Measles infection and vaccine response are complex biological processes that involve both viral and host genetic factors. We have previously investigated the influence of genetic polymorphisms on vaccine immune response, including measles vaccines, and have shown that polymorphisms in HLA, cytokine, cytokine receptor, and innate immune response genes are associated with variation in vaccine response but do not account for all of the inter-individual variance seen in vaccinated populations. In the current study we report the findings of a multigenic analysis of measles vaccine immunity, indicating a role for the measles virus receptor CD46, innate pattern-recognition receptors (DDX58, TLR2, 4, 5,7 and 8) and intracellular signaling intermediates (MAP3K7, NFKBIA), and key antiviral molecules (VISA, OAS2, MX1, PKR) as well as cytokines (IFNA1, IL4, IL6, IL8, IL12B) and cytokine receptor genes (IL2RB, IL6R, IL8RA) in the genetic control of both humoral and cellular immune responses. This multivariate approach provided additional insights into the genetic control of measles vaccine responses over and above the information gained by our previous univariate SNP association analyses.
measles vaccine; immunogenetics; vaccine response; multigenic SNP association; interferon response; cytokines; Toll-like receptors
Associations between HLA genotypes and measles vaccine humoral and cellular immune responses were examined to better understand immunogenetic drivers of vaccine response. Two independent study cohorts of healthy schoolchildren were examined: cohort one, 346 children between 12–18 years of age; and cohort two, 388 children between 11–19 years of age. All received two age-appropriate doses of measles-containing vaccine. The purpose of this study was to identify and replicate associations between HLA genes and immune responses following measles vaccination found in our first cohort. Associations of comparable magnitudes and with similar p-values were observed between B*3503 (1st cohort p=0.01; 2nd cohort p=0.07), DQA1*0201 (1st cohort p=0.03; 2nd cohort p=0.03), DQB1*0303 (1st cohort p=0.10; 2nd cohort p=0.02), DQB1*0602 (1st cohort p=0.07; 2nd cohort p=0.10), and DRB1*0701 (1st cohort p=0.03; 2nd cohort p=0.07) alleles and measles-specific antibody levels. Suggestive, yet consistent, associations were observed between the B7(1 st cohort p=0.01; 2nd cohort p=0.08) supertype and higher measles antibody levels in both cohorts. Also, in both cohorts, the B*0801 and DRB1*0301 alleles, C*0802 and DPA1*0202 alleles, and DRB1*1303 alleles displayed consistent associations with variations in IFN-γ, IL-2 and IL-10 secretion, respectively. This study emphasizes the importance of replicating HLA associations with measles vaccine-induced humoral and cellular immune responses and increases confidence in the results. These data will inform strategies for functional studies and novel vaccine development, including epitope-based measles vaccines. This is the first HLA association replication study with measles vaccine-specific immune responses to date.
Measles vaccine; HLA genotypes; Haplotypes; Antibodies; Cytokines; Replication study
Measles remains a public health concern due to a lack of vaccine use and vaccine failure. A better understanding of the factors that influence variations in immune responses, including innate/inflammatory and adaptive cellular immune responses, following measles-mumps-rubella (MMR) vaccination could increase our knowledge of measles vaccine-induced immunity and potentially lead to better vaccines. Measles-specific innate/inflammatory and adaptive cell-mediated immune (CMI) responses were characterized using enzyme-linked immunosorbent assays to quantify the levels of secreted IL-2, IL-6, IL-10, IFN-α, IFN-γ, IFN-λ1, and TNF-α in PBMC cultures following in vitro stimulation with measles virus (MV) in a cohort of 764 school-aged children. IFN-γ ELISPOT assays were performed to ascertain the number of measles-specific IFN-γ-secreting cells. Cytokine responses were then tested for associations with self-declared demographic data, including gender, race, and ethnicity. Females secreted significantly more TNF-α, IL-6, and IFN-α (p<0.001, p<0.002, p<0.04, respectively) compared to males. Caucasians secreted significantly more IFN-λ1, IL-10, IL-2, TNF-α, IL-6, and IFN-α (p<0.001, p<0.001, p<0.001, p<0.003, p<0.01, and p<0.02, respectively) compared to the other racial groups combined. Additionally, Caucasians had a greater number of IFN-γ-secreting cells compared to other racial groups (p<0.001). Ethnicity was not significantly correlated with variations in measles-specific CMI measures. Our data suggest that innate/inflammatory and CMI cytokine responses to measles vaccine vary significantly by gender and race. These data further advance our understanding regarding inter-individual and subgroup variations in immune responses to measles vaccination.
