【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

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发表于 2016-4-9 15:32 资料个人空间短消息加为好友

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▪ Smallpox vaccine
Immunity to smallpox is an important issue for public health and vaccine development. In this regard, genetics play a critical role in the host immune response variation to smallpox vaccination within a population. The variability of humoral and cellular immune responses modulated by HLA and other genes is a significant factor in the development of a protective effect of smallpox vaccine (or live vaccinia virus). We tested whether associations exist between individual HLA alleles and vaccinia virus-specific humoral (neutralizing antibody) and cellular (IFN-γ-ELISPOT) responses in a group of healthy individuals (n = 1076; age: 18–40 years) who received one dose of smallpox vaccine (Dryvax™). Significant associations were found between class II HLA-DQB1*0302 (p = 0.003) and DQB1*0604 (p = 0.03) alleles and higher vaccinia-induced neutralizing antibody levels (global p-value 0.01). A striking finding was an association of several class I HLA alleles with vaccinia-specific cellular responses. The global tests revealed associations between vaccinia-induced IFN-γ responses and HLA-B and -C loci (p < 0.001 and 0.03, respectively). Specifically, HLA-B*1501 (p = 0.006), B*3508 (p = 0.02), B*4901 (p = 0.04), B*5701 (p = 0.04), B*5802 (p = 0.05), C*0303 (p = 0.01) and C*0704 (p = 0.02) alleles were significantly associated with higher cellular responses to vaccinia virus. In contrast, HLA-B*3701 (p = 0.03), B*4001 (p = 0.03), B*5301 (p = 0.04), B*5601 (p = 0.03), C*0102 (p = 0.03), C*0702 (p = 0.04) and C*0801 (p = 0.01) alleles were significantly associated with lower IFN-γ responses to the smallpox vaccine [100]. These preliminary data suggest that both humoral and cellular immune responses to smallpox vaccine are, in part, genetically restricted by HLA genes.
Associations between smallpox vaccine-induced immunity and SNPs in cytokine and cytokine receptor genes were also studied. A variety of statistically significant associations between SNPs in the cytokine and cytokine receptor genes, in some cases associated with an allele–dose relationship, were found. For example, the minor variant for rs1035130 in the IL18R1 gene was associated with higher (p = 0.0002) vaccinia-specific antibody titers, while the heterozygous variant for rs2230052 in the IL12A gene was associated with lower levels of neutralizing antibodies (p = 0.03). The minor allele of rs2229113 in the IL10RA gene was found to be associated with a dose-related increase in IFN-γ responses (p = 0.03). Furthermore, two SNPs (rs1495963 and rs3024679) in the IL4R gene were associated with a dose-related decrease in IFN-γ production (p ≤ 0.05) [101]. These preliminary data suggest that SNPs in cytokine/cytokine receptor genes may influence immune response following smallpox vaccine. Other genes in the region may also contribute to the genetic control of this immune response. Our group is currently conducting extensive genome-wide association studies of immune responses to the smallpox vaccine.
Severe complications due to the smallpox (live vaccinia virus) vaccine have been reported [102]. The licensed vaccinia vaccine against smallpox (Dryvax) is associated with rare severe side effects, including encephalitis and myopericarditis [47,103]. Common adverse events, such as fever after vaccination, have been observed in 13–15% of newly vaccinated individuals [104,105]. Stanley et al. examined associations between the development of fever (≥37.7°C) and SNPs in 19 candidate genes among 346 individuals assessed for clinical responses to smallpox vaccine [105]. Fever following smallpox vaccination was found to be associated with specific haplotypes in the IL1 gene complex on chromosome 2 and with haplotypes within the IL18 gene on chromosome 11. A specific haplotype in the IL4 gene was significant for reduced risk for the development of fever after smallpox vaccination among vaccinia-naive subjects [105].
Recent papers have confirmed the association between receipt of the Dryvax vaccine and the development of myopericarditis [47,103,106]. It would be clinically important to determine if the individuals who developed myopericarditis after smallpox vaccination carry the IL1, IL18 or other haplotypes. It is conceivable that IL1, IL4 or IL18 gene polymorphisms may also be influencing the development of more common adverse events, such as fever and febrile seizures, after MMR immunization in children [41,107]. Further exploration of the role of specific gene polymorphisms in adverse reactions to vaccines is crucial to our understanding of immune responses to vaccines and to preventing serious adverse events. We are confident that similar immunogenetic work on other vaccines (such as anthrax, yellow fever, avian influenza and so on) will be pursued in the near future.
The above data illustrate the clinical utility in regards to vaccinomics information. If we understood that a polymorphism in the TLR ‘x’ gene led to poor or absent immune response, and we knew the prevalence of that polymorphism, perhaps we could design a specific adjuvant that could overcome the genetic defect coded for by that particular polymorphism and direct the immune response in a favorable manner. For example, CpG oligonucleotide, which stimulates TLR9, was used as an adjuvant with the HBV vaccine to activate innate immune responses to the standard alum formulation of HBV vaccine in healthy adults [108]. Vandenbroeck et al. state that ‘alterations in the expression levels of cytokines typically accompany aberrant immune activation … and demonstrate that cytokine gene association studies (of polymorphisms) are instrumental in identifying these disease states … such findings will ultimately lead to novel therapeutic strategies’ [109]. Large-scale population-based immunogenetic studies will further inform us regarding molecular mechanisms of protective vaccine immunity and provide important clues in the development of novel vaccines. The data discussed above from numerous human studies demonstrate the genetic basis for interindividual variation in immune responses to viral vaccines in genetically heterozygous populations.
What’s next? The developing field of personalized vaccinology
In many ways the era of personalized vaccines has already begun [110]. For example, the rationale behind and utilization of personalized vaccinology in cancer vaccines is increasingly clear and a benchmark in this regard [111,112]. In particular, in the field of cancer vaccines, much thought and progress has been demonstrated with the concept of personalized peptide vaccines [112].
Of particular interest to the personalized peptide vaccines concept is the peptide-based vaccine approach of identification of specific naturally processed pathogen-derived antigenic peptides. Targeting pathogenic T lymphocytes via vaccines consisting of synthetic peptides representing T- and B-cell epitopes is an interesting tactic since peptide-based approaches offer multiple advantages over whole-protein immunization strategies, including ease of manufacture, lower cost and the lack of a requirement for maintaining a cold chain [113–115]. Furthermore, identifying immunogenic peptides that would be restricted by numerous HLA alleles (promiscuous peptides) is one of the critical aspects to designing successful peptide-based vaccines that are useful among populations.

