Genomic analysis may help fine-tune individual flu vaccine response
Everyone knows a person who has received the flu vaccine and still got the flu. Why that happens is a mystery that may be answered in the genome.
Getting to that answer requires a considerable amount of work and new technology, said Dr. John Belmont, professor of molecular and human genetics at Baylor College of Medicine and the corresponding author of the report that appears online in the new open-access journal eLife.
A consortium of researchers led by those at BCM identified 20 genes that contribute to differences in the way individuals respond to the influenza vaccine. Capitalizing on this knowledge could enable researchers to boost the protective potential of the "flu shot."
"The genes we identified as being associated with response appear to affect early processing of the vaccine virions (virus particles)," said Belmont.
"Almost half of these encode proteins that are not specifically associated with the immune system, but have more general roles in processes such as membrane trafficking (the transport of cellular elements within and outside the cell)," said Belmont. "Focusing on these genes may enable researchers to understand why some individuals have lower responses to the vaccine."
When they identified the genes associated with the antibody response, Belmont was surprised that the predictive gene expression changes occur quickly, within 24 hours after receiving the vaccine. That meant that the innate immune response - the body’s immediate activation against invasion - is a major predictor of the specific antibody response of the immune system.
"It surprised me because I did not know that the vaccine would look like a weak natural infection," he said. "The vaccine appears to be stimulating the same pathways that the infection does."
Belmont pointed out that the study design itself was unusual, integrating multiple types of genomic information to obtain a more powerful analysis of a complex trait such as response to a vaccine.
The researchers immunized 119 healthy adult men and 128 healthy adult women with seasonal influenza vaccines. They did a genome-wide analysis of single nucleotide polymorphisms, the most common form of genetic variation in humans. They measured the levels or abundance of gene transcripts (representing the first step in translating a gene into a protein) in peripheral blood before and at days 1, 3 and 14 after vaccination. They also measured levels of antibodies to the three influenza viruses against which the vaccine protected three times--before vaccination and at days 14 and 28 after.
The complex interplay of multiple measurements and understanding the genetic underpinnings in the abundance of the gene transcripts made the method extremely powerful, said Belmont. They only had to look at a little over two hundred people as opposed to the many thousands it would take in a usual genome-wide association study.
"This is the future of GWAS (genome-wide association studies)," said Belmont. "This was a medical experiment. We have taken study subjects and carried out an intervention and then observed them to determine how their genes affect the gene activity response to the intervention." A special aspect of the study is its integrated character, where genotype, gene expression, and the functional antibody response were analyzed together to prioritize the results.
The technique could also be used to analyze a vaccine under development, he said.
Vaccines work by exposing the immune system to weakened or dead pathogens (viruses, bacteria, etc.), a toxin or surface proteins found on organisms. The immune system should then recognize the virus or other pathogen and destroy it when the person is exposed. Some vaccines contain a second agent called an adjuvant that further enhances the response by the immune system.
Identifying the genes
By looking at the genotypes of the subjects in this study as well as the amount of gene transcription and antibody response to vaccination at different time periods, the researchers were able to identify the genes involved in activating the immune system.
"We do not know a lot about the genetics of vaccine response," said Dr. Chad Shaw, assistant professor of molecular and human genetics at BCM and lead statistical analyst for the report.
The scientists took the participants’ blood frequently to see how their bodies responded to the vaccine, said Shaw. After accounting for subjects’ initial antibody levels, they found that people respond to vaccination immediately, making quantities of interferon to alert the immune system to presence of pathogens such as viruses, bacteria, parasites or other potentially harmful organisms.
"After that, it takes longer to develop an antibody response," said Shaw.
Factors affect immune response
Pioneering flu vaccine researcher Dr. Robert Couch, professor emeritus in the department of molecular virology and microbiology at BCM and also an author of the report, said flu vaccine are good model for studying the genetics of response.
"A lot of things affect the immune response," he said. Older people and those with chronic health problems often have inadequate protection sparked by the vaccine.
"What we addressed was what are the genes that function to induce the optimal immune response," he said. It is known that people vary widely in their response to a vaccine - some have good protection and others have poor. All are normal except that they differ genetically, Couch said.
"Remember, vaccines do not protect directly," he said. "They induce immune responses and those protect. A lot of our vaccine development efforts are directed at what would stimulate the best immune response in a safe manner."
The goal, he said, is to take those normal people who are "poor" responders to the vaccine and make them good responders.
"This is only one step, but it is an important step," he said.
Others who took part in this work include first authors Dr. Luis M. Franco, assistant professor of molecular and human genetics at BCM, and Dr. Kristine Bucasas, postdoctoral fellow at BCM; Janet M Wells; Diane Niño; Xueqing Wang; Gladys E Zapata; Molly S. Bray; Alexander Renwick and Peng Yu, all of BCM; and Nancy Arden and John M. Quarles of Texas A&M University Health Science Center in College Station.
Funding came from the National Institute of Allergy and Infectious Diseases (Grants NO1AI030039 and 1K23AI0872101), and the National Institutes of Health (Ruth L. Kirschstein National Research Service
Awards T32GM07526 and F31AI07137203).
The clinical trials were conducted at the Beutel Health Center at Texas A&M University.