“We saw during the 2009 flu pandemic that there’s an epidemiological link between people getting severe flu and being obese,” says Schultz-Cherry, a member (professor) in the infectious diseases department. “Since then it’s been pretty well established that obesity is a risk factor for developing severe disease.”
Erik Karlsson, a staff scientist in Schultz-Cherry’s lab, set out to see if adding an adjuvant to influenza vaccine could boost the immune response in a mouse model of obesity to see if it could protect the obese from infection. The study results, published this week in mBio, demonstrate that adjuvants can increase a host’s immune response but not enough to protect the obese against the ill effects of the flu.
In a series of experiments among lean and obese mice given influenza vaccines with and without alum and AS03 and later exposed to flu, obese mice consistently succumbed to flu whereas their leaner counterparts stayed healthy.
“Adjuvants increased the antibody responses to levels considered protective, yet obese mice still succumbed to infection,” Karlsson said. “This vulnerability likely results from a combination of factors including the increased susceptibility of obese animals to develop severe or lethal disease when infected with even low levels of virus. Our studies highlight the critical public health need to translate these findings and better understand vaccination in the growing obese population.”
Nearly 10 percent of the world’s adult population and 42 million children under the age of 5 are obese, Karlsson said; in the U.S. alone, severe obesity has been forecasted to increase by 130 percent in the next two decades.
“The immune response in our obese animals is reminiscent of the elderly in that you can increase it but there’s something wrong with it,” Schultz-Cherry noted. “They still aren’t protected if they get infected with the virus. We need to focus on understanding why this happens and how to overcome this problem.”
Investigators vaccinated lean and obese mice with the avian influenza A(H7N9) vaccine or with seasonal vaccine against the A/California/04/2009 H1N1 flu strain with or without adjuvants. Both alum and AS03 increased antibody response in lean and obese mice compared to vaccine alone; however, response in the obese animals was about 50 percent less on average. Beyond stimulating a neutralizing antibody response to the head of the spike-shaped influenza hemagglutinin (HA) protein, the vaccines also increased antibodies to the HA stalk, a potential universal influenza vaccine target, as well as the neuraminidase, a second surface protein of the virus.
In additional tests, researchers found that vaccinated lean mice generated stronger and broader antibody responses to the influenza H7HA and N9 proteins compared to obese mice. All lean mice exposed to influenza virus three weeks after vaccination were protected from flu and had minimal weight loss; by contrast, all obese mice lost weight and succumbed to flu infection even if they had received the adjuvanted vaccines. The obese mice also had higher viral loads in the lungs three and five days after infection compared to the lean mice; lean mice who received adjuvanted vaccine had nearly undetectable viral loads in the lungs.
Even increasing the vaccine dose by four times did not protect the obese mice, who were still susceptible to flu infection even when exposed to less virus, indicating that the hypersusceptibility of the obese host to severe disease could contribute to decreased vaccine effectiveness, Karlsson said.
“Maybe we need to go beyond blaming the virus and the group choosing the viral strains that go in the vaccine,” Schultz-Cherry said. “Perhaps it’s the global population that’s also partially responsible for this drop in efficacy for our vaccine.”
Regardless of the results, Schultz-Cherry said it’s still imperative to get a flu shot: “Even if you hear on the news that the flu vaccine doesn’t match the strains circulating, remember there are three to four different strains in the vaccines, and only one may be a mismatch.” Even a less ideal vaccine is better than nothing, she added.
-- Karen Blum
Photo credit: Obese mice