New Frontiers in mRNA Vaccine Development

Since the advent of the COVID pandemic, in 2020, we’ve entered both a scarier and braver new world. Zoonotic viruses making the jump to people is often the cause of outbreaks and pandemics. As COVID continues to smolder, avian flu now threatens to spread beyond dairy farm workers in direct contact with infected animals, raising the specter of another pandemic.

But mRNA vaccine technology is also rapidly evolving alongside current dangers, spurred by the global push for solutions during the pandemic. This resulted in vaccines like Spikevax from Moderna and Comirnaty from Pfizer/BioNTech and marked the start of a medical revolution—cost-effective, easily scalable immunizations that can be quickly adapted to target variants. The field is now poised to prevent, treat, and even eradicate a multitude of diseases.

Here we’ll look at what’s coming down the clinical pipeline, what the sticking points are, and how innovations are optimizing immune responses while minimizing side effects.

Conventional vaccines vs mRNA vaccines

Conventional vaccines

Conventional vaccines directed against viruses (or bacteria) rely on a piece of weakened or inactivated microbe, grown inside of eggs or mammalian cells in a lab. When injected into the body, the foreign material elicits an immune response and subsequent protection. The development process is slow and not easily scalable. Tailoring the vaccine to a new variant requires starting from scratch.

mRNA vaccines

The genetic code of the virus is all that is needed for scientists to get started. A specific region of sequence (in the case of COVID-19, the spike protein) is selected for use in the vaccine. Messenger RNA (mRNA) molecules, acting as a blueprint for the construction of viral protein, are then carefully packaged inside of lipid nanoparticles (LNP), which protects the material from harsh conditions in the body and helps it get delivered to cells. As with traditional vaccines, the immune system produces antibodies against the antigen. The body will retain the ability to make these specific antibodies for months, or even years, after exposure. These inoculations are able to be designed and generated much more quickly, in a matter of weeks, and lend themselves to flexible scalability.

Turbocharging vaccines with fewer side effects

Despite their effectiveness, mRNA vaccines face challenges, including waning immunity and suboptimal responses in older populations. Adjuvants, immune-stimulatory molecules commonly used with traditional vaccines, may be the answer. A research group at Boston Children’s Hospital zeroed in on an interleukin (IL) protein adjuvant candidate critical for an optimized immune response. They previously observed the Pfizer/BioNTech COVID-19 vaccine did not induce production of IL-12p70 in human cells, so they designed mRNA to instruct cells to make it. When delivered alone or as an add-on to the immunization, IL-12p70 heightened not only antibody production, but also cytokine production and immune cell activity, elements vital for protection from COVID-19.

The scientists added another feature, too—a multiorgan protection sequence (MOP). As the name suggests, the MOP ensures mRNA acts in muscle only, despite traveling throughout the entire body. In any other organ, MOP will bind to microRNAs and direct cells to recycle the IL-12p70 mRNA. At the same time, the protective sequence boosts IL-12p70 production in muscle tissue. As a result, very low doses of the Pfizer/BioNTech vaccine produced a potent immune response, something that could translate to more vaccine availability and fewer shortages.

With the adjuvant, protection persisted for one year post-vaccination (instead of only a few months) and restored immunity in aged mice to levels seen in young adults suggesting benefits for vulnerable populations. For now, the group has moved on to testing in non-human primates, with the goal being clinical trials.¹

More power, more options

Harnessing the power of adjuvants unlocks new possibilities such as intranasal delivery. At MIT researchers tweaked the COVID-19 vaccine at two points—the antigen itself and the nanoparticle delivery system—to enhance immune response in mice. The C3d protein, part of the immune complement system, was previously researched as an adjuvant in traditional vaccines. Now the team redesigned the mRNA vaccine to produce a fused protein containing both C3d and the original antigen, allowing cells to generate both simultaneously following injection.

They also modified the nanoparticle delivery system so that it evoked an immune response as well. Mice injected with the redesigned vaccine produced 10 times more antibodies and had a stronger T cell response.

The adjuvanted inoculation elicited a similarly strong response when delivered intranasally. If clinical trials in people prove its effectiveness, it would be another defense against respiratory viruses, like COVID, flu, and RSV, which could be killed at the mucus membrane before ever entering the body.²

Upcoming vaccines to watch

Vaccine development against slippery viruses and formidable cancers is in full swing. Several promising mRNA vaccines are under development:

Pfizer/BioNTech PF-07252220-Influenza

This vaccine outperformed a licensed flu vaccine in Phase III trials for adults.

