Vaccinomics, adversomics, and the immune response network theory: individualized vaccinology in the 21st century.

Vaccines, like drugs and medical procedures, are increasingly amenable to individualization or personalization, often based on novel data resulting from high throughput "omics" technologies. As a result of these technologies, 21st century vaccinology will increasingly see the abandonment of a "one size fits all" approach to vaccine dosing and delivery, as well as the abandonment of the empiric "isolate-inactivate-inject" paradigm for vaccine development. In this review, we discuss the immune response network theory and its application to the new field of vaccinomics and adversomics, and illustrate how vaccinomics can lead to new vaccine candidates, new understandings of how vaccines stimulate immune responses, new biomarkers for vaccine response, and facilitate the understanding of what genetic and other factors might be responsible for rare side effects due to vaccines. Perhaps most exciting will be the ability, at a systems biology level, to integrate increasingly complex high throughput data into descriptive and predictive equations for immune responses to vaccines. Herein, we discuss the above with a view toward the future of vaccinology.

Rubella.

Rubella remains an important pathogen worldwide, with roughly 100,000 cases of congenital rubella syndrome estimated to occur every year. Rubella-containing vaccine is highly effective and safe and, as a result, endemic rubella transmission has been interrupted in the Americas since 2009. Incomplete rubella vaccination programmes result in continued disease transmission, as evidenced by recent large outbreaks in Japan and elsewhere. In this Seminar, we provide present results regarding rubella control, elimination, and eradication policies, and a brief review of new laboratory diagnostics. Additionally, we provide novel information about rubella-containing vaccine immunogenetics and review the emerging evidence of interindividual variability in humoral and cell-mediated innate and adaptive immune responses to rubella-containing vaccine and their association with haplotypes and single-nucleotide polymorphisms across the human genome.

Polymorphisms in HLA-DPB1 are associated with differences in rubella virus-specific humoral immunity after vaccination.

Vaccination with live attenuated rubella virus induces a strong immune response in most individuals. However, small numbers of subjects never reach or maintain protective antibody levels, and there is a high degree of variability in immune response. We have previously described genetic polymorphisms in HLA and other candidate genes that are associated with interindividual differences in humoral immunity to rubella virus. To expand our previous work, we performed a genome-wide association study (GWAS) to discover single-nucleotide polymorphisms (SNPs) associated with rubella virus-specific neutralizing antibodies. We identified rs2064479 in the HLA-DPB1 genetic region as being significantly associated with humoral immune response variations after rubella vaccination (P = 8.62 × 10(-8)). All other significant SNPs in this GWAS were located near the HLA-DPB1 gene (P ≤ 1 × 10(-7)). These findings demonstrate that polymorphisms in HLA-DPB1 are strongly associated with interindividual differences in neutralizing antibody levels to rubella vaccination and represent a validation of our previous HLA work.

Genetic polymorphisms associated with rubella virus-specific cellular immunity following MMR vaccination.

Rubella virus causes a relatively benign disease in most cases, although infection during pregnancy can result in serious birth defects. An effective vaccine has been available since the early 1970s and outbreaks typically do not occur among highly vaccinated (≥2 doses) populations. Nevertheless, considerable inter-individual variation in immune response to rubella immunization does exist, with single-dose seroconversion rates ~95 %. Understanding the mechanisms behind this variability may provide important insights into rubella immunity. In the current study, we examined associations between single nucleotide polymorphisms (SNPs) in selected cytokine, cytokine receptor, and innate/antiviral genes and immune responses following rubella vaccination in order to understand genetic influences on vaccine response. Our approach consisted of a discovery cohort of 887 subjects aged 11-22 at the time of enrollment and a replication cohort of 542 older adolescents and young adults (age 18-40). Our data indicate that SNPs near the butyrophilin genes (BTN3A3/BTN2A1) and cytokine receptors (IL10RB/IFNAR1) are associated with variations in IFNγ secretion and that multiple SNPs in the PVR gene, as well as SNPs located in the ADAR gene, exhibit significant associations with rubella virus-specific IL-6 secretion. This information may be useful, not only in furthering our understanding immune responses to rubella vaccine, but also in identifying key pathways for targeted adjuvant use to boost immunity in those with weak or absent immunity following vaccination.

