Rebekah Honce, Ph.D.

Metabolic health (normal blood pressure, blood sugar and cholesterol levels, among other factors) influences the effectiveness of influenza vaccinations. Vaccination is known to be less effective in people with obesity compared to those with a healthier body mass index (BMI), but St. Jude Children’s Research Hospital and Larner College of Medicine scientists have found it is not obesity itself, but instead metabolic dysfunction, which makes the difference. In a study recently published in Nature Microbiology, the researchers found switching obese mice to a healthy diet before flu vaccination, but not after, completely protected the models from a lethal dose of flu, regardless of BMI.

“We found that the vaccines worked effectively if at the time of vaccination an animal is metabolically healthy,” said corresponding author Stacey Schultz-Cherry, Ph.D., St. Jude Department of Host-Microbe Interactions and Center of Excellence for Influenza Research and Response co-director. “And the opposite was also true: Regardless of what the mice looked like on the outside, if they had metabolic dysfunction, the vaccines did not work as well.”

Prior research has shown that when exposed to influenza virus, even after vaccination, 100 percent of obese mice succumbed to disease. Contrary to the scientists’ original expectations, when mice who were vaccinated while obese returned to a healthy weight, outcomes did not improve. These now outwardly healthy mice still all succumbed to disease when exposed to the real virus. Only switching to a healthy diet four weeks before vaccination improved survival, with drastic effect, despite high BMI.

“Seeing this effect was exciting because obese mice are highly vulnerable to severe illness and often succumb to infection,” said Rebekah Honce, Ph.D., postdoctoral scientist at the Larner College of Medicine, Department of Medicine, Division of Immunobiology, and one of the study’s co-authors. “Achieving 100 percent survival with the vaccine, where previously there was 0 percent survival, was remarkable to see.” The enhanced survival rate indicates that the researchers may have uncovered a fundamental factor influencing influenza vaccine effectiveness.

Metabolic dysfunction hinders the immune system

While studying how metabolic function influences influenza vaccine responses, the scientists found that poor metabolic health causes immune system dysfunction. T cells, the primary immune cells involved in anti-viral responses, failed to act in animals that had been in an unhealthy metabolic state at the time of vaccination, even during later viral exposure. Even when the animals ate a healthy diet after vaccination and maintained a normal BMI, the anti-flu T cells were “frozen” in that dysfunctional state.

However, a healthy diet before vaccination improved T-cell function, which resulted in a robust anti-flu response during later exposure.

“The T cells were better able to do their job in the metabolically healthy mice at the time of vaccination,” Schultz-Cherry said. “It wasn’t a matter of the numbers of them or the types of them. It was their functional activity. There were plenty of them in the lungs, not working. The healthy diet switched them from not working to functioning properly, but only if the switch occurred before vaccination.”

The earlier healthy diet also improved inflammation. Pro-inflammatory cytokines are upregulated in obese animals. Schultz-Cherry’s team found that models also returned to a lower basal cytokine level when switched to a healthy diet before vaccination.

“Giving the animals a healthy diet helped reduce overall inflammation and boosted their immune system,” stated Honce. “We noticed improvements in key immune signals like interferons, which are often problematic in obesity. Essentially, the immune system started working better.”

Improving metabolic health may improve influenza vaccine effectiveness

“What we found and are emphasizing is that it’s not the phenotype of obesity that matters; it’s really about metabolic health,” Schultz-Cherry said. “It’s metabolic health at that moment of vaccination that really makes a difference.”

The study was restricted to mice, but it does open research opportunities to improve influenza vaccine efficacy in humans. The findings suggest that methods of improving metabolic health may also improve subsequent influenza vaccinations. Given the recent introduction of metabolic improvement drugs, especially glucagon-like peptide 1 (GLP-1) agonists, there may be potential for a cooperative effect.

“We don’t know for sure, but if the outcome of using GLP-1 drugs is weight loss and improved metabolic health, we would hypothesize that it will help,” Schultz-Cherry said. “But we do know that we can do better protecting our vulnerable populations, and this study is a start for understanding how.”

Authors and funding

The study’s co–first authors are Rebekah Honce, formerly of St. Jude and now at the Larner College of Medicine, and Ana Vazquez-Pagan, formerly of the St. Jude Graduate School of Biomedical Sciences.

The study’s other authors are R. Chris Skinner, University of Vermont, Brandi Livingston, Alexandra Mandarano, Benjamin Wilander, Sean Cherry, Virginia Hargest, Bridgett Sharp, Pamela Brigleb, Ericka Kirkpatrick Roubidoux, Lee-Ann Van de Velde, Maureen McGargill, and Paul Thomas, St. Jude.

The study was supported by grants and contracts from the National Institute of Allergy and Infectious Diseases (HHSN27220140006C, 75N93019C00052, 75N93021C00016, F31AI161986, R01 AI140766-03 and 32AI106700-07) and ALSAC, the fundraising and awareness organization of St. Jude.

(This article was adapted from a press release produced by St. Jude’s Children Research Hospital.)