The mRNA Revolution: Beyond COVID to Cancer, Flu & Herpes Vaccines
How Moderna and BioNTech are expanding from COVID into CMV, EBV, HSV, and next-gen flu, while scaling personalized cancer vaccines (part 1 of the mRNA mini series).
Welcome back to Biotech Blueprint!
In this special episode, I teamed up again with Hartaj from the Biotech Capital Compass for part one of our mRNA therapeutics mini series. We covered the foundational science behind how RNA became medicine, the decades of bioengineering breakthroughs that made COVID vaccines possible, and what’s coming next in the infectious disease space. From Moderna’s ambitious pipeline targeting everything from flu-COVID combo shots to latent viruses like CMV and EBV, to Moderna’s and BioNTech’s custom cancer vaccines, we mapped out what’s actually coming in the next few years.
The overnight success story (that took 30 years)
The ‘experimental vaccine’ narrative was one of 2020’s most persistent myths. The COVID vaccines weren’t a Hail Mary. They were the culmination of three decades of RNA chemistry, delivery science, immunology, and bioengineering finally having their iPhone moment.
The story starts in the 1961 when scientists first discovered messenger RNA, nature’s elegant system for turning DNA blueprints into functional proteins. By the 1990s, researchers were already testing mRNA-loaded immune cells as cancer vaccines. But here’s the thing. Evolution spent millions of years making sure foreign RNA gets shredded on sight. Enzymes called RNAses chew it up before it even reaches your cells. And inside, immune cells have molecular bouncers called toll-like receptors and other sensors that spot unfamiliar RNA and kick off inflammation.
The breakthrough came in 2005 when Katalin Karikó and Drew Weissman (the 2023 Nobel winners) figured out how to slip mRNA past the alarm system, resulting in less inflammation and more protein. By swapping out uridine for pseudouridine, they allowed mRNA to get past immune surveillance. Add in some clever 5’ cap (a protective front cap that helps cells read the mRNA) engineering and lipid nanoparticle delivery systems, and by 2017, mRNA vaccines were already showing promise in human trials for rabies.
So when SARS-CoV-2 showed up in 2020, mRNA technology was ready for prime time. The only thing that was rushed was the timeline to get these vaccines out there, thanks to unprecedented funding and streamlined trials.
The cytoplasmic gold rush
Here is what makes mRNA therapeutics revolutionary. They deliver instructions so cells make the medicine inside the cytoplasm, opening up targets that small molecules (pocket-limited) and antibodies (can’t enter cells) struggle to reach.
mRNA operates in the cytoplasm where ribosomes, transfer RNAs, and amino acids collaborate in the ancient dance of protein synthesis. It is like having access to a fully equipped manufacturing plant that’s been optimized by 3.8 billion years of evolution. Instead of trying to modulate existing proteins or slip past cellular defenses, you simply hand the cell a new set of blueprints and let it do what it does best.
The numbers tell the story: today’s approved drugs hit only a small slice of the proteome (a few percent of human proteins) and ~85% of proteins don’t have the tidy pockets small molecules need. mRNA doesn’t care about any of that. Got an “undruggable” target? Write the mRNA code. Need a protein that’s impossible to manufacture at scale? Let the patient’s cells make it for you.
This is economically transformative. The marginal cost of adding new antigens to an mRNA vaccine approaches zero once you’ve got the platform figured out. Which brings us to what’s coming next.
The clinical pipeline worth watching
While the COVID vaccine debate raged on, Moderna and BioNTech were already working on their next targets. Here’s what they’re testing now.
Respiratory trifecta: By 2026, you might be getting a single injection that protects against COVID-19 and influenza A/B. Moderna’s mRNA-1083 combo just showed strong immune responses against both COVID and flu strains in phase 3 trials. They’re already working on adding RSV to create a triple vaccine that could replace the messy seasonal vaccination dance with one annual shot.
The economics here are big. The global flu vaccine market alone is worth ~$8 billion annually, and that’s with the current system of trying to guess which strains will dominate months in advance. mRNA vaccines can be reformulated in weeks, not months, and the platform costs scale beautifully.
However, U.S. uptake will hinge on policy. After the FDA’s May 2025 shift, requiring new clinical trials to approve annual boosters for healthy <65, combo-shot timing, adoption, and reimbursement are more constrained than before. Europe is proceeding with annual updates via variations, but U.S. access drives the market.
Latent virus frontier: This is where things get interesting. mRNA’s ability to encode multiple antigens and trigger robust T cell responses makes it uniquely suited to tackle the viruses that traditional vaccines have failed against for decades.
