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. 2024 Dec 19;12(1):ofae718. doi: 10.1093/ofid/ofae718

Initial Effectiveness of mRNA-1273 Against SARS-CoV-2 Infection and Hospitalization in Young Children

Mary Aglipay 1,2, Jonathon L Maguire 3,4,5,6, Sarah Swayze 7, Ashleigh Tuite 8, Muhammad Mamdani 9,10,11,12, Charles Keown-Stoneman 13,14, Catherine S Birken 15,16,17,18,19, Jeffrey C Kwong 20,21,22,23,24,25,✉,2
PMCID: PMC11697100  PMID: 39758749

Abstract

Background

Data on mRNA-1273 (Moderna) vaccine effectiveness (VE) in children aged 6 months to 5 years are limited. The objectives of this study were to assess mRNA-1273 vaccine effectiveness against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19)–related hospitalization among children aged 6 months to 5 years during the initial 5 months of the vaccination campaign rollout, as well as to determine whether VE varied by age group (6 months to <2 years vs 2 to 5 years).

Methods

We used a test-negative study with linked health administrative data in Ontario, Canada, to evaluate vaccine effectiveness of mRNA-1273 against symptomatic SARS-CoV-2 infection and COVID-19-related hospitalization from July 28 to December 31, 2022. Participants included symptomatic children aged 6 months to 5 years who were tested by real-time polymerase chain reaction. The primary outcome was symptomatic infection, and the secondary outcome was COVID-19-related hospitalization.

Results

We included 572 test-positive cases and 3467 test-negative controls. Receipt of mRNA-1273 was associated with reduced symptomatic SARS-CoV-2 infection (VE, 90%; 95% CI, 53%–99%) and COVID-19-related hospitalization (VE, 82%; 95% CI, 4%–99%) ≥7 days after the second dose. We were unable to detect heterogeneity in VE across age groups.

Conclusions

Our findings suggest that mRNA-1273 vaccine effectiveness was initially strong against symptomatic SARS-CoV-2 infection and hospitalization in children aged 6 months to 5 years. Further research is needed to understand long-term effectiveness.

Keywords: COVID-19, children, mRNA-1273, SARS-CoV-2, test-negative study, vaccine effectiveness, vaccination

Vaccination remains an important strategy to mitigate the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and protect individuals from severe illness and death. In the Canadian province of Ontario, the mRNA-1273 (Moderna) coronavirus disease 2019 (COVID-19) vaccine (containing 25 mcg of the antigen) became available for children aged 6 months to 5 years on July 28, 2022, with a recommended interval of at least 8 weeks between the 2 doses [1].

Clinical trial data have shown the efficacy of mRNA-1273 against symptomatic SARS-CoV-2 infection to be 37% (95% CI, 13%–54%) for participants aged 2 to 5 years and 51% (95% CI, 21%–69%) for participants aged 6 months to 23 months during a period of Omicron dominance [2]. However, there were no cases of severe COVID-19 among trial participants who received the vaccine, so efficacy against severe outcomes was not evaluated.

COVID-19 vaccines have also been authorized for emergency use in adolescents and older children, with clinical trials demonstrating high efficacy and safety profiles [3–5]. Real-world studies in children aged 5 to 11 years have shown moderate effectiveness against symptomatic infection and high effectiveness against hospitalization and severe disease, with some reporting outcomes during Delta-dominant phases [6] and others capturing Omicron-dominant periods [7–12]. In Ontario, mRNA vaccines were approved for children aged 5 to 11 years in late November 2021, at which time the Delta variant (B.1.617.2) was predominant until late December 2021, when the Omicron variant (B.1.1.529) replaced it [13].

However, real-world data on COVID-19 vaccine effectiveness in children aged 6 months to 5 years are limited. Moreover, whether vaccine effectiveness is different by child age (eg, infants vs preschool children) or by previous documented infection is also unknown.

