【讨论帖】疫苗研发的新思路 - 经验共享

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标题:【讨论帖】疫苗研发的新思路

mamamiya[使用道具]
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发表于 2016-4-9 15:26 资料个人空间短消息加为好友

小中大

从生产线上看疫苗开发：
我是兽药生产企业的研发着，每次看到关于基因疫苗，感觉无法真正在我们的车间里生产。
主要问题就是成本高。
目前有一种DNA免疫增强剂，是美国动物保健品公司研发主管推荐我们在佐剂开发中添加的成分，20kb左右，但如果大规模合成这个2mg左右需要2000左右人名币，折合到每头份疫苗中约1头猪7块钱，现在市场上疫苗几乎还没有7块1头份的呢。所以说根本无法实现。
另外个人意见：DNA 序列特异性高，这比病原的血清型还要复杂，所以说对疾病的预防特异性达不到要求。

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发表于 2016-4-9 15:27 资料个人空间短消息加为好友

小中大

基于T细胞的HIV-1疫苗开发策略仍有可行性
最近遭受的挫折促使人们对艾滋病疫苗领域进行一次重大的重新评估。人们一直问的一个问题是，是否继续基于T-细胞的HIV-1疫苗的开发。现在，用一种新疫苗在患有“猴免疫缺陷综合症”（SIV）的猴子身上所进行的一项研究表明，基于T-细胞的策略仍然是有潜在可行性的。该疫苗利用两种表达SIV Gag蛋白的腺病毒载体(rAd26 prime/rAd5 boost)制成。它能诱发强效T-细胞免疫反应，并使猴子在病毒感染方面受到一定保护。这些发现为用于防治HIV-1的新一代基于T-细胞的疫苗候选药物的设计提供了线索.
原始出处：
Nature 457, 87-91 (1 January 2009) | doi:10.1038/nature07469
Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys

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发表于 2016-4-9 15:27 资料个人空间短消息加为好友

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即时生效的免疫接种
接种疫苗是预防传染病的极为有效的策略，但是这种预防或治疗的效果可能需要数天到数周才能生效。理想的免疫接种应该是即时的，而且可以应对毒素和恶性细菌。美国斯克利普斯研究所(TSRI)Carlos Barbas及其同事报告了一个提供即时免疫的系统，他们的系统通过用专门的衔接分子改造自然抗体而起作用，然后这可以把免疫细胞导向目标。这组科学家报告说注射了这种衔接分子的小鼠导致了抗体形成，后者自然地结合起来并且可以针对癌细胞。当小鼠接受特定的结肠癌和黑色素瘤移植之后，这些衔接分子锁住了肿瘤，引发了它们的灭亡。这组作者说这种"可编程疫苗接种"的优点是，除了可以对付各种癌症，它可能有效应对一大类病毒病原体，例如艾滋病病毒和流感病毒。这组作者说，这种方法还可能提供一个应对生物恐怖主义的策略。（来源：EurekAlert! 中文版）
（《国家科学院院刊》（PNAS），doi: 10.1073/pnas.0900147106 ，Mikhail Popkov，Carlos F. Barbas III）
Published online before print March 2, 2009 , doi: 10.1073/pnas.0900147106
Instant immunity through chemically programmable vaccination and covalent self-assembly

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发表于 2016-4-9 15:27 资料个人空间短消息加为好友

小中大

亮助先生是善于思考的同志：病毒和机体的关系本身就是哲学问题，处处充满了辩证的思想的......
我的观点：
1：DNA疫苗和各种亚单位疫苗....都是骗人的！新型佐剂的研究...！哈哈！就像寻找“长生不老药”一样可笑！
2. 我们现有的病毒学与免疫学理论，也就是对病毒和机体的关系本身了解了那么一点点......，还等着免疫学的重大新理论！！！！？盲人摸象！耳朵是啥样你还没摸全呢！就喊着要发现“大象的新品种”！！！
3. 各种新型疫苗（多肽疫苗，载体疫苗，DNA疫苗等）至少在未来50年，甚至更长时间，将长期停留在理论研究或者实验室水平上！！！。
4. “绝对安全而又高效的疫苗”我认为在理论上是不存在的！要高效就不会安全！这是生命的基本法则！！
5. 疫苗的研发方向应是“全病原体活疫苗”！把我们的分子与基因工程技术用在全病原体活疫苗吧！专家们教授们！给我们的儿子剩些钱吧！去！去海选“全病原体活疫苗”吧！至于它为什么高效，留给我们的儿子去研究吧！
言辞过激了！为长话短说！

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发表于 2016-4-9 15:28 资料个人空间短消息加为好友