Genome-wide SNP associations with rubella-specific cytokine responses in measles-mumps-rubella vaccine recipients.

Genetic polymorphisms are known to affect responses to both viral infection and vaccination. Our previous work has described genetic polymorphisms significantly associated with variations in immune response to rubella vaccine from multiple gene families with known immune function, including HLA, cytokine and cytokine receptor genes, and in genes controlling innate and adaptive immunity. In this study, we assessed cellular immune responses (IFNγ and IL-6) in a cohort of healthy younger individuals and performed genome-wide SNP analysis on these same individuals. Here, we report the first genome-wide association study focused on immune responses following rubella vaccination. Our results indicate that rs16928280 in protein tyrosine phosphatase delta (PTPRD) and a collection of SNPs in ACO1 (encoding an iron regulatory protein) are associated with interindividual variations in IFNγ response to rubella virus stimulation. In contrast, we did not identify any significant genetic associations with rubella-specific IL-6 response. These genetic regions may influence rubella vaccine-induced IFNγ responses and warrant further studies in additional cohorts in order to confirm these findings.

Curiosity protects against interpersonal aggression: cross-sectional, daily process, and behavioral evidence.

OBJECTIVE: Curiosity is the propensity to recognize and seek out new information and experience, including an intrinsic interest in learning and developing one's knowledge. With few exceptions, researchers have often ignored the social consequences of being curious. METHOD: In four studies using cross-sectional (N = 64), daily diary (Ns = 150 and 110, respectively), and behavioral experimental (N= 132) designs, we tested the hypothesis that individual differences in curiosity are linked to less aggression, even when people are provoked. RESULTS: We showed that both trait and daily curiosity were linked to less aggressive responses toward romantic relationship partners and people who caused psychological hurt. In time-lagged analyses, daily curiosity predicted less aggression from one day to the next, with no evidence for the reverse direction. Studies 3 and 4 showed that the inverse association between curiosity and aggression was strongest in close relationships and in fledgling (as opposed to long-lasting) romantic relationships. That is, highly curious people showed evidence of greater context sensitivity. Intensity of hurt feelings and other personality and relationship variables failed to account for these effects. CONCLUSIONS: Curiosity is a neglected mechanism of resilience in understanding aggression.

The voodoo doll task: Introducing and validating a novel method for studying aggressive inclinations.

Aggression pervades modern life. To understand the root causes of aggression, researchers have developed several methods to assess aggressive inclinations. The current article introduces a new behavioral method-the voodoo doll task (VDT)-that offers a reliable and valid trait and state measure of aggressive inclinations across settings and relationship contexts. Drawing on theory and research on the law of similarity and magical beliefs (Rozin, Millman, & Nemeroff [1986], Journal of Personality and Social Psychology, 50, 703-712), we propose that people transfer characteristics of a person onto a voodoo doll representing that person. As a result, causing harm to a voodoo doll by stabbing it with pins may have important psychological similarities to causing actual harm to the person the voodoo doll represents. Nine methodologically diverse studies (total N = 1,376) showed that the VDT had strong reliability, construct validity, and convergent validity. Discussion centers on the importance of magical beliefs in understanding the causes of aggressive inclinations.

Gratitude and depressive symptoms: the role of positive reframing and positive emotion.

Eight studies (N=2,973) tested the theory that gratitude is related to fewer depressive symptoms through positive reframing and positive emotion. Study 1 found a direct path between gratitude and depressive symptoms. Studies 2-5 demonstrated that positive reframing mediated the relationship between gratitude and depressive symptoms. Studies 6-7 showed that positive emotion mediated the relationship between gratitude and depressive symptoms. Study 8 found that positive reframing and positive emotion simultaneously mediated the relationship between gratitude and depressive symptoms. In sum, these eight studies demonstrate that gratitude is related to fewer depressive symptoms, with positive reframing and positive emotion serving as mechanisms that account for this relationship.