To address these gaps, we collected data from July 2022 to December 2022 to evaluate mRNA-1273 vaccine effectiveness against symptomatic SARS-CoV-2 infection and COVID-19-related hospitalization among children aged 6 months to 5 years. We also sought to examine whether vaccine effectiveness of mRNA-1273 against symptomatic SARS-COV-2 infection varied by age and by previous documented infection.

This research provides an account of the initial vaccine effectiveness of the mRNA-1273 vaccine in reducing symptomatic infection and hospitalization among children aged 6 months to 5 years. These findings contribute valuable evidence for assessing vaccine performance during the early phases of pediatric COVID-19 vaccination efforts. The results can help inform future vaccination strategies and support public health decisions regarding optimal approaches to protect young children through ongoing immunization efforts.

METHODS

We conducted a retrospective test-negative study to evaluate the effectiveness of the mRNA-1273 vaccine in Ontario, Canada, against symptomatic SARS-CoV-2 infection and COVID-19-related hospitalization using linked population-based databases. The test-negative design shares certain features with case–control studies in that individuals are grouped based on the outcome (test-positive or test-negative) and compared by exposure status (vaccinated or unvaccinated). However, it differs in that the controls (test-negative individuals) are not sampled from the underlying source population but instead come from the same group of symptomatic individuals who sought testing [14]. This design is particularly useful for minimizing bias related to health care–seeking behavior and diagnostic practices, as both cases and controls are identified from individuals seeking care within the same context. The test-negative design also reduces misclassification bias by using laboratory-confirmed test results to assign case status [14]. A test-negative design was also used to estimate the effectiveness of mRNA-1273 against hospitalization in young children. Cases were defined as symptomatic patients who were hospitalized due to, or partially due to, COVID-19, while controls were symptomatic patients who tested negative for COVID-19 and may or may not have been hospitalized.

Data sets were linked using unique encoded identifiers and analyzed at ICES. The data linkage process involved a combination of deterministic and probabilistic linkage methods (using health card number or a combination of first and last name, date of birth, sex, and postal code). We included community-dwelling children aged 6 months to 5 years as of July 28, 2022, who underwent testing for SARS-CoV-2 by real-time polymerase chain reaction (RT-PCR) and had documented signs or symptoms consistent with SARS-CoV-2 infection (Supplementary Data). Because date of symptom onset was generally unavailable, we did not specify a requirement regarding the number of days between symptom onset and testing date. Eligibility for testing during this period was conditional on meeting specific criteria, which included hospitalized patients, children presenting to hospital emergency departments, outpatients for whom COVID-19 treatment was being considered, household members of patient-facing healthcare workers, and symptomatic students who received an RT-PCR self-collection kit through their school [15]. Testing during this period was generally restricted to individuals meeting these criteria, rather than restrictions based on age. Testing information and symptoms were captured through the Ontario Laboratories Information System. These data were linked to COVaxON, a comprehensive vaccination database for Ontario residents. The study period was from July 28, 2022, to December 31, 2022, an Omicron-dominant phase of the pandemic (>97% of all cases) [16, 17]. Throughout the study period, Omicron sublineages, primarily BA.4 and BA.5, were dominant, with newer variants such as BQ.1 and BQ.1.1 beginning to emerge by late 2022 [16, 17].

We excluded children who were immunocompromised (defined as solid organ or hematopoietic stem cell transplant recipients, children taking immune suppressive medication, or children with HIV, cancer, sickle cell disease, or any other immunocompromising conditions) [9] because their immune response to vaccination may differ significantly from the general population, and therefore represent a distinct group requiring separate analysis. We also excluded children without provincial health insurance due to incomplete information on health care utilization and children missing birthdate, sex, or postal code information to ensure completeness of sociodemographic covariates. Children who received the BNT162b2 (Pfizer) vaccine, a non–Health Canada–authorized vaccine, or a dose of any COVID-19 vaccine before July 28, 2022, were excluded to maintain consistency in the evaluation of mRNA-1273 VE. We also excluded children who were tested <14 days after their first vaccine dose to ensure that VE estimates reflect a period when immunity would reasonably be expected and children with another positive test ≤90 days before specimen collection to avoid misclassifying persistent viral shedding as a new infection and to ensure that only new cases of SARS-CoV-2 were captured during the study period.

