Introduction
- Viana R
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Subsequently, omicron was declared a variant of concern by WHO on Nov 26, 2021, and has since rapidly become the dominant SARS-CoV-2 variant globally.
COVID-19 weekly epidemiological update, edition 74. Published Jan 11, 2012.
Pfizer and BioNTech provide update on omicron variant.
,
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,
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,
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,
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However, early data suggest that T-cell responses induced by previous SARS-CoV-2 infection and by the BNT162b2 vaccine are not significantly altered against omicron.
- De Marco L
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- Pirronello M
- et al.
,
- GeurtsvanKessel CH
- Geers D
- Schmitz KS
- et al.
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,
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,
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Although these findings suggest that protection against severe SARS-CoV-2 infection with omicron is likely to be better preserved than that against less symptomatic infection in most individuals, the extent of the impact on vaccine effectiveness and potential waning is unclear.
Evidence before this study
We searched PubMed, medRxiv, and press coverage up to March 1, 2022, using the terms “BNT162b2”, “vaccin*”, “COVID-19”, “effective*”, “impact”, “model”, “omicron”, and “delta” for preprint and published studies, without applying any language restrictions. Due to the timing of publications, most reports were unable to describe vaccine effectiveness or durability against SARS-CoV-2 infection with the omicron (B.1.1.529) variant. Available data as of March 1, 2022, suggest that two doses of an mRNA vaccine provide reduced protection against the omicron variant and symptomatic COVID-19 compared with the delta (B.1.617.2) variant, and moderate protection against severe SARS-CoV-2 infection. The effectiveness of a third dose against infection with the omicron variant or symptomatic COVID-19 has been estimated to be higher than that of two doses, but with waning observed in the first few months. Only a few reports have estimated the effectiveness of a third dose against hospital admission due to the omicron variant, with an even smaller number evaluating the durability of a booster dose against severe outcomes. Studies evaluating the longer-term effectiveness of two and three doses of BNT162b2 against the omicron variant, especially for severe outcomes, are urgently needed.
Added value of this study
In this case–control study covering a large, diverse population in the USA, we show that in the first 3 months after receipt of a third dose, the BNT162b2 vaccine provided 85% protection against hospital admission due to the omicron variant but less protection thereafter. Three doses of BNT162b2 were also effective at preventing emergency department admissions due to the omicron variant (albeit slightly less effective than preventing hospital admissions); however, the protection afforded by three doses also waned over time for this milder form of SARS-CoV-2 infection. These are some of the earliest data showing the effectiveness of three doses of BNT162b2 against SARS-CoV-2 infection due to the omicron variant, while also highlighting that this protection is likely to wane after 3 months, even for hospital admissions.
Implications of all the available evidence
In the future, additional doses of current, adapted, or novel COVID-19 vaccines might be needed to maintain high protection against severe SARS-CoV-2 infection and maintain sufficient vaccine-induced pressure on future SARS-CoV-2 outbreaks.
- Collie S
- Champion J
- Moultrie H
- Bekker L-G
- Gray G
and the US Centers for Disease Control and Prevention (CDC),
- Thompson MG
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,
- Ferdinands JM
- Rao S
- Dixon BE
- et al.
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- Danza P
- Koo TH
- Haddix M
- et al.
and preprint reports from the UK,
SARS-CoV-2 variants of concern and variants under investigation in England. Technical Briefing 34: update on hospitalisation and vaccine effectiveness for Omicron VOC-21NOV-01 (B.1.1.529).
the USA,
- Tseng HF
- Ackerson BK
- Luo Y
- et al.
Canada,
- Buchan SA
- Chung H
- Brown KA
- et al.
Qatar,
- Chemaitelly H
- Ayoub HH
- AlMukdad S
- et al.
and Denmark.
- Hansen CH
- Schelde AB
- Moustsen-Helm IR
- et al.
