mRNA vaccine technology moves to flu: Moderna says trial has begun

Moderna has given out the first doses of an mRNA-based influenza vaccine to participants in an early-phase clinical trial, the company announced Wednesday.

Moderna ultimately plans to test the vaccine on about 180 people in the Phase I/II randomized, stratified, observer-blind trial. The trial will look at safety, different doses, and immune responses.

The vaccine, called mRNA-1010, is designed to target four lineages of influenza viruses that circulate seasonally each year, just like the current quadrivalent flu vaccines on the market. The four virus lineages are those identified by the World Health Organization as the ones to target for disease prevention each year—seasonal influenza type A lineages H1N1 and H3N2 as well as influenza type B lineages Yamagata and Victoria. If mRNA-1010 is shown to be effective against the yearly plague in later-stage trials, Moderna aims to eventually bundle it with three other mRNA-based vaccines to create a yearly one-stop shot.

In addition to influenza, this envisioned combination shot would target two other common respiratory viruses that circulate alongside influenza—respiratory syncytial virus (RSV) and human metapneumovirus (hMPV)—as well as the COVID-19 coronavirus, SARS-COV-2, which some experts have speculated could become seasonal. Currently, there are no licensed vaccines against either RSV or hMPV. And it's unclear if SARS-CoV-2 will become seasonal and/or if annual booster vaccines will be necessary.

"We believe that the advantages of mRNA vaccines include the ability to combine different antigens to protect against multiple viruses and the ability to rapidly respond to the evolution of respiratory viruses, such as influenza, SARS-CoV-2 and RSV," Moderna CEO Stéphane Bancel said in a statement. "Our vision is to develop an mRNA combination vaccine so that people can get one shot each fall for high efficacy protection against the most problematic respiratory viruses."

Vaccine design

While the company is aiming high with its seasonal megashot, the influenza component alone stands to offer a significant improvement over current shots. To humanity's chagrin, available quadrivalent and trivalent annual flu vaccines tend to have low efficacy, generally in the range of only 40 percent to 60 percent. Some years, the vaccines' efficacy is even lower.

Moderna expects it can beat those numbers. Soaring on the success of its mRNA-based COVID-19 vaccine—which had a remarkable 94 percent efficacy in late-stage clinical trials—Moderna will aim its more advanced, targeted mRNA vaccine platform to fight influenza. The company currently has three mRNA-based vaccine candidates in development. After mRNA-1010, there's mRNA-1020 and mRNA-1030.

In general, mRNA vaccines work by delivering to human cells a snippet of a virus's genetic code, which is in the form of messenger RNA (mRNA). This type of RNA generally acts as an intermediary, communicating coded instructions from DNA to the cell's molecular machinery that translates the code into proteins. The mRNA snippets in the vaccines, however, communicate the blueprints for viral proteins, which the immune system can use for target practice. Once the cell's machinery translates the vaccine's mRNA code into a viral protein, the immune system uses that protein to train virus-targeting antibodies and cellular defenses.

To prevent COVID-19, the mRNA vaccines include the code for a portion of the SARS-CoV-2 spike protein. Copies of this protein jut from the virus's spherical body and help the virus break into human cells. As such, they're an easy and effective target for antibodies and other immune responses.

To prevent flu, mRNA vaccines could target key proteins that similarly jut from the influenza virus, namely hemagglutinin (HA or H) and neuraminidase (NA or N). Like spike, these proteins are critical for the flu virus's ability to invade human cells. But HA and NA come in different forms, which are represented in flu viruses' names as H and N (as in H1N1 and H3N2).

mRNA advantages

The mRNA-based vaccine strategy offers a highly precise way to target influenza viruses' HA and NA compared with current flu vaccines, which often rely on presenting whole viruses, weakened or inactivated, to the immune system. And the mRNA-based design makes the vaccines easy to tweak. If, for instance, a flu virus appears one season with a slightly different version of HA—as it very often does—the vaccine's coding would potentially take just an update to tailor that year's shot. This is a change that could potentially be done swiftly, too.

When variants of SARS-CoV-2 began raising concern earlier this year, the CEO of BioNTech—which co-developed an mRNA-based COVID-19 with Pfizer—said the company could adjust its mRNA vaccine in just six weeks, if needed.

Perhaps the biggest advantage the mRNA-based strategy has over current flu vaccines, though, is that it doesn't involve eggs. Current flu vaccines are most often manufactured using fertilized hen eggs. Vaccine-makers inject the virus into the eggs and allow the virus to create legions of clones. Then, vaccine-makers harvest the viruses, purify them, weaken or kill them, and use them for vaccines. It's cheap and simple, and it's a method that has been used for decades.

But it's also time consuming, it requires a lot of eggs, and it may not produce high-efficacy vaccines. Weak or inactivated virus vaccines lack the precision of other vaccine strategies, like mRNA or recombinant proteins. With a whole virus, the immune system may try to attack many different features of the virus, some of which may not be very useful for thwarting the invader.

Flu toll

Moreover, humans are, well, different from chickens. And sometimes in the manufacturing process, flu viruses can begin to adapt to their fowl conditions. This appeared to be a problem in the 2017-2018 flu season, when a circulating H3N2 flu virus strain seemed to pick up a mutation in its HA during egg-based vaccine manufacturing. The mutation may have made the virus better at infecting chicken eggs, but in the vaccine, the mutation seemed to result in people developing antibodies that weren't as good at defeating the H3N2 virus circulating in humans.

That flu season, the influenza vaccine was estimated to have an overall efficacy of just 38 percent. The efficacy against type A influenza viruses specifically, which include H3N2, was just 30 percent. The 2017-2018 flu season ended up being the worst in the decade, with estimates of hospitalizations up to 810,000 and deaths up to 61,000.

Still, health experts urge everyone, every year, to get their flu shot. The flu, however benign it may sometimes seem, is a devastating infectious disease. Even a low-efficacy vaccine can help. The CDC estimates that influenza has sickened between 9 million and 45 million people every year since 2010. And in each of those years, it sent between 140,000 to 810,000 people to the hospital and killed between 12,000 to 61,000 people. In addition to the human costs, the economic burden of all of that is estimated to be $11 billion per year.