From Rejection to Revolution: mRNA Vaccines Go Beyond Infections to Diseases in the Brain

Katalin Karikó, PhD, who is now a professor at the University of Szeged, Hungary, had one goal in mind when she was working with messenger RNA (mRNA) to develop therapeutics. It had nothing to do with vaccines—whether for viruses, cancer, or any other condition in which it would make sense to bring in the immune system. “I never thought it would be immunogenic because I was only thinking about using mRNA to produce proteins inside of cells … or more receptors already found in the body,” Karikó told Inside Precision Medicine.

Then, while knee-deep in research literature, the lightbulb moment came. “I was thinking about why the mRNA therapeutics were failing, and then I realized that the body was fighting it with an inflammatory response,” said Karikó. So, in the early 2000s, Karikó teamed up with immunology expert Drew Weissman, MD, PhD, now a professor and the director of vaccine research at the University of Pennsylvania, and the rest is history. Together, they discovered that adding chemical modifications to synthetic mRNA prevented inflammatory immune responses and boosted protein production. By incorporating these modifications, they transformed mRNA into a safe, efficient tool for therapeutic use. This innovation paved the way for cost-effective and scalable mRNA-based vaccines, including the COVID-19 vaccines, revolutionizing medicine and global health. For this work, Karikó and Weissman were awarded the 2023 Nobel Prize in Physiology or Medicine.

The impact of Karikó’s research has taken an even more unexpected turn from her initial work: mRNA vaccines are now being developed beyond infectious diseases to tackle non-communicable conditions. While vaccinating against cancer and neurodegenerative diseases is not a new idea, progress with traditional viral-, peptide-, and cell-based vaccines has been limited. With mRNA vaccines, the ability to mobilize the immune system to fight non-infectious diseases could be headed for a renaissance—especially for treating (and possibly preventing) devastating diseases of the brain.

Inside Precision Medicine spoke with several experts who shared their progress in utilizing mRNA vaccines for treating glioblastoma and Alzheimer’s disease.

Beware: microenvironment

Elias Sayour, MD, PhD, an associate professor of neurosurgery and pediatrics at the University of Florida, was treating cancer patients with immunotherapy during his fellowship at Duke University, where he encountered pediatric oncology’s harsh realities. “We often talk about great outcomes and improved cure rates, but the truth is, curing one child often means harming others,” Sayour told Inside Precision Medicine. “You’re poisoning ten to cure three, four, or five children with cancer, and for those you don’t cure—you’re just hurting them. It’s a brutal equation, one that breaks the ‘do no harm’ rule in every patient we treat.” That’s when Sayour first began to look into mRNA vaccines.

By programming immune cells to recognize and attack cancer as a foreign invader, mRNA vaccines not only combat the disease but also imbue the immune system with a memory that lasts for life. “The immune system doesn’t just fight for you,” Sayour explained. “It remembers. That memory is one of its most powerful features.”

One of the most difficult cancers that Sayour has treated is glioblastoma, a brain tumor that is aggressive and infamously resistant. “If we could cure glioblastoma with mRNA vaccines, I think we could cure all cancers,” he said. “It’s not the easiest target—it’s the hardest—but its complexity offers a blueprint for overcoming even the most resilient cancers.”

According to Sayour, the tumor and its hostile ecosystem pose a great challenge to any immunotherapy. To illustrate the concept of a hostile microenvironment, Sayour tells his students about a situation in which a civilian with no survival training is dropped into the Everglades at night to hunt the invasive Burmese python.

Sayour said, “Go shoot the Burmese python. Bring three of your friends, but good luck. I don’t think you’re going to survive. Even if you do have training, you still need food and shelter. You’re probably going to freeze. That’s what happens to T cells when they get into these environments: they’re frozen. The T cells become anergic—they lose energy—and you find them right near the glioblastoma in the blood vessels as if they can’t penetrate the hostile environment. That’s glioblastoma; it’s not just surviving, it’s reprogramming the immune system to defend it.”