Generally speaking, these data suggest that two doses of the mRNA vaccine are likely to provide only limited and short-lived protection against infection caused by the omicron variant and symptomatic COVID-19,
- Thompson MG
- Natarajan K
- Irving SA
- et al.
,
- Danza P
- Koo TH
- Haddix M
- et al.
,
SARS-CoV-2 variants of concern and variants under investigation in England. Technical Briefing 34: update on hospitalisation and vaccine effectiveness for Omicron VOC-21NOV-01 (B.1.1.529).
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- Tseng HF
- Ackerson BK
- Luo Y
- et al.
,
- Buchan SA
- Chung H
- Brown KA
- et al.
,
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- Ayoub HH
- AlMukdad S
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,
- Hansen CH
- Schelde AB
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- et al.
,
- Accorsi EK
- Britton A
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,
- Andrews N
- Stowe J
- Kirsebom F
- et al.
and two doses have reduced effectiveness against hospital admission due to omicron compared to that seen for previous SARS-CoV-2 variants.
- Collie S
- Champion J
- Moultrie H
- Bekker L-G
- Gray G
,
- Thompson MG
- Natarajan K
- Irving SA
- et al.
,
SARS-CoV-2 variants of concern and variants under investigation in England. Technical Briefing 34: update on hospitalisation and vaccine effectiveness for Omicron VOC-21NOV-01 (B.1.1.529).
Additionally, preliminary data suggest that three doses of the mRNA vaccine provide increased but modest protection against SARS-CoV-2 infection
- Danza P
- Koo TH
- Haddix M
- et al.
,
- Chemaitelly H
- Ayoub HH
- AlMukdad S
- et al.
,
- Accorsi EK
- Britton A
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,
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that wanes quickly,
- Chemaitelly H
- Ayoub HH
- AlMukdad S
- et al.
as well as increased protection against hospital admission in the first few months.
- Danza P
- Koo TH
- Haddix M
- et al.
,
- Chemaitelly H
- Ayoub HH
- AlMukdad S
- et al.
- Thompson MG
- Natarajan K
- Irving SA
- et al.
,
SARS-CoV-2 variants of concern and variants under investigation in England. Technical Briefing 34: update on hospitalisation and vaccine effectiveness for Omicron VOC-21NOV-01 (B.1.1.529).
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- Buchan SA
- Chung H
- Brown KA
- et al.
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Effectiveness of 3 doses of COVID-19 vaccines against symptomatic COVID-19 and hospitalisation in adults aged 65 years and older.
but with waning observed in the first few months.
SARS-CoV-2 variants of concern and variants under investigation in England. Technical Briefing 34: update on hospitalisation and vaccine effectiveness for Omicron VOC-21NOV-01 (B.1.1.529).
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Effectiveness of 3 doses of COVID-19 vaccines against symptomatic COVID-19 and hospitalisation in adults aged 65 years and older.
Only two published reports from the CDC
- Thompson MG
- Natarajan K
- Irving SA
- et al.
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- Ferdinands JM
- Rao S
- Dixon BE
- et al.
and one non-peer-reviewed report
SARS-CoV-2 variants of concern and variants under investigation in England. Technical Briefing 34: update on hospitalisation and vaccine effectiveness for Omicron VOC-21NOV-01 (B.1.1.529).
have estimated the effectiveness of a third dose against hospital admission due to omicron. All studies reported vaccine effectiveness of roughly 90% soon after receipt of the third dose of an mRNA vaccine; however, none reported vaccine-specific estimates
- Thompson MG
- Natarajan K
- Irving SA
- et al.
,
- Ferdinands JM
- Rao S
- Dixon BE
- et al.
,
SARS-CoV-2 variants of concern and variants under investigation in England. Technical Briefing 34: update on hospitalisation and vaccine effectiveness for Omicron VOC-21NOV-01 (B.1.1.529).
and only one provided long-term follow-up after receipt of a booster dose.
- Ferdinands JM
- Rao S
- Dixon BE
- et al.
