Emily
Editor, Senior Moderator
ETA: I just realized that this section seems to be for influenza-specific vaccine information. (Realized that when I was looking for a place for an article about autoimmune genetics.) Sorry if I made work deleting or moving this.
Searching for the Genetics of Immunity
RTI February/March 2009
Cholera strikes quickly, sometimes killing those infected in a matter of hours. The infection, spread through contaminated food and water, remains a scourge of the poorest areas in many developing countries, where safe water supply and sanitation are still elusive. Typhoid haunts many of these same regions.
A substantial obstacle stands in the way of preventing both these infections: The reported effectiveness of the vaccines developed for cholera and typhoid varies greatly among individuals, meaning that as many as a third of people immunized do not actually receive protection from these vaccines.
To improve our understanding of factors that influence the effectiveness of typhoid and cholera vaccines, RTI is investigating the genetics—and other physiologic factors—that influence individual variation in immune response to these vaccines through a field study in India. RTI is conducting the research under a five-year contract from the U.S. National Institute of Allergy and Infectious Diseases (NIAID, 2004–2009).
The study is one of six that make up NIAID’s new Population Genetics Analysis Program, part of a national research effort to improve defenses against bioterrorism and infectious diseases. This RTI project forges a collaboration between private and public sector partners, including Duke University, India’s Institute for Molecular Medicine (IMM), and India’s National Institute of Cholera and Enteric Diseases.
“Immune response is a complicated biological process,” said RTI’s Diane Wagener, Principal Investigator of the study. “This is the first study to pair two powerful research technologies—genomics and proteomics—to try to unravel the process and find why some people respond to these vaccines and others don’t.”
The Beginnings: Field Work
The researchers chose India as the study location for two reasons. First, NIAID required that the study investigate infectious diseases from a specific list that included cholera and typhoid, which are endemic in India. Second, RTI had previously developed a relationship with IMM and this study provided a partnership opportunity. IMM identified the National Institute of Cholera and Enteric Diseases as an important collaborator based on its epidemiological data sets.
The study randomly recruited 4,000 participants from the slums of Kolkata, where cholera and typhoid are rampant. Half the subject pool received the cholera vaccine, and half received the typhoid vaccine. Participants’ families were also offered the vaccines.
“The study is both medically and socially beneficial,” said Partha Majumder of IMM, Co-Principal Investigator.
The study collected baseline blood and saliva samples from participants the day they received the vaccines, then took follow-up samples again three and 28 days following immunization. The researchers used the samples to determine the level of immune response the vaccine prompted in each individual. The study had a dropout rate of 5–6%—quite low for this type of field study.
Once the samples were collected, the genomics and proteomics analyses began. India’s Institute of Molecular Medicine took the lead on the genomics segment, while RTI and Duke worked on proteomics.
Discovering Variations in Genetics and Immune Responses
Genes are the blueprints that instruct the body how to make proteins, which are responsible for the body’s development and functioning on all levels. Different versions of the same gene, known as genotypes, may code for differing proteins. When combined with environmental factors, these proteins may result in different physical or behavioral traits.
Although the human genome has been analyzed extensively over the past 15 years, most of what we know about genes comes from studies involving Caucasian, African, and Asian populations. We have little information on the genetics of the Indian population.
The study team suspected Indians could have greater genetic variation in their gene pool than some other groups, because of the population’s varied demographic history. To determine whether these distinctions occur, the study used participants’ samples to examine 270 genes thought to be involved with the body’s immune response.
What they found: genetic changes in the Indian population that had never been seen in other populations. In addition to uncovering this genetic variation, initial analysis also revealed information on individual immune responses to the vaccines.
“The basic tenet in all of vaccination is that individuals will show an immune response—but that’s an assumption,” Majumder said. “Our study is showing there is a huge amount of variability in immune response, which means that the same vaccine will not be as effective in all individuals.”
The team expects that the greatly differing genomic profiles of the participants explain to some extent the large variability seen in the individual immune response to the vaccine, he said.
The researchers said they believe the study may represent the largest ever examining immune response variability. With the first steps completed, they are now beginning the task of deciphering which genotypes may be associated with which immune responses.
Deciphering Proteins
Back at RTI and Duke, researchers are now delving into the proteomics portion of the study, attempting to determine which proteins are associated with the various immune responses. Protein expression reflects a combination of genetic and environmental factors and could help researchers tease out the influences of each factor when compared to the genomic analyses. For example, an individual could have a genetic predisposition to develop an appropriate immune response to a vaccine, but if that individual’s immune system is suppressed due to malnutrition, an adequate response may not follow, said RTI’s Carol Whisnant, Co-Principal Investigator of the study.
Because the field of proteomics is relatively novel, RTI had to develop new assays to conduct the proteomic analysis.
To conduct this work, the research team had to familiarize themselves with new statistical technology used for proteomic analysis, as well as develop new assays to test for the proteins involved.
“Proteomics is a new field in science and to RTI, so it was important to demonstrate that we could do a number of proteomic assays,” Wagener said.
While some of the proteins involved in immune response are known, the study is working to identify more. In addition, the team is looking for differences in the concentration of proteins from the baseline samples to those taken four weeks after vaccination. If the immune system kicks in following the vaccine, the associated proteins should, in theory, change in concentration to direct the response.
Developing More Effective Vaccines
Genomic and proteomic analysis will continue through the year, the results of which may reveal the role genes play in individuals’ immune responses to cholera and typhoid vaccines. The findings could help pharmaceutical companies reformulate these vaccines to make them more broadly effective. The research may have additional implications, as well. It will contribute to the general body of literature on genetic variation and may offer insight into other types of immune responses.