小中大

Recent attempts for improved influenza vaccines.
Influenza virus’ high rate of mutation is a major obstacle in designing an effective, universal influenza vaccine. Every year, new strains of virus emerge and the seasonal vaccine must be freshly prepared using circulating strains. The WHO’s Global Influenza Surveillance Network monitor and inform governing authorities of the emerging influenza viruses so new vaccines can be produced before the influenza season starts. In addition to the need to prepare seasonal influenza vaccines annually, the imminent threat of a pandemic influenza, especially with the H5N1 avian strain, has facilitated research into universal means to control this mutative virus, using antibodies that can neutralize or a vaccine that can protect against different influenza strains.
Michael Deem and colleagues at Rice University (TX, USA) have used a novel computational method to predict the efficacy of influenza vaccines. Mutations in the virus genes were given numerical scores and the scientists could then estimate whether a vaccine may be effective against divergent viral strains.
“For seasonal influenza, we validated our model against observational data compiled by the World Health Organization’s Global Influenza Surveillance Network,” said Deem. “We also ran tests against bird flu data. We found that multiple-component bird flu vaccines appeared to be helpful in controlling the simultaneous multiple introduction of bird flu strains.”
“Oftentimes, bird flu seems to emerge with multiple strains, and something similar can happen with newly released or evolved strains of seasonal flu as well,” explained Deem. The scientists hope that their new computational approach can help predict the necessity and efficacy of a multiple-component vaccine should multiple influenza strains emerge at the same time.
Screening for antibodies that are able to neutralize divergent strains of influenza virus is another approach in tackling the virus’ high mutation rate. Such antibodies will be useful in passive immunization, as well as in designing new vaccines that can elicit antibodies with similar neutralizing ability. In a recent study published in Science online ahead of print, Ekiert et al. from the Scripps Research Institute (CA, USA) identified CR6261, a human antibody that could neutralize both H1N1 (responsible for the 1918 influenza pandemic) and H5N1 (fear to cause the next pandemic) viruses. The authors wrote: ‘CR6261 recognizes a highly conserved helical region in the membrane-proximal stem of HA1/HA2 [the viral hemagglutinin]. The antibody neutralizes the virus by blocking conformational rearrangements associated with membrane fusion. The CR6261 epitope identified here should accelerate the design and implementation of improved vaccines that can elicit CR6261-like antibodies, as well as antibody-based therapies for the treatment of influenza.’
In another study published in the March issue of Nature Structural and Molecular Biology, Sui et al. from Harvard Medical School (MA, USA) screened an antibody phage-display library and identified ten antibodies that could neutralize all group 1 influenza viruses, including H1N1 and H5N1. The researchers were also able to demonstrate that each of these antibodies neutralized the virus ‘by inserting its heavy chain into a conserved pocket in the stem region [of the viral hemagglutinin], thus preventing membrane fusion.’ They appeared to work by the same mechanism, which was similar to that described by Ekiert et al. In summary, conserved regions in the stem section of influenza virus hemagglutinin may serve as a good antigen candidate for future vaccine design, and antibodies that bind these regions may be able to neutralize divergent viral strains, thus they may be used as therapeutics in an emergency where vaccines cannot be used.
Sources: Ekiert DC, Bhabha G, Elsliger MA et al. Antibody recognition of a highly conserved influenza virus epitope. Science 324(5924), 246–251 (2009); Sui J, Hwang WC, Perez S et al. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat. Struct. Mol. Biol. 16(3), 265–273 (2009); Rice University, TX,

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发表于 2016-4-9 15:29 资料个人空间短消息加为好友