Outcomes

The primary outcome was a positive test for symptomatic SARS-CoV-2 infection, ascertained through RT-PCR. Children who tested positive for symptomatic SARS-CoV-2 infection at least once during the study period were considered cases. In our analysis, children were censored after their first relevant test. If a child had multiple positive tests, only the first positive was used. For children with multiple negative tests, 1 negative test was randomly selected for inclusion. The index date was the date of specimen collection.

The secondary outcome was hospitalization due to, or partially due to, COVID-19. Hospitalizations were captured through the Case and Contact Management system and the Canadian Institute for Health Information's Discharge Database (for hospital admissions; a positive test must have occurred within 14 days before to 3 days after admission). According to the guidelines for data entry information about COVID-19, hospitalization was included if the patient was admitted to the hospital for COVID-19 treatment or if their hospital stay was prolonged as a result of COVID-19. No deaths related to COVID-19 were recorded, defined as a positive test 30 days before death or within 7 days postmortem, either in the Case and Contact Management system or the Ontario Registered Persons Database, so deaths were not included as an outcome in this study. A test-negative design was also used to estimate the effectiveness of mRNA-1273 against hospitalization in young children. Cases were symptomatic patients who tested positive for SARS-CoV-2 and were hospitalized due to, or partially due to, COVID-19, while controls were symptomatic patients who tested negative for SARS-CoV-2 and may or may not have been hospitalized.

Exposure and Covariates

The primary exposure was receipt of the mRNA-1273 vaccine, as recorded in COVaxON, a centralized immunization information system that includes comprehensive information on all COVID-19 vaccination events in Ontario, including vaccination status, vaccine product, dose administered, date of administration, dose number, and dosing interval [9, 18].

Covariates were chosen a priori and evaluated as potential confounders (Supplementary Tables 1 and 2) based on their known relationships with SARS-CoV-2 infection or severity and receipt of a COVID-19 vaccine. We obtained age, sex, and postal code from the Ontario Registered Persons Database. To ascertain comorbidities, we applied validated algorithms and commonly used diagnostic codes on several databases, described elsewhere [19]. As one indicator of health-seeking behavior, we determined whether patients ever received an influenza vaccination through the Ontario Health Insurance Plan and Ontario Drug Benefit Databases. We obtained number of physician visits from birth as another indicator of health-seeking behavior. We ascertained COVID-19 vaccination of the child's mother using COVaxON and the MOMBABY database, an ICES-derived data set that links children born in Ontario to their mothers through birth hospitalization records. To obtain a proxy measure of whether children had mothers who were health care workers, we identified mothers who received vaccination before April 1, 2021, as the only individuals eligible for COVID-19 vaccines at that time were residents and staff of long-term care facilities, Indigenous adults, and health care workers. Using the postal code and Statistics Canada Postal Code Conversion File Plus, we identified the public health unit of residence. Residential postal code was also used to obtain neighborhood-level data from the 2016 Census on household income quintile, household density quintile, visible minority quintile, and essential worker quintile.

Statistical Analysis

We calculated descriptive statistics of baseline characteristics including standardized differences (SDs) for the overall sample, by test status, and by vaccination status (≥1 dose). SD is defined as the difference in means or proportions divided by the pooled standard deviation, with values >0.15 indicating a meaningful imbalance between groups [20].

