Inna G. Ovsyannikova

Heterogeneity in Vaccine Immune Response: The Role of Immunogenetics and the Emerging Field of Vaccinomics

Recent advances in the fields of immunology, genetics, molecular biology, bioinformatics, and the Human Genome Project have allowed for the emergence of the field of vaccinomics. Vaccinomics encompasses the fields of immunogenetics and immunogenomics as applied to understanding the mechanisms of heterogeneity in immune responses to vaccines. In this study, we examine the role of HLA genes, cytokine genes, and cell surface receptor genes as examples of how genetic polymorphism leads to individual and population variations in immune responses to vaccines. In turn, this data, in concert with new high‐throughput technology, inform the immune‐response network theory to vaccine response. Such information can be used in the directed and rational development of new vaccines, and this new golden age of vaccinology has been termed “predictive vaccinology”, which will predict the likelihood of a vaccine response or an adverse response to a vaccine, the number of doses needed and even whether a vaccine is likely to be of benefit (i.e., is the individual at risk for the outcome for which the vaccine is being administered?).

Influenza Virus Resistance to Antiviral Agents: A Plea for Rational Use

Although influenza vaccine can prevent influenza virus infection, the only therapeutic options to treat influenza virus infection are antiviral agents. At the current time, nearly all influenza A/H3N2 viruses and a percentage of influenza A/H1N1 viruses are adamantane resistant, which leaves only neuraminidase inhibitors available for treatment of infection with these viruses. In December 2008, the Centers for Disease Control and Prevention released new data demonstrating that a high percentage of circulating influenza A/H1N1 viruses are now resistant to oseltamivir. In addition, oseltamivir-resistant influenza B and A/H5N1 viruses have been identified. Thus, use of monotherapy for influenza virus infection is irrational and may contribute to mutational pressure for further selection of antiviral-resistant strains. History has demonstrated that monotherapy for influenza virus infection leads to resistance, resulting in the use of a new monotherapy agent followed by resistance to that new agent and thus resulting in a background of viruses resistant to both drugs. We argue that combination antiviral therapy, new guidelines for indications for treatment, point-of-care diagnostic testing, and a universal influenza vaccination recommendation are critical to protecting the population against influenza virus and to preserving the benefits of antiviral agents.

Personalized vaccines: the emerging field of vaccinomics.

The next ‘golden age’ in vaccinology will be ushered in by the new science of vaccinomics. In turn, this will inform and allow the development of personalized vaccines, based on our increasing understanding of immune response phenotype: genotype information. Rapid advances in developing such data are already occurring for hepatitis B, influenza, measles, mumps, rubella, anthrax and smallpox vaccines. In addition, newly available data suggest that some vaccine-related adverse events may also be genetically determined and, therefore, predictable. This paper reviews the basis and logic of personalized vaccines, and describes recent advances in the field.

Identification of an association between HLA class II alleles and low antibody levels after measles immunization

This is the first large cohort study to report a genetic association between humoral antibody level after measles vaccine and the HLA class II genes. The WHO goal to eradicate measles world-wide magnifies the importance of data relating to the influence of immunogenetics on measles vaccine-induced antibody responses. We present here the analysis of 242 individuals who received one dose of measles-mumps-rubella-II (MMR-II) vaccine at the age of 15 months and were genotyped for HLA class II alleles. These subjects fit into one of three categories; 72 were classified as seronegative, 93 were seropositive and 77 were serohyperpositive. HLA-DRB1*03 (odds ratio (OR), 2.22) and HLA-DPA1*0201 (OR, 1.71) were significantly associated with measles vaccine seronegativity, while additional alleles provided suggestive evidence of association with seronegativity: DQA1*0201, DQB1*0201, and DQA1*0501. The alleles DRB1*03 and DQA1*0201 remained statistically significant after accounting for the effects of other alleles. These findings are crucial in designing both measles eradication by the use of vaccine, and future vaccines to be used in genetically heterozygous populations.

Monoclonal antibodies to group II Dermatophagoides spp. allergens: Murine immune response, epitope analysis, and development of a two-site ELISA

BACKGROUND Group II allergens are a major cause of sensitization in patients allergic to mites. To facilitate the antigenic analysis of group II allergens and to develop improved methods of allergen detection, we compared IgG anti-group II antibody responses in inbred mouse strains and raised a panel of monoclonal antibodies (mAbs). METHODS IgE antibody responses were compared by antigen-binding radioimmunoassay. Epitope specificity of the mAbs was analyzed by two-site binding assays and by cross-inhibition radioimmunoassays. RESULTS Comparison of polyclonal IgG antibody responses in five BALB congenic strains showed that H-2d mice had poor responses, whereas H-2b and H-2k mice had strong, cross-reactive, IgG anti-group II responses. The specificities of nine anti-Der p II IgE mAbs raised in A/J mice were compared with specificities of seven mAbs produced previously. Most mAbs (11 of 16) recognized common epitopes on Der p II and Der f II: three were specific to Der p II, and two showed high binding to Der f II. Epitope analysis showed that the mAbs defined four cross-reactive, nonoverlapping sites on the group II allergens. Binding of several combinations of mAbs was compared, and a two-site ELISA for group II antigens was developed. Linear regression analysis showed an excellent correlation between results of this assay and group II radioimmunoassay of house dust samples (n = 40, r = 0.85, p < 0.001). CONCLUSIONS There are multiple cross-reactive B-cell epitopes on group II allergens. The group II ELISA has several important applications, including assessment of environmental allergen exposure, monitoring of the efficacy of avoidance procedures, and standardization of commercial mite allergen extracts.

Frequency of measles virus-specific CD4+ and CD8+ T cells in subjects seronegative or highly seropositive for measles vaccine.