This is where mRNA’s versatility becomes a game-changer. Unlike traditional treatments that rely on toxic chemotherapy or radiation, which Sayour compared to “dropping a nuke on the Everglades,” mRNA trains the immune system to target cancer with precision. It is software for the body’s hardware, capable of adapting to cancer’s relentless evolution. “Cancer is an organism within an organism, constantly reshaping its environment,” he explained. “RNA can fight evolution with evolution, reprogramming the immune response in ways we’ve never been able to before.”

The mRNA vaccine approach to cancer is risky, especially for aggressive glioblastoma, Sayour warned, as extreme immune responses can cause serious side effects. However he believes the pros outweigh the cons in the long-term. “The immune system is like fire,” Sayour said. “Controlled, it’s powerful. Unchecked, it’s destructive. But if we can harness it effectively, the possibilities are endless.”

Dancing to the algorithm

During the COVID-19 pandemic, CureVac, a pioneer of mRNA vaccine technology, failed to deliver its first-generation vaccine candidate. “We weren’t lucky with our initial mRNA backbone used during the pandemic,” Myriam Mendila, MD, chief scientific officer and head of R&D at CureVac, told Inside Precision Medicine. But as the saying goes, it is not whether you fall, but whether you get up. “Since then, our team has refined our platform using cutting-edge skills in protein design, mRNA formulation, and—most importantly—proprietary algorithms.”

At the heart of CureVac’s updated approach to designing their second-generation mRNAs is a sophisticated system of artificial intelligence (AI) for stimulating an immune response. CureVac’s process begins with identifying the cancer antigen, typically a protein or smaller peptides, that is then designed to behave exactly as needed within the cell, irrespective of whether it is secreted, presented on the cell surface, or anchored through major histocompatibility complexes. The optimal antigen presentation design is determined by advanced computational tools and iterative testing.

Once the protein design is finalized, CureVac uses another algorithm to optimize how the designed protein will be encoded in mRNA. “Our proprietary mRNA design algorithm ensures optimal codon usage for translational efficiency,” Mendila said. “By selecting the perfect combination of nucleotide triplets, the algorithm maximizes protein production from the mRNA sequence. That’s our secret sauce.”

CureVac is developing two arms for their mRNA vaccine programs: personalized cancer vaccines (PCVs) and shared antigen cancer vaccines (SACVs), each with its own benefits. Commercially available SACVs that target common patient antigens are faster, cheaper, and easier to make than the customized approach, which theoretically maximizes vaccine efficacy. PCVs involve sequencing a patient’s tumor to identify unique antigens, which are ranked for their ability to provoke an immune response. To expedite mRNA vaccine production, CureVac has also developed an mRNA printer—a fully automated system that can transcribe mRNA for PCVs in mere days. “We can go from sequence to vaccine in about four to six weeks,” said Mendila. “For cancer patients, that speed can be life-saving.”

CureVac’s efforts are still in the earliest stages of clinical testing, but the results they have presented on their vaccine for glioblastoma, CVGBM, have been promising. CVGBM encodes eight carefully chosen antigens, offering a ready-to-use option for patients who need immediate treatment.

At the European Society for Medical Oncology 2024, CureVac demonstrated that the CVGBM mRNA vaccine made with lipid nanoparticles (LNPs) for glioblastoma was safe at the highest dose tested, with no serious side effects, and successfully triggered an immune response in 77% of patients. Of these immune responses, 84% were de novo, seen in patients who did not have any previous T cell activity against the cancer antigens. It’s still early days, as the trial is currently in Phase Ib, but it looks like CureVac, which recently won a patent battle in court against BioNTech, may be back on track.

Alzheimer’s disease, not today, not tomorrow

During her graduate studies, Rebecca Nisbet, PhD, who was fascinated by prion protein mechanics, encountered a harsh reality: funding for prion disease research was scarce, so she pivoted to Alzheimer’s disease, for which there was—and still is—greater financial support. This pragmatic decision marked the start of a distinguished career, largely centered on Alzheimer’s and related tauopathies like frontotemporal dementia. During her time as a postdoctoral researcher in antibody engineering at the Commonwealth Scientific and Industrial Research Organisation in Australia, Nisbet fell in love with antibodies and immunotherapy.

