Unexpected findings: Immunosuppressant drug paradoxically may provide cross-protection against multiple strains of influenza, suggesting the potential of a universal vaccine

Mice vaccinated with Rapamycin along with single-strain flu virus develop immunity to several other types of flu, including deadly pandemic strains, suggesting the potential of a universal vaccine
Dr. Tomer Hertz
Dr. Tomer Hertz is a scientist in Fred Hutch's Vaccine and Infectious Disease Division.

A new study published in the online edition of Nature Immunology describes a novel approach for developing a universal influenza vaccine that could protect against multiple flu strains, including deadly pandemic strains.

Researchers, including Drs. Tomer Hertz, Zachary Wilson and Philip Bradley of Fred Hutchinson Cancer Research Center’s Vaccine and Infectious Disease Division, immunized mice against the H3N2 influenza virus along with Rapamycin, an immunosuppressant drug that paradoxically produced protective immunity against other strains of influenza not included in the vaccine, including the newly emergent H7N9 strain. They also used H1N1 as the prime vaccination along with Rapamycin and found that it also protected against H7N9. Control group mice who were not treated with Rapamycin succumbed to new virus subtypes, but all mice treated with the drug survived.

“This is a surprising finding, since Rapamycin is an immunosuppressant,” Hertz said.

A novel antibody response

Rapamycin is used during organ and bone marrow transplants to keep the body from rejecting foreign tissues and organs and also blocks a protein involved in cell division. Seemingly illogically, by reducing the immune function during vaccination, Rapamycin improved protection against a broader range of influenza strains.

The bulk of the research detailed in the study, led by researchers at St. Jude Memorial Children’s Hospital in Memphis, Tenn., involved determining the underlying mechanisms responsible for the immune response. While the researchers hypothesized that the protection provided by Rapamycin was the result of the ability of CD8+ T cells — also known as “killer T cells”, through a series of classical immunological experiments with mice they found instead that it was a novel antibody response.

The drug inhibited the generation of antibodies against the H3N2 influenza virus instead producing immune memory and antibody responses against conserved viral sequences. “We found that the Rapamycin treatment significantly altered the antibody profile following vaccination, suggesting that the drug may shift the immunodominance pattern – i.e. the specific antigens that are targeted by the immune system,” Hertz said.

Toward a universal vaccine

According to Hertz, a breakthrough in influenza protection is an urgent public health need. “Influenza viruses infect a broad range of avian and mammalian species and every year more than 250,000 people die from influenza infection. Current vaccines need to be administered yearly and are not cross-protective. In addition, we are under constant threat of transfer of novel influenza strains from avian and swine species,” Hertz said.

The reason influenza remains a public health challenge is because strains of the virus can mutate rapidly, and antibodies produced from current vaccines cannot recognize these altered versions of the virus. This is why vaccinations against new flu strains are required every year. However, newly emerging viral strains which are not represented in the annual vaccine, leave even vaccinated people unprotected against these novel strains.

A universal vaccine that creates immunity in multiple strain subtypes of influenza could protect against newly emergent strains, including highly virulent pandemic strains, but the immunological mechanisms that create responses to subtypes are poorly understood and attempts to generate broadly protective vaccines have had little success.

Further, existing vaccines do not protect against pandemic viruses that come about from the re-assortment of gene segments between different strains of influenza, leading to the emergence of subtypes that have never been encountered before in human populations. Despite extensive surveillance of these viral strains, it is difficult to predict which ones may become pandemic.

Hertz indicated that more study on the effects of low-dose Rapamycin treatment on influenza needs to be done, but the research is promising.

“This work may lead to a novel way to make universal vaccines. While significant additional work is required to further study this and we are still far from clinical trials in humans, Rapamycin is an FDA-approved drug, and as such may be easier to test in the context of influenza vaccinations in humans,” Hertz said.

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