ABSTRACT The protective effect of measles immunization is due to humoral and cell-mediated immune responses. Little is known about cell-mediated immunity (CMI) to measles vaccine virus, the relative contribution of CD4+ and CD8+ T cells to variability in such immune responses, and the immunologic longevity of the CMI after measles vaccination in humans. Our study characterizes cellular immune response in subjects seronegative or highly seropositive for measles vaccine immunoglobulin G-specific antibody, aged 15 to 25 years, previously immunized with two doses of measles-mumps-rubella II vaccine. We evaluated the ability of subjects to respond to measles vaccine virus by measuring measles virus-specific T-cell proliferation. We examined the frequencies of measles virus-specific memory Th1 and Th2 cells by an ELISPOT assay. Our results demonstrated that proliferation of T cells in seronegative subjects was significantly lower than that for highly seropositive subjects (P = 0.003). Gamma interferon (IFN-γ) secretion predominated over interleukin 4 (IL-4) secretion in response to measles virus in both groups. The median frequency of measles virus-reactive CD8+ T cells secreting IFN-γ was 0.09% in seronegative subjects and 0.43% in highly seropositive subjects (P = 0.04). The median frequency of CD4+ T cells secreting IL-4 in response to measles virus was 0.03% in seronegative subjects and 0.09% in highly seropositive subjects (P = 0.005). These data confirm the presence of measles virus-specific cellular immune responses post-measles vaccine immunization in humans. The detection of measles virus-induced IFN-γ and IL-4 production by ELISPOT can be used to identify measles virus-specific low-frequency memory T cells in subjects immunized with measles vaccine. These differences agree in directionality with the observed antibody response phenotype.

Vaccinomics and Personalized Vaccinology: Is Science Leading Us Toward a New Path of Directed Vaccine Development and Discovery?

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 laboratorys 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.

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

To elucidate the contribution of human leukocyte antigen (HLA) haplotypes and their genotypic combinations to immune status after measles-mumps-rubella (MMR) vaccination, 346 children 12-18 years of age were studied. The class I A*29-Cw*16-B*44 haplotype was associated with lower levels of immunoglobulin G (IgG) antibody to both measles (P=.08) and mumps (P=.03) viral antigens. The A*26-Cw*12-B*38 haplotype was associated with higher cellular immune responses to measles (P=.02) and mumps (P=.01) vaccine viruses. Subjects with the class II DRB1*03-DQB1*02-DPB1*04 haplotype had higher lymphoproliferative responses to measles virus (P=.01) and mumps virus (P=.006). The DRB1*15/16-DQB1*06-DPB1*03 haplotype was associated with high levels of IgG antibody to measles virus (P=.09) but low levels of IgG antibody to rubella virus (P=.02), whereas DRB1*04-DQB1*03-DPB1*03 was associated with high lymphoproliferative responses to both measles (P=.01) and rubella (P=.002) vaccine viruses. A*26-Cw*12-B*38 was associated with both mumps virus-specific humoral (P=.007) and cell-mediated (P=.01) immune responses after 2 doses of MMR vaccine. Haplotype DRB1*04-DQB1*03-DPB1*03 was associated with both lower rubella virus IgG antibody levels (P=.02) and higher rubella virus-specific lymphoproliferation (P=.002). Better characterization of such HLA profiles could inform and improve the design of novel epitope-rich vaccines and help to predict protective immune responses at the individual and population level.

Associations between Measles Vaccine Immunity and Single-Nucleotide Polymorphisms in Cytokine and Cytokine Receptor Genes

BACKGROUND Cytokines are key regulators of measles vaccine humoral and cellular immunity. Single-nucleotide polymorphisms (SNPs) that are associated with differences in cytokine levels should also influence measles vaccine-induced immunity. METHODS We genotyped 118 measles-mumps-rubella-vaccinated subjects for SNPs from 6 cytokine genes (interleukin [IL]-2, IL-4, IL-10, IL-12A, IL-12B, and interferon [IFN]-gamma) and their receptors (IL-2RA, IL-2RB, IL-4RA, IL-10RA, IL-10RB, IL-12RB1, IL-12RB2, and IFN-gamma R). Associations of SNPs with measles-specific antibodies, lymphoproliferation, and secreted cytokines were determined using chi2 tests and analyses of covariance. RESULTS We found significant associations (P<.05) between SNPs in the IL-2, IL-10, and IL-12RB genes and measles vaccine-induced immunity. The IVS1-100G (rs2069762) and the Ex2-34G (rs2069763) SNPs within the IL-2 gene were associated with high antibody and high lymphoproliferative responses, whereas SNPs within the IL-10 and IL-12R genes were associated with low antibody and lymphoproliferative responses to measles. SNPs within the IL-4RA and IL-12B genes varied significantly (P<.05) across immune response measures. Significant associations were also found between SNPs and secreted cytokine levels. CONCLUSIONS Specific SNPs in the cytokine and cytokine receptor genes are significantly associated with variations in measures of the immune response to measles vaccination. These results need to be further validated in a larger cohort.

Understanding the immune response to seasonal influenza vaccination in older adults: a systems biology approach

Annual vaccination against seasonal influenza is recommended to decrease disease-related mortality and morbidity. However, one population that responds suboptimally to influenza vaccine is adults over the age of 65 years. The natural aging process is associated with a complex deterioration of multiple components of the host immune system. Research into this phenomenon, known as immunosenescence, has shown that aging alters both the innate and adaptive branches of the immune system. The intricate mechanisms involved in immune response to influenza vaccine, and how these responses are altered with age, have led us to adopt a more encompassing systems biology approach to understand exactly why the response to vaccination diminishes with age. Here, the authors review what changes occur with immunosenescence, and some immunogenetic factors that influence response, and outline the systems biology approach to understand the immune response to seasonal influenza vaccination in older adults.