Resistance to Yersinia pestis infection decreases with age in B10.T(6R) mice.

We demonstrate that 2-month-old female B10.T(6R) mice are highly resistant to systemic infection with the KIM5 strain of Yersinia pestis and that B10.T(6R) mice become susceptible to Y. pestis infection by the age of 5 months. In this study, young (2-month-old) and middle-aged (5- to 12-month-old) B10.T(6R) mice were infected with equal CFU counts of Y. pestis. The 50% lethal dose (LD(50)) for young B10.T(6R) mice was ∼1.4 × 10(4) CFU, while middle-aged B10.T(6R) mice exhibited an LD(50) of ∼60 CFU. Elevated bacterial burdens were found in the spleens of middle-aged mice at 24 and 60 h and in the livers at 60 h postinfection. Immune cell infiltration was greater in the livers of resistant young mice than in those of middle-aged mice and mice of the susceptible C57BL/6N strain. Unlike susceptible mice, young B10.T(6R) mice did not develop necrotic lesions throughout the liver. Instead, livers from young B10.T(6R) mice contained granuloma-like structures. Immunohistochemical staining of liver sections from these mice at 60 h postinfection revealed that the majority of immune cells present in these structures were neutrophils. These findings suggest that resistance to plague in B10.T(6R) mice correlates with early formation of neutrophilic lesions in the liver.

Benefits of expressing gratitude: expressing gratitude to a partner changes one's view of the relationship.

This research was conducted to examine the hypothesis that expressing gratitude to a relationship partner enhances one's perception of the relationship's communal strength. In Study 1 (N = 137), a cross-sectional survey, expressing gratitude to a relationship partner was positively associated with the expresser's perception of the communal strength of the relationship. In Study 2 (N = 218), expressing gratitude predicted increases in the expresser's perceptions of the communal strength of the relationship across time. In Study 3 (N = 75), participants were randomly assigned to an experimental condition, in which they expressed gratitude to a friend, or to one of three control conditions, in which they thought grateful thoughts about a friend, thought about daily activities, or had positive interactions with a friend. At the end of the study, perceived communal strength was higher among participants in the expression-of-gratitude condition than among those in all three control conditions. We discuss the theoretical and applied implications of these findings and suggest directions for future research.

Motivating change in relationships: can prayer increase forgiveness?

The objective of the current studies was to test whether praying for a relationship partner would increase willingness to forgive that partner. In Study 1 (N = 52), participants assigned to pray for their romantic partner reported greater willingness to forgive that partner than those who described their partner to an imagined parent. In Study 2 (N = 67), participants were assigned to pray for a friend, pray about any topic, or think positive thoughts about a friend every day for 4 weeks. Those who prayed for their friend reported greater forgiveness for their friend than did those in the other two conditions, even when we controlled for baseline forgiveness scores. Participants who prayed for their friend also increased in selfless concern during the 4 weeks, and this variable mediated the relationship between experimental condition and increased forgiveness. Together, these studies provide an enhanced understanding of the relationship benefits of praying for a partner and begin to identify potential mediators of the effect.

Estimated susceptibility of Canadian meningococcal B isolates to a meningococcal serogroup B vaccine (MenB-FHbp).

