Cincinnati Children's Hospital Medical Center will use a $30 million federal grant--the second-largest the center has ever received--to accelerate the chase for one of medicine's most elusive goals: a universal influenza vaccine.
Public health organizations have long clamored for a flu vaccine that can provide longer-lasting protection to people and be stockpiled beyond a single flu season. Yet despite decades of effort, flu vaccines still must be re-formulated every year, with effectiveness ranging from a modest 60 percent to a dismal 20 percent.
As a result, many people lack confidence in the flu vaccine and choose not to receive it. This, in turn, helps to keep flu-related complications among the nation's top 10 leading causes of death. An estimated 46,000 Americans died in the 2018-19 flu season, according to the Centers for Disease Control and Prevention (CDC).
Now, a $30 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) will fund research based here to dig deeper into how the immune systems of infants and growing children are affected by their first exposures to flu viruses. Gathering the information required will involve asking more than 2,000 sets of mothers and infants from the Cincinnati area and from Mexico City to participate in at least three years of weekly medical testing.
"We have to do better. Most other vaccines have effectiveness rates above 90 percent. We need a flu vaccine that reaches those levels," says Mary Allen Staat, MD, MPH, the principal investigator for the new grant. "To achieve that goal, we need much more data from real people. That's what our study will seek to generate. Then, the vaccine makers will have the information they need to make a better, longer-lasting vaccine."
A rising sense of urgency
For many public health leaders, the flu season of 2017-18 was a wake-up call. The vaccine did not work well, and the CDC estimated that 80,000 Americans died from flu-related pneumonias, heart attacks, and organ failures. That was the worst flu death toll in nearly 40 years.
In response, a group of senators introduced the Flu Vaccine Act in February 2018 to provide up to $1 billion to the National Institutes of Health to support influenza research grants across five years. The bill did not pass, but was re-introduced earlier this year. In the meantime, Congress has boosted flu vaccine research funding from about $60 million two years ago to more than $140 million for fiscal 2019.
The grant to Cincinnati Children's is one large part of this growing nationwide effort.
"We are delighted that the NIAID has recognized the outstanding expertise of Drs. Staat and Morrow and their team by awarding the second-largest grant in Cincinnati Children's history," says Margaret Hostetter, MD, Director of the Cincinnati Children's Research Foundation. "There are many unanswered questions about influenza exposure and protection in mothers and babies. Dr. Staat's study--coupled with the systems biology expertise of Drs. Paul Spearman, Sing Sing Way, and colleagues at Emory University--promises to unlock the mysteries with an unrivaled combination of epidemiology, global health expertise, and vaccine immunology."
What is 'imprinting'?
One reason scientists have struggled to find a universal flu vaccine is that the two major types of flu virus (H and N) come in no less than 28 subtypes.
The new Influenza IMPRINT Cohort study will explore the emerging idea that a person's very first influenza virus exposure impacts the magnitude, durability and breadth of their immune response to all future flu exposures. For example, does a person have better resistance to future flu outbreaks if their first exposure was to a wild virus, or to weakened forms used in vaccines? How much does a person's future resistance depend on the specific strain of flu they encounter first? Or, if a person's immune system was primed by one strain, does that make it harder for their bodies to respond well to a vaccine that targets a different strain?
"This type of immunological imprinting likely explains much about the wide variation in vaccine effectiveness year-to-year," Staat says.
Better information about how imprinting works could help vaccine researchers determine the ideal mix of flu strains to use in a universal flu vaccine that has the best odds of protecting people years later as other flu strains emerge. Beyond the mix of strains, experts want to figure out the best age for infants to receive their first vaccine, the best vaccine timing during pregnancy for expectant mothers, even the specific best time of year in the US and globally to get the shots.
Seeking dedicated volunteers
Research partners in Cincinnati and Mexico City will work with local hospital birthing centers to invite mothers to join the IMPRINT study.
Each mother will be asked to respond to texts about their child's symptoms and provide fresh nasal swabs every week for her child for at least three years. The research teams also will collect blood and other samples to track responses to influenza vaccine and wild influenza virus exposures.
Staat says Cincinnati Children's won this grant in part because it was successful at building a similar cohort of volunteers for a different natural history of infection study called PREVAIL, which also required weekly involvement.
Staat knows in person just how much effort the IMPRINT study will ask of its participants, because her family participated in the PREVAIL study. Staat recalls personally delivering samples and bringing her granddaughter to the hospital for testing days.
"It was intense, but it became our Saturday routine," Staat says. "The moms who join IMPRINT are going to be part of something that is going to make a real difference."