Thus, studies evaluating the effectiveness of BNT162b2 against omicron in other robust health systems across the world, especially for severe outcomes and with sufficient follow-up, are urgently needed to inform public-health decision making about the need for (and timing of) additional boosters, improved COVID-19 vaccines tailored to target the omicron variant, or other effective COVID-19 vaccines. We aimed to evaluate the age-specific effectiveness and durability of two and three doses of BNT162b2 against hospital and emergency department admissions due to the omicron variant in a large integrated health system in the USA.
Methods
Study design and participants
- Koebnick C
- Langer-Gould AM
- Gould MK
- et al.
KPSC electronic health records integrate clinical data across all settings of care, including care delivered to members outside of the KPSC system. The study protocol was reviewed and approved by the KPSC institutional review board, which waived requirement for informed consent (number 12816).
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- Walaza Sibongile
- et al.
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- Scott L
- Hsiao NY
- Moyo S
- et al.
An internal validation study of 1477 SARS-CoV-2 isolates that underwent whole genome sequencing resulted in confirmation of the omicron lineage in all SGTF samples (382 [100·0%] of 382) and the delta lineage was confirmed in 1092 (99·7%) of 1095 non-SGTF samples. Thus, samples with SGTF were characterised as omicron and those without as delta. We also included specimens not tested with the ThermoFisher TaqPath kit that were collected during periods when there was a 7-day rolling average with at least 95% predominance of a single variant lineage (ie, delta or omicron). Specifically, specimens collected from Dec 1, 2021, to Dec 9, 2021, were characterised as delta, and those from Dec 20, 2021, through to the end of the study period characterised as omicron (appendix pp 3–4). Specimens not tested on the ThermoFisher TaqPath COVID-19 Combo Kit or outside of our specified delta or omicron time periods were excluded from the analyses.
Exposures
COVID-19 vaccines were provided at no cost to KPSC members following emergency use authorisation. Vaccinations administered outside of KPSC were captured via the California Immunization Registry, to which providers are required to report all COVID-19 vaccine administrations within 24 h.
- Tartof SY
- Slezak JM
- Fischer H
- et al.
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- Polack FP
- Thomas SJ
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- et al.
Individuals with partial vaccination were excluded; partial vaccination was defined as receipt of only one dose of BNT162b2, receipt of a third dose less than 21 days after a second dose of BNT162b2, or having a hospital or emergency department admission up to and including 7 days since the second dose or 14 days since the third dose. Individuals were considered unvaccinated if they had never received BNT162b2 or any other COVID-19 vaccine.
Outcomes
Cases of hospital admission or an emergency department admission without a subsequent hospital admission were defined as those with a diagnosis of acute respiratory infection and a KPSC laboratory-confirmed positive SARS-CoV-2 PCR test from a sample collected within 14 days before the initial admission date through to 3 days after the admission. Controls were defined as those with a KPSC laboratory-confirmed negative SARS-CoV-2 PCR test collected within 14 days before a hospital or emergency department admission for acute respiratory infection to 3 days after the admission, and no laboratory-confirmed positive SARS-CoV-2 PCR tests within 90 days before the initial admission. Patients could contribute more than one event to the study if a subsequent event for the same patient occurred more than 30 days after the previous event.