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An increasing number of articles, editorials and scientific efforts are being directed toward personalized medicine [116–118]. These efforts will affect everything in medicine, and vaccines are no exception [110,111]. At a minimum, we predict that the role of genomics in the field of vaccinology will serve to elucidate new mechanisms and biologic pathways in understanding vaccine-induced immune responses and adverse responses, as well as provide new insights into vaccine development [119]. With high-throughput, low-cost genetic sequencing, large-scale phenotype/genotype databases, and bioinformatics; personalized vaccinology at the subpopulation and the individual level will occur. Of most value early in the development of this field will be associations with major or even dominant impacts (e.g., the SNP or allele that imparts a clinically impactful high relative risk ratio for poor response or adverse effect, or conversely protection from adverse events [120,121]. Such work will provide studies useful in clinical decision-making at the individual level. As sophistication increases, the ability to detect meaningful associations through the contributions of multiple genes will be discernible and potentially clinically useful. Finally, the ability to understand and predict the effect of the presence/absence and interactions of the entire genome or heritable non-DNA encoded differences (epigenetics, complementation and so on) may prove the most useful in understanding an individual patient’s benefit or risk in receiving a specific vaccine [122,123]. In such a scenario, the finding of a particular SNP that confers a very high risk of a major adverse event to a vaccine, may be outweighed or mitigated by the simultaneous finding of other specific SNPs that confer protection against such a side effect. In this manner, the totality of the genetic risk or protective effects could be assessed and integrated with other aspects of a patient’s personalized profile in regards to receiving a vaccine. Of course, to be useful we again caution that determining such a genetic profile will need to be inexpensive, easy to interpret and easy for physicians to understand and synthesize as clinical data. Thus, we see the following broad steps as necessary for the development of personalized vaccinology. If carried out such steps are likely to rapidly accelerate advances in the science and improve our ability to advise our patients on an individual (as opposed to a population level) level [124]. Without a coordinated approach, advances in the science are likely to be slow, uneven, disjointed, and less predictable and useful. ▪ Better designed gene-association studies are critical to advancing the science. Much has been written regarding this, but briefly such studies should be powered to detect scientifically and clinically meaningful associations [125–131];
▪ Studies should examine clinically meaningful end points. Studies designed to detect risks of vaccinia-associated encephalopathy are more important than studies defining the risk of transient, low grade and spontaneously resolving local or systemic side effects such as fever;
▪ Studies should be designed to maximize the amount of genetic information derived. Initial studies of a small number of gene candidates are likely to be less promising than either genome-wide association studies or large candidate gene set studies for example, but may be appropriate as initial exploratory studies;
▪ Once initial genotype:phenotype association studies are completed and candidate SNPs or alleles identified, follow-up validation studies are critical to confirming true associations and to determining if such associations are also found in other ethnic/racial groups;
▪ The costs for such studies are currently high. Because of this, we applaud the NIH’s efforts at directing funding toward such studies and in developing public databases that will allow other investigators access to study results and protocols so that results can be duplicated in other settings. It would be helpful, if possible, to develop biobanks of DNA material under study protocols so that studies could later be performed of vaccine immune response genotype:phenotype associations in as expeditious and inexpensive a manner as possible. By analogy, we need a ‘Framingham study’ [132] approach in order to develop clinically meaningful information;
▪ We must develop genetic tests that are reliable and reproducible, of low cost, for use in clinical settings, rapid, and are accompanied by sophisticated analytic tools in bioinformatics, informed by increasingly sophisticated understanding of genetics, immunology and immunogenetics.
Conclusion
The field of vaccinomics, adversomics and personalized vaccinology represents the evolution of new fields of study with new scientific possibilities informed by new paradigms and discoveries in immunology, genetics and bioinformatics. Growth in this field will be driven not only by scientific reasons, but also by consumer demands for increasingly safe and risk-free medical treatment, prevention and the desire to understand and prevent serious and severe vaccine adverse events. In turn, we believe that vaccinomics and an increasingly personalized vaccine approach will lead to new and better directed vaccine development – including the development of niche vaccines for those persons who are susceptible to serious or chronic outcomes from a given infectious disease and who are unlikely to, or have not, responded with protective immune responses to standard vaccines.
The finding that approximately 90% of the variation in measles vaccine immune response is explainable genetically provides but one insight into the importance of the field of vaccinomics. Understanding and defining associations between important immune response gene polymorphisms and subsequent immune response can aid in not only designing new vaccines, but also in developing new concepts that lead to a better understanding of viral vaccine-induced immune response variability in all human vaccines. In addition, such understandings may well allow us to predict who will not respond to a vaccine (and hence shouldn’t receive the vaccine) or who is likely to suffer a serious adverse effect from a given vaccine. Thus, the broader development of vaccinomics data can be used to make individualized decisions regarding vaccine practice.
Nonetheless, as we have previously pointed out, difficulties remain in the study and application of the immunogenetics and immunogenomics of vaccine-induced immune responses [11]. First and foremost, the science base needed is still developing. We have yet to identify genotype:phenotype associations that would reliably call for variations in vaccinations (e.g., one more or one less dose, higher or lower concentration, or other changes in schedule). In addition, for the most part we do not yet have alternative vaccines to use to address poor immunogenetic responses (e.g., peptide cocktails and cytokine adjuvanted vaccines). The complexity and extensive polymorphic nature of immune response genes will require improved and increasingly powerful bioinformatic approaches in order to inexpensively acquire, display and understand complex genetic information. Further complexity results from issues of multigenic and gene–gene interactions and response effects such as complementation and heritable epigenetic modifications. Once initial data are available, validation studies in broader and more diverse subpopulations will need to be done in order to better understand the significance of gene-specific polymorphisms and to sort true-positive from spurious false-positive associations [133]. A recent editorial succinctly states that ‘use of genetic risk information to guide intervention must be justified by data demonstrating improved outcomes, reduced costs, or both’ [117]. We would endorse such a statement.
Second, to proceed with a program of personalized vaccines, the economics of the genotype:phenotype associations and the alternative interventions would need to lend themselves favorably to adjust vaccination. Vaccination succeeds currently as a population-level public health measure because it is cost-effective and that cost–effectiveness is driven by the universal application of a one-dose-fits-all model. We would need a situation with personalized vaccines that similarly saved costs. To illustrate, imagine a vaccine usually given in three doses at a cost of US$100 a dose. Let us assume a genetic association with complete penetrance that would permit us to give only two doses to a subgroup of individuals to get the same level of protection. With two doses, we would save US$100 for each of those individuals. Assume the genetic association occurs in the population at a rate of 10%. Identification of such individuals requires testing all in the population. As long as the test costs less than US$10 an individual, the new program would break even. For the program to save money, the test would need to be cheaper. To save an average of US$5, the test would need to cost only US$5. Third, such testing in practice would need a high diagnostic accuracy in order to base clinical decisions on the result.