Vitamin A and D, and their receptors, are important regulators of the immune system, including vaccine immune response. We assessed the association between polymorphisms in the vitamin A (RARA, RARB and RARG) and vitamin D receptor (VDR)/RXRA genes and inter-individual variations in immune responses after two doses of measles vaccine in 745 subjects.
Using a tagSNP approach, we genotyped 745 healthy children for the 391 polymorphisms in vitamin A and D receptor genes.
The RARB haplotype (rs6800566/rs6550976/rs9834818) was significantly associated with variations in both measles antibody (global p=0.013) and cytokine secretion levels, such as IL-10 (global p=0.006), IFN-α (global p=0.008), and TNF-α (global p=0.039) in the Caucasian subgroup. Specifically, the RARB haplotype AAC was associated with higher (t-statistic 3.27, p=0.001) measles antibody levels. At the other end of the spectrum, haplotype GG for rs6550978/rs6777544 was associated with lower antibody levels (t-statistic −2.32, p=0.020) in the Caucasian subgroup. In a sensitivity analysis, the RARB haplotype CTGGGCAA remained marginally significant (p<0.02) when the single SNP rs12630816 was included in the model for IL-10 secretion levels. A significant association was found between lower measles-specific IFN-γ Elispot responses and haplotypes rs11102986/rs11103473/rs11103482/rs10776909/rs12004589/rs35780541/rs2266677/rs875444 (global p=0.004) and rs6537944/rs3118571 (global p<0.001) in the RXRA gene for Caucasians. We also found associations between multiple RARB, VDR and RXRA SNPs/haplotypes and measles-specific IL-2, IL-6, IL-10, IFN-α, IFN-γ, IFNλ-1, and TNF-α cytokine secretion.
Our results suggest that specific allelic variations and haplotypes in the vitamin A and D receptor genes may influence adaptive immune responses to measles vaccine.
Single Nucleotide Polymorphisms; Measles Vaccine Immunity; Vitamin A Receptor; Vitamin D Receptor; Genes; Immunogenetics
The U.S. FDA/CDC Vaccine Adverse Event Reporting System (VAERS) provides a valuable data source for post-vaccination adverse event analyses. The structured data in the system has been widely used, but the information in the write-up narratives is rarely included in these kinds of analyses. In fact, the unstructured nature of the narratives makes the data embedded in them difficult to be used for any further studies.
We developed an ontology-based approach to represent the data in the narratives in a “machine-understandable” way, so that it can be easily queried and further analyzed. Our focus is the time aspect in the data for time trending analysis. The Time Event Ontology (TEO), Ontology of Adverse Events (OAE), and Vaccine Ontology (VO) are leveraged for the semantic representation of this purpose. A VAERS case report is presented as a use case for the ontological representations. The advantages of using our ontology-based Semantic web representation and data analysis are emphasized.
We believe that representing both the structured data and the data from write-up narratives in an integrated, unified, and “machine-understandable” way can improve research for vaccine safety analyses, causality assessments, and retrospective studies.
The measles virus (MV) interacts with two known cellular receptors: CD46 and SLAM. The transmembrane receptor CD209 interacts with MV and augments dendritic cell infection.
764 subjects previously immunized with measles-mumps-rubella vaccine were genotyped for 66 candidate SNPs in the CD46, SLAM and CD209 genes as part of a larger study.
