mRNA flu vaccines are under study (2023)

Following the successful use of mRNA vaccines to prevent COVID-19, three major drug manufacturers have introduced seasonal influenza vaccine candidates made using the technology in early clinical trials. Other companies intend to follow suit next year (Table 1).

If successful, these candidates could dramatically increase the effectiveness of a vaccine class that often offers lackluster protection. For mRNA advocates - led by Moderna, Pfizer and Sanofi, which began Phase I trials in recent months - new flu vaccines could be profitable or help maintain their position in a faltering global market, estimated at more of $10 billion by end of the decade.

But flu shots can also be a tougher test for mRNA than COVID-19. Because, unlike SARS-CoV-2 – for which there were no established medical interventions – nine flu vaccines from four different vaccine manufacturers are now available in the US alone.

These vaccines are safe, but their effectiveness leaves room for improvement. Existing flu vaccines, whether built around inactivated viruses or recombinant proteins, typically offer only 40 to 60 percent protection against infections. In theory, mRNA could be a better product: the induced immune responses could be broader, the expressed proteins should have better sequence fidelity, strain selection could be more precise, and the technology facilitates the incorporation of large numbers of antigens. All these properties can lead to better immune protection.

But mRNA, at least when formulated into lipid nanoparticles (LNPs), is prone to compatibility issues. Moderna and Pfizer/BioNTech approved mRNA syringes for COVID-19 commonly cause arm aches, headaches, low-grade fever, and fatigue. The same symptoms can occur with approved flu shots, but they are usually much milder.

mRNA "is a tool that has some positive potential," says Gary Nabel, former CSO of Sanofi, founding director of the NIH's Vaccine Research Center (VRC) and CEO of immunotherapeutic company ModeX Therapeutics. "The big hurdle is security."

To impact the established market, the platform would need to find a more forgiving sweet spot and deliver big power benefits.

And yet, it is not certain that the mRNA will be able to efficiently transport the hemagglutinin glycoproteins, the main antigen of flu vaccines. “Have we really had incredible luck with COVID vaccines because of the antigenic design and immunodominance of this protein?” asks Anna Blakney, an RNA bioengineer at the University of British Columbia. "Or have we stumbled upon something that also works for other viral glycoproteins?"

I'll do it

Many of the leading mRNA-based influenza candidates were working on influenza vaccine candidates prior to the pandemic. Then came the new coronavirus, and "we literally swapped the flu coding sequences and the SARS-CoV-2 sequences," says Philip Dormitzer, Pfizer's head of viral vaccine research.

The whole field benefited from it. Seqirus was left out of the COVID-19 vaccine race despite having a self-amplifying mRNA platform that provides both the antigen coding sequence and the necessary replication machinery for the construct to replicate in the host cell. (Seqirus acquired this platform from Novartis in 2015.) "Seeing an mRNA vaccine work and getting such a robust response has alleviated some of the outside concerns people might have had about the technology overall," says Ethan Settembre, vice president of research and development on Seqirus.

And the potential benefits of mRNA for flu prevention are many.

Part of that comes down to how vaccines are made. Because mRNA vaccines are produced synthetically by encoding a target antigen sequence on a plasmid template, they offer high fidelity: the encoded antigens exactly match the influenza strains selected for each year's vaccine. In contrast, inactivated virus vaccines made in egg- and cell-based systems often undergo sequence mutations that weaken their effectiveness.

Vaccines using recombinant proteins offer the same fidelity benefit, but the manufacturing process for them is comparatively complicated. The flexibility and speed of manufacturing mRNA vaccines means that vaccine manufacturers can wait longer before starting to manufacture - for example, for the Northern Hemisphere, they can start production in May instead of February. This would allow them to make more informed decisions about which tribes to include.

"All the time helps," says Sally Mossman, director of GlaxoSmithKline's vaccine research and development center in the United States.

enter the multiplex

There may be other efficacy benefits. The US has quadrivalent vaccines containing hemagglutinin antigens (purified from inactivated viruses or produced recombinantly) or live attenuated viruses that provide protection against four strains of influenza. (Other jurisdictions still use trivalent vaccines.) Some researchers have argued for additional protection against additional strains, but this is logistically difficult with existing platforms.