To estimate vaccine effectiveness of 1 or 2 doses of mRNA-1273 against symptomatic laboratory-confirmed SARS-CoV-2 infection or COVID-19-related hospitalization, we used multivariable logistic regression to estimate the adjusted odds ratio of vaccination among cases compared with controls [21]. Vaccine effectiveness was defined as 1 minus the adjusted odds ratio. Confounders included in the model were week of test, age, sex, medical comorbidities, having a health care worker mother, positive SARS-CoV-2 RT-PCR test ≥90 days before the index date, household income quintile, household density quintile, visible minority quintile, essential workers quintile, and public health unit. We also included prior influenza vaccination and the number of physician visits as proxies for health-seeking behavior, as individuals with more frequent healthcare interactions may be more likely to seek testing for COVID-19-related symptoms. See Supplementary Figure 1 for a proposed directed acyclic graph illustrating the relationship between mRNA-1273 and symptomatic SARS-CoV-2 infection in this age group. We used likelihood ratio tests to determine whether week of test should be modeled as a nonlinear continuous variable or remain a categorical variable. Number of physician visits was modeled as a nonlinear continuous variable using restricted cubic splines. To examine effect modification by age (6 months to <2 years and 2 years to 5 years) and positive SARS-CoV-2 RT-PCR test ≥90 days before index date, we used interaction terms in multivariable logistic regression models and compared models with and without interaction terms using likelihood ratio tests (LRTs). All analyses were conducted using R, version 4.1.3 (R Foundation for Statistical Computing, Vienna, Austria), and SAS, version 9.4 (SAS Institute, Cary, NC, USA).

RESULTS

From July 28, 2022, to December 31, 2022, 5502 SARS-CoV-2 RT-PCR testing episodes occurred in children aged 6 months to 5 years. We excluded 1027 episodes based on exclusion criteria defined at study outset, resulting in 4481 episodes. After removing 392 randomly selected episodes from test-negative participants with multiple testing episodes, 4089 participants were considered for analysis. A further 53 participants were excluded based on predefined testing and vaccine eligibility criteria. Overall, 4039 children were included in the analysis, with 572 (14.2%) symptomatic test-positive cases and 3467 (85.8%) symptomatic test-negative controls (Figure 1).

Figure 1.

Figure 1.

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Flowchart of children aged 6 months to <5 years old tested for symptomatic SARS-CoV-2 infection during the study period from July 28 to 31 December 2022. Abbreviations: OHIP, Ontario Health Insurance Plan; PCR, real-time polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Test-positive cases were more likely to be <1 year of age (SD, 0.30), more likely to live in areas with the highest household density (SD, 0.20), and more likely to live in areas other than the middle quintile for visible minority (Table 1). They were also more likely to live in areas with the lowest proportions of essential workers (SD, 0.19).

Table 1.

Descriptive Characteristics of Children Aged 6 Months to 5 Years Tested for SARS-CoV-2 With COVID-19-Related Symptoms Between July 28, 2022, and December 31, 2022, Comparing Test-Positive Cases With Test-Negative Controls (n = 4039)

