Correspondence

BNT162b2 Protection against the Omicron Variant in Children and Adolescents

To the Editor

Price and colleagues (published online on March 30 at NEJM.org)1 describe the effectiveness of the BNT162b2 vaccine (Pfizer–BioNTech) against the B.1.1.529 (omicron) variant of SARS-CoV-2 in children and adolescents, findings that have important clinical relevance and policy implications. However, the study was designed without the inclusion of previous Covid-19 status as a confounding factor. It is well known that SARS-CoV-2 infection confers immune protection and appears to result in increased protection against severe Covid-19,2 factors that could affect the evaluation of vaccine effectiveness. For instance, the vaccine effectiveness against hospitalization for Covid-19 did not appear to diminish over time during the surge in the B.1.617.2 (delta) variant, although studies have shown that levels of neutralizing antibodies decrease over time after receipt of the BNT162b2 vaccine whereas neutralizing-antibody and T-cell responses were retained 12 months after initial infection.3,4 Thus, the inclusion of previous Covid-19 status should have been clearly mandated in the study design.

Guangting Zeng, M.M.
First People’s Hospital of Chenzhou, Chenzhou, China

No potential conflict of interest relevant to this letter was reported.

This letter was published on May 11, 2022, at NEJM.org.

  1. 1. Price AM, Olson SM, Newhams MM, et al. BNT162b2 protection against the omicron variant in children and adolescents. N Engl J Med 2022;386:1899-1909.

  2. 2. León TM, Dorabawila V, Nelson L, et al. COVID-19 cases and hospitalizations by COVID-19 vaccination status and previous COVID-19 diagnosis — California and New York, May–November 2021. MMWR Morb Mortal Wkly Rep 2022;71:125-131.

  3. 3. Levin EG, Lustig Y, Cohen C, et al. Waning immune humoral response to BNT162b2 Covid-19 vaccine over 6 months. N Engl J Med 2021;385(24):e84-e84.

  4. 4. Guo L, Wang G, Wang Y, et al. SARS-CoV-2-specific antibody and T-cell responses 1 year after infection in people recovered from COVID-19: a longitudinal cohort study. Lancet Microbe 2022;3(5):e348-e356..

Response

The authors reply: Zeng notes that previous SARS-CoV-2 infection can provide protective immunity against subsequent infection and could bias estimates of vaccine effectiveness if unaddressed. Although the inclusion of such data in our study would have been ideal, we were not able to assess whether vaccine effectiveness varied according to previous infection because we lacked access to past Covid-19 testing results in most of the patients. In addition, serologic testing for SARS-CoV-2 antibodies cannot accurately distinguish between previous and current infection. Previous infection can provide protective immunity, especially when coupled with vaccination, and thus can modify vaccine effectiveness.1 However, the presence of previous infection causes confounding bias of vaccine effectiveness only when it influences vaccination decisions differentially in those without previous infection. If previous infection had reduced the likelihood of both subsequent infection and vaccination, the controls in our study would have been enriched with unvaccinated participants and would have biased vaccine effectiveness downward.2 In reality, most SARS-CoV-2 infections in children are undiagnosed because they are asymptomatic or result in mild symptoms and thus are unlikely to directly affect subsequent vaccination decisions.2,3 Thus, we infer a low likelihood of substantial confounding bias from previous infection in our study.

Ashley M. Price, M.P.H.
Samantha M. Olson, M.P.H.
Manish M. Patel, M.D.
Centers for Disease Control and Prevention, Atlanta, GA

Since publication of their article, the authors report no further potential conflict of interest.

This letter was published on May 11, 2022, at NEJM.org.

  1. 1. Hall V, Foulkes S, Insalata F, et al. Protection against SARS-CoV-2 after Covid-19 vaccination and previous infection. N Engl J Med 2022;386:1207-1220.

  2. 2. Patel MK, Bergeri I, Bresee JS, et al. Evaluation of post-introduction COVID-19 vaccine effectiveness: summary of interim guidance of the World Health Organization. Vaccine 2021;39:4013-4024.

  3. 3. Hobbs CV, Drobeniuc J, Kittle T, et al. Estimated SARS-CoV-2 seroprevalence among persons aged <18 years — Mississippi, May–September 2020. MMWR Morb Mortal Wkly Rep 2021;70:312-315.

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