Cytomegalovirus (CMV) infects most of the population asymptomatically but can cause devastating birth defects. Moderna’s mRNA-1647, encoding six different viral proteins, is wrapping up phase 3 trials in women of childbearing age. If successful, it could prevent thousands of congenital infections annually.
Epstein-Barr Virus (EBV) is even more intriguing. Beyond causing mono, EBV is increasingly linked to multiple sclerosis and various cancers. Moderna has two shots at this target: mRNA-1189 for primary prevention and mRNA-1195 for preventing long-term complications. Given MS affects nearly 3 million people and the drug market is in the tens of billions, the upside is huge, but it still hinges on clinical proof.
Herpes simplex virus (HSV) has been the vaccine graveyard where promising candidates go to die, thanks to the virus’s masterful immune evasion tactics. But mRNA’s ability to present multiple antigens simultaneously might finally crack this nut. BioNTech’s BNT163 prophylactic vaccine should read out by the end of 2026.
Personalized cancer vaccines: Cancer vaccines represent mRNA’s highest stakes bet. Unlike infectious disease vaccines that use one-size-fits-all antigens, cancer vaccines need to be as unique as each patient’s tumor. This was impossible with traditional vaccine platforms but mRNA makes it feasible at speed.
The playbook: sequence the tumor, use AI to rank neoantigens, then manufacture a custom mRNA mix, typically dozens of targets (mRNA-4157 encodes up to 34), and start dosing within weeks of surgery. In melanoma, Moderna/Merck’s mRNA-4157 + Keytruda cut the risk of recurrence or death by about 49% in phase 2b and is now in phase 3. If results hold across more cancers, the opportunity is huge. Oncology drug spending (~$223B in 2023) already dwarfs the global vaccines market ($77-88B), but scale, manufacturing timelines, and uptake will matter.
The investment thesis
From a market perspective, this is a true platform, proven to scale to billions of doses during COVID. The question now is whether companies can execute across multiple therapeutic areas simultaneously.
Moderna’s bet is particularly bold. They describe their mRNA as an “operating system,” a plug-and-play platform powering vaccines, protein-replacement therapies, and cancer immunotherapies. It’s either visionary or a high risk, execution-dependent bet.
BioNTech is more focused on oncology, while still advancing infectious-disease vaccines (TB, malaria, mpox/HSV). Its partner-heavy model, including Pfizer (COVID), Genentech (neoantigen cancer vaccine), BMS (BNT327, 2025), and Fosun (China) spreads cost and risk more broadly than Moderna’s mostly in house approach.
The key metrics to watch over the next 18 months:
CMV and HSV vaccine readouts (proof that mRNA works beyond respiratory viruses). mRNA-1647 (CMV) phase 3 efficacy data expected in late 2025. HSV trials are slightly behind (mRNA-1608 ended phase 2 and BioNTech’s BNT163 is in phase 1, so expect early human immunogenicity and safety, not pivotal outcomes).
Cancer vaccine data (the ultimate platform validation). Watch mRNA-4157 + Keytruda phase 3s progress (melanoma + two NSCLC trials) and whether benefit generalizes beyond melanoma. Large readouts expected in 2029-2033.
Combo vaccine adoption rates (evidence of market evolution beyond COVID)
Manufacturing cost curves (the path to true platform economics)
Regulatory updates (especially in the US). The FDA’s May 2025 shift, requiring clinical trials to approve annual COVID boosters for healthy <65 directly affects combo-shot timing, uptake and reimbursement. But transformative platforms tend to route around obstacles and mRNA is global. Europe is still green-lighting annual strain updates, and China is investing in home grown mRNA beyond COVID.
The long game
The next several months and years will be telling. CMV (mRNA-1647) could deliver the first pivotal, non-respiratory proof of the platform by late 2025. Cancer vaccines will be about execution (turnaround time, on-time dosing) as the big phase 3 readouts sit further out in melanoma and NSCLC. Combo-shot adoption will depend less on consumer preference than on policy and reimbursement.
The technology is solid, the pipelines are real, and the prize is substantial. Whether that becomes truly transformative medicine depends on several high stakes readouts coming out in the next year or two. Keep an eye on CMV’s readout, oncology throughput, and regulator green lights.
And stay tuned for our second podcast episode, which will focus on latent viruses and take a closer look at the oncology pipelines.
Thanks for reading Biotech Blueprint.
DISCLAIMER: This content is for informational purposes only. It should not be taken as legal, tax, investment, financial, or other advice. The views expressed here are my own and do not reflect the opinions of any company or institution.
DISCLOSURE: I have no business relationships with any company mentioned in this article.