A previously detected association of the CD46 SNP rs2724384 with measles-specific antibodies was successfully replicated in this study. Increased representation of the minor allele G for an intronic CD46 SNP was associated with an allele dose-related decrease (978 vs. 522 mIU/ml, p = 0.0007) in antibody levels. This polymorphism rs2724384 also demonstrated associations with IL-6 (p = 0.02), IFN-α (p = 0.007) and TNF-α (p = 0.0007) responses. Two polymorphisms (coding rs164288 and intronic rs11265452) in the SLAM gene that were associated with measles antibody levels in our previous study were associated with IFN-γ Elispot (p = 0.04) and IL-10 responses (p = 0.0008), respectively, in this study. We found associations between haplotypes, AACGGAATGGAAAG (p = 0.009) and GGCCGAGAGGAGAG (p < 0.001), in the CD46 gene and TNF-α secretion.
Understanding the functional and mechanistic consequences of these genetic polymorphisms on immune response variations could assist in directing new measles and potentially other viral vaccine design, and in better understanding measles immunogenetics.
Measles virus receptors; Single nucleotide polymorphisms; Measles vaccine immunity; SNP; CD46; SLAM; CD209; Replication study
Previously we found Human Leukocyte Antigen (HLA) associations with humoral immunity following a single dose of measles-containing vaccine. In this study, we sought to determine if HLA associations exist with humoral and cellular immunity following a second dose of measles-containing vaccine and if the associations we found with humoral immunity after the first dose persist following a second dose.
We recruited a population-based sample of 346 schoolchildren, all who previously received two doses of a measles-containing vaccine. Molecular HLA class I and II typing as well as humoral and cellular immune assays (measles-specific IgG antibody levels and lymphoproliferative response) were performed in these subjects.
We found significant associations with class I HLA-B (p=0.05) as well as class II HLA-DPB1 (p=0.01) and -DPA1 (p=0.03) genes for measles vaccine-induced antibody levels after the second dose. Similarly, we found significant associations with class II HLA-DQB1 (p=0.05) and -DRB1 (p=0.01) genes for measles-specific lymphoproliferation after the second dose.
While we found HLA associations after the second dose that we previously found after the first dose of measles containing vaccine, fewer alleles had statistically significant associations, suggesting that the second dose had a dampening or extinguishing effect on the HLA associations. It appears that the second dose overcomes HLA restriction through an as yet unknown mechanism. Future studies of HLA associations should consider both the effect of dose and the role that subsequent doses might play on genetic associations found with the response to a first dose.
Antibody Formation; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Immunogenetics; Lymphocyte Activation; Measles Antibody; Measles Vaccine; Measles-Mumps-Rubella Vaccine
Identification of host genetic determinants of measles vaccine-induced immunity can be used to design better vaccines and ultimately predict immune responses to vaccination. We performed a comprehensive candidate gene association study across 801 genetic markers in 56 cytokine/cytokine receptor genes, in a racially diverse cohort of 745 schoolchildren after two doses of MMR vaccine. Using linear regression methodologies we examined associations between SNPs/haplotypes and measles virus-specific immunity.
Forty-eight significant SNP associations with variations in neutralizing antibodies and measles-specific IFNγ Elispot responses were identified (p<0.05). Our study replicated an important previously found association of a functional IL12B genetic variant rs3212227 with variations in measles-specific humoral immunity (p=0.037). Similarly, two previously reported promoter IL10 and IL2 polymorphisms (rs1800890 and rs2069762) demonstrated associations with measles-specific cellular immunity in Caucasians (p≤0.034). Multiple IL7R polymorphisms, including a non-synonymous functional SNP (rs6897932/Thr244Ile), were associated with humoral (p≤0.024) and/or cellular (IFNγ Elispot, p≤0.023) measles-specific immune responses in Caucasians, but not African-Americans. Haplotype level analysis confirmed the association of IL7R genetic variants with measles vaccine-induced immunity in the Caucasian group (global p-value=0.003). Our results validate previous findings and identify new plausible genetic determinants, including IL7R polymorphisms, regulating measles vaccine-induced immunity in a race-specific manner.
