A collaboration among researchers at the Yale School of Medicine and 10 other research institutions has discovered gene signatures — or related sets of genes — associated with the immune response to the influenza vaccination.

The researchers found nine genes and three gene clusters by studying antibody response in over 500 people. Findings from the study could be used to develop strategies to predict and improve the immune system’s response to vaccines. The research was published in the journal Science Immunology in August.

Antibodies induced by vaccination are an important mechanism of protection against infection. Despite the overall public health success of influenza vaccination, many individuals fail to induce a substantial antibody response. The study aimed to identify the immune response mechanisms underlying differences in influenza vaccination responses.

Previous research in identifying these gene signatures was unsuccessful, in part due to the relatively small sizes of the cohorts, according to Steven Kleinstein, a professor at the medical school and a co-author on the study.

Because the failure to respond to the flu vaccine is so rare in young people, a single research site is only going to have a very small number of younger subjects , explained Ruth Montgomery, associate dean of scientific affairs at the medical school and co-author on the study.

In 2010, the Division of Allergy, Immunology, and Transplantation at the National Institute of Allergy and Infectious Diseases established the Human Immunology Project Consortium program. One of the major goals of the program was to define gene signatures of human immune systems. The study grew out of a collaboration between many institutional projects exploring immune response to the influenza vaccination.

“The beauty of this publication is that it combined the results from a number of groups in the country who were studying similar outcomes to the flu,” Montgomery said. “Because we worked together, using sophisticated bioinformatics analysis, we were able to find signatures that are relevant for important pathways in younger and older people.”

The researchers identified nine genes and three gene modules that were associated with the magnitude of the antibody response.

Researchers also said they found that these gene signatures had an inverse correlation in young and older individuals. For example, while the presence of a B cell receptor signaling signature was associated with better antibody responses in young individuals, it was associated with worse responses in older individuals, according to Kleinstein.

The multicohort analysis used the transcriptional baseline — the expression before vaccination — of the genes, which suggests that the basal immunological states can potentially be used to predict influenza vaccination responses, said Hailong Meng, a scientist at the medical school and co-author on the study.

The response to the flu vaccine, measured by production in antibodies that neutralize the virus, can then be predicted by looking at expression levels of the relevant genes, said Stefan Avey GRD ’17, a co-author on the study.

Avey added that the results could be used to potentially change treatment options for individuals with a lower response by combining the vaccine with drug therapies or using a different dose of vaccine.

The next step will be to investigate why the increased expression levels of the gene signature, which were associated with better antibody responses in the young, inversely correlated with those in older individuals, according to the researchers.

“Figuring out what drives this inverse effect should help us better understand how age influences the immune response and why older individuals are less successful in generating antibody responses following vaccination,” Kleinstein said.

Montgomery added that the researchers will also perform similar analyses on elements of the immune response to the flu vaccine that have not been studied in detail previously, such as neutrophils — the most abundant type of white blood cell — and platelets, which have recently been discovered to play an important role in inflammation and other parts of immunity.

According to the World Health Organization, annual influenza epidemics result in 3 million to 5 million cases of severe illness worldwide.                                                                                                                                                                                                                                                                                                            

Amy Xiongamy.xiong@yale.edu | @amyxiong_