Not necessarily with mRNA.

A team led by Norbert Pardi of the University of Pennsylvania Perelman School of Medicine and Raffael Nachbagauer, then at the Icahn School of Medicine at Mount Sinai, demonstrated this last year. They immunized mice against an influenza subtype with amRNA vaccine encoding four different proteins: Hemagglutinin rod, neuraminidase, matrix 2 ion channel and nucleoprotein. Along with Meagan McMahon of Mount Sinai, Pardi and her colleagues repeated the exercise for two other flu subtypes. They plan to test a combination vaccine with 10-12 antigens in mice and ferrets. Ideally, this achieves such broad immune protection that it does not need to be taken every year.

Many researchers also expect mRNA to stimulate stronger or more diverse immune responses than traditional platforms. If this is truemay be particularly beneficial for older adultsthat often respond poorly to flu shots, notes Jenna Bartley, who studies immune aging at the University of Connecticut School of Medicine.

It could even help develop a universal flu vaccine that protects against all strains of the virus, says Tony Moody of Duke University. With support from the NIH, he is now developing an mRNA-based hemagglutinin-stabilized parental vaccine that is modeled on a protein-based vaccine already available in the clinic. "It's an informative experiment," says VRC director John Mascola. "We don't know how to induce high levels of persistent antibodies, and the mRNA may differ in how it triggers that response."

Current vaccine technologies often elicit only humorous responses that block viral invasion. mRNA vaccines may elicit better T-cell responses because they mimic natural infections.

Barney Graham also sees a broader societal opportunity: by working with seasonal mRNA candidates today, companies should be better prepared to fight influenza pandemics in the future. "This is where mRNA can really change the business," says Graham, who retired as associate director of the VRC at the end of August. "If we really had a pandemic, you could design [a new vaccine] within 10 minutes of getting the sequence, and you could get your hands on the mRNA within a few weeks."

show me the dates

The only human data reported to date on an mRNA-based flu vaccine comes from Moderna's initial foray into the clinic. As of late 2015, the company was evaluating two two-dose vaccines, each designed to target a different strain of avian flu.

According to former Moderna CMO Tal Zaks, the main purpose of these attempts was to test the company's mRNA. "If you want to show that the technology works, the easiest place to start is with a flu shot," he says. In the flu, he explains, the correlates of protection – measurements of immunological parameters that allow predicting the effectiveness of the vaccine – are well defined. There are also established vaccines to which clinical outcomes can be linked.

For many viewers, Moderna's first attempts were a disappointment. Although most study participants who received higher doses of the experimental vaccines developed influenza-specific antibody titers above the threshold considered protective - as measured using the well-validated haemagglutination inhibition assay (HAI) - theseantibody levels have decreasedjust a few months after vaccination. This suggests that the protection they offer may be short-lived. T cell immunity was not detectable.

Former heads of companies who were involved in the lawsuits see things differently. Both Giuseppe Ciaramella, former head of infectious disease research, and Michael Watson, former president of Moderna's vaccines division, argue that the vaccines induced a robust set of memory B cells that remember antigens and the rapid production of antibodies can trigger when people are sick - exposed to the virus.

They highlight data from 5 participants who received their two injections 6 months apart, rather than 3 weeks apart like everyone else. These subjects achieved much higher mean HAI titers - "proof", says Watson, "that the first dose prepared very well".

However, Watson is less optimistic about the tolerability results. Although Moderna has since changed its LNP formulation and aspects of its mRNA design, its data from early studies suggested that the therapeutic index for an mRNA-based influenza vaccine could be low. This can be problematic for multicomponent seasonal flu vaccines that aim to train the immune system to recognize at least four antigens.

Moderna is still making clinical progress - and has already started adding additional antigens to its next generation of flu products. Neuraminidase, another surface glycoprotein, will be included in the company's follow-up clinical candidates. Other antigens that may better stimulate T-cell immunity are also being considered. The company is also preparing combination vaccine candidates that can protect against several respiratory viruses. One, for COVID-19 and flu, is scheduled to enter clinical trials next year.