Measles vaccine; Immunity; Single Nucleotide Polymorphisms; Haplotypes; Cytokine; Cytokine receptor
Widespread vaccination with vaccinia virus (VACV) resulted in the eradication of smallpox; however, the licensed VACV-containing vaccines are associated with adverse events (AEs), making them unsuitable for certain high-risk populations. A better understanding of the host immune response following smallpox vaccination could result in vaccines with similar immunogenicity profiles to pre-eradication vaccines with a lower incidence of AEs. To study the immune response to VACV, we recruited 1,076 armed forces members who had been vaccinated with one dose of Dryvax®. We measured multiple VACV-specific immune responses: neutralizing antibody titer, the level of 12 secreted cytokines in peripheral blood mononuclear cell (PBMC) cultures (IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, TNF-α, IFN-γ, IFN-α, IFN-β, and IL-18), and the number of IFN-γ- and CD8+ IFN-γ-secreting cells. We analyzed these data to determine correlations between immune response measures. We detected a strong proinflammatory response in concert with a Th-1-like cytokine response pattern at a median time point of 15.3 mo following primary vaccination. We also detected correlations between neutralizing antibody titer and secreted IL-2, as well as secreted IFN-γ (p=0.009 and p=0.0007, respectively). We also detected strong correlations between the proinflammatory cytokines IL-1β, TNF-α, IL-6, and IL-12p40 (p<0.0001). These results further advance our knowledge of vaccinia-specific cellular immune responses. Notably, vaccine-induced proinflammatory responses were not correlated with neutralizing antibody titers, suggesting that further attenuation to reduce inflammatory immune responses may result in decreased AEs without sacrificing VACV immunogenicity and population seropositivity.
Despite the tremendous success of the classical “isolate, inactivate, and inject” approach to vaccine development, new breakthroughs in vaccine research are increasingly reliant on novel approaches that incorporate cutting edge technology and advances in innate and adaptive immunology, microbiology, virology, pathogen biology, genetics, bioinformatics, and many other disciplines in order to: (1) deepen our understanding of the key biological processes that lead to protective immunity, (2) observe vaccine responses on a global, systems level, and (3) directly apply the new knowledge gained to the development of next-generation vaccines with improved safety profiles, enhanced efficacy, and even targeted utility in select populations. Here we highlight five key components foundational to vaccinomics efforts: applied immunogenomics, next generation sequencing and other cutting-edge “omics” technologies, advanced bioinformatics and analysis techniques, and finally, systems biology applied to immune profiling and vaccine responses. We believe these “game changers” will play a critical role in moving us toward the rational and directed development of new vaccines in the 21st century.
In this article we define vaccinomics as the integration of immunogenetics and immunogenomics with systems biology and immune profiling. Vaccinomics is based on the use of cutting edge, high-dimensional (so called “omics”) assays and novel bioinformatics approaches to the development of next-generation vaccines and the expansion of our capabilities in individualized medicine. Vaccinomics will allow us to move beyond the empiric “isolate, inactivate, and inject” approach characterizing past vaccine development efforts, and toward a more detailed molecular and systemic understanding of the carefully choreographed series of biological processes involved in developing viral vaccine-induced “immunity.” This enhanced understanding will then be applied to overcome the obstacles to the creation of effective vaccines to protect against pathogens, particularly hypervariable viruses, with the greatest current impact on public health. Here we provide an overview of how vaccinomics will inform vaccine science, the development of new vaccines and/or clinically relevant biomarkers or surrogates of protection, vaccine response heterogeneity, and our understanding of immunosenescence.
Background. Identifying genetic factors that influence poxvirus immunity across races may assist in the development of better vaccines and approaches for vaccine development.