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In general, while substantial difficulties need to be solved, we nonetheless believe that the vaccinomics era of personalized predictive vaccinology [11,110] is coming and that this will eventually allow clinicians to predict the likelihood of a significant adverse event to a specific vaccine [105], develop novel vaccines in a directed, nonempiric manner, predict the necessity for a given vaccine as well as the dose and number of doses of a given vaccine needed to produce the desired immunologic outcome, and identify approaches to vaccination for individuals and groups (based on age, gender, race and other) based on genetic predilections to vaccine response and reactivity. As stated by one investigator ‘just as pharmacogenetics has suggested ways of designing drugs to minimize population variability, understanding mechanisms of immunogenetic variation may lead to new vaccines designed specifically to minimize immunogenetically based vaccine failure’ [134].
At the current time, a major barrier to vaccinomics and personalized vaccinology remains the cost. For the widespread application of personalized vaccinology, much data remains to be developed, genetic sequencing costs must be inexpensive and rapidly obtained with high-throughput sequencers, and increasingly more sophisticated and less labor-intensive bioinformatic approaches will need to be developed and validated. All these issues continue to experience substantial scientific and public interest, with regular new discoveries. Hence we believe that the future of vaccinology is bright indeed, and the era of empiric vaccine development, and a strict one-size-fits-all public health approach to vaccine delivery will diminish, with adoption instead of a philosophy of the best vaccine solution for each individual or subgroup of individuals. How fast and whether public health paradigms of vaccination against infectious diseases will evolve is unknown, but critical to the public’s health, particularly in an era of consumer concern over safety, is the growing realization in healthcare policy that prevention is cheaper than treatment, and ultimately this will successfully drive advances in vaccine sciences to the benefit of all. In this regard, comprehensive and stable funding for childhood and adult immunization programs is critical to protecting the citizenry and national security.
Future perspective
Associations between HLA and other immune response gene polymorphisms, as well as innate and adaptive immune responses to vaccines are presently the best illustration of vaccine pharmacogenomics and pharmacogenetics (collectively called vaccinomics). To date, a number of immune response gene polymorphisms have been described that are associated with variations in vaccine-induced immune responses in genetically heterogeneous populations. This information, in combination with individual high-throughput genetic sequencing and bioinformatics will accelerate the field of vaccinomics and individualized vaccinology. Genetic sequencing approaches are critical for recognizing regulatory components of genes that are important in understanding immune responses following vaccination. Analysis of potential transcriptomic biomarkers for vaccine immune responses is another important technique informing the development of the next generation of prophylactic vaccines. Epigenetic aspects of heritable changes in gene-expression patterns in the absence of DNA sequence modifications of vaccine-related immune response genes will also be defined. Over the next decade, the role of immunogenetics relevant to personalized vaccines will also be further developed. We believe that the future of personalized medicine is such that with the appropriate enabling technology, one will be able to predict the likelihood of vaccine response, of numbers of doses need to achieve protection and the likelihood of serious adverse events due to vaccination. At the same time, additional immune response genes that influence variations in vaccine response will also be discovered, providing strategies for new immunotherapy approaches, novel vaccines and vaccine adjuvants. Prospective vaccine population-based studies should center on comprehensive genetic sequencing and epigenetic (DNA methylation, histone modifications) studies and on the mechanisms by which genetic polymorphisms and/or epigenetic modifications regulate gene expression and influence immune responses to vaccine antigens