BACKGROUND: Invasive meningococcal disease caused by Neisseria meningitidis serogroup B (MenB) remains a health risk in Canada and globally. Two MenB vaccines are now approved for use. An understanding of the genotype of Canadian strains and the potential strain coverage conferred by the MenB-FHbp vaccine is needed to inform immunization policies. METHODS: Serogroup B Neisseria meningitidis strains responsible for meningococcal disease in Canada from 2006 to 2012 were collected as part of the Canadian Immunization Monitoring Program Active surveillance network. Genotypic analysis was done on MenB isolates from 2006 to 2012 with determination of fHbp surface expression for a subset of isolates: those occurring from 2010 to 2012. RESULTS: Two clonal complexes (cc269 and cc41/44) were observed in 68.8% of the 276 isolates. A total of 50 different fHbp peptides were identified among isolates from 2006 to 2012. Surface expression of fHbp was detected on 95% of MenB isolates from 2010 to 2012 and 91% of isolates expressed fHbp at levels that are predicted to be susceptible to the bactericidal immune response elicited by the MenB-FHbp vaccine. Some regional differences were observed, particularly in isolates from British Columbia and Quebec. CONCLUSION: The majority of MenB isolates responsible for meningococcal disease in Canada expressed fHbp at levels predicted to be sufficient for complement mediated bactericidal activity in the presence of MenB-FHbp induced serum antibodies.

A prototype analysis of gratitude: varieties of gratitude experiences.

The present research tested the hypothesis that concepts of gratitude are prototypically organized and explored whether lay concepts of gratitude are broader than researchers' concepts of gratitude. In five studies, evidence was found that concepts of gratitude are indeed prototypically organized. In Study 1, participants listed features of gratitude. In Study 2, participants reliably rated the centrality of these features. In Studies 3a and 3b, participants perceived that a hypothetical other was experiencing more gratitude when they read a narrative containing central as opposed to peripheral features. In Study 4, participants remembered more central than peripheral features in gratitude narratives. In Study 5a, participants generated more central than peripheral features when they wrote narratives about a gratitude incident, and in Studies 5a and 5b, participants generated both more specific and more generalized types of gratitude in similar narratives. Throughout, evidence showed that lay conceptions of gratitude are broader than current research definitions.

Predicting the Susceptibility of Meningococcal Serogroup B Isolates to Bactericidal Antibodies Elicited by Bivalent rLP2086, a Novel Prophylactic Vaccine.

Bivalent rLP2086 (Trumenba), a vaccine for prevention of Neisseria meningitidis serogroup B (NmB) disease, was licensed for use in adolescents and young adults after it was demonstrated that it elicits antibodies that initiate complement-mediated killing of invasive NmB isolates in a serum bactericidal assay with human complement (hSBA). The vaccine consists of two factor H binding proteins (fHBPs) representing divergent subfamilies to ensure broad coverage. Although it is the surrogate of efficacy, an hSBA is not suitable for testing large numbers of strains in local laboratories. Previously, an association between the in vitro fHBP surface expression level and the susceptibility of NmB isolates to killing was observed. Therefore, a flow cytometric meningococcal antigen surface expression (MEASURE) assay was developed and validated by using an antibody that binds to all fHBP variants from both fHBP subfamilies and accurately quantitates the level of fHBP expressed on the cell surface of NmB isolates with mean fluorescence intensity as the readout. Two collections of invasive NmB isolates (n = 1,814, n = 109) were evaluated in the assay, with the smaller set also tested in hSBAs using individual and pooled human serum samples from young adults vaccinated with bivalent rLP2086. From these data, an analysis based on fHBP variant prevalence in the larger 1,814-isolate set showed that >91% of all meningococcal serogroup B isolates expressed sufficient levels of fHBP to be susceptible to bactericidal killing by vaccine-induced antibodies.IMPORTANCE Bivalent rLP2086 (Trumenba) vaccine, composed of two factor H binding proteins (fHBPs), was recently licensed for the prevention of N. meningitidis serogroup B (NmB) disease in individuals 10 to 25 years old in the United States. This study evaluated a large collection of NmB isolates from the United States and Europe by using a flow cytometric MEASURE assay to quantitate the surface expression of the vaccine antigen fHBP. We find that expression levels and the proportion of strains above the level associated with susceptibility in an hSBA are generally consistent across these geographic regions. Thus, the assay can be used to predict which NmB isolates are susceptible to killing in the hSBA and therefore is able to demonstrate an fHBP vaccine-induced bactericidal response. This work significantly advances our understanding of the potential for bivalent rLP2086 to provide broad coverage against diverse invasive-disease-causing NmB isolates.

