mRNA Vaccines Beyond COVID: Cancer, Flu, and the Personalized Medicine Revolution

# mRNA Vaccines Beyond COVID: Cancer, Flu, and the Personalized Medicine Revolution

The development of the BioNTech/Pfizer and Moderna mRNA vaccines against SARS-CoV-2 in
late 2020 was celebrated — correctly — as a triumph of scientific speed and regulatory
agility. What was perhaps underappreciated at the time was that the COVID vaccines were
not simply an emergency response to a specific virus. They were the proof of concept for
a platform technology that had been in development for decades, repeatedly stalled by
technical obstacles that the COVID crisis both demanded and incentivized solving. With
those obstacles largely overcome, the mRNA platform is now advancing into applications
that could transform medicine in ways that dwarf the already-remarkable achievement
of ending the acute phase of a global pandemic.

## How mRNA Vaccines Work

A messenger RNA (mRNA) molecule carries instructions from DNA to the cellular machinery
that builds proteins. A conventional vaccine introduces a weakened or inactivated pathogen,
or a protein derived from it, to provoke an immune response. An mRNA vaccine instead
delivers the genetic instructions for the cell itself to manufacture the target protein.
The cell's ribosomes read the mRNA and produce the antigen, the immune system recognizes
the antigen as foreign and mounts a response, and the mRNA itself is degraded within
days — it does not integrate into DNA. The critical advantages are speed (designing a
new mRNA sequence requires weeks rather than months of protein production), scalability
(manufacturing is cell-free and standardizable), and flexibility (the same manufacturing
infrastructure can produce vaccines against any target for which a suitable mRNA sequence
can be designed).

## Cancer Vaccines: The Most Ambitious Frontier

The application of mRNA technology to cancer represents the platform's most scientifically
ambitious and potentially most consequential extension. Cancer cells accumulate mutations
that produce abnormal proteins — neoantigens — that are specific to a particular patient's
tumor and not present in normal cells. If the immune system could be trained to recognize
and attack these neoantigens, it could kill cancer cells while sparing normal tissue.

BioNTech — the German company that developed the Pfizer COVID vaccine — has been developing
personalized neoantigen vaccines since before the pandemic. The clinical approach involves
sequencing the patient's tumor genome, identifying the neoantigens most likely to provoke
an immune response, designing an individualized mRNA vaccine encoding those neoantigens,
manufacturing that vaccine specifically for the individual patient, and administering it
within weeks of tumor sequencing. In 2023, a Phase 2 trial combining BioNTech's mRNA
melanoma vaccine (mRNA-4157/V940) with Merck's immunotherapy drug pembrolizumab showed
a 44 percent reduction in the risk of death or recurrence compared to pembrolizumab alone.
BioNTech and Merck subsequently announced a broad expansion of the program across multiple
cancer types including lung, colorectal, and bladder cancers. Phase 3 trials are ongoing,
with potential regulatory submissions expected in 2025-2026.

Moderna has its own personalized cancer vaccine program (mRNA-4157), developed in
partnership with Merck. The manufacturing challenge is formidable: each vaccine is
unique to its patient, requiring a de novo design and manufacturing process completed
within roughly six weeks of tumor biopsy. Automation and AI-assisted sequence selection
are critical to making this pipeline viable at scale. The economics of personalized
manufacturing are also challenging — these are inherently expensive treatments for now,
though manufacturing costs are expected to fall substantially as the processes mature.

## Influenza mRNA Vaccines: Solving a Decades-Old Problem

Seasonal influenza vaccines have a fundamental limitation: they must be designed six
to nine months before the flu season based on predictions about which viral strains will
be dominant. When the prediction is wrong — as it frequently is — vaccine effectiveness
drops sharply. The mRNA platform's speed advantage could potentially compress the
design-to-manufacture timeline to weeks, allowing vaccines to be updated based on
observed circulating strains much later in the process.

Moderna's mRNA seasonal flu vaccine (mRNA-1010) completed Phase 3 trials in 2023-2024,
showing superior immunogenicity (antibody response) compared to standard flu vaccines,
though the primary efficacy endpoint required continued evaluation. Multiple mRNA flu
vaccine programs from different developers are in late-stage trials, and the first
mRNA flu vaccine approvals could come in 2025-2027. The longer-term ambition is a
universal influenza vaccine targeting conserved viral regions that change slowly,
potentially providing multi-season or even lifetime protection against a disease
that kills 300,000 to 650,000 people globally each year.

## HIV, RSV, and the Expanding Pipeline

The HIV vaccine challenge — 40 years of failure — may be approachable with mRNA technology.
The HIV virus mutates rapidly and evades immune responses that would neutralize
most other viruses. mRNA's ability to encode complex immunogen sequences and to
be rapidly iterated has opened new approaches. Moderna's mRNA-1644, targeting
broadly neutralizing antibody precursors, entered Phase 1 trials in 2022 as part
of IAVI's research program. The goal is to prime the immune system to generate the
rare type of antibodies that can neutralize diverse HIV strains.

In respiratory syncytial virus (RSV) — a major killer of infants and elderly adults
— Moderna's mRNA-1345 received FDA approval in May 2024, becoming the second approved
mRNA vaccine after the COVID vaccines. The RSV approval demonstrates that the platform's
success is not limited to pandemic emergencies. Combined CMV, Epstein-Barr virus, and
Nipah virus programs are in various stages of development across multiple developers.

## Manufacturing Advantages and Remaining Challenges

mRNA manufacturing is faster and more standardizable than traditional vaccine production,
but it is not without challenges. The lipid nanoparticle delivery system that carries
mRNA into cells requires cold-chain storage (typically -20°C for modern formulations,
down from the -70°C required for the original Pfizer COVID vaccine). Cost per dose
remains higher than for some conventional vaccines. And for cancer applications,
the complexity and cost of truly personalized manufacturing represent real barriers
to broad access. The next decade will test whether the platform's scientific promise
can be translated into treatments that are accessible across income levels and
healthcare systems globally — a challenge as much economic and political as scientific.

mRNA Vaccines Beyond COVID: Cancer, Flu, and the Personalized Medicine Revolution

// COMMENTS

ON THIS PAGE