Elapsed time since BNT162b2 vaccine and risk of SARS-CoV-2 infection in a large cohort

  1. Ariel Israel
  2. Eugene Merzon
  3. Alejandro A. Schäffer
  4. Yotam Shenhar
  5. Ilan Green
  6. Avivit Golan-Cohen
  7. Eytan Ruppin
  8. Eli Magen
  9. Shlomo Vinker

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Abstract

Importance

Israel was among the first countries to launch a large-scale COVID-19 vaccination campaign, and quickly vaccinated its population, achieving early control over the spread of the virus. However, the number of COVID-19 cases is now rapidly increasing, which may indicate that vaccine protection decreases over time.

Objective

To determine whether time elapsed since the second BNT162b2 messenger RNA (mRNA) vaccine (Pfizer-BioNTech) injection is significantly associated with the risk of post-vaccination COVID-19 infection.

Design

This is a retrospective cohort study performed in a large state-mandated health care organization in Israel.

Participants

All fully vaccinated adults who have received a RT-PCR test between May 15, 2021 and July 26, 2021, at least two weeks after their second vaccine injection were included. Patients with a history of past COVID-19 infection were excluded.

Main Outcome and Measure

Positive result for the RT-PCR test.

Results

The cohort included 33,993 fully vaccinated adults, 49% women, with a mean age of 47 years (SD, 17 years), who received an RT-PCR test for SARS-CoV-2 during the study period. The median time between the second dose of the vaccine and the RT-PCR test was 146 days, interquartile range [121-167] days. 608 (1.8%) patients had positive test results. There was a significantly higher rate of positive results among patients who received their second vaccine dose at least 146 days before the RT-PCR test compared to patients who have received their vaccine less than 146 days before: odds ratio for infection was 3.00 for patients aged over 60 (95% CI 1.86-5.11); 2.29 for patients aged between 40 and 59 (95% CI 1.67-3.17); and 1.74 for patients aged between 18 and 39 (95% CI 1.27-2.37); P<0.001 in each age group.

Conclusions and Relevance

In this large population study of patients tested for SARS-CoV-2 by RT-PCR following two doses of mRNA BNT162b2 vaccine, we observe a significant increase of the risk of infection in individuals who received their last vaccine dose since at least 146 days ago, particularly among patients older than 60.

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  1. NCRC

    Our take

    This study, available as a preprint and thus not yet peer-reviewed, is one of the first to investigate a potential decrease in effectiveness with increasing time since second dose of the Pfizer vaccine. Overall, very few breakthrough infections were detected, and some were caused by the Delta variant. However, experiencing a breakthrough infection was independently associated with being vaccinated >146 days (median time since vaccination) before the test date, and the odds were highest among those aged 60 years and older. The study did not investigate whether those experiencing breakthrough infections were more likely to have severe infections. These results suggest that there may be some reduction in the effectiveness of the vaccine to prevent infection over time, though more information on the frequency of severe disease among those infected would be helpful to determine whether there is any change in protection against hospitalization or death.

    Study design

    retrospective-cohort

    Study population and setting

    This study was a retrospective cohort study using data from Leumit Health Services (LHS), which is a large, nation-wide healthcare provider in Israel. The main objective of this study was to determine whether the amount of time elapsed since a person’s second dose of the BNT162b2 (Pfizer) vaccine was significantly associated with an increased risk of post-vaccination SARS-CoV-2 infection. Individuals included in the study were LHS members who were fully vaccinated with the Pfizer vaccine and who were tested for SARS-CoV-2 infection by PCR between May 15, 2021 and July 26, 2021. The PCR test had to be performed at least two weeks following the second dose of vaccination. These criteria yielded test results from 33,993 individuals for analysis, who were divided into three age groups to reflect vaccine rollout stages: 18-39, 40-59, and 60 years and older. Models were developed for each age group to identify whether the time since vaccination was independently associated with the risk of having a positive PCR test, after adjusting for sex, ethnicity, socioeconomic status, and comorbidities.

    Summary of main findings

    Of the 33,993 individuals tested, there were only 608 positive PCR tests. The median time between second dose of vaccine and PCR test, for both positive and negative tests, was 146 days. The only factor independently associated with having a positive test in each age group was the elapsed time since the second dose of vaccine. Individuals were more likely to test positive via PCR if the time elapsed since the second dose of the Pfizer vaccine was longer than 146 days, compared to those vaccinated less than 146 days prior. The odds ratio for individuals 18-39 years was 1.67, 2.22 for ages 40-59 years, and 2.76 for ages 60 years and older.

    Study strengths

    This study included a large and well-defined cohort of fully vaccinated individuals (with the Pfizer vaccine) with similar health insurance, and therefore, similar access to healthcare services. Israel was one of the first countries to achieve high levels of vaccination within its population, so this population is optimal for assessing any potential waning of vaccine effectiveness over time. Finally, many infections during this time were attributed to the Delta variant, which allows for some interpretation of the ability of vaccines to protect against this variant.

    Limitations

    A major limitation of this study is that individuals who were vaccinated earlier may have been at higher risk for infection than those who elected to be vaccinated later, even after accounting for sex, ethnicity, socioeconomic status and comorbidities; although individuals were analyzed by age group, there could be differences by age even within age groups though no adjustments were made to account for this in the models. In addition, this study did not investigate whether longer elapsed time since second vaccine dose was associated with increased risk of severe disease when breakthrough infections occur.

    Value added

    This is one of the first studies investigating potential reductions in effectiveness of Pfizer vaccination over time.

  2. ScreenIT

    SciScore for 10.1101/2021.08.03.21261496: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: The study protocol was approved by the statutory clinical research committee of Leumit Health Services and the Shamir Medical Center Institutional Review Board (129-2-LEU).
    Consent: Informed consent was waived because only deidentified routinely collected data were used.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version 1 published on medRxiv