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Application of pharmacogenomics to vaccines
Pharmacogenomics
May 2009, Vol. 10, No. 5, Pages 837-852
内容提要
▪ The application of the science of pharmacogenomics and pharmacogenetics to vaccines has led to a new science of vaccinomics.
▪ Twin studies offer an ideal system for understanding the genetic contribution to variation in the immune response to vaccines, and for identification of SNPs.
▪ The activation and/or suppression of specific immune response pathway genes associated with response to vaccines provide a basis for the theory of the immune response gene network.
▪ HLA gene polymorphisms are important contributors to human immune responses to prophylactic vaccines.
▪ Genetic variants in immune response genes have important associations with immune responses to measles–mumps–rubella, influenza, HIV, hepatitis B vaccine and smallpox vaccines.
▪ A number of polymorphisms in SLAM, CD46, cytokine, cytokine receptor and TLR genes have been discovered that are associated with variations in both humoral and cellular immune responses to the measles–mumps–rubella vaccine.
▪ It may be feasible to design new personalized vaccines based on complex interactions of host genetic, environmental and other factors that control immune responses to vaccines.
▪ An emerging field associated with vaccinomics is the area of genetically determined vaccine-associated adverse events and atypical immune responses – collectively called adversomics.
▪ At the current time, cost is a major obstacle to vaccinomics and personalized vaccinology approach.
===============================
What is vaccinomics?
The development of the field of pharmacogenomics (associations of whole genomes and drug or vaccine response) and pharmacogenetics (associations of individual genes and drug or vaccine response) has provided both the science base and clinical outcomes that together increasingly allow for the practice of individualized drug therapy. The application of this same science when applied to vaccines we have labeled ‘vaccinomics’ [1]. Thus, just as we now recognize that a variety of drugs, such as antidepressant and antihypertensive medications, may require different dosing based on individual genetic differences and result in different side-effect profiles, resulting in variations in therapeutic effect based on genetically-based individual variations; we have now begun to recognize similar attributes in terms of vaccine indications, dosing, side effects and outcomes. As one clinician noted, ‘…vaccines licensed in the USA are safe and effective. However, not every vaccine is equally safe or equally effective in every person’ [2].
As discussed later in this paper, we have done extensive work identifying associations between immune response gene polymorphisms and variations in immune responses to several prophylactic live viral vaccines [3–13]. Such phenotype/genotype data, in combination with high throughput genetic sequencing and bioinformatics, we believe will accelerate the field of vaccinomics and personalized vaccinology. In turn, the growth of this area of inquiry will increasingly allow us to understand and predict immune responses to vaccines, adverse events to vaccines and accelerate new vaccine development. Such research is a logical extension of what physicians now do – tailor any intervention to the unique characteristics of the patient before them. For example, patients with renal failure or who are immunocompromised may get a hepatitis B antigen dose two- to four-times the usual dose in order to improve the chances of seroconversion and protection. Similarly, an HLA-extended haplotype that is associated with nonresponse to this vaccine has been defined [14]. Multiple repeat dosing may seroconvert such identified individuals [15]. Thus, such findings result in changes in clinical care, such as requiring higher doses, alternative vaccines, and accelerated or enhanced schedules. Vaccinomics will also chart new courses for novel vaccine development. It will drive novel scientific approaches and solutions to vaccine nonresponse, such as new vaccine adjuvants and peptide cocktail vaccines based on HLA supertype and other approaches.
How does vaccinomics inform vaccine development & vaccine science?
It is clear that the ability to respond to the threat of infectious disease depends on the ability of the host to mount an effective defense against an invading pathogen. However, for this to occur, a variety of biologic systems must be activated by the host, eventually resulting in the activation and secretion of cytokines, antibodies, chemokines and immune effector cells. In turn, for these events to take place, a variety of genes must be activated or suppressed and their products transcribed and their proteins translated, modified, expressed and secreted. In this regard, we have previously discussed the theory of the ‘immune response gene network’ whereby it is clear that the interactive and iterative activation and suppression of specific pathway genes must occur in a choreographed fashion in order for a coherent immune response to result after recognition of a pathogen [11]. Genes involved in virus binding and cell entry, antigen recognition, processing and presentation, immune effector cell function and immunoregulation are all necessary for a coordinated attack against an invading pathogen. Our work with the measles–mumps–rubella (MMR) vaccine, for example, has illustrated significant associations between class I and II HLA, cytokine, cytokine receptor, signaling lymphocyte activation molecule (SLAM) and CD46, and other immune response gene polymorphisms, humoral immune responses (IgG enzyme-linked immunosorbent assay [ELISA] and neutralizing antibody levels) and markers of cell-mediated immune responses (lymphoproliferative assays, cytokine secretion, enzyme-linked immunosorbent spot [ELISPOT] assays, and so on) [3,5,7–9,16–19]. In addition, we have advanced such work by expanding the scientific NIH data-sharing database to include microarray data, and more recently, transcriptomics data at increasingly remarkable levels of sensitivity [20].
The next evolution in understanding such data will be in analyzing and better understanding such issues as gene family pathways, epigenetic modifications and complementation. For example, we have developed protocols whereby ex vivo infection of human peripheral blood mononuclear cell (PBMC) cultures and the application of mass spectrometry tools have allowed us to identify naturally processed and presented pathogen-derived peptides – the very entity responsible for pathogen-induced adaptive immune responses [21]. Coupled with a growing body of data regarding pathogen-derived peptide promiscuity and HLA supertypes, such data will lead to identification of peptides capable of stimulating humoral and recall immunity [21–23]. A repertoire of such peptides (peptide cocktail) may permit the design and development of new vaccines for particular subpopulations [24]. For example, certain polymorphisms in the SLAM (CDw150) receptor for live measles vaccine virus are associated with poor humoral immune responses [7]. Since both vaccine and wild-type measles virus strains infect host cells via the interaction of the measles virus hemagglutinin protein with the V-domain of the SLAM receptor, SNPs in the SLAM gene are significantly associated with variations in immune responses to measles vaccine. Microarray experiments demonstrate gene-expression patterns (13 upregulated and 206 downregulated genes) in PBMCs from children with acute measles and children in the convalescent phase, which were consistent with the prolonged alteration of lymphocyte responses to measles [25]. It may well be possible to design new vaccines for use in individuals who suffer from variant cell-based receptors for viral recognition and do not respond well to current vaccines. Investigators may develop new vaccine models that do not depend upon such receptors or develop new vaccines that effectively allow vaccine virus to bind to a range of receptor polymorphic areas [26,27].
The goal of pharmacogenomics and vaccinomics is to identify genetic variants that predict adverse responses to vaccines, predict aberrant immune responses, contribute to personalized therapy and that predict susceptibility to diseases and response to vaccines [28]. Vaccinomics may also be useful in the development and use of existing and novel vaccine adjuvants and stimulants. For example, specific polymorphisms of the TLR3 gene are associated with significantly diminished humoral and cell-mediated immune responses to the measles vaccine [8]. Understanding the mechanism by which such polymorphisms diminish innate and other immune responses may offer a critical insight into designing work around the limitations imposed by such polymorphisms – either by developing new adjuvants that utilize other receptors, or by the addition of stimulant molecules that can potentiate or augment the immune response.