Since monoclonal antibodies have high production costs, require large doses, and need intravenous infusion infrastructure, the COVID-19 pandemic piqued Nisbet’s interest in mRNA technologies. At The Florey, Australia’s leading brain research center, Nisbet heads the Antibody Therapeutics Group, which focuses on mRNA vaccines that encode amyloid beta antigens, stimulating the immune system to produce antibodies against this hallmark protein of Alzheimer’s disease. “I believe the future of immunotherapy for Alzheimer’s lies in vaccines,” Nisbet said. “We’re striving for a therapeutic strategy that is accessible, effective, and preventive, making this as simple as a flu shot. Many people with Alzheimer’s live in rural areas without access to infusion clinics, so intramuscular vaccines could revolutionize treatment.”

Overcoming the blood-brain barrier (BBB) is one of the greatest obstacles to treating Alzheimer’s, and Nisbet is taking two mRNA approaches to get around the problem. One involves using LNPs conjugated to BBB-penetrating peptides to deliver mRNA encoding an antibody towards tau. The other approach does not require the mRNA itself to traverse the BBB, but uses mRNA encoding an amyloid beta peptide to stimulate the immune system to generate anti-amyloid beta antibodies that can reach the brain. Nisbet’s team has shown that this mRNA vaccine does stimulate an immune response that generates high levels of anti-amyloid beta antibodies circulating within the serum in wild-type mice.

The major unknown now is how many of these anti-amyloid beta antibodies can cross the BBB and stimulate an immune response to clear out amyloid beta plaques. “What we don’t know is how much of these antibodies get into the brain once they’re made,” said Nisbet. “The estimate is that about 0.1% of those antibodies can transverse the BBB naturally. So, we’re relying on the endogenous low level of antibodies to cross the BBB. If we’re using our vaccine as more of a preventative, I don’t think we’ll need that much to get into the brain to clear the increased amount of amyloid beta there before it forms plaques. We’re quite optimistic that although these antibodies aren’t designed to cross the BBB, we’ll still get brain amyloid beta clearance.”

Nisbet is adamant that the neurodegeneration field needs to shift focus, and she is working tirelessly to develop a vaccine that will stop the progression of Alzheimer’s and save millions of lives. “We’ve spent too long targeting late-stage pathology when it’s already too late—neurons are essentially dead by then,” Nisbet said. “Alzheimer’s begins decades before symptoms appear. We need to shift the conversation toward prevention. By clearing amyloid beta before it forms plaques, the vaccine could halt disease progression early.”

It remains to be seen whether the mRNA vaccine approach will be able to muster a therapeutic response in animal disease models and Alzheimer’s patients. This approach, if successful, could pave the road to other neurodegenerative diseases driven by toxic peptide buildup in the brain, such as those caused by alpha-synuclein in Parkinson’s disease. If so, an entirely new movement in precision medicine could be launched involving personalized genomics and prophylactic neurodegenerative diseases, where people with pathological mutations or high-risk variants could opt for protective mRNA vaccines far before neurodegenerative processes take hold. That would be quite the leap for neurodegenerative diseases, going from a lack of therapeutics to stopping or slowing down disease and then to population-level prevention.

The paradigm of preventing complex noninfectious diseases with mRNA vaccines appears to be expanding into fields where immunotherapies are being explored, such as the treatment and prevention of atherosclerosis and myocardial infarction. Amongst all this speculation, one thing is clear—that Karikó, when beginning her work on mRNA over 30 years ago, absolutely did not see this coming. As such, her work on mRNA is a testament to the value of “basic science” as a springboard for therapeutic innovations. Karikó’s persistence has sent reverberations through the world with mRNA vaccines, and that’s just one of the many tools provided by this Swiss Army Knife-like platform provided by the single-stranded genetic molecule.

Jonathan D. Grinstein, PhD, North American editor for Inside Precision Medicine, investigates the most recent research and developments in a wide range of human healthcare topics and emerging trends, such as next-generation diagnostics, cell and gene therapy, genome engineering, and AI/ML for drug discovery for publications like Scientific American and Genetic Engineering and Biotechnology News (GEN). Jonathan earned his PhD in biomedical science from the University of California, San Diego, and a BA in neural science from New York University.