Trading Later Rewards for Current Pleasure: Pornography Consumption and Delay Discounting.

Internet pornography is a multi-billion-dollar industry that has grown increasingly accessible. Delay discounting involves devaluing larger, later rewards in favor of smaller, more immediate rewards. The constant novelty and primacy of sexual stimuli as particularly strong natural rewards make Internet pornography a unique activator of the brain's reward system, thereby having implications for decision-making processes. Based on theoretical studies of evolutionary psychology and neuroeconomics, two studies tested the hypothesis that consuming Internet pornography would relate to higher rates of delay discounting. Study 1 used a longitudinal design. Participants completed a pornography use questionnaire and a delay discounting task at Time 1 and then again four weeks later. Participants reporting higher initial pornography use demonstrated a higher delay discounting rate at Time 2, controlling for initial delay discounting. Study 2 tested for causality with an experimental design. Participants were randomly assigned to abstain from either their favorite food or pornography for three weeks. Participants who abstained from pornography use demonstrated lower delay discounting than participants who abstained from their favorite food. The finding suggests that Internet pornography is a sexual reward that contributes to delay discounting differently than other natural rewards. Theoretical and clinical implications of these studies are highlighted.

Taxa of the Nasal Microbiome Are Associated with Influenza-Specific IgA Response to Live Attenuated Influenza Vaccine.

Live attenuated influenza vaccine (LAIV) has demonstrated varying levels of efficacy against seasonal influenza; however, LAIV may be used as a tool to measure interactions between the human microbiome and a live, replicating virus. To increase our knowledge of this interaction, we measured changes to the nasal microbiome in subjects who received LAIV to determine if associations between influenza-specific IgA production and the nasal microbiome exist after immunization with a live virus vaccine. The anterior nares of 47 healthy subjects were swabbed pre- (Day 0) and post- (Days 7 and 28) LAIV administration, and nasal washes were conducted on Days 0 and 28. We performed next-generation sequencing on amplified 16s rRNA genes and measured mucosal influenza-specific IgA titers via enzyme-linked immunosorbent assay (ELISA). A significant increase in alpha diversity was identified (Observed, CHAO, and ACE) between Days 7 vs 0 (p-values = 0.017, 0.005, 0.005, respectively) and between Days 28 vs 0 (p-values = 0.054, 0.030, 0.050, respectively). Several significant associations between the presence of different microbial species, including Lactobacillus helveticus, Prevotella melaninogenica, Streptococcus infantis, Veillonella dispar, and Bacteroides ovatus, and influenza-specific H1 and H3 IgA antibody response were demonstrated. These data suggest that LAIV alters the nasal microbiome, allowing several less-abundant OTUs to establish a community niche. Additionally, specific alterations in the nasal microbiome are significantly associated with variations in influenza-specific IgA antibody production and could be clinically relevant.

Power and the pursuit of a partner's goals.

We investigated how power dynamics in close relationships influence the tendency to devote resources to the pursuit of goals valued by relationship partners, hypothesizing that low (vs. high) power in relationships would lead individuals to center their individual goal pursuit around the goals of their partners. We study 2 related phenomena: partner goal prioritization, whereby individuals pursue goals on behalf of their partners, and partner goal contagion, whereby individuals identify and adopt as their own the goals that their partner pursues. We tested our ideas in 5 studies that employed diverse research methods, including lab experiments and dyadic studies of romantic partners, and multiple types of dependent measures, including experience sampling reports, self-reported goal commitment, and behavioral goal pursuit in a variety of goal domains. Despite this methodological diversity, the studies provided clear and consistent evidence that individuals with low power in their relationships are especially likely to engage in both partner goal prioritization and partner goal contagion. (PsycINFO Database Record

The impact of immunosenescence on humoral immune response variation after influenza A/H1N1 vaccination in older subjects.

