccine doses in adolescent and pediatric populations on SARS-CoV-2 hospitalization risk with emerging variants.

Conclusions

In this evaluation of the effectiveness of SARS-CoV-2 vaccination in adolescent and pediatric Omicron cases ages 4 to 17 in Ontario, Canada, we found that vaccination with two doses among adolescents and one dose among children is associated with a decreased likelihood of hospitalization, even when the vaccines do not prevent infection. SARS-CoV-2 vaccines remain an effective intervention to prevent severe outcomes in adolescent and pediatric populations, and continued efforts are needed to increase vaccine uptake in these populations.

Supporting information

Acknowledgments

We wish to thank the staff at Public Health Ontario and Ontario’s public health units for collecting, sequencing, analyzing, and providing access to the data used for this analysis. We are also appreciative to the reviewers for providing comprehensive and constructive reviews.