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发表于 2016-4-9 15:30 资料个人空间短消息加为好友

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Similarly, complement components are key factors of the innate and adaptive immune response against pathogens. Without a fully functioning complement system normal immune response, lymph node organization and B-cell maturation, differentiation, responsiveness and tolerance is adversely affected [29]. Products from the cleavage of complement or component proteins can bind to cell-surface receptors to influence inflammation [30], T-cell immunity [31] and B-cell response [32]. These receptors are known as regulators of complement activation (RCA) and are a family of common receptors present on most cells [33]. It has been demonstrated that any deficiencies in C4, C2 or C3 proteins can lead to a weakened antibody response to bacterial infections [34]. For example, targets for complement components C4b and C3b on both Neisseria meningitidis and Neisseria gonorrhoeae have been described [35]. Most genes of the complement system are polymorphic, with the C4 molecule having over 35 identified variants [36]. While it has been demonstrated that complement genes play a critical role in the immune response to influenza [37,38], rubella [39] and other viral infections, there have been no studies to date investigating how complement gene polymorphisms may affect immune response to viral infections and/or viral vaccines.
Another area of importance is genetically determined vaccine-associated adverse events, which we have called ‘adversomics’. Scarce data are available regarding the immunogenetics of adverse vaccine responses. Black et al. recognized differing and more severe adverse events to receipt of the measles vaccine in Amazon Basin Indians compared with other groups – suggesting a possible genetic contribution [40]. More recently, Vestergaard et al. demonstrated an association between receipt of the MMR vaccine and subsequent febrile reactions and febrile seizures [41], providing a logical genetic basis for increased susceptibility to adverse events to live viral vaccines. Very recently, debate has arisen over the hypothesis that live viral vaccines could in some fashion exacerbate pre-existing genetically-coded problems such as mitochondrial or metabolic defects, for example, inborn errors of amino acid and organic acid metabolism, lipid metabolism, carbohydrate metabolism and of purine and pyrimidine metabolism [2,42]. Mitochondrial disorders in particular are estimated to occur at an incidence of 1 in 4000–5000 births [43]. If knowledge of such disorders were to be identified as important in predicting vaccine-induced immune responses or adverse events, screening for such genetic defects or polymorphisms might become more commonplace. In an analogous manner, the routine screening for such disorders among all live children born in the USA, represents personalized and predictive medicine, particularly to the extent that findings of concern would result in different specific vaccine recommendations.
Concerns over more severe vaccine-related side effects, such as neurotropic and viseotropic reactions to yellow fever vaccine, encephalitis-related reactions to smallpox vaccine, Guillain-Barré reactions temporally occurring with vaccination and others, warrant further investigation for the potential of identifying genetic predictors of risk [44–47]. With the availability of high-throughput sequencing and large patient databases that allow identification of serious adverse events related to immunization, such studies are increasingly feasible. Such studies would be further enhanced by reliable and stable funding mechanisms for broader population-based studies of adverse events for other commonly administered vaccines.