  Test-Negative Controls, No. (%)a Test-Positive Cases, No. (%)a SDb
Total 3467 572
Age groupc
 Age 6 mo to <1 y 665 (19.2) 184 (32.2) 0.30
 Age 1 to <2 y 892 (25.7) 121 (21.2) 0.11
 Age 2 to <3 y 736 (21.2) 106 (18.5) 0.07
 Age 3 to <4 y 670 (19.3) 94 (16.4) 0.08
 Age 4 to <5 y 504 (14.5) 67 (11.7) 0.08
Male sex 1915 (55.2) 309 (54.0) 0.02
Any comorbidityd 184 (5.3) 32 (5.6) 0.01
Past influenza vaccination 844 (24.3) 133 (23.3) 0.03
Mother health care worker status 380 (11.0) 56 (9.8) 0.04
Public health unit regione
 Central East 171 (4.9) 32 (5.6) 0.03
 Central West 630 (18.2) 100 (17.5) 0.02
 Durham 64 (1.8) 14 (2.4) 0.04
 Eastern 115 (3.3) 27 (4.7) 0.07
 Northern 1245 (35.9) 127 (22.2) 0.31
 Ottawa 46 (1.3) 25 (4.4) 0.18
 Peel 271 (7.8) 91 (15.9) 0.25
 South West 723 (20.9) 78 (13.6) 0.19
 Toronto 140 (4.0) 42 (7.3) 0.14
 York 47 (1.4) 30 (5.2) 0.22
Area-level income quintile
 1 (lowest)e,f 739 (21.3) 121 (21.2) 0.00
 2 659 (19.0) 102 (17.8) 0.03
 3 712 (20.5) 113 (19.8) 0.02
 4 699 (20.2) 126 (22.0) 0.05
 5 (highest) 615 (17.7) 101 (17.7) 0.00
Area-level household density quintilee
 1 (lowest) 674 (19.4) 86 (15.0) 0.12
 2 900 (26.0) 134 (23.4) 0.06
 3 544 (15.7) 78 (13.6) 0.06
 4 695 (20.0) 117 (20.5) 0.01
 5 (highest) 613 (17.7) 149 (26.0) 0.20
Area-level visible minority quintilee
 1 (lowest) 1155 (33.3) 151 (26.4) 0.15
 2 863 (24.9) 96 (16.8) 0.20
 3 538 (15.5) 85 (14.9) 0.02
 4 426 (12.3) 108 (18.9) 0.18
 5 (highest) 445 (12.8) 124 (21.7) 0.23
Essential workers quintilee,g
 1 (lowest) 304 (8.8) 86 (15.0) 0.19
 2 776 (22.4) 130 (22.7) 0.01
 3 782 (22.6) 124 (21.7) 0.02
 4 795 (22.9) 118 (20.6) 0.06
 5 (highest) 770 (22.2) 106 (18.5) 0.09
Days since last dose
 Unvaccinated 3227 (93.1) 545 (95.3) 0.09
 14+ days since dose 1 175 (5.0) 26–30 (4.5–5.2)h 0.02
 7+ days since dose 2 65 (1.9) <6 (<0.01)h 0.17
 Hospitalization related to COVID-19 0 (0.0) 222 (38.8) N/A
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Abbreviations: COVID-19, coronavirus disease 2019; DA, dissemination area; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

aProportion reported, unless stated otherwise.

bStandardized differences of >0.15 are considered clinically relevant. Comparing test-negative subjects with test-positive subjects.

cEligibility was determined based on age as of July 28, 2022. Children were included if they were between 6 months and 5 years of age on this date. Children who fell outside this age range on July 28, 2022, but were within it during the testing period (July 28 to December 31, 2022) were excluded.

dComorbidities include asthma, diabetes, immunocompromising conditions caused by underlying diseases or therapy, autoimmune diseases, active cancer, or pediatric complex chronic conditions.

eThe sum of counts does not equal the column total because of individuals with missing information (≤2.0%) for this characteristic.

fHousehold income quintile has variable cutoff values in each city or Census area to account for cost of living. A DA being in quintile 1 means it is among the lowest 20% of DAs in its city by income.

gPercentage of people in the area working in the following occupations: sales and service occupations; trades, transport, and equipment operators and related occupations; natural resources, agriculture, and related production occupations; and occupations in manufacturing and utilities. Census counts for people are randomly rounded up or down to the nearest number divisible by 5, which causes some minor imprecision.

hDue to institutional privacy policies, any cells ≤5 (except for missing values) must be suppressed, and ranges must be provided for complementary cells to prevent back calculation.

Overall vaccine effectiveness against symptomatic SARS-CoV-2 infection was 20% (95% CI, −27% to 51%) ≥14 days following a first dose and 90% (95% CI, 53%–99%) ≥7 days following a second dose (Figure 2).

Figure 2.

Figure 2.

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Vaccine effectiveness estimatesa in children aged 6 months to 5 years old against (A) symptomatic SARS-CoV-2 infection and (B) COVID-19-related hospitalizations. aConfounders included in the model were week of test, age, sex, medical comorbidities, prior influenza vaccination, having a health care worker mother, positive SARS-CoV-2 RT-PCR test ≥90 days before the index date, household income quintile, household density quintile, visible minority quintile, essential workers quintile, public health unit, and number of physician visits. Abbreviations: COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Vaccine effectiveness for a single dose peaked at 68% (95% CI, 18%–90%) between 14 and 29 days after a first dose and waned thereafter (Supplementary Figure 2). We had an insufficient sample size to assess vaccine effectiveness at monthly intervals after a second dose.

