# A Reanalysis of the FDA’s Benefit–Risk Assessment of Moderna’s mRNA-1273 COVID Vaccine Based on a Model Incorporating Benefits Derived from Prior COVID Infection

## TL;DR

This study reevaluates the FDA's benefit-risk analysis of Moderna's mRNA-1273 vaccine for young adult males, finding that vaccine risks may outweigh benefits unless Omicron infection rates are very high.

## Contribution

The study introduces a refined benefit-risk model that incorporates benefits from prior infection and provides more accurate risk stratification for vaccination.

## Key findings

- Vaccine risks outweigh benefits for 18–25-year-old males unless Omicron infection rates are implausibly high.
- Vaccination of 18–25-year-old males resulted in 8% to 52% more hospitalizations for VAM/P than prevented by the vaccine.
- Model inputs and outputs were validated by data available after the FDA's original assessment.

## Abstract

Background: The U.S. Food and Drug Administration (FDA) conducted a benefit–risk assessment for Moderna’s COVID vaccine mRNA-1273 prior to its full approval, announced 31 January 2022. The FDA’s assessment focused on males 18–64 years old because its risk analysis was limited to vaccine-attributable myocarditis/pericarditis (VAM/P), given the excess risk among males. The FDA’s analysis concluded that vaccine benefits outweighed risks, even for 18–25-year-old males (those at highest VAM/P risk). We reanalyze the FDA’s benefit–risk assessment using information available through the third week of January 2022 and focusing on 18–25-year-old males. Methods: We develop a benefit–risk model, extending the FDA’s, that can stratify benefits and risks of vaccination by prior-infection and comorbidity status. We use the FDA’s framework but apply our model to account for benefits derived from prior COVID infection, while also accounting for finer age stratification in COVID-hospitalization rates, incidental hospitalizations (those of patients who test positive for COVID but receive treatment for something else), more realistic projections of Omicron-infection rates, and more accurate VAM/P rates. Results: With hospitalizations as the principal endpoint of the analysis (those prevented by vaccination vs. those caused by VAM/P), our model finds vaccine risks outweighed benefits for 18–25-year-old males, except in scenarios projecting implausibly high Omicron-infection prevalence. Our assessment suggests that mRNA-1273 vaccination of 18–25-year-old males generated between 8% and 52% more hospitalizations for VAM/P compared to COVID hospitalizations prevented (over a five-month period of vaccine protection assumed by the FDA). The preceding assessment uses model inputs based on data available at the time of the FDA’s mRNA-1273 assessment. Moreover, these inputs as well as model outputs are validated by subsequently available data. Conclusions: The outcome of a vaccine benefit–risk assessment may be dramatically impacted by accounting for the benefits derived from prior infection by the vaccine-targeted disease. To increase public confidence in vaccines and thereby reduce vaccine hesitancy, public-health agencies should employ benefit–risk models capable of supporting stratification of vaccination recommendations not only based on age and sex but also on prior-infection and comorbidity status.