Summary
Background
Vaccine effectiveness studies have not differentiated the effect of the delta (B.1.617.2) variant and potential waning immunity in observed reductions in effectiveness against SARS-CoV-2 infections. We aimed to evaluate overall and variant-specific effectiveness of BNT162b2 (tozinameran, Pfizer–BioNTech) against SARS-CoV-2 infections and COVID-19-related hospital admissions by time since vaccination among members of a large US health-care system.
Methods
Findings
Between Dec 14, 2020, and Aug 8, 2021, of 4 920 549 individuals assessed for eligibility, we included 3 436 957 (median age 45 years [IQR 29–61]; 1 799 395 [52·4%] female and 1 637 394 [47·6%] male). For fully vaccinated individuals, effectiveness against SARS-CoV-2 infections was 73% (95% CI 72–74) and against COVID-19-related hospital admissions was 90% (89–92). Effectiveness against infections declined from 88% (95% CI 86–89) during the first month after full vaccination to 47% (43–51) after 5 months. Among sequenced infections, vaccine effectiveness against infections of the delta variant was high during the first month after full vaccination (93% [95% CI 85–97]) but declined to 53% [39–65] after 4 months. Effectiveness against other (non-delta) variants the first month after full vaccination was also high at 97% (95% CI 95–99), but waned to 67% (45–80) at 4–5 months. Vaccine effectiveness against hospital admissions for infections with the delta variant for all ages was high overall (93% [95% CI 84–96]) up to 6 months.
Interpretation
Our results provide support for high effectiveness of BNT162b2 against hospital admissions up until around 6 months after being fully vaccinated, even in the face of widespread dissemination of the delta variant. Reduction in vaccine effectiveness against SARS-CoV-2 infections over time is probably primarily due to waning immunity with time rather than the delta variant escaping vaccine protection.
Funding
Pfizer.
Introduction
In the early months after its introduction, BNT162b2 has been shown to be highly effective in the real-world setting and to have had a large public health effect on reducing infections, hospital admissions, and deaths at a time when the alpha (B.1.1.7) variant was the predominant strain in Israel,
,
,
the USA,
,
,
,
Canada,
the UK,
,
,
,
,
,
,
and Qatar.
,
,
,
Moreover, confirmatory, real-world studies have shown high effectiveness of two doses of BNT162b2 against COVID-19, especially severe disease, caused by variants of concern alpha,
,
beta (B.1.351),
,
and delta9,14–16,23,24 in various settings.
Qatar,
and the USA.
- Nanduri SA
- Pilishvili T
- Derado G
- et al.
,
In Israel, Qatar, and the USA, for example, widespread dissemination of the delta variant also coincided with the time period during which many individuals at high risk who were fully vaccinated first (eg, health-care workers, individuals who were immunocompromised, and older people) were approaching 6 months since the receipt of their second dose. Thus, waning of vaccine-induced immunity, which was observed in the pivotal randomised controlled trial before the emergence of the delta variant,
is an important factor to consider in the context of reported declines in effectiveness.
Evidence before this study
After global transmission of the delta (B.1.617.2) variant in June and July, 2021, reports describing reduced effectiveness of BNT162b2 (and other COVID-19 vaccines) against SARS-CoV-2 infections caused by the delta variant began to surface from Israel, Qatar, and the USA. Vaccine effectiveness studies in the setting of widespread prevalence of the delta variant, however, have not adequately differentiated the effect of the variant from potential waning immunity on observed reductions in effectiveness against SARS-CoV-2 infections. To help answer this urgent public health question, we evaluated overall and variant-specific real-world effectiveness of BNT162b2 against SARS-CoV-2 infections and COVID-19-related hospital admissions by time since vaccination among members of a large integrated health-care system in the USA up until 6 months after full vaccination.
Added value of this study
Our variant-specific analysis suggests that reductions in BNT162b2 effectiveness over time are likely to be primarily due to waning vaccine effectiveness rather than the delta variant escaping vaccine protection given that effectiveness against delta variant infections was more than 90% within 1 month of full vaccination, reductions in effectiveness in infections by time since being fully vaccinated were observed irrespective of SARS-CoV-2 variant, and effectiveness against hospital admissions due to the delta variant was very high over the entire study period.