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Specific examples of prophylactic vaccines
▪ Twin studies
Twin studies provide opportunities to explore genetic contribution to vaccine response and to identify specific gene polymorphisms. This benefit occurs for two reasons. First, a number of nongenetic factors may influence antibody levels (and cellular immune responses) following vaccination, including the presence of maternal antibodies [48], race [49], differences in vaccine storage, handling and administration [50,51], and concurrent illness at the time of vaccine administration [52–54]. However, twins who are raised together are highly likely to share these and other factors (such as exposure to viral diseases) that may influence measures of vaccine immunity. In addition, twins are also highly likely to be vaccinated at the same time with the same lot of vaccine, which has been stored and administered under the same conditions. They are also matched on age, exposure to older and younger siblings, and on overall family environment. Therefore, twin studies provide an ideal way to control for shared environmental factors. Second, monozygotic (MZ) twins share all of their genes, while dizygotic (DZ) twins share half their parents’ genes. Therefore, differences in immune responses within MZ twin pairs can be attributed to differential environmental exposures and chance variation, while differences in immune responses within DZ twins can be attributed to differential environmental exposures, chance variation and genetic differences.
Investigators have used twin studies to estimate the genetic and environmental contributions to a variety of different diseases, including determining the genetic contribution to variation in total immunoglobulin levels and specific IgG antibody levels to pneumococcal capsular polysaccharides [55,56]. Recent studies have observed a high heritability of 77% (95% CI: 63–85) for antibody response to hepatitis B vaccine in 207 Gambian twin pairs aged 5 months [57]. Heritabilities for antibody responses to oral polio, tetanus and diphtheria vaccines were 60% (95% CI: 43–73), 44% (95% CI: 16–70) and 49% (95% CI: 17–77), respectively [57]. In addition, significant heritability was also observed for IFN-γ and IL-13 cytokine immune responses to tetanus, pertussis and several Bacillus Calmette–Guérin (BCG) vaccine antigens, ranging between 39 and 65% [57]. Another study among 147 DZ and 43 MZ Gambian twin pairs showed that the IgG antibody response to Haemophilus influenzae type b (Hib) vaccine is highly heritable among Gambian infants. Heritability of antibody responses to Hib conjugate vaccine was estimated to be 51% (95% CI: 32–66), indicating a significant genetic contribution to the variation of antibody response to the polysaccharide antigen of Hib [58].
Since twin studies provide an ideal method for quantifying the magnitude of genetic contributions to the variability in vaccine-induced immunity, determining the proportion of variation attributable to specific genes in healthy individuals following live attenuated MMR vaccination was investigated. The Mayo Vaccine Research Group (MN, USA) conducted a twin study to determine the magnitude of genetic influence on variability in circulating antibody levels to measles, mumps and rubella viruses [59,60]. A total of 100 twin pairs (45 MZ and 55 DZ) residing in Minnesota were recruited and information regarding demographic characteristics, vaccine history and exposure to or occurrence of any vaccine-preventable diseases collected. Blood samples were collected from each child and viral-specific IgG antibody levels were quantified by ELISA. The genetic variance and heritability of the IgG levels were examined using analysis of variance techniques. It was found that the heritability was 88.5% for measles (95% one-sided CI: 52.4), 38.8% for mumps (95% one-sided CI: 1.6) and 45.7% for rubella (95% one-sided CI: 4.9). These data demonstrate that genetic influences play a substantial role in antibody levels following measles vaccination, and a somewhat lesser role in the antibody levels following mumps and rubella vaccination. Others have commented that ‘Knowledge that a trait of interest has high heritability can support a study that proposes to investigate the genetic determinants of that trait’ [61]. It is important to note that the unique genetic and environmental characteristics of different individuals and vaccines demand a clear understanding of the role of critical aspects of vaccine pharmacogenomics [11,62].
The pathways by which protective humoral and cellular immune responses develop to live viral vaccines is a multistep process: the vaccine virus (such as measles) must first be recognized by its cellular receptors (SLAM and CD46) and also activate toll-like receptors (TLRs) or other innate sensors, triggering innate immune responses. After antigen presentation by HLA molecules, cytokine and cytokine receptor gene activation occurs, along with signaling molecules, resulting in secretion of cytokines as intercellular messengers to stimulate Th1 and Th2 immune responses [63–65]. Individual variations within any of these relevant genes could effect gene transcription, regulation or expression, and thereby influence immune responses or the propensity to an adverse reaction to the vaccine antigen. Below we will give specific examples of genetic associations with immune responses to live viral vaccines.