BACKGROUND: Although influenza causes significant morbidity and mortality in the elderly, the factors underlying the reduced vaccine immunogenicity and efficacy in this age group are not completely understood. Age and immunosenescence factors, and their impact on humoral immunity after influenza vaccination, are of growing interest for the development of better vaccines for the elderly. METHODS: We assessed associations between age and immunosenescence markers (T cell receptor rearrangement excision circles - TREC content, peripheral white blood cell telomerase - TERT expression and CD28 expression on T cells) and influenza A/H1N1 vaccine-induced measures of humoral immunity in 106 older subjects at baseline and three timepoints post-vaccination. RESULTS: TERT activity (TERT mRNA expression) was significantly positively correlated with the observed increase in the influenza-specific memory B cell ELISPOT response at Day 28 compared to baseline (p-value=0.025). TREC levels were positively correlated with the baseline and early (Day 3) influenza A/H1N1-specific memory B cell ELISPOT response (p-value=0.042 and p-value=0.035, respectively). The expression and/or expression change of CD28 on CD4+ and/or CD8+ T cells at baseline and Day 3 was positively correlated with the influenza A/H1N1-specific memory B cell ELISPOT response at baseline, Day 28 and Day 75 post-vaccination. In a multivariable analysis, the peak antibody response (HAI and/or VNA at Day 28) was negatively associated with age, the percentage of CD8+CD28 low T cells, IgD+CD27- naïve B cells, and percentage overall CD20- B cells and plasmablasts, measured at Day 3 post-vaccination. The early change in influenza-specific memory B cell ELISPOT response was positively correlated with the observed increase in influenza A/H1N1-specific HAI antibodies at Day 28 and Day 75 relative to baseline (p-value=0.007 and p-value=0.005, respectively). CONCLUSION: Our data suggest that influenza-specific humoral immunity is significantly influenced by age, and that specific markers of immunosenescence (e.g., the baseline/early expression of CD28 on CD4+ and/or CD8+ T cells and T cell immune abnormalities) are correlated with different humoral immune response outcomes observed after vaccination in older individuals, and thus can be potentially used to predict vaccine immunogenicity.

The personal touch: strategies toward personalized vaccines and predicting immune responses to them.

The impact of vaccines on public health and wellbeing has been profound. Smallpox has been eradicated, polio is nearing eradication, and multiple diseases have been eliminated from certain areas of the world. Unfortunately, we now face diseases such as hepatitis C, malaria or tuberculosis, as well as new and re-emerging pathogens for which we lack effective vaccines. Empirical approaches to vaccine development have been successful in the past, but may not be up to the current infectious disease challenges facing us. New, directed approaches to vaccine design, development, and testing need to be developed. Ideally these approaches will capitalize on cutting-edge technologies, advanced analytical and modeling strategies, and up-to-date knowledge of both pathogen and host. These approaches will pay particular attention to the causes of inter-individual variation in vaccine response in order to develop new vaccines tailored to the unique needs of individuals and communities within the population.

A systems biology approach to the effect of aging, immunosenescence and vaccine response.

Aging can lead to immunosenescence, which dramatically impairs the hosts' ability to develop protective immune responses to vaccine antigens. Reasons for this are not well understood. This topic's importance is reflected in the increases in morbidity and mortality due to infectious diseases among elderly persons, a population growing in size globally, and the significantly lower adaptive immune responses generated to vaccines in this population. Here, we endeavor to summarize the existing data on the genetic and immunologic correlates of immunosenescence with respect to vaccine response. We cover how the application of systems biology can advance our understanding of vaccine immunosenescence, with a view toward how such information could lead to strategies to overcome the lower immunogenicity of vaccines in the elderly.