Searching for the Genetics of Immunity
RTI February/March 2009
Cholera strikes quickly, sometimes killing those infected in a matter of hours. The infection, spread through contaminated food and water, remains a scourge of the poorest areas in many developing countries, where safe water supply and sanitation are still elusive. Typhoid haunts many of these same regions.
A substantial obstacle stands in the way of preventing both these infections: The reported effectiveness of the vaccines developed for cholera and typhoid varies greatly among individuals, meaning that as many as a third of people immunized do not actually receive protection from these vaccines.
To improve our understanding of factors that influence the effectiveness of typhoid and cholera vaccines, RTI is investigating the genetics—and other physiologic factors—that influence individual variation in immune response to these vaccines through a field study in India. RTI is conducting the research under a five-year contract from the U.S. National Institute of Allergy and Infectious Diseases (NIAID, 2004–2009).
The study is one of six that make up NIAID’s new Population Genetics Analysis Program, part of a national research effort to improve defenses against bioterrorism and infectious diseases. This RTI project forges a collaboration between private and public sector partners, including Duke University, India’s Institute for Molecular Medicine (IMM), and India’s National Institute of Cholera and Enteric Diseases.
“Immune response is a complicated biological process,” said RTI’s Diane Wagener, Principal Investigator of the study. “This is the first study to pair two powerful research technologies—genomics and proteomics—to try to unravel the process and find why some people respond to these vaccines and others don’t.”
The Beginnings: Field Work
The researchers chose India as the study location for two reasons. First, NIAID required that the study investigate infectious diseases from a specific list that included cholera and typhoid, which are endemic in India. Second, RTI had previously developed a relationship with IMM and this study provided a partnership opportunity. IMM identified the National Institute of Cholera and Enteric Diseases as an important collaborator based on its epidemiological data sets.
The study randomly recruited 4,000 participants from the slums of Kolkata, where cholera and typhoid are rampant. Half the subject pool received the cholera vaccine, and half received the typhoid vaccine. Participants’ families were also offered the vaccines.
“The study is both medically and socially beneficial,” said Partha Majumder of IMM, Co-Principal Investigator.
The study collected baseline blood and saliva samples from participants the day they received the vaccines, then took follow-up samples again three and 28 days following immunization. The researchers used the samples to determine the level of immune response the vaccine prompted in each individual. The study had a dropout rate of 5–6%—quite low for this type of field study.
Once the samples were collected, the genomics and proteomics analyses began. India’s Institute of Molecular Medicine took the lead on the genomics segment, while RTI and Duke worked on proteomics.
Discovering Variations in Genetics and Immune Responses
Genes are the blueprints that instruct the body how to make proteins, which are responsible for the body’s development and functioning on all levels. Different versions of the same gene, known as genotypes, may code for differing proteins. When combined with environmental factors, these proteins may result in different physical or behavioral traits.
Although the human genome has been analyzed extensively over the past 15 years, most of what we know about genes comes from studies involving Caucasian, African, and Asian populations. We have little information on the genetics of the Indian population.
The study team suspected Indians could have greater genetic variation in their gene pool than some other groups, because of the population’s varied demographic history. To determine whether these distinctions occur, the study used participants’ samples to examine 270 genes thought to be involved with the body’s immune response.
What they found: genetic changes in the Indian population that had never been seen in other populations. In addition to uncovering this genetic variation, initial analysis also revealed information on individual immune responses to the vaccines.
“The basic tenet in all of vaccination is that individuals will show an immune response—but that’s an assumption,” Majumder said. “Our study is showing there is a huge amount of variability in immune response, which means that the same vaccine will not be as effective in all individuals.”
The team expects that the greatly differing genomic profiles of the participants explain to some extent the large variability seen in the individual immune response to the vaccine, he said.
The researchers said they believe the study may represent the largest ever examining immune response variability. With the first steps completed, they are now beginning the task of deciphering which genotypes may be associated with which immune responses.
Deciphering Proteins
Back at RTI and Duke, researchers are now delving into the proteomics portion of the study, attempting to determine which proteins are associated with the various immune responses. Protein expression reflects a combination of genetic and environmental factors and could help researchers tease out the influences of each factor when compared to the genomic analyses. For example, an individual could have a genetic predisposition to develop an appropriate immune response to a vaccine, but if that individual’s immune system is suppressed due to malnutrition, an adequate response may not follow, said RTI’s Carol Whisnant, Co-Principal Investigator of the study.
Because the field of proteomics is relatively novel, RTI had to develop new assays to conduct the proteomic analysis.
To conduct this work, the research team had to familiarize themselves with new statistical technology used for proteomic analysis, as well as develop new assays to test for the proteins involved.
“Proteomics is a new field in science and to RTI, so it was important to demonstrate that we could do a number of proteomic assays,” Wagener said.
While some of the proteins involved in immune response are known, the study is working to identify more. In addition, the team is looking for differences in the concentration of proteins from the baseline samples to those taken four weeks after vaccination. If the immune system kicks in following the vaccine, the associated proteins should, in theory, change in concentration to direct the response.
Developing More Effective Vaccines
Genomic and proteomic analysis will continue through the year, the results of which may reveal the role genes play in individuals’ immune responses to cholera and typhoid vaccines. The findings could help pharmaceutical companies reformulate these vaccines to make them more broadly effective. The research may have additional implications, as well. It will contribute to the general body of literature on genetic variation and may offer insight into other types of immune responses.
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