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发表于 2016-4-9 15:31 资料个人空间短消息加为好友

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▪ MMR vaccine
As discussed above, we have performed and reported a twins study of measles vaccine immunogenicity. This study demonstrated that antibody levels to measles vaccine have a very high heritability of 88.5% [59,60]. Informed by advances in basic immunology on the role of the HLA complex in immune recognition and response, a series of immunogenetic studies designed to answer questions on the role of HLA in vaccine immune responses was performed.
The HLA proteins play an essential role in generating an immune response against pathogens. Generally, the class I A, B and C alleles bind and present peptides to CD8+ T lymphocytes, while the class II DR, DQ and DP alleles bind and present peptides to CD4+ T cells. The peptide-binding clefts of the HLA molecules contain highly polymorphic clusters of amino acids that act to control or restrict the spectrum of peptides capable of being bound and presented by a given HLA molecule. A single HLA molecule is able to bind self- and pathogen-derived peptides that share common amino acid motifs [66,67]. Differences in HLA-binding affinities may result in decreased binding of specific pathogen-derived peptides and inefficient peptide presentation to T lymphocytes [68–70]. Inefficient peptide presentation may, in turn, result in decreased T-cell activation and cytolytic function, decreased cytokine production and decreased B-cell production of pathogen-specific antibodies.
We have reported a number of findings in relation to measles, mumps and rubella vaccine antigens and HLA genetics [9,17,71–73]. Recent reviews of these population-based clinical studies have revealed a number of findings of interest. Specific class I and class II HLA alleles are associated with variations in antibody levels after a single dose of measles vaccine [3–5]. In particular, class II DRB1*03, DQA1*0201 and the class I B8, B13 and B44 alleles are associated with lower levels of measles antibodies in healthy schoolchildren. In the case of HLA homozygosity it was also demonstrated that overall lack of variation in the HLA alleles is associated with decreased measles-specific antibody levels following a single dose of vaccine, with increasing risks of vaccine nonresponse with increasing homozygosity [16]. The role of HLA molecules in vaccine-induced immune responses after two doses of MMR vaccine was also examined [6,9,17]. Little verification was found that either homozygosity at specific HLA loci or overall homozygosity had any disadvantage in terms of measles-specific cytokine immune responses, such as IFN-γ, IL-2, IL-4, IL-10 and IL-12p40, following two doses of measles vaccine, suggesting that at some level genetic restriction could be overcome by higher or repeated doses of vaccine [73]. In addition, associations between HLA haplotypes and HLA supertypes and MMR vaccine-specific humoral and cellular immune responses following two doses of MMR vaccine were investigated [23,74]. The haplotypes with the strongest evidence for association with lower measles-induced antibodies were DRB1*07–DQB1*02–DPB1*02 and DRB1*07–DQB1*03–DPB1*04. Haplotype A*26–Cw*12-B*38 was significantly associated with higher antibody levels and higher lymphocyte proliferation and response to the mumps vaccine [74]. Among our study subjects, the supertypes B44 and B58 were strongly associated with lower measles vaccine-specific antibody levels. In contrast, the most common B7 supertype was associated with higher measles vaccine antibody response. For the mumps vaccine, it was found that the HLA-DQB1*0303 allele was associated with lower mumps-specific antibody titers and the B62 supertype was suggestive of an association with mumps-specific higher lymphoproliferation after the MMR vaccine [9,23]. Further, alleles of the DRB1, DQA1 and DQB1 loci were associated with significant variations in lymphoproliferative immune responses to mumps vaccine [9]. It was also demonstrated that HLA-A (*2402 and *6801) alleles were associated with lower vaccine-induced IFN-γ secretion levels in response to rubella virus antigens [19]. Associations were further observed between measles (IFN-γ and IL-4) and rubella (IFN-γ and IL-10) specific cytokine responses and class I and class II HLA gene polymorphisms [19,75–77]. Class I HLA-A (*0101, *3101), HLA-C (*0303, *0501), and class II HLA-DRB1 (*0301, *1501) and HLA-DQB1 (*0201, *0303 and *0602) alleles were significantly associated with variations in measles-virus-induced in vitro IFN-γ secretion [75,76]. These studies demonstrated that both humoral (antibody) and cellular (lymphoproliferation and secreted cytokines) immune responses to MMR vaccine are clearly influenced by polymorphisms of the HLA genes.
