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Additives to boost vaccine responses not sufficient to protect obese mice from influenza

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WASHINGTON, DC – August 2, 2016 – Adjuvants – ingredients added to vaccinations for influenza and other viruses to help boost their effectiveness – can increase a host's immune response but not enough to protect the obese against the ill effects of the flu, according to a mouse study published this week in mBio®, an online open-access journal of the American Society for Microbiology.

In a series of experiments among lean and obese mice given influenza vaccines with and without the adjuvants alum and AS03 and later exposed to flu, the obese mice consistently succumbed to flu whereas their leaner counterparts stayed healthy.

"Adjuvants increase the antibody responses during vaccination of lean and obese mice to levels considered protective, yet obese mice still succumb to infection," said lead study author Erik Karlsson, PhD, a staff scientist with the infectious diseases department at St. Jude Children's Research Hospital in Memphis, Tenn. "This vulnerability is likely due to a combination of factors including the increased susceptibility of obese animals to develop severe and even 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.

"Our study was conducted in a mouse model so we don't know how this will translate directly to humans," added senior study author Stacey Schultz-Cherry, PhD, full member (professor) in the infectious diseases department at St. Jude. "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. 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."

During the study, the 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 laboratory tests, the researchers found that vaccinated lean mice generated stronger and broader antibody responses to the influenza H7HA and N9 proteins compared to obese mice. Exposing the mice to influenza virus three weeks after the vaccines, they found that all lean mice 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.

Increasing the vaccine dose by four times to try to better protect against influenza did not protect the obese mice, and obese mice were susceptible to flu infection even when exposed to less virus, indicating that the hypersusceptibility of the obese host to severe disease could be contributing to decreased vaccine effectiveness, Karlsson said.

Researchers may need to look at different vaccine approaches in the obese population, Schultz-Cherry said. But while more studies are needed, "regardless of these results, you need to get a flu vaccine," she said. "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 if the vaccine is not ideal, it's still better than nothing. If you are not vaccinated you are susceptible and can develop severe infection."

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The study was coauthored by investigators at Ben-Gurion University of the Negev and the National Institute of Biotechnology in the Negev in Beer-Sheva, Israel; Fred Hutchinson Cancer Research Center in Seattle; the University of Wisconsin-Madison; and the Icahn School of Medicine at Mount Sinai, New York, N.Y. The work was supported by the NIH Centers of Excellence in Influenza virus Research and Surveillance, the National Institute of Allergy and Infectious Diseases, the American Lebanese Syrian Associated Charities (the fund-raising arm of St. Jude), and Sanofi-Pasteur. Two of the coauthors' laboratories receive funding from GlaxoSmithKline and Sanofi-Pasteur.

mBio® is an open access online journal published by the American Society for Microbiology to make microbiology research broadly accessible. The focus of the journal is on rapid publication of cutting-edge research spanning the entire spectrum of microbiology and related fields. It can be found online at http://mbio.asm.org.

The American Society for Microbiology is the largest single life science society, composed of over 47,000 scientists and health professionals. ASM's mission is to promote and advance the microbial sciences.

ASM advances the microbial sciences through conferences, publications,certifications and educational opportunities. It enhances laboratory capacity around the globe through training and resources. It provides a network for scientists in academia, industry and clinical settings. Additionally, ASM promotes a deeper understanding of the microbial sciences to diverse audiences.

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Aleea Khan
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