Statistical analysis
We described the distribution of demographic and clinical characteristics of the study cohort by outcome status and COVID-19 vaccination status. Characteristics of cases and controls were compared by use of χ2 test for categorical variables and Fisher’s exact text for binary variables. Crude and adjusted vaccine effectiveness estimates following receipt of both two and three doses of BNT162b2 in the hospital and emergency department setting were constructed and compared with odds ratios (ORs) and 95% CIs from logistic regression models. Vaccine effectiveness was calculated as 1–OR multiplied by 100%, with corresponding 95% CIs calculated with the Wald method. Adjusted ORs and 95% CIs were estimated by adjusting for age (18–49, 50–64, and ≥65 years), sex (male and female), race or ethnicity (Hispanic, non-Hispanic White, non-Hispanic Black, non-Hispanic Asian or Pacific Islander, and other or unknown), body-mass index (<18·5 kg/m2, 18·5–24·9 kg/m2, 25·0–29·9 kg/m2, 30·0–34·9 kg/m2, >35·0 kg/m2, and unknown), Charlson Comorbidity Index (0, 1, 2, 3, and ≥4), receipt of influenza vaccine in the year before admission (ever vs never), receipt of pneumococcal vaccine in the 5 years before admission (ever vs never), and documentation of previous SARS-CoV-2 infection (ever vs never) in multivariable logistic regression models. Analyses were done separately for hospital and emergency department admissions. Analyses were further stratified by variant (delta vs omicron) and by age group (18–64 years vs ≥65 years). We also assessed vaccine effectiveness by time since vaccination (months since completion of a two-dose [only] or three-dose series).
Role of the funding source
This study was sponsored by Pfizer. The study design was developed by KPSC but approved by Pfizer. KPSC alone collected and analysed the data. KPSC and Pfizer participated in the interpretation of data and the writing of the report.
Results
Figure 1Flowchart for study population
Table 1Characteristics of cases and test-negative controls among patients diagnosed with acute respiratory infection from Dec 1, 2021, to Feb 6, 2022
Table 2Characteristics by vaccination status among patients with a diagnosis of acute respiratory infection from Dec 1, 2021, to Feb 6, 2022
Figure 2Adjusted vaccine effectiveness of mRNA COVID-19 vaccine BNT162b2 (Pfizer–BioNTech) against hospital and emergency department admission among individuals diagnosed with acute respiratory infection by variant of concern, from Dec 1, 2021, to Feb 6, 2022
Estimates adjusted for age, sex, race or ethnicity, body-mass index, Charlson comorbidity index, previous SARS-CoV-2 infection, previous influenza vaccination, and previous pneumococcal vaccination.
Discussion
In the first few months after receiving a booster dose of BNT162b2, it confers high protection (around 80–90%) against hospital and emergency department admission caused by the delta and omicron variants. Against the omicron variant, however, this protection is likely to wane significantly over time—even after a third dose. Specifically, in the present study, 3–5 months after receiving a booster dose of BNT162b2, effectiveness against hospital admission due to the omicron variant fell to 55% (95% CI 28–71), and effectiveness against emergency department admission due to the omicron variant (without subsequent hospital admission) fell to 53% (36–66), although confidence intervals were wide around the point estimate for hospital and emergency department admissions.
- Thompson MG
- Natarajan K
- Irving SA
- et al.
,
- Ferdinands JM
- Rao S
- Dixon BE
- et al.
and the UK Heath Security Agency (which reported effectiveness of approximately 85–90% for all vaccines used in the UK combined).
SARS-CoV-2 variants of concern and variants under investigation in England. Technical Briefing 34: update on hospitalisation and vaccine effectiveness for Omicron VOC-21NOV-01 (B.1.1.529).
Our study, to the best of our knowledge, is one of the first to report long-term follow-up outcomes after receipt of a booster dose, stratified by age. Similar to a recent CDC report showing waning effectiveness of mRNA COVID-19 vaccines after a third dose,
- Ferdinands JM
- Rao S
- Dixon BE
- et al.
we also detected early signs of waning against severe outcomes caused by the omicron variant from 3 months onwards after the receipt of a booster dose. More long-term follow-up data are needed, however, to fully understand the true magnitude of this decline.
- Turner JS
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- Kalaidina E
- et al.
and laboratory results have suggested that T-cell epitopes have remained mostly unaltered for the omicron variant.
- De Marco L
- D’Orso S
- Pirronello M
- et al.
,
- GeurtsvanKessel CH
- Geers D
- Schmitz KS
- et al.