HLA gene polymorphisms may also be related to variations in cytokine production following measles immunization through variations in T-cell activation; however, variation in the cytokine genes themselves may also directly affect cytokine secretion after antigen stimulation [10]. It is also possible that other immune response genes or other currently unknown genes may also influence vaccine immunity more strongly than the HLA genes. In this regard, polymorphisms in cytokine and cytokine receptor genes may also contribute to variations in vaccine immune response [78]. SNPs that are associated with differences in cytokine secretion levels could also influence vaccine-induced immune responses [18]. For example, the presence of minor allele T for intronic SNP rs2201584 within the IL12RB2 gene and the presence of minor allele A of the rs373889 within the IL12RB1 gene were strongly associated with an allele dose-related decrease in antibody titer and lymphoproliferation, respectively, after two doses of mumps viral vaccine [9]. More recent preliminary data demonstrate that specific SNPs in the IL10 and IL12RB2 genes are associated with low antibody and low cell-mediated immune responses to the measles vaccine, while SNPs in the IL2 gene are associated with high antibody and cellular immune responses to measles [18]. The same IL2 promoter SNP (rs2069762) identified in our study was also found to be associated with the responder phenotype following hepatitis B virus (HBV) vaccination [79]. Significant associations were also found between IL4R gene polymorphisms and levels of measles-specific secreted IL-4 (major alleles for four SNPs were associated with lower levels of IL-4) [18], indicating that cytokine and cytokine receptor gene polymorphisms may be significant factors in the development of vaccine immunity.
We also examined gene polymorphisms in the two known genes that code for the measles virus receptors – SLAM and membrane cofactor protein – CD46. Both SLAM and CD46 are known to play a role in measles virus binding and entry into the host cell, as well as in cell tropism and pathogenesis. Our study demonstrates that increased representation of minor alleles for rs3796504 and rs164288 in the SLAM gene were associated with a significant allele dose-related decrease in measles-specific antibodies [7]. The SNP rs3796504 leads to an amino acid change of threonine to proline at position 333 of the SLAM gene, and may change the conformation of the SLAM receptor, making it unsuitable for binding to the measles virus hemagglutinin protein. Within the CD46 gene, the minor allele C for intronic SNP (rs11118580) was associated with an allele-dose related decrease in measles-specific antibodies [7]. Although the mechanism is unclear, intronic SNP rs11118580 may also play a critical role in the regulation of gene transcription. Thus, variations in measles vaccine-induced antibody levels may be influenced by polymorphisms in the genes for the SLAM and CD46 measles virus receptors.
Discovery of genetic variation (e.g., immunogenetic profiling) in a population is important for understanding its role in vaccine-induced immunity [26]. In this regard, polymorphisms of the TLR genes involved in innate immune responses have also been demonstrated to influence the susceptibility to infection and immune responses to pathogens. For example, Heer et al. have shown that TLR signaling is not required for anti-influenza effector T-cell responses, but through both direct and indirect ways it orchestrates anti-influenza B-cell responses [80]. It has been reported that laboratory adapted and vaccine strains of measles virus, including the Edmonston vaccine strain, induce TLR3 in human dendritic cells, which may be associated with protective immunity against measles via enhanced IFN-β secretion [81]. This suggests that measles virus-induced expression of TLR3 may be a sign of augmented IFN production that plays an important role in host defense to viral infection. Specific SNPs in the coding and regulatory regions of the TLR3 (and associated intracellular signaling molecule MyD88) were also associated with variations in antibody and cellular immune responses to measles vaccine, suggesting that TLR signaling may be required for antimeasles T- and B-cell immune responses [8,10]. However, more work in this area is required in order to understand how immune responses to vaccines can be impaired by SNPs within the genes encoding TLRs.

