Vaccine immunogenetics: Bedside to bench to population
Section snippets
Background
Recently the Centers for Disease Control and Prevention identified ten of the greatest public health achievements and placed vaccination at the top of the list [1]. Vaccines are among the most effective and cost-effective of our public health initiatives [2]. Bunker et al. reported that the lifespan of a U.S. resident improved from 1900 to 1999 by 30 years with 25 of these years being due to public health interventions such as vaccines [3].
A great deal of the success with implementation of
The immune response network theory
A variety of factors impact the heterogeneity of vaccine-induced immune responses. Some of these include gender, vaccine dose, the integrity of vaccine storage and cold chain maintenance, immune system function and integrity, age, body mass index, and others. Our laboratory has been working on the “immune response network theory” [5]. The basic underlying concept of this theory states that the response to a vaccine is the cumulative result of interactions driven by a host of genes and their
Immunogenetic determinants of vaccine response
Genetic influences can occur via polymorphisms of a variety of genes involved directly or indirectly in the generation of the immune response. This can include membrane-based viral receptors, innate toll-like receptors (TLRs), signaling molecules, cytokine genes, cytokine receptor genes, human leukocyte antigen (HLA) genes, immunoglobulin Gm and Km allotypes, vitamin A and D receptor genes as well as many others. In addition, it is important to consider the mechanisms for such polymorphism
The measles example
A useful model for further examining this issue of the immunogenetics of vaccine responses has been examined by our laboratory in regards to live measles virus vaccine. Interestingly, measles was thought to be well controlled and on its way to eradication in the late 1980s in the US. However, beginning in 1989 a measles resurgence occurred which lasted until 1991 and led to an estimated 55,000 documented cases, >11,000 hospitalizations, approximately 155 deaths, and direct medical expenses
The role of twin studies
An important method in which to study genetic causes of variations in vaccine response is through the use of twin studies. Twin studies provide the ability to separate genetic and environmental factors and to explore the contribution of genetic factors related to variability and immune response. In particular, twin studies allow the determination of the proportion of variation attributed to specific genes and this enables the concept of heritability which is defined as the ratio of genetic
HLA gene polymorphisms
Given the finding of very high heritability of immune responses to measles vaccine, our laboratory embarked on a series of studies designed to answer questions such as “how important are immune response gene polymorphisms in the immune response to measles vaccine, and what is the role of gene homozygosity and of more than one dose?” We also were interested in whether our answers would be generalizable across other viral vaccines and if so might we be able to identify new immunogenetic
Measles virus receptor gene polymorphisms
These results prompted additional studies examining immunogenetic markers of measles vaccine-induced response heterogeneity [27], [28], [29]. We started by examining gene polymorphisms in the two genes coding for the measles receptors – signaling lymphocyte activation molecule (SLAM, also known as CDw150) and membrane cofactor protein – CD46 [30], [31]. SLAM and CD46 both have measles virus binding domains extending upward from the cell membrane-based receptors. We reasoned that polymorphisms
Cytokine and cytokine receptor gene polymorphisms
Polymorphisms in coding and noncoding regions of cytokine and cytokine receptor genes can influence many aspects of cytokine biology, for instance, transcriptional activity, protein secretion, receptor binding, direct interactions with viral proteins and functional activity [34]. These observations prompted additional work studying the role of cytokine and cytokine receptor SNPs reasoning that cytokines play an essential role in regulating viral vaccine-induced humoral and cellular immunity [35]
Toll-like receptor polymorphisms
Since viral infections can also be initially recognized by innate receptors, such as the TLRs, we also examined the potential role of TLR polymorphisms in measles vaccine-induced immune responses. This was logical as the laboratory adapted attenuated Edmontson strain of measles virus is known to upregulate the expression of TLR3 in human dendritic cells via enhanced interferon alpha and beta (IFN-α/β) secretion [38]. Of the 10 human TLRs, 3, 7, 8 and 9 are endosomal and specialize in viral
Summary
Through the data discussed above, we have illustrated important preliminary associations between measles vaccine immune responses and class I and class II HLA alleles, HLA supertypes and HLA haplotypes, SLAM and CD46 receptor SNPs, cytokine and cytokine receptors, TLR and MyD88 SNPs. The observation that polymorphisms in these genes modulate the humoral and cellular immune responses to measles virus vaccination is significant, but further investigations are clearly required to confirm these
Acknowledgments
We thank the many subjects and Mayo Vaccine Research Group staff who have participated in our studies. We thank Cheri A. Hart for her editorial assistance. In addition, we acknowledge support from the National Institutes of Health grants AI 33144, AI 40065 and AI 48793 for this work.
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