Previous Infection and Effectiveness of COVID-19 Vaccination in Middle- and High-School Students | Pediatrics

In the context of a surge in SARS-CoV-2 infections due to the emergence of omicron BA.1 sub-lineage, we evaluated 2- and 3-dose VE and protection from previous infection in a population of almost 18 000 students who underwent school-based testing as part of a local TTS strategy to keep schools open. Our findings reveal that point estimates for infection paired with vaccination (ie, hybrid immunity) were higher than either previous infection or vaccination alone against presumed omicron (BA.1) infection, but confidence intervals often overlapped. Among students aged 16 to 19 years, point estimates for 2-dose hybrid immunity were significantly higher than 2 doses of vaccine alone. However, in the same age group, only the estimate for 3-dose hybrid immunity was higher than vaccine or previous infection only. Regardless of previous infection status, VE was higher for students with a recent vaccination with a third dose compared with 2-dose VE among students aged 16 to 19 years.

Our findings align with other studies revealing that hybrid immunity improves the overall protection and duration of protection against omicron (BA.1)^18,–20 and our estimates for 3-dose VE are comparable with studies assessing VE against omicron (BA.1) infection in similar age groups. The authors of at least 3 studies found BNT162b2 2-dose VE against infection for persons aged 12 and older ranging from 40% to 59% for those without previous infection.^21,–23 The authors of at least 1 study noted significantly higher 2-dose mRNA VE against omicron infection for previously infected compared with noninfected (68% vs 42%, respectively) in persons 12 years of age and older.¹⁸ Studies not excluding persons with previous infection revealed a 2-dose mRNA VE against omicron infection from 51% to 78% in adolescents 12 to 17 years of age, although both studies revealed declines in VE against infection as time since the second dose increased.^24,–26 

Among students aged 16 to 19 years with 2-dose hybrid immunity, protection against infection <180 days since vaccination was moderate yet not significant after 180 days. In the same age group, 2 doses with no previous infection were not protective against infection. In contrast, 2 doses, <120 days since vaccination, and with no previous infection were moderately effective for students aged 12 to 15 years. The differences in protection between age groups may be due to changes in risky behavior after vaccination, given comparable median days since the second dose for both age groups. Age-group differences may be explained by risk compensation (ie, a tendency to adjust behavior given perceived risk), potentially leading to riskier behavior. Risk compensation is more likely to occur when people are both highly motivated to take on risky behavior and it is within their control to do so.²⁷ There are likely important differences in the opportunities for independent decision-making for students aged 16 to 19 years compared with those aged 12 to 15 years. This, paired with the demonstrated efficacy reported postclinical trials for COVID-19 mRNA vaccines,²⁸ may have led to further reduced adherence to other precautions, such as mask-wearing, physical distancing, and increased participation in higher-risk behaviors among those vaccinated with 2 doses.

Although 3 doses among students aged 16 to 19 years were moderately effective (44.2%), protection increased to 70% among students with 3-dose hybrid immunity, although confidence intervals overlap. The addition of a third dose increased protection regardless of previous infection status, highlighting the importance of booster doses. In assessing the effect of previous infection on VE, students aged 16 to 19 years with previous infection had better protection with 2 and 3 doses compared with those without previous infection. The rates of past infection and vaccination likely affected the overall observed school attack rates during the omicron (BA.1) surge. These observations suggest that, absent infection-induced and vaccine-induced immunity, the school-level impact of the BA.1 surge on students may have been much worse.

This analysis is subject to several limitations. First, we were unable to evaluate VE for 12- to 15-year-olds receiving 3 doses of an mRNA vaccine because of a low sample size, given the short time window between the recommendation of a third dose for this age group and the TTS events analyzed. Second, we were unable to distinguish between students vaccinated with a third dose because of a risk-based indication (ie, immunocompromising status), which may lead to an underestimated VE. Third, most schools used antigen tests during TTS events because of ease of use and rapid results turn-around. Antigen test sensitivity for SARS-CoV-2 is generally lower compared with nucleic acid amplification tests, increasing the potential for false-negatives and the misclassification of outcomes, which may impact estimated effects. Fourth, this analysis was based on data from a single state; there may be individual-level (socioeconomic, behavioral) or state-level characteristics (variations in mandates of mitigation measures) that differ across the country. In addition, race/ethnicity was included in adjusted models, although race/ethnicity is likely a proxy for other unmeasured social/behavioral drivers of risk. Fifth, for children with hybrid immunity, we stratified by time since vaccination rather than time since last exposure (vaccine or past infection). Thus, students who were vaccinated a long time before, but had a more recent infection, may not be comparable to those who were vaccinated at the same time but were infected before vaccination because the time from the last exposure to an immunity-producing event (vaccination or infection) will differ. Sixth, previous infection status may be misclassified if it was not captured by the state surveillance system (eg, positive on an at-home antigen test and not reported). Finally, individual students/parents could opt out of TTS testing, and during the time period for this analysis, the participation of students in TTS events was 71% median (range: 48%–90%) across all schools. We were unable to assess the differences between those opting in compared with those opting out of TTS testing, and students opting in may have higher risk tolerance of SARS-CoV-2 exposure. These factors limit the generalizability of the findings.

The continual circulation of SARS-CoV-2 in the United States in the context of the reduction of other prevention measures highlights the importance of vaccination to protect both individuals and communities. Although protection with primary series vaccination against infection for previously SARS-CoV-2 naïve students was not found, our results reveal that protection against infection increased for those with hybrid immunity or with the addition of a third vaccine dose in the absence of infection-induced immunity. We were unable to measure protection against other severe outcomes of SARS-CoV-2 infection, such as hospitalization, yet current evidence suggests that VE remains strong against these severe outcomes.^24,–26,29 Real-world VE estimates can guide the prioritization of resources and help focus messaging needed, particularly at the state and local levels to protect against the risk of infection.