Methods. We performed an extensive candidate-gene genetic screen (across 32 cytokine and cytokine receptor genes) in a racially diverse cohort of 1056 healthy adults after a single dose of smallpox vaccine. Associations between single-nucleotide polymorphisms (SNPs)/haplotypes and vaccinia virus–specific neutralizing antibodies were assessed using linear regression methodologies.
Results. The combined analysis identified 63 associations between candidate SNPs and antibody levels after smallpox vaccination with P < .05. Thirty-one of these were within the IL18R1 and IL18 genes. Five IL18R1 SNPs, including a coding synonymous polymorphism rs1035130 (Phe251Phe) and 2 promoter SNPs (rs6710885, rs2287037), all in linkage disequilibrium, were associated with significant variations in antibody levels in both Caucasians (P ≤ .016) and African Americans (P ≤ .025). Similarly, associations with 2 intronic IL18 SNPs (rs2043055 and rs5744280) were consistent in the Caucasian (P ≤ .023) and African American samples (P ≤ .014). Haplotype analysis revealed highly significant associations between IL18R1 haplotypes and vaccinia virus–specific antibody levels (P < .001, by combined analysis) that were consistent across races.
Conclusions. Our study provides evidence for IL18 and IL18R1 genes as plausible genes regulating the humoral immune response to smallpox vaccine in both Caucasians and African Americans.
mRNA expression data from next generation sequencing platforms is obtained in the form of counts per gene or exon. Counts have classically been assumed to follow a Poisson distribution in which the variance is equal to the mean. The Negative Binomial distribution which allows for over-dispersion, i.e., for the variance to be greater than the mean, is commonly used to model count data as well.
In mRNA-Seq data from 25 subjects, we found technical variation to generally follow a Poisson distribution as has been reported previously and biological variability was over-dispersed relative to the Poisson model. The mean-variance relationship across all genes was quadratic, in keeping with a Negative Binomial (NB) distribution. Over-dispersed Poisson and NB distributional assumptions demonstrated marked improvements in goodness-of-fit (GOF) over the standard Poisson model assumptions, but with evidence of over-fitting in some genes. Modeling of experimental effects improved GOF for high variance genes but increased the over-fitting problem.
These conclusions will guide development of analytical strategies for accurate modeling of variance structure in these data and sample size determination which in turn will aid in the identification of true biological signals that inform our understanding of biological systems.
The measurement of measles-specific neutralizing antibodies, directed against the surface measles virus hemagglutinin and fusion proteins, is considered the gold standard in measles serology. We assessed functional measles-specific neutralizing antibody levels in a racially diverse cohort of 763 young healthy adolescents after receipt of two doses of measles-mumps-rubella vaccine, by the use of an automated plaque reduction microneutralization (PRMN) assay, and evaluated their relevance to protective antibody levels, as well as their associations with demographic and clinical variables. We also concurrently assessed measles-specific IFNγ Elispot responses and their relation to the observed antibody concentrations.
The geometric mean titer for our cohort was 832 mIU/mL (95% CIs: 776; 891). Sixty-eight subjects (8.9%) had antibody concentrations of less than the protective threshold of 210 mIU/mL (corresponding to PRMN titer of 120; suggesting protection against symptomatic disease), and 177 subjects (23.2%) demonstrated persisting antibody concentrations above 1,841 mIU/mL (corresponding to PRMN titer of 1,052; suggesting total protection against viral infection), 7.4 years after vaccination, in the absence of wild-type virus boosting. The mean measles-specific IFNγ Elispot response for our cohort was 46 (95% CIs: 43; 49) IFNγ-positive spots per 200,000 cells with no relation of cellular immunity measures to the observed antibody concentrations. No significant associations between antibody titers and demographic and clinical variables, including gender and race, were observed in our study.