We observed only a small number of COVID-19-related hospitalizations (n = 222). Fewer than 10 COVID-19-related hospitalizations occurred among children who had received at least 1 dose of mRNA-1273. Vaccine effectiveness against COVID-19-related hospitalization was 58% (95% CI, 0%–86%) ≥14 days after a first dose and 82% (95% CI, 4%–99%) ≥7 days after a second dose (Figure 2).

We did not detect differences in vaccine effectiveness against symptomatic SARS-CoV-2 infection by age comparing children aged 6 months to 2 years vs those aged 2 to 5 years (LRT P = .56). We also did not detect differences in vaccine effectiveness against symptomatic SARS-CoV-2 infection by previous documented SARS-CoV-2 infection status (LRT P = .15).

DISCUSSION

Our findings suggest that 2 doses of mRNA-1273 were associated with protection against symptomatic SARS-CoV-2 infection and COVID-19-related hospitalization in children aged 6 months to 5 years in the first 5 months of vaccine rollout.

An earlier test-negative study of vaccine effectiveness of mRNA-1273 against symptomatic infection among uninsured children aged 3 to 5 years in the United States (n = 37 010) found a vaccine effectiveness of 40% (95% CI, 26%–52%) 2 weeks after a first dose and a peak of 60% (95% CI, 49%–68%) 2 weeks after a second dose [22]. Vaccine effectiveness against COVID-19-related hospitalization was not evaluated in that study. However, that population of children had several differences from our own (ie, communities without health insurance), making direct comparisons challenging. Children in these communities may have faced higher exposure to infection due to socioeconomic factors, such as parental employment in essential jobs and higher density households. In another study, vaccine effectiveness against emergency department or urgent care encounters related to COVID-19 among children aged 6 months to 5 years was 36% 2 weeks after a second dose and decreased to 21% >2 months after vaccination (although the CI included the null value) [23]. These studies collectively demonstrate evidence of moderate protective benefits of mRNA-1273 vaccine lasting up to 1 month following the initial dose and extending to 2 months post–administration of the second dose in children <5 years of age.

Compared with other studies in children in Ontario, vaccine effectiveness against symptomatic infection among children aged 6 months to 5 years was comparable to children aged 5 to 11 years after a first dose (20% vs 24% 14 to 29 days after a first dose), with higher vaccine effectiveness after a second dose (90% vs 66% 7 to 29 days after a second dose) [9]. Although no deaths related to COVID-19 were recorded in our study, vaccine effectiveness against either hospitalization or death in children aged 5 to 11 years was comparable to our findings (82% vs 79% ≥7 days after a second dose).

The large difference in VE between 1 and 2 doses likely reflects the partial and short-lived immunity provided by a single dose, which peaks within the first 14–29 days but declines thereafter. In contrast, the second dose elicits a more robust and durable immune response, offering stronger protection during the early postvaccination period, consistent with the expected immunological response to mRNA vaccines.

In our study, waning of protection was observed starting 14 days after the first dose. Because few children with 2 vaccine doses subsequently presented for testing in our study, we were unable to evaluate waning of protection at monthly intervals after a second dose. Waning of protection after each vaccine dose has been demonstrated in multiple studies of mRNA vaccines in older children and adults [11, 24, 25].

Although we did not observe a difference in vaccine effectiveness against symptomatic infection between children younger than 2 years and children aged 2 to 5 years, this should not be interpreted as definitive evidence of no difference. Rather, our study had limited statistical power to detect heterogeneity across age groups. As such, larger studies with increased statistical power are needed to reliably assess whether age-related differences in VE exist. Further, our study may reflect vaccine effectiveness in a population with a high prevalence of previous infection. Our study did not observe a difference in vaccine effectiveness by previously documented infection. However, we may not have had sufficient statistical power to detect heterogeneity of effects. Although <15% of our study sample had a provincial laboratory-confirmed previous infection, studies from Toronto and Montreal, Canada, have demonstrated that 45% to 74% of children in this age group demonstrated evidence of infection-acquired immunity by June 2022 [26]. In the United States, 90% of children aged 6 months to 4 years demonstrated evidence of infection-acquired SARS-CoV-2 immunity by the end of 2022 [27].

