Although clinical trials and real-world studies have affirmed the effectiveness and safety of the FDA-authorized COVID-19 vaccines, reports of breakthrough infections and persistent emergence of new variants highlight the need to vigilantly monitor the effectiveness of these vaccines. Here we compare the effectiveness of two full-length Spike protein-encoding mRNA vaccines from Moderna (mRNA-1273) and Pfizer/BioNTech (BNT162b2) in the Mayo Clinic Health System over time from January to July 2021, during which either the Alpha or Delta variant was highly prevalent. We defined cohorts of vaccinated and unvaccinated individuals from Minnesota (n = 25,589 each) matched on age, sex, race, history of prior SARS-CoV-2 PCR testing, and date of full vaccination. Both vaccines were highly effective during this study period against SARS-CoV-2 infection (mRNA-1273: 86%, 95%CI: 81-90.6%; BNT162b2: 76%, 95%CI: 69-81%) and COVID-19 associated hospitalization (mRNA-1273: 91.6%, 95% CI: 81-97%; BNT162b2: 85%, 95% CI: 73-93%). In July, vaccine effectiveness against hospitalization has remained high (mRNA-1273: 81%, 95% CI: 33-96.3%; BNT162b2: 75%, 95% CI: 24-93.9%), but effectiveness against infection was lower for both vaccines (mRNA-1273: 76%, 95% CI: 58-87%; BNT162b2: 42%, 95% CI: 13-62%), with a more pronounced reduction for BNT162b2. Notably, the Delta variant prevalence in Minnesota increased from 0.7% in May to over 70% in July whereas the Alpha variant prevalence decreased from 85% to 13% over the same time period. Comparing rates of infection between matched individuals fully vaccinated with mRNA-1273 versus BNT162b2 across Mayo Clinic Health System sites in multiple states (Minnesota, Wisconsin, Arizona, Florida, and Iowa), mRNA-1273 conferred a two-fold risk reduction against breakthrough infection compared to BNT162b2 (IRR = 0.50, 95% CI: 0.39-0.64). In Florida, which is currently experiencing its largest COVID-19 surge to date, the risk of infection in July after full vaccination with mRNA-1273 was about 60% lower than after full vaccination with BNT162b2 (IRR: 0.39, 95% CI: 0.24-0.62). Our observational study highlights that while both mRNA COVID-19 vaccines strongly protect against infection and severe disease, further evaluation of mechanisms underlying differences in their effectiveness such as dosing regimens and vaccine composition are warranted.

Competing Interest Statement

AP, PJL, ES, MJN, JC, AJV, and VS are employees of nference and have financial interests in the company. nference is collaborating with Moderna, Pfizer, Janssen, and other bio-pharmaceutical companies on data science initiatives unrelated to this study. These collaborations had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. JCO receives personal fees from Elsevier and Bates College, and receives small grants from nference, Inc, outside the submitted work. ADB is supported by grants from NIAID (grants AI110173 and AI120698), Amfar (#109593), and Mayo Clinic (HH Shieck Khalifa Bib Zayed Al-Nahyan Named Professorship of Infectious Diseases). ADB is a paid consultant for Abbvie, Gilead, Freedom Tunnel, Pinetree therapeutics Primmune, Immunome and Flambeau Diagnostics, is a paid member of the DSMB for Corvus Pharmaceuticals, Equilium, and Excision Biotherapeutics, has received fees for speaking for Reach MD and Medscape, owns equity for scientific advisory work in Zentalis and nference, and is founder and President of Splissen Therapeutics. MDS received grant funding from Pfizer via Duke University for a vaccine side effect registry. JH, JCO, AV, MDS and ADB are employees of the Mayo Clinic. The Mayo Clinic may stand to gain financially from the successful outcome of the research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.

Funding Statement

No external funding was received for this study.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.


The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was reviewed and approved by the Mayo Clinic Institutional Review Board (IRB 20-003278) as a minimal risk study. Subjects were excluded if they did not have a research authorization on file. The approved IRB was titled: Study of COVID-19 patient characteristics with augmented curation of Electronic Health Records (EHR) to inform strategic and operational decisions with the Mayo Clinic. The study was deemed exempt by the Mayo Clinic Institutional Review Board and waived from consent. The following resource provides further information on the Mayo Clinic Institutional Review Board and adherence to basic ethical principles underlying the conduct of research, and ensuring that the rights and well-being of potential research subjects are adequately protected: www.mayo.edu/research/institutional-review-board/overview.

All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.


I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).


I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.


Data Availability

After publication, the data will be made available upon reasonable requests to the corresponding author. A proposal with a detailed description of study objectives and the statistical analysis plan will be needed for evaluation of the reasonability of requests. Deidentified data will be provided after approval from the corresponding author and the Mayo Clinic.

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