mRNA flu shots: What changes beyond COVID-19?

mRNA drugs can preempt infectious disease and treat Mendelian disorders, such as sickle cell anemia, muscular dystrophy, and cystic fibrosis, as well as autoimmunity and cancer.^1-3 Thirty years ago, researchers demonstrated that introducing in vitro transcribed mRNA intramuscularly resulted in detectable protein expression for specific antigens, protecting against influenza and cancer.^1-3

Utilizing mRNA as a therapeutic modality presents challenges. mRNA is large and anionic, preventing passive diffusion across the negatively charged plasma membrane. RNases in the bloodstream and tissues rapidly degrade mRNA, and its administration can induce an innate immune response.^1-3 To overcome these hurdles, lipid-, polymer-, dendrimer-, and natural membrane-based mRNA drug delivery systems have been developed to deliver mRNA to target cells.^1-3

The mechanism of mRNA delivery

Significant efforts and investments have translated some of these delivery systems into clinical use. Systemically administered lipid nanoparticles (LNPs) have delivered mRNA to the liver, while intramuscularly administered LNPs have delivered mRNA to immune cells to protect against coronavirus disease of 2019.^1-3 But, clinically relevant delivery in non-liver tissues such as the spleen, lungs, heart, eye, central nervous system, and lymphatics requires improved drug delivery systems.^1-3

Advances in chemical modifications and sequence optimization have improved mRNA potency, leading to greatly improved pharmacokinetics. Researchers have focused on what constitutes an ideal mRNA payload and reviewed drug delivery systems to get that payload into target cells. Efforts to reduce clearance by the liver, a key obstacle to developing non-liver therapies, have been a major focus.^1-3 Recent examples of nanoparticles have delivered mRNA to non-liver tissues, expanding the potential therapeutic reach.^1-3

"The rapid development and early success of Covid 19 vaccines have raised hopes for accelerating the cancer treatment mechanism."Amanpour S, Arch Razi Inst 2021

The COVID-19 vaccines provided critical lessons for future mRNA drugs. The Pfizer/BioNTech mRNA-based vaccine against SARS-CoV-2 received Food and Drug Administration approval, and the Moderna mRNA-based vaccine against the same disease received Emergency Use Authorization.^1-3 These developments contribute to the clinical translation of mRNA therapeutics targeted outside of the liver.^1-3 The Oxford Handbook of Infectious Diseases and Microbiology (3rd ed) provides a practical guide to understanding such advancements.

The approval of mFlusiva for influenza represents a direct application of these lessons. It confirms the viability of mRNA technology for widespread vaccination against common infectious diseases. The clinical data supporting mFlusiva's approval demonstrated its ability to induce an immune response comparable to, or superior to, traditional flu vaccines, though specific efficacy numbers were not detailed in the provided abstracts. The safety profile was consistent with other mRNA vaccines, primarily involving local injection site reactions and transient systemic symptoms.^1-3

What the approval means for future vaccines

This approval opens the door for faster vaccine development cycles, particularly for pathogens with high antigenic drift, like influenza. Traditional egg-based vaccine production can take months, a timeline mRNA platforms significantly shorten. This speed allows for quicker adaptation to emerging strains, potentially improving vaccine matching and overall effectiveness each season.^1,2

But the logistical challenges of mRNA vaccines, such as cold chain requirements, remain a consideration for global distribution. While not explicitly detailed in the provided research, these practical aspects influence real-world implementation. The long-term durability of the immune response from mRNA flu vaccines compared to conventional options will also require ongoing surveillance.^1,2

The trial was not powered to detect differences in specific high-risk subgroups, such as the immunocompromised or the elderly, and that gap matters for comprehensive clinical guidance. Future studies will need to address these populations to fully understand the breadth of mFlusiva's utility. The next step involves observing real-world effectiveness and safety data as the vaccine rolls out.