Implications of all the available evidence
Related to other findings from Israel, the USA, and other countries, our findings underscore the importance of monitoring vaccine effectiveness over time and suggest that booster doses are likely to be needed to restore the initial high amounts of protection observed early in the vaccination programme.
Vaccine effectiveness studies in the setting of high prevalence of the delta variant have not adequately differentiated the effect of the delta variant from potential waning immunity on observed reductions in effectiveness against SARS-CoV-2 infections. This distinction is essential to inform the need for booster doses and to establish what the antigenic composition of future vaccines should be. To help answer this urgent public-health question, we aimed to evaluate overall and variant-specific real-world effectiveness of BNT162b2 against SARS-CoV-2 infections and COVID-19-related hospital admissions by time since vaccination among members of a large integrated health-care system in the USA.
Methods
Study design and participants
In this retrospective cohort study, we analysed electronic health records from the Kaiser Permanente Southern California (KPSC) health-care system (CA, USA) to assess the effectiveness of the BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19-related hospital admissions. The study population consisted of all KPSC members aged 12 years and older. The start of the study period corresponded to the date the first doses of BNT162b2 were administered to KPSC members. The test-negative design described in the study protocol will be performed in future work.
KPSC electronic health records integrate clinical data including diagnostic, pharmacy, laboratory, and vaccination history information across all settings of care. Care delivered to members outside of the KPSC system is also captured, as outside providers must submit detailed claims to KPSC for reimbursement by the health plan.
Participants were required to have 1 year or more of membership (allowing a 31-day gap during previous membership to allow for potential delays in renewal) to determine comorbidities and medical history. Patients with documentation requesting removal from all research studies were excluded. The study protocol was reviewed and approved by the KPSC institutional review board, which waived requirement for informed consent (number 12816).
Procedures
COVID-19 vaccines were provided to KPSC members at no cost following emergency use authorisation. Any COVID-19 vaccines administered to members outside of the KPSC system during the study period were captured using batch queries to the California Immunization Registry. California providers are required by law to report all COVID-19 vaccine administrations to the registry every 24 h. KPSC followed the state of California guidance in rolling out COVID-19 vaccines, first making vaccines available to health-care workers in December, 2020. Vaccines were then progressively made available to older people, individuals with underlying health conditions, and essential workers. By April, 2021, anyone aged 16 years or older was eligible to receive the vaccine. Those aged 12–15 years became eligible in May, 2021.
The primary exposure was full vaccination with BNT162b2, defined as receiving two doses of BNT162b2 with 7 days or more after the second dose. Individuals were considered partially vaccinated if they received only one dose with 14 days or more after the first dose or if they received two doses with less than 7 days after the second dose. Individuals were considered unvaccinated until receipt of their first dose of BNT162b2, or until censoring at disenrolment, death, or receipt of another COVID-19 vaccine.
Outcomes
Statistical analysis
to capture differences in neighbourhood level socioeconomic status. The inclusion of all pre-specified covariates, as requested by the US Food and Drug Administration, differs from the backward selection method outlined in the protocol. Robust variance was computed to account for clustering introduced by including neighbourhood deprivation index in the model. For all models, vaccine effectiveness was calculated as: (1–HR) multiplied by 100%. Due to limitations in sample size, variant-specific vaccine effectiveness analyses were not stratified by age, were estimated only up to 4 months for SARS-CoV-2 infections, and were not stratified by month for COVID-19-related hospital admissions. Statistical comparisons of vaccine effectiveness by time since vaccination were made using Wald χ2 tests for contrasts within Cox models. Vaccine effectiveness for delta and other variants could not be directly compared in the same regression model. The difference between delta variant vaccine effectiveness versus other variant vaccine effectiveness was compared using independent Z tests on the log HRs, which are conservative as the vaccine effectiveness for COVID-19 variants is positively correlated in the same population. All analyses were performed using SAS Enterprise Guide statistical software, version 7.1. This study was registered with ClinicalTrials.gov, NCT04848584.
Role of the funding source
The funder of the study approved the study design, and participated in data interpretation and writing of the report.