In conclusion, in a large observational study of measles immunity, we used an automated high-throughput measles virus-specific neutralization assay to measure humoral immunity, and concurrently determined measles-specific cellular immunity to aid the assessment of potential susceptibility to measles in vaccinated populations.
measles; vaccine; neutralizing antibodies; cellular immunity; plaque reduction microneutralization
Recent years have witnessed a growing interest in a field of vaccinology that we have named vaccinomics. The overall idea behind vaccinomics is to identify genetic and other mechanisms and pathways that determine immune responses, and thereby provide new candidate vaccine approaches. Considerable data show that host genetic polymorphisms act as important determinants of innate and adaptive immunity to vaccines. This review highlights examples of the role of immunogenetics and immunogenomics in understanding immune responses to vaccination, which are highly variable across the population. The influence of HLA genes, non-HLA, and innate genes in inter-individual variations in immune responses to viral vaccines are examined using population-based gene/SNP association studies. The ability to understand relationships between immune response gene variants and vaccine-specific immunity may assist in designing new vaccines. At the same time, application of state-of-the-art next-generation sequencing technology (and bioinformatics) is desired to provide new genetic information and its relationship to the immune response.
genetic association; HLA; immunogenetics; polymorphisms; SNPs; vaccines; vaccinomics
Background. The role of human leukocyte antigen (HLA) genes in mediating adaptive immune responses to smallpox vaccine remains unknown.
Methods. We determined genotypes for a group of individuals (n = 1071) who received a single dose of smallpox vaccine (Dryvax, Wyeth Laboratories) and examined associations between HLA alleles and 15 immune outcomes to smallpox vaccine on a per-locus and a per-allele level.
Results. We found significant associations between the HLA-B and HLA - DQB1 loci and vaccinia-induced antibodies (P = .04 for each locus), with the HLA-B*1302 (P = .036), B*3802 (P = .011), DQB1*0302 (P = .015), and DQB1*0604 (P = .017) alleles being associated with higher levels. Significant global associations were identified between vaccinia-specific interferon (IFN)–γ and DQA1 (P = .003), interleukin (IL)–1β and HLA-B (P = .004), tumor necrosis factor (TNF)–α and HLA-B (P = .006), and IL-6 and HLA-B locus (P = .016) for secreted cytokines, as well as between CD8α+ IFN-γ Elispot responses and DQB1 (P = .027). Subjects carrying B*3906 (P = .006) and B*5701 (P < .001) secreted higher levels of IL-1β than did subjects who did not carry these alleles. Subjects carrying the B*5301 (P = .047) and B*5601 (P = .008) alleles secreted less IL-1β, compared with subjects who did not carry these alleles. The B*3502 (P = .009), B*5601 (P = .004), and B*5701 (P < .001) alleles were significantly associated with variations in TNF-α secretion.
Conclusions. These data suggest that variations in antibody and cellular IFN-γ, IL-1β, TNF-α, and IL-6 immune responses after receipt of smallpox vaccine are genetically controlled by HLA genes or genes in close linkage disequilibrium to these alleles.
The current “isolate, inactivate, inject” vaccine development strategy has served the field of vaccinology well, and such empirical vaccine candidate development has even led to the eradication of smallpox. However, such an approach suffers from limitations, and as an empirical approach, does not fully utilize our knowledge of immunology and genetics. A more complete understanding of the biological processes culminating in disease resistance is needed. The advent of high-dimensional assay technology and “systems biology” along with a vaccinomics approach [1;2] is spawning a new era in the science of vaccine development. Here we review recent developments in systems biology and strategies for applying this approach and its resulting data to expand our knowledge base and drive directed development of new vaccines. We also provide applied examples and point out new directions for the field in order to illustrate the power of systems biology.
system biology; bioinformatics; immune response; vaccines
We sought to determine the time and vaccinia virus dose combination that would maximize the number of acute immune response changes in response to vaccinia stimulation in preparation for a large gene expression microarray experiment.
