# Dose-dependent IFN programs in myeloid cells after mRNA and adenovirus COVID-19 vaccination

## TL;DR

This study compares immune responses to three FDA-approved COVID-19 vaccines, revealing distinct interferon programs in myeloid cells after first and booster doses.

## Contribution

The study identifies a novel transient IFN program (ISG-dim) specific to first mRNA doses and distinct from boosting or adenovirus vaccines.

## Key findings

- A transient ISG-dim IFN program occurs in ~10% of myeloid cells 1–2 days after first mRNA vaccination.
- ISG-dim is driven by IFN-α alone, while ISG-high requires both IFN-α and IFN-γ.
- The findings highlight mechanistic differences between priming and boosting immune responses.

## Abstract

The SARS-CoV-2 pandemic provided a rare opportunity to study how human immune responses develop to a novel viral antigen delivered through different vaccine platforms. However, to date, no study has directly compared immune responses to all 3 FDA-approved COVID-19 vaccines at single-cell multiomic resolution.

We longitudinally profiled SARS-CoV-2–naive adults (n = 31) vaccinated with BNT162b2, mRNA-1273, or Ad26.COV2.S, integrating plasma cytokines, antibody titers, and single-cell multiomic data (DOGMA-Seq).

We discovered a distinct, transient IFN program termed ISG-dim, which emerged specifically 1–2 days after the first mRNA dose in approximately 10% of myeloid cells. This state was characterized by ISGF3 complex activation and its target genes (e.g., MX1, MX2, DDX58), with transcriptional and epigenetic profiles distinct from the robust IFN program observed after mRNA boosting or a single Ad26.COV2.S dose (ISG-high). In vitro stimulation of human monocytes showed that IFN-α alone recapitulates ISG-dim, whereas both IFN-α and IFN-γ are required for ISG-high.

These findings define dose-dependent IFN programming in human myeloid cells and highlight mechanistic differences between priming and boosting, with implications for optimizing vaccine platform choice, dose scheduling, and formulation.

NIH grants AI142086, U19 AI135972, U01 AI165452, U01 AI165452, R01 AI160706, and P30 AG067988.

A high-resolution multi-omics study reveals that the primary and secondary mRNA vaccines elicit distinct innate responses driven by Type-I and Type-II interferons, respectively.