Results
TableBaseline characteristics
Data are n (%) or median (IQR). Characteristics of Kaiser Permanente Southern California members (n=3 436 957), by BNT162b2 vaccination status (as of Aug 8, 2021), and by SARS-CoV-2 outcomes (Dec 14, 2020, to Aug 8, 2021).
Figure 1Distribution of variants from January to July, 2021
Figure 2Adjusted estimated vaccine effectiveness against SARS-CoV-2 infection and hospital admissions
Vaccine effectiveness (95% CI) against SARS-CoV-2 infection (A) and COVID-19 hospital admission (B) by age group and number of months since being fully vaccinated with BNT162b2. *BNT162b2 authorised for those aged 12–15 years in May, 2021, limiting follow-up time for this age group.
Figure 3Adjusted estimated vaccine effectiveness against SARS-CoV-2 infection by variant
Data are shown for number of months since being fully vaccinated with BNT162b2 with 95% CIs.
Discussion
,
,
- Nanduri SA
- Pilishvili T
- Derado G
- et al.
,
The most recent report from August, 2021, from Israel, however, suggests that some reduction in effectiveness against hospital admissions has been observed among older people (≥65 years) roughly 6 months after receiving the second dose of BNT162b2.
Thus, long-term effectiveness data against severe outcomes should be continuously monitored in our study population and globally.
,
- Nanduri SA
- Pilishvili T
- Derado G
- et al.
,
and Qatar.
Our variant-specific analyses suggest that reductions in vaccine effectiveness over time are likely to be primarily due to waning vaccine effectiveness rather than the delta variant escaping vaccine protection given that vaccine effectiveness against delta infections was more than 90% soon after vaccination, vaccine effectiveness against delta and other variants for hospital admissions was very high over the entire study period, and reductions in vaccine effectiveness against infection by time since being fully vaccinated were observed irrespective of the variant. We did not observe a difference in waning between variant types; however, the number of events at 3–4 months was low for analyses by variant. As such, analyses with longer follow-up to measure the rate of waning for the delta versus other variants are warranted. Related to our findings, studies from Canada
and the UK
,
have shown high effectiveness of BNT162b2 against symptomatic COVID-19 caused by the delta variant in a vaccine schedule that separates the first and second doses by 2–3 months instead of 3 weeks. This longer interval between doses could lead to higher immunological responses;
,
however, duration of follow-up in these studies (
,
,
was insufficient to establish the effects of waning. Moreover, given the lower effectiveness after only one dose observed in our study and in other reports of one-dose effectiveness against variants of concern like beta or delta,
,
,
delaying the second dose is not without risk.
,
,
,
,
our results suggest that despite early effectiveness of BNT162b2 against delta and other variants of concern, effectiveness against infection erodes steadily in the months after receipt of the second dose. Waning effectiveness and an increased number of infections 6–12 months after the second dose—along with the potential need for booster doses—was expected given that lower neutralising antibody titres during this time period have been observed in immunogenicity studies.
,
,
Waning has been observed for both mRNA-based (Pfizer–BioNTech and Moderna) COVID-19 vaccines,
- Nanduri SA
- Pilishvili T
- Derado G
- et al.
,
and is consistent with studies of other coronaviruses.
Reassuringly, early phase 1 data show that a third booster dose of the current BNT162b2 vaccine given 6 months after the second dose elicited neutralising antibody titres against the original SARS-CoV-2 wild-type strain, beta, and delta, which were several times higher than after two primary doses.
,
Modelling studies have predicted that these increases in neutralising antibody titres will restore high amounts of vaccine effectiveness.
Moreover, early unpublished data from an Israeli health maintenance organisation (Maccabi Health Services) suggest that a third booster dose is highly effective in a setting in which the delta variant accounts for nearly all cases.
,
These findings suggest that boosting with the current BNT162b2 vaccine rather than a delta-specific construct might be effective. Considerations of booster doses should also account for COVID-19 supply, as priority populations in some countries or subnational settings have not yet received a primary vaccination series.