But adding antigenic targets will likely require higher total vaccine doses, Watson points out, potentially triggering more serious side effects. "It's definitely the yin and yang," he says.

open session

Nachbagauer, who joined Moderna last year to lead its infectious disease research and development efforts, is aware of the safety concerns but is taking a wait-and-see approach to the issue. The company's first seasonal influenza vaccine candidate, mRNA-1010, consists of four mRNA sequences encoding hemagglutinin glycoproteins from viral lineages recommended by global health authorities and formulated into the same LNPs used to deliver the COVID-19 vaccine. 19 of the company. "We're really interested in how our reactogenicity is," he says.

The immune connections between pandemic and seasonal flu vaccines are completely different, adds Nachbagauer. Pandemic flu vaccines are supposed to protect against a new threat. As people generally do not have pre-existing immunity to them, a two-dose vaccination schedule is critical. With seasonal flu, most people have been exposed to the related strains or have received previous flu shots. Just one shot can therefore be enough to protect against the latest adaptation of an ever-changing opponent. If the COVID-19 vaccines are any guide, a one-dose candidate may be more tolerable than a two-dose product.

Moderna began a mRNA-1010 dose-ranging study with 180 people in July. It is expected to run until early 2022.

Sanofi and Pfizer have also placed their first mRNA-based flu vaccines in Phase I testing. These companies are taking measured approaches to de-risking mRNA platforms, starting with candidates that contain only a single mRNA that encodes the hemagglutination head domain of an influenza virus type.

Sanofi is evaluating its monovalent H3N2 vaccine candidate in two different LNP formulations. "If the results are positive, clinical development of a quadrivalent influenza vaccine would be the next step," said Frank DeRosa, chief technology officer at Sanofi subsidiary Translate Bio. (Sanofi acquired Translate for $3.2 billion earlier this year.)

The company's flu vaccine, for now, uses a form of mRNA that lacks the chemical modifications found in most other mRNA products. Sanofi's COVID-19 vaccine based on this unmodified mRNA platform successfully elicited antibody responses in early clinical trials. But it has not yet been proven in an efficacy study. CureVac's unmodified mRNA COVID-19 vaccinestumbled upon phase III trials, raising the possibility that this strategy may be inferior to modified mRNA candidates.

This may explain why Sanofi also plans to have a modified mRNA-based quadrivalent vaccine in clinics next year. CureVac is considering both mRNA options for its flu vaccine in partnership with GlaxoSmithKline.

Meanwhile, Pfizer is developing two parallel programs: one with modified mRNA and the other with an auto-amplifying construct. Their modified mRNA candidate, PF-07252220, is first. (Pfizer licensed the technology from BioNTech and chose to go it alone in the influenza program.) In September, the company began a Phase I trial of this monovalent vaccine at four dosage levels, each injection containing a single influenza A or B contained stress. It is planned to combine them later into a bivalent vaccine, given in different doses, before moving to a quadrivalent product - all compared to an approved flu vaccine.

Pfizer also plans to begin testing its self-amplifying mRNA candidate in the coming months.

A well trodden path

For each mRNA-based vaccine that advances to the later testing phase, the regulatory path to approval is well defined: companies must either demonstrate efficacy through classic clinical trials or demonstrate non-inferiority to an approved comparator in a surrogate measure of protection. as the title of HAI. "That's the beauty of the flu," said Pad Chivukula, chief scientific officer and chief operating officer of Arcturus Therapeutics. "The path to approval is very easy."

The correlation approach is less expensive and involves less risk, especially for vaccines optimized to induce antibody production. But it won't capture the protection that comes from inducing responses from T cells or other arms of the immune system, a potential downfall for mRNA candidates. The correlated approach also does not support claims of platform superiority when it comes to breadth or longevity of protection. Most companies that have mRNA-based vaccines in the works, therefore, assume that they will eventually conduct large-scale studies over one or more flu seasons.

"Ultimately," says Dormitzer, "to really convince people to switch to a new vaccine platform, they're going to want to see efficacy alongside all the immunological comparisons."

While there has been a sharp drop in flu cases around the world over the past year, likely due to mask wearing and social distancing in response to COVID-19, most experts expect the flu to return. When that happens, the companies hope that their mRNA-based vaccine candidates will be ready.