In the aftermath of Moderna's historic rally on Wednesday, it is becoming clear that many of the stocks pulled along in its wake aren't guaranteed to be long-term winners.

Moderna and Merck on Wednesday shared positive results from a late-stage trial evaluating the efficacy of their mRNA-based cancer vaccine, intismeran autogene. In a trial of 1,100 patients, a treatment combining intismeran and Merck's Keytruda was more effective at preventing the recurrence of melanomas than Keytruda alone.

Investors were giddy. Moderna added over $44 billion to its market capitalization on Wednesday as shares nearly tripled in a historic stock surge. Merck's market value rose by nearly as much.

Both stocks earned upgrades at major firms: William Blair and BofA raised their ratings on Moderna, while Morgan Stanley elevated Merck to Overweight from Equal Weight.

Short covering likely amplified Moderna's rise, but the momentum spilled over to other vaccine stocks. BioNTech spiked 22% in its best day since 2023, while Novavax gained nearly 11%.

The trial marked the first the first Phase 3 success for an mRNA cancer vaccine, opening the door to Food and Drug Administration approval and subsequent commercialization. The partners are also testing the combination against non-small cell lung cancer, bladder cancer and renal cell carcinoma.

Barclays projects sales for melanoma treatments alone could reach $3 billion by 2035. Barclays analyst Eliana Merle says intismeran has a 60% probability of success across late-stage trials, regulatory clearance, and commercialization. That suggests it is more likely than not to capture a slice of that market.

Leerink Partners analyst Lili Nsongo, a former neurogeneticist, noted Thursday that the trial success "provides significant de-risking of mRNA vaccine's expansion into cancer treatment." At their core, mRNA vaccines give cells a blueprint to produce a target protein. This triggers the immune system to build lasting defenses that recognize and destroy the target on future contact.

The science may be straightforward, but the current regulatory environment poses a challenge. Although global data from billions of doses confirms the underlying technology is safe, its rapid rollout during the pandemic made it a target for scrutiny.

One of the most outspoken critics, Health and Human Services Secretary Robert F. Kennedy Jr., terminated 22 federal contracts for mRNA-based vaccines last year, falsely claiming that the vaccines were responsible for "new mutations." This hostility means safety and efficacy alone cannot make the technology a safe bet for investors. Nsongo emphasized that this challenging regulatory backdrop has already stalled the launch of next-generation Covid vaccines.

Although she views the risk as a "more short-to-midterm hurdle" that may evaporate during the 2028 U.S. election cycle, there are even bigger hurdles impeding the adoption of mRNA vaccines.

Just look at Moderna's mRESVIA. Although it offers a convenient mRNA option for respiratory syncytial virus, a common respiratory infection, the vaccine has struggled to compete with established treatments with strong pricing power and proven durability-especially where no clear benefit over traditional protein-based vaccines.

Outside standard respiratory vaccines, most mRNA programs remain in early development. Moderna has faced notable hurdles here-its cytomegalovirus vaccine failed to meet efficacy targets in Phase 3 trials, while its norovirus program fell short of early success criteria. The vaccines target viruses responsible for severe pregnancy complications and acute gastroenteritis, respectively.

While Nsongo didn't go so far as to issue an explicit "Sell" recommendation, she singled out several stocks that may struggle. For instance, the analyst sees little upside for BioNTech and Pfizer, which remain heavily exposed to a Covid vaccine market that has collapsed from $50 billion to roughly $7 billion in spite of their efforts to diversify.

Meanwhile, commercial delays are piling up. A major late-stage trial failure forced the partners to restart early testing on their combined flu-Covid shot, delaying its approval.

Other major players including CureVac, Sanofi, and GSK have pursued mRNA vaccines of their own, but early-to-mid-stage viral programs across their portfolios have faced pauses, terminations, or regulatory roadblocks.

As for cancer vaccines, their trajectory is even less clear. Nsongo noted that "historical failures paint a complex picture for mRNA cancer vaccines." Individual mRNA platforms rely on different technologies, meaning intismeran autogene's latest trial success won't necessarily translate to other platforms.

Many analysts view the trial results as highly specific to Moderna rather than a broad endorsement of mRNA technology, offering little relevance to competitor stocks. At most, the data simply bodes well for ongoing intismeran trials.

The data offers a "positive read-through for ongoing studies of intismeran in other cancer types," according to William Blair analyst Myles Minter, who upgraded the stock to Outperform from Market Perform.

Nsongo herself singled out one potential mRNA winner: Arcturus Therapeutics. The tiny, California-based biotech has grappled with the same postpandemic slump in demand as larger players like Moderna, BioNTech, and Pfizer.

While concerns remain around the uptake of its approved mRNA Covid vaccine, and emerging rare disease portfolio, these stumbles may not rule out a lucrative exit. As Nsongo sees it, the latest trial result from Merck and Moderna increases the likelihood of companies like Arcturus being bought out by bigger drug companies, with Arcturus being the only one with an approved product.

Bottom line: The intismeran milestone won't trigger a rising tide for all mRNA vaccine stocks. With infectious disease programs stalled by market saturation and regulatory headwinds, the technology's commercial potential is shifting decisively toward cancer treatment. Yet even in that promising frontier, success is far from guaranteed.