Our study took place during fall 2022, a period with the circulation of other respiratory viruses such as influenza and RSV, which could overlap with COVID-19 symptoms. To address this, we used a broad clinical disease definition to capture a range of symptomatic presentations potentially related to COVID-19. This approach minimizes the risk of missing atypical or mild COVID-19 cases, especially in children, where symptoms can vary.

We were limited to children who were able to access testing during a time of restricted testing in the province, which may have reduced the transportability of our findings. The findings may not be generalizable to children who have limited access to testing or whose families choose not to test. During the follow-up period (July 28, 2022, to December 31, 2022), rapid antigen tests (RATs) were widely available across Ontario free of charge through pharmacies, schools, workplaces, and local businesses [28]. There was no formal requirement for a nucleic acid amplification test (NAAT; such as RT-PCR) after a positive RAT, and individuals were often advised to assume infection without confirmatory testing unless clinically or publicly required. This could result in underrepresentation of positive cases in NAAT testing data. Unvaccinated children may be underrepresented among positive cases due to lower concern for SARS-CoV-2 infection and fewer overall tests (whether RAT or NAAT). If unvaccinated children are less likely to be tested due to lower perceived risk, positive cases among unvaccinated children could be underrepresented, potentially underestimating VE. Conversely, vaccinated children with mild symptoms or negative RATs may also skip further testing, which could lead to an underestimation of positive cases among the vaccinated group. While we aimed to capture symptomatic cases regardless of vaccination status, some underestimation of cases in each group is possible, making the precise direction of bias in VE estimates difficult to determine.

This study has several limitations. We could not examine deaths, as no deaths occurred during the study period. We were limited to children who were able to access testing during a time of restricted testing in the province, which may have reduced the transportability of our findings. The findings may not be generalizable to children who have limited access to testing or whose families choose not to test. We are unable to make inferences to immunocompromised children as they were excluded from our study. Residual confounding due to health-seeking behaviors may still be an issue in test-negative studies [14], though we included past influenza vaccination and number of physician visits in our models as proxies of health-seeking behavior. We were also limited to symptomatic infection using the test-negative design. Test-negative studies focusing on asymptomatic infections can suffer from collider stratification bias, as testing behavior may be influenced by both vaccination and disease status. This occurs when testing acts as a common effect (collider), introducing bias. By restricting the analysis to symptomatic individuals, we help ensure consistent testing behavior across vaccinated and unvaccinated groups, reducing the risk of bias in VE estimates. Finally, due to the decreasing number of children undergoing provincial RT-PCR testing, we were unable to examine vaccine effectiveness beyond the initial 5-month period following vaccine rollout. Comprehensive primary research studies may be necessary to obtain vaccine effectiveness data given the decline in provincial testing.

CONCLUSIONS

This study found that 2 doses of the mRNA-1273 (Moderna) COVID-19 vaccine offered protection against symptomatic SARS-CoV-2 infection and COVID-19-related hospitalization in children aged 6 months to 5 years in the first 5 months of vaccine rollout. While the vaccine's effectiveness was modest after the first dose, it increased after the second dose, which is aligned with previous studies in older age groups. The observed waning of protection after the first dose highlights the need for continued monitoring of vaccine effectiveness over time, especially as new variants of the virus emerge. The study adds to the growing body of evidence supporting the effectiveness of COVID-19 vaccines in children and emphasizes the importance of vaccination in reducing the risk of severe disease and hospitalization.

Supplementary Material

ofae718_Supplementary_Data
ofae718_supplementary_data.docx (671.5KB, docx)

Acknowledgments

We would like to acknowledge Public Health Ontario for access to vaccination data from COVaxON case-level data from the Public Health Case and Contact Management Solution (CCM) and COVID-19 laboratory data, as well as assistance with data interpretation. We also thank the staff of Ontario's public health units, who are responsible for COVID-19 case and contact management and data collection within CCM. This document used data adapted from the Statistics Canada Postal CodeOM Conversion File, which is based on data licensed from Canada Post Corporation, and/or data adapted from the Ontario Ministry of Health Postal Code Conversion File, which contains data copied under license from Canada Post Corporation and Statistics Canada. Parts of this material are based on data and/or information compiled and provided by MOH, CIHI, Statistics Canada, and IQVIA Solutions Canada Inc. The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. Adapted from Statistics Canada, Canadian Census 2016. This does not constitute an endorsement by Statistics Canada of this product. We thank IQVIA Solutions Canada Inc. for use of their Drug Information File.