,
- Liu J
- Chandrashekar A
- Sellers D
- et al.
,
- Tarke A
- Coelho CH
- Zhang Z
- et al.
,
- Keeton R
- Tincho MB
- Ngomti A
- et al.
The relationship between cell-mediated immunity and protection against severe infection, however, needs more research. It is also likely that trained innate immunity has an important role in durable protection, particularly against severe infection. Unrelated live attenuated vaccines and adjuvanted vaccines can provide sustained protection against heterologous infections and severe outcomes, including COVID-19, possibly through induction of trained innate immunity, which mRNA vaccines also induce.
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,
,
- Bruxvoort KJ
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- Tartof SY
- Slezak JM
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and with preliminary studies showing waning effectiveness against the omicron variant and symptomatic SARS-CoV-2 infection.
SARS-CoV-2 variants of concern and variants under investigation in England. Technical Briefing 34: update on hospitalisation and vaccine effectiveness for Omicron VOC-21NOV-01 (B.1.1.529).
,
- Tseng HF
- Ackerson BK
- Luo Y
- et al.
,
- Buchan SA
- Chung H
- Brown KA
- et al.
,
- Hansen CH
- Schelde AB
- Moustsen-Helm IR
- et al.
After a third dose, effectiveness against emergency department admission increased to 84% (95% CI 80–87) for the delta variant and 77% (72–81) for the omicron variant. Waning of immunity against emergency department admission after three doses was moderate for the delta variant but was more pronounced for the omicron variant, falling to 53% (36–66) at 3 months or more after the third dose. This finding is consistent with early reports from the UK Health Security Agency suggesting that even after three doses, vaccine effectiveness against symptomatic SARS-CoV-2 infection due to the omicron variant wanes rapidly.
SARS-CoV-2 variants of concern and variants under investigation in England. Technical Briefing 34: update on hospitalisation and vaccine effectiveness for Omicron VOC-21NOV-01 (B.1.1.529).
,
- Buchan SA
- Chung H
- Brown KA
- et al.
Age-stratified analyses showed that effectiveness was generally higher in adults aged 65 years and older. However, this finding might reflect enhanced risk-mitigating behaviours, especially among vaccinated people in this age group, or the potential dilution of vaccine effectiveness among adults younger than 65 years.
- Tartof SY
- Slezak JM
- Fischer H
- et al.
in the omicron era three doses appear to be necessary to achieve high levels of protection against severe COVID-19 outcomes. These findings are consistent with laboratory data reporting that neutralising antibody concentrations not only improved after a third dose (compared to after two doses) but also that the breadth of coverage against variants of concern seemed to increase.
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,
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,
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however, continual evaluation of booster strategies will be needed in the future. Preliminary data from Israel have shown improved protection against SARS-CoV-2 infection with the omicron variant and severe COVID-19 in individuals who received a fourth dose of BNT162b2 compared to those who had received only three doses at least 4 months ago.
- Bar-On YM
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However, data describing the durability of additional booster doses (beyond the third dose) are needed.
