In the world of clinical trials, missing the primary endpoint of a pivotal trial typically spells real trouble for a drug program. But for Valneva CEO Thomas Lingelbach, the regulatory future of the company’s Pfizer-partnered Lyme disease vaccine, VLA15, is very much “a matter of negotiation.”
“It’s a matter of bringing all the arguments together that could allow them to show a certain degree of flexibility,” Lingelbach said of the FDA in an interview with Fierce on the sidelines of the World Vaccine Congress Washington 2026.
The phase 3 Valor trial technically failed to meet its primary endpoint, which measured the rate of Lyme disease among participants 28 days after they received the fourth dose of either the vaccine or placebo. In the study, the lower bound of the 95% confidence interval dipped below the predetermined threshold of 20%, causing the miss. But from an efficacy standpoint, the six-valent shot, also dubbed PF-07307405, showed a 73.2% improvement compared with placebo at that point.
Yet, despite the phase 3 miss and a U.S. regulatory environment that’s become notably wary of vaccines, Valneva and Pfizer remain hopeful of an approval. The reason, according to Lingelbach, is “the totality of clinical evidence.”
For one thing, the companies selected the 20% lower bound for the purpose of forming a study protocol, rather than based on a fixed threshold below which a vaccine would be deemed ineffective under any medical guidelines, Lingelbach explained.
Second, the p-value itself is “compelling” and would be statistically significant, he added, lending support to the strength of the 73.2% readout. Pfizer and Valneva have not disclosed the exact p-value.
The 95% confidence interval—which is a range that will contain the trial’s efficacy result 95% of the time if the study is repeated—spanned all the way from 15.8% to 93.5%. This was the product of a small total number of cases recorded by investigators, Lingelbach said.
“It’s simply a function of the n,” he explained. “Because the n, in comparison to the total number of study subjects, is so small that automatically your confidence interval gets so wide, despite a high statistical power.”
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When it came to another predefined endpoint that measured Lyme cases starting day 1 after the fourth dose—a booster after the three-dose primary series—the lower bound of the 95% CI rose to 21.7%, with an efficacy readout of 74.8%.
The partners and the FDA picked day 28 from last vaccination as the primary analysis to match the phase 2 immunogenicity analysis, according to Lingelbach. And that measurement timing was based on an uncorroborated belief that the peak immunogenicity titers would be reached a month after vaccination. That knowledge gap, plus an understanding that patients’ immune defenses would already have started building after the three priming doses, was why Pfizer insisted on having another prespecified endpoint for day 1 post-booster shot.
On top of efficacy, VLA15 also showed a “very favorable safety profile,” according to Lingelbach.
Those clinical data, plus an immunological analysis that elucidates a level that’s likely to correlate with protection, will support VLA15’s case with the FDA, he said.
But Pfizer and Valneva aren’t just making a math argument; they are navigating an FDA that’s getting tougher on vaccine regulation under U.S. healthcare leadership that has shown increased skepticism toward immunizations and a willingness to restrict vaccines on multiple fronts.
The fight beyond the data
The main target of the ongoing U.S. crackdown on vaccines is related to the pediatric schedule, Lingelbach contends. While not specifically a pediatric vaccine, VLA15 was also tested in children as young as 5 years old in the phase 3 Valor trial. In terms of a potential restriction of use in children, Lingelbach said it will depend on the outcome of subgroup analyses, which Valneva currently does not have.
One limitation is clear, though. The companies have said that, if approved, such a vaccine would be recommended not for the general population but for people living in high-risk areas of Lyme disease. That covers about 80 million people currently in the U.S., according to Lingelbach.
VLA15 could offer a tangible advance in combating a disease that currently does not have a vaccine, Lingelbach argued. Lyme disease treatments, primarily antibiotics, are effective only when administered early. The average patient costs for treating Lyme disease are about $1,200 per infection, emphasizing “the importance of effective prevention and early diagnosis to reduce illness and associated costs,” according to a CDC study based on data from 2014 to 2016.
In a March 23 joint press release, Pfizer said it’s confident in the vaccine’s potential and is planning regulatory submissions for approval. Citing Pfizer’s communication, Lingelbach said a filing is planned for the second half of 2026.
It’s difficult to predict how the FDA will handle VLA15, Lingelbach said, but “given the huge unmet medical need, I’m absolutely convinced that they will look at the totality of evidence and not only the simple case count.”
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If approved, VLA15 will also be fighting the ghost of Lymerix, the short-lived Lyme vaccine that GSK withdrew from the market in the early 2000s amid low demand and high-profile reports of alleged side effects despite a similar 70%-plus efficacy level.
The efficacy results between Lymerix and VLA15 are not comparable, Lingelbach argued. Lymerix targeted only one serotype of Borrelia burgdorferi responsible for Lyme, whereas VLA15 covers Borrelia species expressing six different OspA serotypes. Besides, the diagnosis standards for Lyme are different now versus 30 years ago, as there is more knowledge now about the clinical manifestations of the disease.
Autoimmune responses were the main sticking point against Lymeric, even though the FDA’s own study later found no causal link. Valneva designed its shot by avoiding a human T-cell epitope to reduce any potential autoimmunity risks.
Beyond Lyme
VLA15 won’t be Valneva’s first go-around with the FDA. The French vaccine specialist recently pulled its first-of-its-kind chikungunya vaccine Ixchiq from the U.S. market after the FDA raised some serious safety concerns, including one death from encephalitis that the agency said was “directly attributable” to the vaccine.
Even before the market withdrawal, Valneva had committed to conducting certain post-marketing studies to accumulate more evidence on Ixchiq’s efficacy and safety.
Valneva has donated about half a million Ixchiq doses to Brazil and launched a pilot vaccination campaign in the country with support from local health authorities and Instituto Butantan to gather real-world data.
“We will definitely use this data to then reevaluate whether to go back into the United States,” Lingelbach said.
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Further in the pipeline, Valneva is developing a Shigella candidate licensed from LimmaTech. The company is pursuing two development paths in parallel, one focused on shigellosis’ impact on mortality in children younger than 5 years old in low- and middle-income countries and the other on travelers. Shigella are bacteria that can cause severe diarrhea.
Valneva now expects phase 2 readout from a human challenge study among adults “probably into the third quarter,” Lingelbach said. The company will also look at the level of immunological titers needed to confer protection in adults, with the hope of guiding its development of the vaccine in children, where a human challenge design is not feasible.
If everything goes to plan, after dose or formulation optimization, Valneva hopes to move into adult phase 3 testing in 2027, the chief executive said.
Valneva currently is still operating at a loss despite generating total revenues of 175 million euros in 2025. That means any future dealmaking to augment the company’s pipeline will depend on funding.
“Strategically, I think we are one of the very few companies that have proven to be able to develop vaccines from bench to licensure, which is not something that many smaller companies can say,” Lingelbach said, noting that Valneva is technology-agnostic.
Recent U.S. health policies have put pressure on the entire vaccine field, potentially making companies like Valneva targets for acquisitions if larger companies are feeling opportunistic about muted stock prices in the space. Sanofi recently scooped up Dynavax Technologies after the stock price of the hepatitis B vaccine maker suffered in 2025.
“What I’ve learned in my 30-plus years,” Lingelbach said, “it’s not a good idea to shape a company for being bought. It is a good idea to do your job properly, and if someone comes and buys you that creates value, […] we’re gonna deal with it. That’s our job. But we are not shaping the company or building a strategy for exit.”
