Influenza vaccine designs typically rely on laboratory findings from antigens examined in the form of purified proteins introduced into a cell culture. Antigen-presenting cells (APCs) then digest the proteins into peptides, which stimulate the CD4+T cells that prevent infectious agents.

But data from the Children’s Hospital of Philadelphia (CHOP) suggest there are an array of biological pathways involved in  influenza infection that may offer opportunities for additional vaccine targets.

“During infection, viral proteins are present throughout the cell, not just in the limited compartments that have been the focus of attention in classical immunology,” lead researcher Laurence Eisenlohr, PhD, a viral immunologist in the Department of Pathology and Laboratory Medicine at CHOP,  explained in a press release about the study, published recently in Nature Medicine. “By investigating how active infections interact with mechanisms deep inside immune cells, we can design vaccines with broader protection against invading pathogens.”

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Dr Eisenlohr and his colleagues noted that during active infections, viral proteins are delivered to regions of the APC outside of the endosome, where the proteins are typically digested. This leads to a higher rate of peptides with a broader variety than the conventional vaccine design.

The conventional vaccine model introduces antigens to the APC from outside of the cell, but the study suggests that an endogenous process could be more effective for the vaccine.  In this process, the virus would infect APC and the viral proteins that are being produced inside the cell, which leads to more diverse peptides and, consequently, diverse CD4+T cells.

“Live vaccines are generally more effective than inactivated vaccines,” Dr Eisenlohr explained in the release. “That supports the concept that natural infection elicits a larger, more comprehensive immune response than a killed virus. Therefore, if safety concerns preclude use of a live vaccine, we may need to modify inert vaccines to better mimic natural infection—accessing a broader variety of peptides and thus generating a more protective immune response.”


1. Miller MA, Ganesan APV, Lukashenak N, et al. Endogenous antigen processing drives the primary CD4+ T cell response to influenza. Nat Med. 2015; 21:1216–1222.