Vaccine immunogenetics: Bedside to bench to population

doi:10.1016/j.vaccine.2008.06.057

Vaccine

Volume 26, Issue 49, 18 November 2008, Pages 6183-6188

https://doi.org/10.1016/j.vaccine.2008.06.057 Get rights and content

Abstract

The immunogenetic basis for variations in immune response to vaccines in humans remains largely unknown. Many factors can contribute to the heterogeneity of vaccine-induced immune responses, including polymorphisms of immune response genes. It is important to identify those genes involved directly or indirectly in the generation of the immune response to vaccines. Our previous work with measles reveals the impact of immune response gene polymorphisms on measles vaccine-induced humoral and cellular immune responses. We demonstrate associations between genetic variations (single nucleotide polymorphisms, SNPs) in HLA class I and class II genes, cytokine, cell surface receptor, and toll-like receptor genes and variations in immune responses to measles vaccine. Such information may provide further understanding of genetic restrictions that influence the generation of protective immune responses to vaccines, and eventually the development of new vaccines.

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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At the current time, the field of vaccinology remains empirical in many respects. Vaccine development, vaccine immunogenicity, and vaccine efficacy have, for the most part, historically been driven by an empiric “isolate-inactivate-inject” paradigm. In turn, a population-level public health paradigm of “the same dose for everyone for every disease” model has been the normative thinking in regard to prevention of vaccine-preventable infectious diseases. In addition, up until recently, no vaccines had been designed specifically to overcome the immunosenescence of aging, consistent with a post-WWII mentality of developing vaccines and vaccine programs for children. It is now recognized that the current lack of knowledge concerning how immune responses to vaccines are generated is a critical barrier to understanding poor vaccine responses in the elderly and in immunoimmaturity, discovery of new correlates of vaccine immunogenicity (vaccine response biomarkers), and a directed approach to new vaccine development.
The new fields of vaccinomics and adversomics provide models that permit global profiling of the innate, humoral, and cellular immune responses integrated at a systems biology level. This has advanced the science beyond that of reductionist scientific approaches by revealing novel interactions between and within the immune system and other biological systems (beyond transcriptional level), which are critical to developing “downstream” adaptive humoral and cellular responses to infectious pathogens and vaccines. Others have applied systems level approaches to the study of antibody responses (a.k.a. “systems serology”), [1] high-dimensional cell subset immunophenotyping through CyTOF, [2,3] and vaccine induced metabolic changes [4]. In turn, this knowledge is being utilized to better understand the following: identifying who is at risk for which infections; the level of risk that exists regarding poor immunogenicity and/or serious adverse events; and the type or dose of vaccine needed to fully protect an individual. In toto, such approaches allow for a personalized approach to the practice of vaccinology, analogous to the substantial inroads that individualized medicine is playing in other fields of human health and medicine. Herein we briefly review the field of vaccinomics, adversomics, and personalized vaccinology.
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Genetic factors in class II human leukocyte antigen (HLA) have been reported to be associated with inter-individual variation in hepatitis B virus (HBV) vaccine response. However, the mechanism underlying the associations remains elusive. In particular, the broad linkage disequilibrium in HLA region complicates the localization of the independent effects of genetic variants. Thus, the present study aimed to identify the most probable causal variations in class II HLA loci involved in the immune response to HBV vaccine.
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Vaccine immunogenetics: Bedside to bench to population

Abstract

Section snippets

Background

The immune response network theory

Immunogenetic determinants of vaccine response

The measles example

The role of twin studies

HLA gene polymorphisms

Measles virus receptor gene polymorphisms

Cytokine and cytokine receptor gene polymorphisms

Toll-like receptor polymorphisms

Summary

Acknowledgments

Am J Hum Genet

Vaccine

Blood

Vaccine

Hum Immunol

Vaccine

Vaccine

Vaccine

Cytokine

Hum Immunol

Virology

Cell

J Allergy Clin Immunol

Curr Opin Immunol

Biochem Biophys Res Commun

J Biol Chem

Vaccine

Lancet Infect Dis

Improving health: measuring effects of medical care

Milbank Q

Genetic prediction of nonresponse to hepatitis B vaccine

N Engl J Med

Heterogeneity in vaccine immune response: The role of immunogenetics and the emerging field of vaccinomics

Clin Pharmacol Ther

Therapeutics and toxicology

Curr Opin Pediatr

Failure to reach the goal of measles elimination. Apparent paradox of measles infections in immunized persons

Arch Intern Med

Biodistribution of oncolytic measles virus after intraperitoneal administration into Ifnar-CD46Ge transgenic mice

Hum Gene Ther

The genetic basis for variation in antibody response to vaccines

Curr Opin Pediatr

Human leukocyte antigen haplotypes in the genetic control of immune response to measles-mumps-rubella vaccine

J Infect Dis