Another mRNA vaccine for both influenza and COVID-19 is facing challenges as it worked well against flu A, but not flu B. Potentially delayed approval may allow competitors to catch up.

Moderna mRNA-1083-COVID/Influenza

Moderna's vaccine is on track to be the first combination vaccine to market. Phase III trial results demonstrated a strong immune response against both diseases, making it the only company to report such results.

Additionally, the company plans to incorporate its newly approved RSV vaccine into the mix, creating a triple vaccine for COVID-19, influenza, and RSV.

GSK4388067-COVID-19 & GSK4382276-Influenza

GSK is advancing its efforts against influenza and COVID-19 through separate mRNA vaccines. Both candidates are in Phase II trials. In July, GSK acquired global rights to develop these investigational vaccines from CureVac, and may move to develop a combination vaccine and one for avian flu.

Moderna mRNA-4157-head and neck cancer, melanoma

Oncology is a vital market for biopharma, and the success of mRNA vaccines could validate their broader potential. Moderna, in collaboration with Merck, is developing a therapeutic vaccine in Phase III trials to enhance the efficacy of Merck’s PD-1 inhibitor, Keytruda, for improved anti-tumor effects. Trials are ongoing for various cancers, including head and neck cancer and melanoma.

Moderna mRNA-1647-cytomegalovirus

Cytomegalovirus (CMV) is the leading infectious cause of birth defects in the U.S. Currently in Phase III trials for women aged 16 to 40, interim efficacy results are expected by the end of 2024. Expansion studies are also underway for adolescents and adult transplant patients. Phase II results demonstrated safety and immune responses at all dose levels. There are no approved vaccines or treatments for congenital CMV, which primarily affects infants and immunocompromised individuals.

Moderna mRNA-1403-Norovirus

Moderna has launched a Phase III trial for its investigational norovirus vaccine, with the first participant dosed in the U.S. and global recruitment underway. This randomized, observer-blind, placebo-controlled trial aims to enroll about 25,000 participants aged 18 and older, with a focus on those 60 and older, to assess the vaccine's effectiveness against moderate to severe norovirus gastroenteritis. Norovirus is highly contagious, contributing to around 200,000 deaths annually. This trivalent vaccine targets multiple norovirus genotypes to prevent severe outcomes.

Beyond infectious disease, mRNA vaccines as promising new cancer treatments

The success of mRNA vaccines for COVID-19 has already addressed many technical challenges, leading to improved stability and expression efficiency. Progress in delivery systems also benefits mRNA cancer vaccines, which are becoming a hopeful new avenue for cancer treatment, as evidenced by the growing number of advancing clinical trials.

In May, scientists reported encouraging results of four adult patients with glioblastoma, an aggressive and deadly form of brain cancer. The vaccine was previously tested in ten pet dogs with gliomas where lifespan was significantly extended—a median of 139 days compared to 30 to 60 days typical for dogs with the disease. In the clinical trial of patients, all had previously relapsed. Vaccines were designed using RNA from the patients’ own cancer cells as template for the mRNA. Then researchers maximized the amount of RNA delivered by the vaccine by packaging it in between layers of lipid, like an onion, to increase the likelihood that an immune response is triggered. With this strategy, tumor reprogramming was observed within several hours of intravenous infusion. All patients lived several months longer than expected, but the study is ongoing.³ Next up the group will attempt to treat children with recurrent high-grade glioma by the end of the year. Similarly designed vaccines can be used as immune-based therapies for many other kinds of deadly cancers.

The rapid evolution of mRNA vaccine technology marks a pivotal shift in public health, enabling swift responses to emerging diseases and innovative treatments for conditions like cancer. With ongoing advancements, the future holds great promise for enhancing vaccine efficacy and expanding their applications.

References

1. Brook, B. et al (2024). Adjuvantation of a SARS-CoV-2 mRNA vaccine with controlled tissue-specific expression of an mRNA encoding IL-12p70. Science translational medicine, 16(757), eadm8451. 

2. Li, B. et al. (2023). Enhancing the immunogenicity of lipid-nanoparticle mRNA vaccines by adjuvanting the ionizable lipid and the mRNA. Nature biomedical engineering, 10.1038/s41551-023-01082-6. Advance online publication. 

3. Mendez-Gomez, H. R. et al.  (2024). RNA aggregates harness the danger response for potent cancer immunotherapy. Cell, 187(10), 2521–2535.e21.