Data availability. The data set from this study is held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (eg, health care organizations and government) prohibit ICES from making the data set publicly available, access may be granted to those who meet prespecified criteria for confidential access, available at https://www.ices.on.ca/DAS (email: das@ices.on.ca).

Code availability. The full data set creation plan and underlying analytic code are available from the authors upon request, with the understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification. Correspondence and requests for materials should be addressed to J.C.K.

Financial support. This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). This study also received funding from the Ontario Health Data Platform (OHDP), a Province of Ontario initiative to support Ontario's ongoing response to COVID-19 and its related impacts, and the Dalla Lana School of Public Health Data Science for Population Health Seed Grant. The opinions, results, and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by the OHDP, its partners, or the Province of Ontario is intended or should be inferred. The funders had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. J.C.K. is supported by a Clinician-Scientist Award from the University of Toronto. J.L.M. is supported by a Lawson Chair in Patient Engagement in Child Nutrition from the University of Toronto. C.S.B. is supported by the Edwin S.H. Leong Chair in Child Health Intervention​ at the University of Toronto. M.M. has received honoraria from Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, and Bayer. M.A. is supported by a trainee grant from Canadian Institutes for Health Research and the Unity Health Toronto Research Training Centre.

Role of funder/sponsor. The funders had no role in the design and conduct of the study.

Author contributions. Ms. Aglipay and Drs. Kwong and Maguire conceptualized and designed the study, contributed to the analysis plan, interpreted the results, and drafted the initial manuscript; Ms. Aglipay conducted the analyses, generated the figuresm and interpreted the results; Ms. Swayze contributed to the analysis plan, obtained the data, and interpreted the results; Dr. Keown-Stoneman contributed to the analysis plan and interpreted the results; Drs. Birken, Tuite, and Mamdani interpreted the results; and all authors reviewed, edited, and approved the final version of the manuscript, authorized its submission for publication, and agree to be accountable for all aspects of the work.

Patient consent. ICES is a prescribed entity under Ontario's Personal Health Information Protection Act (PHIPA). Section 45 of PHIPA authorizes ICES to collect personal health information, without consent, for the purpose of analysis or compiling statistical information with respect to the management of, evaluation or monitoring of, allocation of resources to, or planning for all or part of the health system. Projects that use data collected by ICES under section 45 of PHIPA and use no other data are exempt from Research Ethics Board review. The use of the data in this project is authorized under section 45 and approved by ICES’ Privacy and Legal Office.

Dissemination to participants and related patient and public communities. The results of this study have been made available to the public on a preprint server and have been shared with the Ministry of Health and ICES. Following peer review publication, they will be further disseminated by ICES through news media and social media. It is not possible to send study results to participants because all personal identifying information has been removed from the data set.

Contributor Information

Mary Aglipay, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.

Jonathon L Maguire, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Pediatrics, St Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.

Sarah Swayze, ICES, Toronto, Ontario, Canada.

Ashleigh Tuite, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

Muhammad Mamdani, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; ICES, Toronto, Ontario, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.

Charles Keown-Stoneman, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.

Catherine S Birken, Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; Division of Pediatric Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Jeffrey C Kwong, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; ICES, Toronto, Ontario, Canada; Public Health Ontario, Toronto, Ontario, Canada; Centre for Vaccine Preventable Diseases, University of Toronto, Toronto, Ontario, Canada; Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada; University Health Network, Toronto, Ontario, Canada.

Supplementary Data

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

References

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ofae718_Supplementary_Data
ofae718_supplementary_data.docx (671.5KB, docx)

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