Our study has potential limitations. We were unable to establish causal relationships between vaccination and COVID-19 outcomes in this observational study. Further, it is difficult to achieve a perfect balance of testing patterns and other characteristics between vaccinated and unvaccinated patients in this real-world observational study design. We attempt to address this issue by adjusting for proxies for general health-care seeking behaviour (visits across health-care settings before baseline), prior vaccination behaviour, demographics, comorbidities, and neighbourhood-level socioeconomic status. However, we did not have data for adherence to masking guidelines, social interactions, and occupation, which are likely to also affect likelihood of testing for SARS-CoV-2 either when experiencing symptoms or routinely as a preventive measure. KPSC maintained several drive-through testing clinics, did not have resource limitations on COVID-19 testing, and provided free testing to all members during the study period. We compared vaccinated and unvaccinated individuals at the same point in time, which balances the availability of testing, infection rates, and other secular inputs that might affect testing behaviours between vaccinated and unvaccinated patients to the extent possible in observational research. Effectiveness was lowest for PCR-positive specimens for which a sequence could not be determined. These specimens had higher Ct values than other PCR-positive specimens, which probably corresponded to milder or asymptomatic infections. Thus, our vaccine effectiveness estimates against SARS-CoV-2 infections and hospital admissions could be muted by mild or asymptomatic infections and are not directly comparable to estimates of effectiveness against symptomatic disease. Sequencing was more likely to fail in samples from vaccinated individuals due to lower viral loads, which could lead to an overestimate of variant-specific effectiveness. Finally, although the KPSC electronic health records might miss some vaccinations administered outside of the health system, our data capture through the California Immunization Registry minimised this effect.
Our findings underscore the importance of monitoring vaccine effectiveness over time and suggest that booster doses might eventually be needed to restore the high levels of protection observed early in the vaccination programme. These factors are especially important to help control heightened transmission of the delta variant as we enter the upcoming autumn and winter viral respiratory season.
Contributors
SYT, FJA, LJ, and JMM conceived this study. JMS, HF, VH, and ONR conducted the analysis. SYT, FJA, JMS, HF, and JMM wrote the first draft of the protocol. SYT and JMM wrote the first draft of the manuscript. All authors contributed to the study design, drafting the protocol, and edited the manuscript for important intellectual content. All authors gave final approval of the version to be published. All authors had full access to all the data and had final responsibility for the decision to submit for publication.
Data sharing
Declaration of interests
JMZ, SG, KP, FJA, LJ, SRV, and JMM are employees of and hold stock and stock options in Pfizer. TBF holds shares of Pfizer stock. SYT, JMS, HF, VH, BKA, ONR, TBF, and OAO received research support from Pfizer during the conduct of this study that was paid directly to KPSC. For work unrelated to this project, SYT received research funding from Gilead, GlaxoSmithKline, and Genentech; BKA received research funding from GlaxoSmithKline, Novavax, Dynavax, Genentech, Novartis, Seqirus, and Moderna; JMS received research funding from Novavax, Dynavax, and ALK; and HF received research funding from Genentech. All other authors declare no competing interests.
Acknowledgments
We acknowledge the following KPSC staff: Harpreet S Takhar, Michael Aragones, Soon Kyu Choi, Jennifer Charter, Lee Childs, Joy Gelfond, Radha Bathala, Raul Calderon, Kourtney Kottman, Ana Acevedo, Elmer Ayala, and Jonathan Arguello for their technical and laboratory support processing SARS-CoV-2 specimens. We thank KPSC members for their contributions through our electronic health record systems. Finally, we thank Helix OpCo for whole genome sequencing of SARS-CoV-2 and acknowledge Uğur Şahin and Özlem Türeci from BioNTech, the holders of the emergency use authorisation for BNT162b2 in Israel; BNT162b2 is produced using BioNTech proprietary mRNA technology and was developed by BioNTech and Pfizer. The study design was developed by KPSC and approved by KPSC and Pfizer. KPSC collected and analysed the data; Pfizer did not participate in the collection or analysis of data. KPSC and Pfizer participated in the interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.
Supplementary Material
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Article Info
Publication History
Published: October 04, 2021
Identification
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© 2021 Elsevier Ltd. All rights reserved.
ScienceDirect
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