Immunopeptidomics Unlocks New Paths for mRNA Vaccine Design

Insights from the Listeria Study Published in Nature Communications (2022), researchers led by Rupert L. Mayer and colleagues demonstrated how mass spectrometry–based immunopeptidomics can be used to design mRNA vaccines with unprecedented precision. Their study, “Immunopeptidomics-based design of mRNA vaccine formulations against Listeria monocytogenes”, offers a powerful blueprint for next-generation vaccine development—one that aligns closely with Alithea Bio’s mission to make immunopeptidomics data actionable for precision immunotherapy.

Mapping the Immune-Presented Proteome
The team applied a mass spectrometry immunopeptidomics workflow to two infected human cell lines, HeLa and HCT-116, to identify which bacterial peptides are actually presented on the cell surface by HLA class I molecules.
Out of more than 15,000 human peptides, they discovered 68 unique Listeria-derived peptides from 42 bacterial proteins, several of which were previously unknown antigens. Many originated from bacterial surface proteins, marking them as highly promising vaccine candidates.
When these highly presented antigens were encoded into mRNA-lipid nanoparticle (LNP) formulations, the vaccines triggered robust CD8⁺ T-cell responses and conferred protective immunity in mouse models.
This experiment not only proves the power of immunopeptidomics to pinpoint functional epitopes but also highlights how antigen presentation data can directly translate into effective vaccine design.

Why This Matters for Vaccine and Immunotherapy Development
Traditional vaccine design often relies on predicted or known antigens. However, immunopeptidomics provides empirical evidence—identifying the exact peptides naturally displayed on HLA molecules. This ensures that vaccine antigens are biologically relevant and capable of eliciting strong cytotoxic T-cell responses.
By linking peptide presentation to HLA allele specificity, the Listeria study also offers insights into epitope dominance and pMHC stability—key parameters that determine immune breadth and effectiveness. These are precisely the challenges modern cancer vaccine and immunotherapy developers face today.

Alithea Bio’s Perspective: From Pathogens to Cancer Immunotherapy
At Alithea Bio, we leverage HLA immunopeptidomics and AI-powered analytics to translate such principles into oncology and immunotherapy.
Our proprietary HLA-Compass platform maps naturally presented peptides across HLA alleles and tissues, building one of the world’s largest HLA-peptidome datasets. By quantifying epitope dominance, binding stability, and off-target presentation, we enable smarter antigen prioritization and dosing strategies—helping researchers design vaccines and T-cell therapies that maximize immune breadth without compromising safety.
The findings from the Listeria study reaffirm our belief: immunopeptidomics is the key to rational, data-driven vaccine development, whether targeting pathogens or tumors.

From Bacteria to Tumors: The Broader Impact
The same logic that guided antigen selection in Listeria can be applied to cancer immunotherapy, where understanding the naturally presented immunopeptidome is crucial. By integrating immunopeptidomics with proteogenomics and AI, researchers can now:

Identify neoantigens unique to tumor tissues,
Predict off-target toxicity with higher accuracy, and
Optimize personalized cancer vaccine formulations.
At Alithea Bio, we’re pioneering this transformation—bringing data-backed precision to the design of next-generation immunotherapies.