PBMCs from ten subjects were exposed to five vaccinia virus doses for three lengths of time. Gene expression was measured for 90 immune response genes via Taqman® Low Density Immune Arrays. Expression data were normalized via model-based non-linear normalization. Linear mixed effects model results were used to standardize changes across genes and determine the time/multiplicity of infection (MOI) combination with the largest number of changes.
The greatest number of changes occurred with a MOI of 5.0 and exposure time of 48 hours. Further inspection revealed that most changes had occurred earlier and faded at this combination. The second highest number of changes was found at a MOI of 0.5 PFU/cell and time of 18 hours.
We conclude a time of 18 hours with a MOI of 0.5 PFU/cell is the optimal time/MOI combination for the full scale gene expression study. The strategy described herein is a general and resource efficient way to make critical decisions regarding experimental parameters for studies utilizing expensive assays that interrogate a large number of variables.
Smallpox; Microarray; TLDA; vaccinia virus
Background. The current US national stockpile of influenza H5 vaccine was produced using the antigen from the strain A/Vietnam/1203/2004 (a clade 1 H5 virus). Recent H5 disease has been caused by antigenically divergent H5 viruses, including A/Indonesia/05/2005 (a clade 2 H5 virus).
Methods. The influence of schedule on the antibody response to 2 doses of H5 vaccines (one a clade 1 hemagglutinin protein [HA] vaccine and one a clade 2 HA vaccine) containing 90 μg of antigen was evaluated in healthy adults 18–49 years of age.
Results. Two doses of vaccine were required to induce antibody titers ≥1:10 in most subjects. Accelerated schedules were immunogenic, and antibody developed after vaccinations on days 0 and 7, 0 and 14, and 0 and 28, with the day 0 and 7 schedule inducing lower titers than those induced with the other schedules. With mixed vaccine schedules of clade 1 followed by clade 2 vaccine administration, the first vaccination primed for a heterologous boost. The heterologous response was improved when the second vaccination was given 6 months after the first, compared with the response when the second vaccination was given after an interval of 1 month.
Conclusions. An accelerated vaccine schedule of injections administered at days 0 and 14 was as immunogenic as a vaccine schedule of injections at days 0 and 28, but both schedules were inferior to a vaccine schedule of injections administered at 0 and 6 months for priming for heterologous vaccine boosting.
Clinical Trial Registry Number: NCT00703053
Host genetic variation, particularly within the human leukocyte antigen (HLA) loci, reportedly mediates heterogeneity in immune response to certain vaccines; however, no large study of genetic determinants of anthrax vaccine response has been described. We searched for associations between the IgG antibody to protective antigen (AbPA) response to Anthrax Vaccine Adsorbed (AVA) in humans and polymorphisms at HLA class I (HLA-A, -B, and -C) and class II (HLA-DRB1, -DQA1, -DQB1, -DPB1) loci. The study included 794 European-Americans and 200 African-Americans participating in a 43-month, double-blind, placebo-controlled, clinical trial of AVA (clinicaltrials.gov identifier NCT00119067). Among European-Americans, genes from tightly linked HLA-DRB1-DQA1-DQB1 haplotypes displayed significant overall associations with longitudinal variation in AbPA levels at 4, 8, 26, and 30 weeks from baseline in response to vaccination with 3 or 4 doses of AVA (global p=6.53×10−4). In particular, carriage of the DRB1-DQA1-DQB1 haplotypes *1501-*0102-*0602 (p=1.17×10−5), *0101-*0101-*0501 (p=0.009), and *0102-*0101-*0501 (p=0.006) was associated with significantlylower AbPA levels. In carriers of two copies of these haplotypes, lower AbPA levels persisted following subsequent vaccinations. No significant associations were observed amongst African-Americans or for any HLA class I allele/haplotype. Further studies will be required to replicate these findings and to explore the role of host genetic variation outside of the HLA region.