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References:
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▪▪ Recent review of the field of vaccinomics.
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[CrossRef] [Medline]
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▪▪ Comprehensive overview of the field of vaccinomics and the role of immunogenetics in understanding the mechanisms of heterogeneity in immune responses to vaccines.
[CrossRef] [Medline]
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发表于 2016-4-9 15:37 资料个人空间短消息加为好友

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从我们实验室的肿瘤疫苗的结果来看比较悲观，疫苗一定程度上减缓了肿瘤的过程，但是一旦免疫后动物的肿瘤突破免疫进入快速生长的时期生长速度超过PBS的快速生长速度。就像是低浓度抗生素前期减缓了细菌生长，但是耐药菌比例的增加使得细菌不再受低浓度抗生素的影响。而且免疫系统在促进肿瘤生长方面的研究结果很可能显示如果肿瘤疫苗效果丧失也许加速肿瘤生长，这和我们实验室的前面观察到的现象比较吻合。

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发表于 2016-4-9 15:37 资料个人空间短消息加为好友

小中大

请问禽流感疫苗、SARS疫苗一直没有生产出来，而HINI流感疫苗却为什么已能够生产

ritou1985[使用道具]
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发表于 2016-4-9 15:38 资料个人空间短消息加为好友

小中大

QUOTE:

原帖由 tears 于 2016-4-9 15:37 发表 bbcodeurl('http://bbs.antpedia.com/images/common/back.gif', '%s')
请问禽流感疫苗、SARS疫苗一直没有生产出来，而HINI流感疫苗却为什么已能够生产

