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Science: Should you pick Novavax’s COVID-19 shot over mRNA options?

Limited data and lack of head-to-head studies make comparisons tricky
October 6, 2023

For cardiologist Eric Topol, this week’s vaccine news presented a personal dilemma. Topol, who directs the Scripps Research Translational Institute and is a popular commenter on COVID-19 research, had hoped to get an updated COVID-19 vaccine from Novavax, rather than a messenger RNA (mRNA) shot from Pfizer or Moderna. Novavax relies on an older, protein-based approach that has shown long-lasting effects against other pathogens, and Topol wondered whether it might produce more durable protection. On Tuesday, it seemed he might get his chance: a drugstore he visited for an mRNA vaccine ran out of doses, and hours later the U.S. Food and Drug Administration authorized a Novavax shot well-matched to current COVID-19 variants. The green light marks the first time Novavax will be widely available to teens and adults.

“It’s hard to know how it compares” to mRNA vaccines, Topol admits; there are no head-to-head studies to rely on. In clinical trials, Novavax appeared less likely than mRNA shots to cause side effects like headache and fatigue. But how does it stack up against mRNA vaccines when it comes to protection against SARS-CoV-2? The question has been vexingly difficult to answer.

Some hints are emerging, including the first large study of Novavax in the real world, published this week by a team in Italy. The results are far from definitive, but they suggest “there aren’t massive differences” between the vaccines, says Alberto Mateo Urdiales, an epidemiology and infectious disease researcher at the Italian National Institute of Health, who led the study.

Whereas mRNA vaccines carry instructions for making a SARS-CoV-2 protein, Novavax directly delivers a fragment of that viral spike protein with an adjuvant for boosting immune response. Such protein subunit vaccines have yielded durable protection against various pathogens including hepatitis B and shingles, along with some respiratory ailments such as pneumonia. A version of the Novavax vaccine targeting the original SARS-CoV-2 variant was approved as a primary vaccination series and first booster in the United States in 2022; it also became available in Europe that year. Its tried-and-true technology appealed to some people wary of the new mRNA approach. And unlike the more fragile mRNA shots, it lasts for months in the refrigerator. But uptake has been low and the company is banking on more shots in arms this fall.

The Italian team tried to pin down how well the shot actually works, analyzing data on more than 20,000 Italians who had received two doses as their primary vaccine series in 2022. After 4 months, the vaccine was 55% effective at staving off symptoms from a SARS-CoV-2 infection and 28% effective at preventing infection altogether, the researchers reported in JAMA Network Open. That’s roughly comparable to how the mRNA vaccines have performed, Mateo Urdiales says. He cautions that the emergence of SARS-CoV-2 variants, repeated boosting, and swelling numbers of infections make it hard to compare numbers across the studies of effectiveness conducted to date.

Smaller studies, meanwhile, have tried to address another reason a Novavax booster appeals to people like Topol: the possibility that “mixing and matching” various COVID-19 vaccines might provide better protection than any single vaccine brand. “There was theoretical hope that since these vaccines work in slightly different ways, they would have different strengths in terms of which part of the immune system they activate best,” says Angela Branche, an infectious disease specialist at the University of Rochester. She co-chairs a mix-and-match study called COVAIL that includes another protein subunit vaccine from the company Sanofi, which is not available in the U.S.

At the University of Maryland School of Medicine, infectious disease specialist and vaccine researcher Kirsten Lyke is leading a mix-and-match study in which 67 of the roughly 830 participants got the original Novavax vaccine as a first booster, having received Pfizer, Moderna, or Johnson & Johnson as their primary vaccination. Three months after that booster, their levels of neutralizing antibodies were similar to those in people who got an mRNA booster instead, the team reported in July in NPJ Vaccines. (Neutralizing antibodies may help protect against infection and illness.)

Mixing and matching has sometimes produced superior immune responses, both for COVID-19 and other vaccines. But Branche notes that protein and mRNA vaccines may be more similar, immunologically, than they appear at first blush, because both rely on the same SARS-CoV-2 spike protein to trigger an immune response.

Researchers also want to know how long protection lasts with Novavax versus mRNA vaccines. Mateo Urdiales found that protection from infection dropped in the first 4 months after Novavax vaccination, but it seemed to hold steady against symptoms; other studies have shown that with mRNA vaccines, protection against symptoms also declines in that time frame.

Lyke’s analysis hinted that levels of neutralizing antibodies waned more slowly after a Novavax booster than after an mRNA booster. But that doesn’t prove Novavax’s protection is more durable, she stresses: Novavax hit the scene much later, when many recipients had enhanced immunity from a previous infection. “This durability question is influenced by many different factors other than what the vaccine does,” Branche notes.

Ultimately, “I’m not sure that on their face any of the vaccines are particularly better than the other,” Lyke says.

Comparisons of safety are uncertain, too. A key concern for mRNA vaccines is myocarditis, an inflammation of the heart, which occurs, rarely, after vaccination, especially in young men. In Novavax trials, there were four cases of myocarditis in the vaccine arm within 20 days of vaccination and none in the placebo group during that time frame. June data from the Australian government noted myocarditis reports for three to four of every 100,000 Novavax doses, a rate roughly similar to what Australia reports for the mRNA vaccines.

But because the side effect is so uncommon and Novavax has been much less widely used, “I don’t think anyone can know the true rate yet of myocarditis from Novavax,” says Walid Gellad, a physician who studies drug safety at the University of Pittsburgh. “I would not assume yet that Novavax is the solution to the myocarditis issue of mRNA” vaccines, he adds.

Scientists hope more data on Novavax will come. Lyke is examining immune responses 6 months and 12 months after the original Novavax booster in her small cohort. Meanwhile, a rare head-to-head clinical trial began in February in Melbourne, Australia. It includes almost 500 people who already received three vaccine doses. Some are being randomized to get either a Moderna bivalent booster, which became available last fall, or the original Novavax vaccine. Others who opted against any booster will serve as a control group. “We want to determine the best vaccine for ongoing boosters,” says Claire von Mollendorf, who co-leads the study at the Murdoch Children’s Research Institute. Von Mollendorf expects initial results from a month after vaccination to be published around the end of the year. Results from a 12-month follow-up won’t come until early 2025.

The best time to pit Novavax head-to-head against the other COVID-19 vaccines may be right now, with updated boosters becoming available that all target the same version of Omicron, called XBB. This fall, “I think most people will take what they are offered, and then you can compare,” Mateo Urdiales says. He’s hoping to launch such a study, using the Italian registry data on vaccination.

As for Topol, upcoming travel and uncertainty about Novavax’s availability led him to opt against waiting. He got a Pfizer shot at a nearby grocery store this week—though he still wonders whether and how a dose of Novavax might have been different.

Source: https://www.science.org/content/article/should-you-pick-novavax-s-covid-19-shot-over-mrna-options