Why flu shots fail even when the match is right

In 2009, two flu vaccines manufactured by the same company did not equally protect against the circulating H1N1 flu virus. A study published Wednesday in the journal Science Translational Medicine examines the question: Why did one vaccine offer 35% less protection against the flu?

The less-effective vaccine failed to activate dendritic cells, which are key to the immune system’s defense, the researchers discovered, and it failed to stimulate an early immune response.

Vaccine effectiveness for any given season varies, in part, based on how well the vaccine matches the circulating virus strains. Sometimes, a vaccine corresponds to the predominant virus and yet its effectiveness is not what scientists would hope. Trying to determine which element of the vaccine failed is a challenge.

For the new study, Shruti Athale, first author and a researcher at the Baylor Institute for Immunology Research, investigated the interferon responses to the two vaccines.

“Vaccines work by eliciting an immune response. In order to do this, they have to be recognized as foreign material,” said Dr. Matthew Collin, a professor of hematology at the Institute of Cellular Medicine at Newcastle University. “One of the key responses to pathogens or foreign material is the production of chemicals called interferons.”

The cells that produced this essential interferon are dendritic cells, noted Collin, who was not involved in the research.

What are dendritic cells?

Although dendritic cells are found in most tissues of your body, they are most abundant in the parts that traffic with the external environment, such as your skin, your lungs and your gastrointestinal lining. These immune cells work as sentinels, initiating the first response to pathogens entering the body. Among their duties, these cells release interferon, a signaling chemical that assists in mounting an immune system defense against foreign substances.

For the study, Athale and her co-researchers measured the production of interferon induced by the stronger trivalent vaccine and compared this to the effects of the weaker monovalent vaccine, neither of which contained adjuvants: substances added to a vaccine formula to increase its power.

Monovalent vaccines protect against a single flu virus strain, whereas trivalent formulations protect again three strains. The study accounted for these differences when comparing the vaccines.

The team discovered that both vaccines activated one set of dendritic cells, yet only the trivalent vaccine aroused an interferon response in other dendritic cells. Athale and her colleagues also found that the monovalent vaccine inhibited the secretion of interferon.

The researchers concluded that their results may help explain vaccine underperformance that is not due to a mismatch of viral strains. Additionally, they suggest that for any nonadjuvant vaccine, dendritic cell activation might be crucial for generating a more robust immune response.

The future of vaccines

The strength of the study, said Collin, “is that it figures out a potential explanation for why two very similar flu vaccines had a dramatic difference in efficacy.” That said, more research would be needed to understand the exact mechanism of why one vaccine triggered more interferon than the other.

Understanding a greater level of detail about a vaccine’s effects “open the possibility of specifically targeting the interferon-producing dendritic cells to improve vaccine efficacy,” he said. “In particular, the production of a high level of interferon may be sufficient to avoid the use of non-specific inflammatory vaccine enhancers or ‘adjuvants.’ ”

Adjuvants, which are usually irritant chemicals, have been shown to promote vaccine efficacy, but they can produce unwanted side effects, Collin said.

“Dendritic cells are the basis of many new advances in medicine, including some cancer vaccines,” he said.

Various intensities of flu pandemics have occurred throughout history. The 1918 pandemic, commonly referred to as “Spanish flu,” claimed the lives of an estimated 50 million to 100 million people worldwide.

Two decades later, Jonas Salk and Thomas Francis developed the first flu vaccine. Today, the production of flu vaccines is a global endeavor.

The process begins each year with the World Health Organization consulting laboratories around the world to make a recommendation on what virus strains should be included in the vaccine for the upcoming season. In the United States, the Advisory Committee on Immunization Practices, a group of medical and public health experts, then decides which virus strains will go into vaccines. Finally, manufacturers produce formulations with the selected strains.

Although progress has been made over time refining the flu vaccine, the holy grail remains a “universal” vaccine.

“The ideal influenza vaccine would be one that is safe, elicits … responses identical to those triggered by a natural infection, provides long-lasting and cross-strain protection, and can be manufactured rapidly in large amounts under well-controlled conditions,” wrote Linda C. Lambert, a researcher at the National Institute of Allergy and Infectious Diseases, and Dr. Anthony S. Fauci, director of the institute, in a 2010 New England Journal of Medicine article headlined “Influenza Vaccines for the Future.”

Optimism about the ability to develop a universal vaccine is based on studies using two-step vaccination strategies in animal models, Lambert and Fauci wrote. Though a truly universal vaccine providing lifelong protection against any strain of flu may not be achievable, some variant of this concept should be considered.

“For example, the strategy of periodic vaccinations, given every few years, with a product that … would induce full or partial protection against drifting strains, as well as against newly emerging pandemic strains, is certainly a goal that is worth pursuing,” Lambert and Fauci concluded.