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▪ Influenza vaccine
Influenza is a single-stranded RNA virus that causes substantial morbidity and mortality. Influenza vaccines prevent disease in 80% of healthy subjects [82] Therefore, it is important to investigate the effect of immune response gene polymorphisms on humoral (and cellular) immune responses following influenza immunization [83]. While a variety of genes and gene pathways are involved in whole influenza virus immunity, it is essential to understand gene polymophisms that may be involved with generating an immune response to the influenza hemagglutinin (H) and neuraminidase (N) transmembrane glycoproteins, as these proteins form the sole influenza virus-derived components of inactivated influenza vaccine. Serum antibody titers, measured by a hemagglutination inhibition assay, are believed to be a reliable correlate of immunity to influenza viruses [84]. Associations between HLA gene polymorphisms and influenza A virus H1- and H3-specific hemagglutination inhibition antibody titers in healthy subjects who received trivalent influenza vaccine, containing A/H1N1 New Caledonia/20/99, A/H3N2 California/7/2004 and B/Shanghai/361/2002 influenza virus antigens were examined. HLA-A*1101 (p = 0.0001) and A*6801 (p = 0.09) alleles (global p-value for HLA-A locus 0.007) were associated with higher median levels of influenza H1 vaccine-induced antibodies [12]. Gelder et al. demonstrated an increased frequency of HLA-DRB1*0701 and a decreased frequency of HLA-DQB1*0603–9/14 in individuals who were nonresponders to the influenza subunit vaccine [85]. Significant associations between both H1- and H3-specific antibody immune responses and polymorphisms of cytokine and cytokine receptor genes (such as IL1R1, IL2RA, IL6, IL10RA, IL12B and other genes) were also identified, suggesting that SNPs present in HLA, cytokine and cytokine receptor genes may influence humoral response(s) following seasonal influenza vaccination [12]. Further examination of the role of immune response gene polymorphisms and variations in influenza vaccine-induced immunity is warranted, particularly given the public health impact of both seasonal and pandemic influenza.
▪ HIV vaccine
Variations within the host’s genome may contribute substantially to the individual immune response to vaccination and susceptibility to infectious diseases. For example, evidence demonstrates that class I HLA-B*35 and B*08 alleles are associated with faster HIV type 1 (HIV-1) disease progression, and homozygosity at class I loci confers a significant risk of accelerated infection [86,87]. A study of canarypox vector-based HIV (vCP1433) vaccine (ALVAC)-HIV-1 recombinant canarypox vaccines showed that the HLA-B*27 and B*57 (the two alleles best known for an association with slower disease progression) were associated with earlier and positive CD8+ cytotoxic T lymphocyte responses to Gag and Env viral proteins [88]. However, homozygosity at class I loci, although conferring an unfavorable prognosis following natural HIV-1 infection, showed no such disadvantage for ALVAC-HIV-1 vaccine response [88]. For class II, associations with the DRB1*1300–DQB1*0603 haplotype and transporter gene products (TAP2 Ala665) and progression of HIV-1 infection have been also reported [89]. There appears to be a strong association between polymorphisms in the CCR5 chemokine receptor gene, located on the short arm of chromosome 3 and HIV-1 infection [90]. Caucasian individuals homozygous for a deletion of CCR5 (CCR5-Δ32), which encodes the cell entry co-receptor for HIV, appear to be at lower risk of acquiring HIV/AIDS [91]. Likewise, genetic studies of HIV demonstrate that the presence of the most frequent TLR8 polymorphism, TLR8 A1G (rs3764880), confers a significantly protective effect against disease progression [92]. Recently, de la Torre et al. demonstrated the contribution of five polymorphisms in the vitamin D receptor (VDR) gene to HIV-1 susceptibility among Spanish HIV-infected patients [93]. Specifically, haplotypes for VDR (SNPs rs11568820, rs4516035, rs10735810, rs1544410 and rs17878969) polymorphisms revealed important associations with protection against HIV-1 infection (OR: 0.4; 95% CI: 0.22–0.72; p = 0.0025).
▪ HBV vaccine
Hepatitis B vaccination of twin pairs is a valuable model with which to study the importance of host-genetic factors for the immune response to HBV antigens. The vaccine licensed throughout much of the world consists of recombinant hepatitis B surface antigen (HBsAg) and alum and induces protective antibodies (>10 IU/ml) in 95% of vaccinees following three doses. Hohler et al. studied 96 DZ and 95 MZ twin pairs and demonstrated that genetic factors have a significant effect on the immune response to the HBsAg vaccination [94]. In this study more than 60% of the observed variability in anti-HBsAg immune responses was attributed to genetic factors. The heritability of the HBsAg vaccine response accounted for by the HLA-DRB1 locus (such as DRB1*01, DRB1*11 and DRB1*15) was estimated to be 0.25, leaving the remaining heritability of 0.36 to other gene loci, suggesting that approximately 40% of the genetic contribution to HBsAg response is affected by HLA genes and approximately 60% by non-HLA genes [94]. This study suggests that while genes encoded within the HLA complex are important for the immune response to HBsAg, more than half the heritability is determined outside of this complex, with strong evidence that other immune response genes (complement factor C4A, IL2, IL4 and IL12B) are also important determinants of nonresponsiveness to HBV vaccination [95,79]. In addition, increased antibody levels and lymphoproliferative immune responses to HBV vaccination were found to be influenced by polymorphisms within the IL1β gene [96].
Several HLA association studies have demonstrated that the DRB1*03 and/or DRB1*07 alleles confer a higher possibility of HBV vaccine failure [97,98]. Further, analyses of genotyping data from 164 North American adolescents vaccinated with recombinant HBV vaccine demonstrated that the HLA-DRB1*07 allele (relative odds [RO]: 5.18; p < 0.0001) was associated with nonresponse to full-dose vaccination [79]. However, when HBsAg-specific T-cell responses following HBsAg vaccination were compared ex vivo in 24 MZ and three DZ twin pairs, it appeared that the DRB1 alleles associated with vaccine failure (such as DRB1*0301 and *0701), were able to competently present HBsAg-derived peptides [99]. This argues that HLA-DRB1 allelic associations with HBV-specific immune response are not caused by differences in peptide binding or by a change in the ELISPOT Th1 (IFN-γ)/Th2 (IL-10) profile. The authors suggested that the defect in nonresponse to the HBV vaccine may be on the side of the T-helper cells and not on the side of the antigen-presenting cells [99].

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