Vaccines are smothering everyone’s current news feed, but how do researchers ensure their efficacy? Through science, data and controlled clinical trials. One vaccine — the seasonal flu — was the object of study by Orly Vardeny, PharmD, MS, an associate professor in the Department of Medicine and adjunct associate professor in the College of Pharmacy, who led the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) study, funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health.

INVESTED was a randomized, double-blind, active-controlled trial that enrolled more than 5,000 participants across 157 clinical sites in the U.S. and Canada. The study analyzed if different influenza vaccines — with varying dosage — impacted the risk of death or hospitalization, due to heart or lung causes, for people with pre-existing cardiovascular issues.

“We know that these patients are more likely to get hospitalized if they do get influenza or a viral illness, so that got me thinking about whether or not people with heart failure make the same immune response to influenza vaccines. In our preliminary work that preceded the INVESTED study, we wanted to know if they are as well-protected as they could be compared to people without heart issues,” Dr. Vardeny said. 

The trial enrolled an extremely high-risk group. Participants were previously hospitalized for heart failure in the past two years or had suffered a myocardial infarction (MI) within the last year. MI is colloquially known as a heart attack, which is a blockage of blood flow to the heart muscle. Researchers also required at least one additional risk factor, such as older age, diabetes, kidney disease, obesity, prior stroke, or tobacco use.

Dr. Vardeny and her fellow researchers hypothesized that the high-dose vaccine would amplify an immune response compared to the standard dose, and this would subsequently lead to better outcomes for the patient. 

“The importance of studying this is to eventually make vaccines that are effective in everybody and to protect the most people as possible. As with anything in medicine, you want to individualize treatments, including vaccines, to a point where they are most effective to an individual. When they’re studied it’s often in thousands of people, making it important to fine-tune them after they’re found to be effective so you know if specific people may benefit more from one vaccine versus another. It’s always important to individualize, and that brings it down to patient care,” Dr. Vardeny said. 

INVESTED compared two different commercial formulations that were FDA approved and available on the market; the high-dose vaccine is indicated for people aged 65 years and older, and the standard dose vaccine for those aged six months or older. The high-dose vaccine contained four times as much antigen, or hemagglutinin, which is what your body produces antibodies in response to when it encounters a viral invasion. It’s a piece of the killed virus that primes your body for future moments when it detects a foreign viral substance. 

The high-dose option was a trivalent vaccine, meaning it contained three different strains of influenza — two A versions and one B version. The standard dose, considered standard of care, was a quadrivalent formulation, containing four antigens, which left the researchers wondering if the extra virus offset the potential benefits someone could get from the high-dose vaccine. However, prior data demonstrated that most patients in this group (age 65 or older) who became more severely sick through one of the A viruses and B viruses only accounted for a small percentage. So, for this specific group, they think it’s unlikely the extra virus played a huge role, but for pediatric patients or another disparate group, that could change.

“You should always look at the effectiveness of vaccines and think about improvements. When a vaccine is not as effective as it could be, then we start asking questions about why that might be and what we can do to make it work better,” Dr. Vardeny said.

Overall, the high-dose, trivalent influenza vaccine was no more effective than the standard dose quadrivalent vaccine at reducing the risk of death or hospitalization for heart or lung-related causes among patients with heart disease. In addition, the number of hospitalizations caused by influenza was smaller than researchers originally predicted. The findings suggest risk for hospitalization was already so high that it was difficult to change the trajectory. If they had studied a group with lower risk, such as those with stable coronary artery disease, the results could differ.

Publication Link on JAMA