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,
,
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Furthermore, although we attempted to control for previous SARS-CoV-2 infection, we were not able to assess previous infections among those who do not seek testing at KPSC. If undocumented previous infection was more likely in unvaccinated individuals, for example, this could contribute to underestimation of vaccine effectiveness, which might be more likely in the omicron era. In addition to using a time window where the omicron variant accounted for at least 95% of all new incident cases, we identified omicron cases based on SARS-CoV-2 samples with SGTF on the Thermo Fisher TaqPath assay. This approach could have led to misclassification of some samples. Misclassification, however, occurred in less than 1% of samples tested on ThermoFisher in our small validation study that compared PCR results to those from whole-genome sequencing. It is possible that some emergency department or hospital admissions were “with COVID-19” rather than “for COVID-19.” This could lead to spurious findings of waning against severe outcomes if in fact vaccine breakthroughs were only incidental infections among patients admitted to hospital for something other than COVID-19. This could explain why we found higher effectiveness estimates in adults aged 65 years and older (who are likely to be admitted to hospital for and have more severe COVID-19) compared to those aged 18–64 years who might be more likely to have incidental positivity for the omicron variant. By restricting our analysis to patients with a diagnosis of an acute respiratory infection, we attempted to mitigate this potential bias. However, it remains possible (especially in the emergency department setting) that milder COVID-19 or incidental SARS-CoV-2 infection was included in our analysis, which is likely to bias vaccine effectiveness estimates downwards, especially for the omicron variant given its milder clinical presentation and higher levels of antibody escape. Moreover, it is possible that hospital admission practices changed during our study period. For example, if larger numbers of less severe patients were admitted during the omicron wave, as was reported by the CDC,
- Iuliano AD
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this could also bias vaccine effectiveness estimates for the omicron variant downwards. Finally, given the study period, effectiveness estimates 3 months or more after the booster dose are likely to represent findings for individuals who first received booster doses, and additional follow-up will be needed to understand the effectiveness of booster doses over time in the general population and at different stages of the pandemic. Due to limitations in sample size, we were unable to assess long-term durability of the third dose or to provide vaccine effectiveness estimates specific to age groups or high-risk groups. Furthermore, due to the rapid influx of at-home antigen tests and increasing variation in clinic-based testing practices, we were not able to assess vaccine effectiveness against symptomatic or asymptomatic SARS-CoV-2 infection not requiring hospital or emergency department admission.
In conclusion, BNT162b2 provided 85% protection against hospital admission due to the omicron variant in the first 3 months after receipt of a third dose but less protection thereafter. Three doses of BNT162b2 were also effective at preventing emergency department admission due to the omicron variant (albeit slightly less effective than at preventing hospital admission); however, protection also waned for this milder form of infection. These findings reiterate the need to continue the development of additional strategies to ensure long-term protection against severe SARS-CoV-2 infection caused by the omicron variant or future variants that stem from this variant of concern. In the future, additional doses of current, adapted, or novel COVID-19 vaccines might be needed to maintain high protection against severe infection and sufficient vaccine pressure on future waves of SARS-CoV-2 infection.
SYT, JMS, LJ, and JMM conceived this study. JMS, VH, and FX analysed the data, and SYT, VH, JMS, and FX had access to the raw data and verified the data. SYT, JMS, JMM, BKA, SRV, and LP 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 and had final responsibility for the decision to submit for publication.
Declaration of interests
SRV, LJ, LP, and JMM are employees of and hold stock or stock options, or both, in Pfizer. SYT, JMS, VH, FX, and BKA received research support from Pfizer during the conduct of this study that was paid directly to KPSC. BKA received research support for work unrelated to this study, provided by Pfizer, Moderna, Dynavax, Seqirus, GlaxoSmithKline, and Genentech. JMS received research support from ALK-Abelló, Dynavax, and Novavax for work unrelated to this study. SYT received research support from Genentech for work unrelated to this study.
Acknowledgments
We thank Timothy Frankland, Harpreet S Takhar, Oluwaseye A Ogun, Donald McCarthy, Errol Lopez, Joann M Zamparo, Kaije Pan, and Sharon Gray for assistance with management and data support on this study. We thank Michael Aragones, Soon Kyu Choi, Lee Childs, Julie Stern, Joy Gelfond, Kourtney Kottman, Ana Acevedo, Jonathan Arguello, Samantha Quinones, Samantha Baluyot, and Elmer Ayala for their technical and laboratory support processing SARS-CoV-2 specimens. We thank Deborah Malden for graphic assistance. We acknowledge Uğur Şahin and Özlem Türeci from BioNTech, the holder of the emergency use authorisation for BNT162b2 in Israel; BNT162b2 is produced with BioNTech proprietary mRNA technology and was developed by BioNTech and Pfizer.