2019-10-01

Improved protection against influenza through mucous surface guards

HZI researchers develop an innovative vaccination strategy that triggers a cellular immune response against the influenza virus

An influenza vaccination causes the body to form antibodies that circulate in the blood, but which are directed against constantly changing virus components. This means that the vaccine must be re-administered each year. Researchers at the Helmholtz Centre for Infection Research (HZI) in Braunschweig have now shown that the antibody-independent, cellular arm of the immune system can also provide immune protection against influenza. The researchers integrated an influenza antigen into cytomegaloviruses (CMV) and triggered a strong response from the T lymphocytes. The special thing about it: The hybrid viruses, when administered via the nose, attract T cells from the bloodstream into the mucous membranes of the respiratory tract. These immune cells are quickly activated when they come into contact with influenza viruses and then act as guards that block the virus at the most common entry point in the body. The results were published in the journal PLoS Pathogens.

3D illustration of immune reaction to a virus attack. ©Adobe Stock/Mike Mareen3D illustration of immune reaction to a virus attack. ©Adobe Stock/Mike Mareen The influenza vaccine with inactivated influenza viruses stimulates the immune system to produce antibodies against surface characteristics of the seasonal influenza strain. These surface characteristics are highly variable, meaning updated vaccines must be administered annually. The cellular arm of the immune system, in addition to the antibody-dependent arm of the immune system, is also able to fend off foreign substances or pathogens. Immune cells from the T lymphocyte group, known as cytotoxic T cells, can detect and attack cells in the body infected by bacteria or viruses. “No other virus triggers such a strong immune response from T cells as the cytomegalovirus (CMV),” says Prof Luca Čičin-Šain, head of the research group “Immune Aging and Chronic Infections” at the HZI. “We are exploiting this characteristic by using CMV as the vehicle to smuggle a small protein fragment of the influenza virus into host cells.”

Using a mouse model, the researchers investigated the reaction to the influenza antigen introduced in this way and discovered a strong activation of the cytotoxic T cells by the CMV-based vaccine. The administration route of the vaccine defines the protective effect. Although cytomegaloviruses administered through the nose produced less T cell activation in the blood than those that were injected with a syringe, nasal vaccination resulted in better protection against influenza infection. Cytotoxic T cells located in the mucous membrane are the decisive factor for this. The vaccine causes the immune cells to leave the bloodstream and settle in the target tissue, where they reside for long periods of time. When they come into contact with influenza viruses, they produce messenger substances that attract other immune cells to the site of the infection.

“We were able to show that the location of an immune response plays an important role. T cells located in the mucous membranes of the respiratory tract are particularly effective in protecting against influenza, as this is a typical infection pathway. This means they come into contact with the influenza viruses very early and ‘guard’ the entry points,” says Prof Dunja Bruder, whose research group “Immune Regulation” was also involved in the study.

This study was designed to test immunity that is based exclusively on the cellular arm of the immune system and rules out involvement from antibodies. This was the first time that a functioning T cell-based influenza vaccine had been developed, thanks to the interdisciplinary collaboration between four groups and facilities at the HZI. “In infection research, we need to keep an eye on the entire system. All tissues – not just the blood – are involved in the course of infection and the building of immunity,” says Čičin-Šain. “The influenza vaccine of the future could therefore target combined immunity through antibodies circulating in the blood and T cells that ‘guard’ the mucous membranes.” [cwe]

Original publication

Xiaoyan Zheng, Jennifer D. Oduro, Julia D. Boehme, Lisa Borkner, Thomas Ebensen, Ulrike Heise, Marcus Gereke, Marina C. Pils, Astrid Krmpotic, Carlos A. Guzmán, Dunja Bruder, Luka Čičin-Šain: Mucosal CD8+ T cell responses induced by an MCMV based vaccine vector confer protection against influenza challenge. PLoS Pathogens 2019. DOI: 10.1371/journal.ppat.1008036

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