2009的HINI流感实际上和每年发生的普通流感没有本质的区别,当然，其超强的传播能力是需要重视,这个从2009H1N1发病短段几个月后,全球不同国家和地区的好几万分离株保持高度同源性可以看出.
而每年用于流感病毒预防的流感疫苗(包括B型和A型流感)研发生产是非常成熟的.基本套路还是美国上世纪60年代制定的标准, PR8重组然后鸡胚大量繁殖做全病毒苗.
所以,当2009H1N1来的时候,只不过是换过毒株而已.但是,是否有效还得看用后评价了.
而禽流感(H5N1)则不同,这个是禽源的病毒,许多安全性需要考虑.
SARS就更难了.
其他搞SARS的战友来补充.

8princess8[使用道具]
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发表于 2016-4-9 15:40 资料个人空间短消息加为好友

小中大

我就知道有疫苗是“人痘”和“牛痘”
国家还得多多的研究下其他疫苗才对！

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发表于 2016-4-9 15:40 资料个人空间短消息加为好友

小中大

我是学呼吸的。应用于呼吸系统疾病的疫苗不多，我所知的有肺炎链球菌多糖疫苗、流感杆菌疫苗、流感疫苗、多价细菌疫苗（lantigen，兰菌净）等。它们都被写入了慢性阻塞性肺疾病全球防治创议（GOLD指南），经实验证实可以提高呼吸道粘膜的特异和非特异免疫，促进DC和淋巴细胞活化，促进上呼吸道定植病原的清除，增加粘膜sIgA含量，减少呼吸道感染和COPD急性加重。
疫苗研发这个论题给了我很大教育。对此的一些菜鸟问题和外行想法。
1 粘膜的细菌定植有些是有害的，如幽门螺杆菌（Hp），那是必须清除的。有些则是条件致病的，比如上呼吸道的流感嗜血杆菌H.influenzae定植，很多健康人都可以有，吸烟者更多（尼古丁可促进流感杆菌生长），稳定期COPD患者尤可占到30-40%。而COPD的发病率，在中国达到8.2%之多。那么，是对所有人都有必要应用流感杆菌疫苗，还是只针对吸烟者和COPD患者，或COPD患者？能否通过某种方法，如前面有战友提到用疫苗给机体正常细胞加“盔甲”的思路，通过改变抗原表位、粘附分子/受体结合位点、细胞形态等等，使细胞从向病原体“敞开大门”转变为“百毒不侵”，不受病原体侵害？
2 肺这种特定的器官，维持通气和换气功能始终是最重要的。得了肺癌切去一侧肺也不要紧，只要爬楼梯不喘即可。肺炎链球菌（S.pneumoniae）以菌毛侵袭致病，无内外毒素，通过7-14天的抗生素治疗后肺炎易吸收消散。而金葡菌则容易“烂肺”，肺上这里一个洞那里一个洞。很多病毒如麻疹、鼻病毒感冒的病程是自限的。能否通过某些疫苗，将金葡菌肺炎“转变”成自限性和容易吸收消散的类型，或者让这种致病菌变成不影响肺功能的定植菌？能否将导致慢性感染和潜伏（如单纯疱疹病毒）的病毒感染转变成麻疹那样容易好透的感染？
3 对不同目标人群，如对于免疫功能正常者/免疫功能低下者，对免疫功能低下是否需要按原发性（遗传性的）/继发性、体液为主（如丙球低下）和细胞为主（如AIDS），分别采用不同的疫苗免疫策略？
4 与感染不相关的疫苗研究，发展似乎总是不尽如人意。如支气管哮喘、食物过敏、变应性鼻炎等无菌性的过敏性炎症，至今治疗策略的第一条仍是“避免接触抗原刺激”。对于这种本质是粘膜慢性炎症的疾病，除广谱变应原疫苗之外，可否在Treg等细胞免疫学的基础上，开发出广谱的细胞疫苗？
5 接上，疫苗何时可以定制和个体化，是对90%的人有效转变成对每个个人都有效？
6 从来没想过，肺表面蛋白-A（SPA）还有这种作用：2008年JI的一篇文章讲SPA可与HIV结合，抑制HIV对CD4+T细胞的感染和促进DC对病毒的吞噬。粘膜免疫学（mucosal immunology）的进展对疫苗的研究到底有多大作用？
cuturl('http://www.jimmunol.org/cgi/content/abstract/181/1/601?maxtoshow=&HITS=&hits=&RESULTFORMAT=&fulltext=mucosal+anal+hiv+gp120&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&fdate=1/1/2006&resourcetype=HWCIT')
7 疫苗的给予方法，是全身给予还是局部给予更好？

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