Fine-tuning the flu vaccine for broader protection

A multi-institutional team led by Stephen C. Harrison, PhD, chief of the Division of Molecular Medicine at Children's Hospital Boston, report their work and its implications for improving influenza vaccination this week in the Early Edition of the Proceedings of the National Academy of Sciences.

With each passing season, the two primary components of the influenza virus's outer coat, neuraminidase and hemagglutinin (the annual flu vaccine's primary target), mutate, allowing the virus to dodge any anti-flu immunity an individual may have generated in previous years. This evasion strategy, called antigenic drift, is why a new flu vaccine is necessary every year, a process that can take upwards of seven months.

From a public health perspective, an ideal influenza vaccine would protect against multiple strains of the virus, regardless of their hemagglutinin structure. The antibody, discovered by Harrison's collaborators at Duke University Medical Center and called CH65, gives new insights into how the immune system's response to hemagglutinin evolves over time, knowledge that could guide the development of just such a vaccine.

The researchers started with cells donated by an individual who received the flu vaccine for 2007. From those cells, they used genomic tools to generate a suite of antibodies, including CH65, that bound to and neutralized hemagglutinin from several seasonal flu strains. CH65 alone could bind to and neutralize hemagglutinin from 30 of the 36 strains tested.

"While it's unusual to find such broadly effective antibodies to the flu virus, they may actually be more common than we realize," noted Harrison, who is also an investigator with the Howard Hughes Medical Institute. "What this tells us is that the human immune system can fine-tune its response to the flu and actually produce, albeit at a low frequency, antibodies that neutralize a whole series of strains."

CH65 mimics many key aspects of sialic acid, hemagglutinin's natural receptor, and binds to portions of hemagglutinin that the virus cannot mutate without reducing its ability to infect human cells. After comparing CH65 with other antibodies produced from the donor's cells, the team was able to deduce how the donor's anti-flu immune response had evolved to produce such broadly reactive antibodies as a consequence of multiple virus exposures over time.

With this knowledge, Harrison believes it may be possible to develop vaccines that actively direct the immune response to provide broad protection against multiple strains of the influenza virus, ideally by targeting the same portions of hemagglutinin as CH65.

"Developing a flu vaccine is currently a hit-or-miss enterprise," according to Harrison. "We vaccinate with a virus or part of a virus and hope that the immune response will evolve in a useful direction.

But for viruses like influenza that mutate rapidly," he continued, "we want to have a response that does a really good job at blocking both the strain of the virus in the vaccine and many related strains as well. These results point out what strategies we might employ to achieve that goal."

This study was supported by the Howard Hughes Medical Institute, the US Department of Energy, and the National Center for Research Resources and National Institute of Allergy and Infectious Diseases of the National Institutes of Health.