Anthrax vaccines; Bacillus anthracis; Bacterial vaccines; Vaccination; HLA Antigens
As is apparent in many fields of science and medicine, the new biology, and particularly new high-throughput genetic sequencing and transcriptomic and epigenetic technologies, are radically altering our understanding and views of science. In this article, we make the case that while mostly ignored thus far in the vaccine field, these changes will revolutionize vaccinology from development to manufacture to administration. Such advances will address a current major barrier in vaccinology—that of empiric vaccine discovery and development, and the subsequent low yield of viable vaccine candidates, particularly for hyper-variable viruses. While our laboratory's data and thinking (and hence also for this paper) has been directed toward viruses and viral vaccines, generalization to other pathogens and disease entities (i.e., anti-cancer vaccines) may be appropriate.
Though recommended by many and mandated by some, influenza vaccination rates among health care workers, even in pandemics, remain below optimal levels. The objective of this study was to assess vaccination uptake, attitudes, and distinguishing characteristics (including doctor-nurse differences) of health care workers who did and did not receive the pandemic H1N1 influenza vaccine in late 2009.
In early 2010 we mailed a self-administered survey to 800 physicians and 800 nurses currently licensed and practicing in Minnesota. 1,073 individuals responded (cooperation rate: 69%). 85% and 62% of Minnesota physicians and nurses, respectively, reported being vaccinated. Accurately estimating the risk of vaccine side effects (OR 2.0; 95% CI 1.5–2.7), agreeing with a professional obligation to be vaccinated (OR 10.1; 95% CI 7.1–14.2), an ethical obligation to follow public health authorities' recommendations (OR 9.9; 95% CI 6.6–14.9), and laws mandating pandemic vaccination (OR 3.1; 95% CI 2.3–4.1) were all independently associated with receiving the H1N1 influenza vaccine.
While a majority of health care workers in one midwestern state reported receiving the pandemic H1N1 vaccine, physicians and nurses differed significantly in vaccination uptake. Several key attitudes and perceptions may influence health care workers' decisions regarding vaccination. These data inform how states might optimally enlist health care workers' support in achieving vaccination goals during a pandemic.
Three decades after the eradication of smallpox, the threat of bioterrorism and outbreaks of emerging diseases such as monkeypox have renewed interest in the development of safe and effective next-generation poxvirus vaccines and biodefense research. Current smallpox vaccines contain live virus and are contraindicated for a large percentage of the population. Safer, yet still effective inactivated and subunit vaccines are needed, and epitope identification is an essential step in the development of these subunit vaccines. In this study we focused on 4 vaccinia membrane proteins known to be targeted by humoral responses in vaccinees. In spite of the narrow focus of the study we identified 36 T cell epitopes, and provide additional support for the physical linkage between T and B epitopes. This information may prove useful in peptide and protein-based subunit vaccine development as well as in the study of CD4 responses to poxviruses.
Vaccinia virus; smallpox vaccine; cellular immunity; T cell epitopes; CD4+ T cells
Linkage Disequilibrium (LD) bin-tagging algorithms identify a reduced set of tag SNPs that can capture the genetic variation in a population without genotyping every single SNP. However, existing tag SNP selection algorithms for designing custom genotyping panels do not take into account all platform dependent factors affecting the likelihood of a tag SNP to be successfully genotyped and many of the constraints that can be imposed by the user.
SNPPicker optimizes the selection of tag SNPs from common bin-tagging programs to design custom genotyping panels. The application uses a multi-step search strategy in combination with a statistical model to maximize the genotyping success of the selected tag SNPs. User preference toward functional SNPs can also be taken into account as secondary criteria. SNPPicker can also optimize tag SNP selection for a panel tagging multiple populations. SNPPicker can optimize custom genotyping panels including all the assay-specific constraints of Illumina's GoldenGate and Infinium assays.
A new application has been developed to maximize the success of custom multi-population genotyping panels. SNPPicker also takes into account user constraints including options for controlling runtime. Perl Scripts, Java source code and executables are available under an open source license for download at http://mayoresearch.mayo.edu/mayo/research/biostat/software.cfm