With multiple viruses circulating around the United States and multiple vaccines to try to prevent some of them, there is increasing effort to streamline and improve the process and ultimately make one vaccine to attack most — if not all — of the viruses at the same time.

Scientists are trying several approaches to stay ahead of not only influenza and SARS-Cov-2, but also respiratory syncytial virus (RSV), ideally in one convenient combination vaccine. Whether one vaccine or more, though, the technology and science behind how vaccines are made need to continue expanding.

While we already have vaccines for the flu and COVID-19, an effective and safe RSV vaccine has proven more difficult to bring to market, but several companies have experimental products that have reached advanced stages of development.

GSK plc said it could be first to the market with an RSV vaccine for people ages 60 and older. The US Food and Drug Administration has a target decision date on this product of May 3, 2023. 

Moderna also has an RSV vaccine in a late-stage study for the disease in adults over 60.

The vaccine relies on the same mRNA technology used in Moderna’s COVID vaccines.

The tech is also part of the company’s  experimental mRNA-1230, which is designed to work against COVID, influenza, and RSV. Moderna began a phase 1 study of the vaccine (NCT05585632) in October 2022, which is recruiting adults ages 50 to 75. CBC News reports that the vaccine may even be up for regulatory consideration in Canada in the next year.

“If results from this trial suggest mRNA-1230 will at least match the current standard of care for vaccines against these three viruses, we would indeed take the investigational product through Phase 2 and 3 studies,” Christine Shaw, PhD, Moderna vice president and portfolio head for respiratory vaccines, told Medscape Medical News. “Evaluation of the vaccine in other age groups is also under consideration, pending results of the ongoing Phase 1 study.”

mRNA Advantage?

The duo that brought the first COVID shot to market, New York-based Pfizer and Germany’s BioNTech, also are working to use mRNA technology to improve flu shots, and combine them with a COVID vaccine.

Pfizer and BioNTech in November announced that the first participant had been dosed in a phase 1 test of their experimental mRNA-based combination vaccine candidate for the two viruses. This product combines a Pfizer influenza vaccine candidate, qIRV (22/23), which is currently in phase 3 clinical development, and an authorized COVID-19 vaccine, each of which is based on BioNTech’s proprietary mRNA.

Moderna also is testing different kinds of COVID and flu shots using mRNA. There’s widespread agreement that the mRNA technology in the Moderna and Pfizer-BioNTech COVID-19 shots reflects major advances in vaccine development.

For decades, scientists sought to move vaccine production from a process that depended heavily on chicken eggs. In contrast, mRNA vaccines effectively use the human body as their vaccine-production facilities, with several accompanying advantages including more flexible scale-up and tweaking, wrote Ann Barbier, MD, PhD, and coauthors in a May paper in the journal Nature Biotechnology.

In an email exchange with Medscape Medical News, Moderna’s Shaw said that mRNA-based influenza vaccines may allow for later strain selections that could improve match between shots and the circulating viruses of the season. The Centers for Disease Control and Prevention says that, in years where most circulating flu viruses are well matched to the flu vaccine, these shots may reduce risk for illness due to influenza by between 40% and 60%. Mismatches between the circulating strain and the shots result in poorer results.

Looking for Viral Vulnerabilities

Researchers have been looking for decades for ways to make flu shots that can do a better job in outsmarting the mutating virus.

Put in simple terms, traditional flu shots target the “head” region of the protein hemagglutinin (HA) that is critical in allowing the virus to attach itself to cells. Compared with the “stem” or “stalk” region of HA, the HA head tolerates the antibody-evading mutations while preserving its function, making it a challenge to keep ahead of the virus, said Ivan Kosik, PhD, a staff scientist at the National Institute of Allergy and Infectious Diseases (NIAID).

For many years, researchers have been looking at other targets on the influenza virus, such as the “stem” region of HA and neuraminidase (NA), an enzyme that also plays an essential role in release and spread of these microbes.

“We’re trying to combine these different approaches,” Kosik told Medscape Medical News. “As we’re doing it, we’re discovering the virus will come up with another trick but it doesn’t mean that we won’t succeed. We need to keep going.”

Just as there are attempts to target less mutable parts of influenza’s armature with an aim at the stalk of HA instead of the head, scientists are already looking for ways to strike a tougher blow against SARS-CoV-2.

Instead of focusing on the SARS-CoV-2 spike protein, NIAID scientists are studying the virus’s nucleocapsid (N) protein, which rarely mutates. This approach may also have applications in developing better flu vaccines, Alberto D. López-Muñoz, PhD, MSc, a postdoctoral fellow at NIAID, told Medscape Medical News. 

These nucleocapsid proteins appear to play a role in helping SARS-CoV-2 evade the immune system’s early lines of defense. Nucleocapsid proteins produced by cells infected with SARS-CoV-2 neutralize multiple chemokines, which are signaling proteins that should attract white blood cells to attack infected cells.

If scientists can target these nucleocapsid proteins outside of infected cells, they may be able to neutralize their actions and thus allow the immune system to better do its work in protecting against infection, López-Muñoz said.

“Explosion” in mRNA Vaccine Candidates

The COVID-19 pandemic accelerated work long under way in seeking to develop mRNA vaccines.

There’s been an unprecedented “explosion” in efforts to use this technology to develop vaccines for viruses for which there are no current shots, but also to improve on existing ones, López-Muñoz said.

For example, the National Institutes of Health in March announced the launch of a phase 1 clinical trial evaluating three experimental HIV mRNA vaccines. Moderna’s Shaw told Medscape Medical News that the company is working on influenza vaccines that include additional HAs to broaden neutralizing responses against circulating viruses, as well as NA antigens, which can provide additional and broader protection compared with HA-only vaccines.

There’s long been discussion of a “universal” flu vaccine, a goal that may prove ultimately undoable, although there is such a vaccine currently in animal studies that uses mRNA to target 20 flu strains in one shot. 

But mRNA could help human beings develop vaccines with broader ability to fight infection as well as aid in rapid response, as was seen in COVID-19. The 21st century has already seen the emergence of several major viral threats before SARS-CoV-2, including the original SARS virus and Middle East Respiratory Syndrome (MERS), López-Muñoz said.

“Could we win against Nature at some point? That’s very unlikely. It’s a constant race,” López-Muñoz said. “We are trying to adapt and use the tools we have and develop new ones to fight off these current and new threats.”

Kerry Dooley Young is a freelance journalist based in Miami Beach. She earlier covered health policy and the federal budget for Congressional Quarterly/CQ Roll Call and the pharmaceutical industry and the Food and Drug Administration for Bloomberg.

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