Poland, Gregory A.

AbstractGenetic pleiotropy is when a single gene influences more than one trait. Detecting pleiotropy and understanding its causes can improve the biological understanding of a gene in multiple ways, yet current multivariate methods to evaluate pleiotropy test the null hypothesis that none of the traits are associated with a variant; departures from the null could be driven by just one associated trait. A formal test of pleiotropy should assume a null hypothesis that one or no traits are associated with a genetic variant. For the special case of two traits, one can construct this null hypothesis based on the intersection-union (IU) test, which rejects the null hypothesis only if the null hypotheses of no association for both traits are rejected. To allow for more than two traits, we developed a new likelihood-ratio test for pleiotropy. We then extended the testing framework to a sequential approach to test the null hypothesis that k+1 traits are associated, given that the null of k traits are associated was rejected. This provides a formal testing framework to determine the number of traits associated with a genetic variant, while accounting for correlations among the traits. By simulations, we illustrate the type I error rate and power of our new methods; describe how they are influenced by sample size, the number of traits, and the trait correlations; and apply the new methods to multivariate immune phenotypes in response to smallpox vaccination. Our new approach provides a quantitative assessment of pleiotropy, enhancing current analytic practice.

Health-care providers (HCPs) are at increased risk for exposure to vaccine-preventable diseases (VPDs) in the workplace. The rationale for immunization of HCPs relies on the need to protect them and, indirectly, their patients from health-care-associated VPDs. Published evidence indicates significant immunity gaps for VPDs of HCPs globally. Deficits in knowledge and false perceptions about VPDs and vaccines are the most common barriers for vaccine uptake and may also influence communication about vaccines between HCPs and their patients. Most countries have immunization recommendations for HCPs; however, there are no universal policies and significant heterogeneity exists between countries in terms of vaccines, schedules, frame of implementation (recommendation or mandatory), and target categories of HCPs. Mandatory influenza immunization policies for HCPs have been implemented with high vaccine uptake rates. Stronger recommendations for HCP immunization and commitment at the level of the health-care facility are critical in order to achieve high vaccine coverage rates. Given the importance to health, mandatory immunization policies for VPDs that can cause serious morbidity and mortality to vulnerable patients should be considered.

SummaryInfluenza causes significant morbidity and mortality annually. Although vaccination offers a considerable amount of protection, it is far from perfect, especially in aging populations. This is due to age‐related defects in immune function, a process called immunosenescence. To date, there are no assays or methods to predict or explain variations in an individual's level of response to influenza vaccination. In this study, we measured levels of several immune cell subsets at baseline (Day 0) and at Days 3 and 28 post‐vaccination using flow cytometry. Statistical modelling was performed to assess correlations between levels of cell subsets and Day 28 immune responses – haemagglutination inhibition (HAI) assay, virus neutralizing antibody (VNA) assay, and memory B cell ELISPOT. Changes in several groups of cell types from Day 0 to Day 28 and Day 3 to Day 28 were found to be significantly associated with immune response. Baseline levels of several immune cell subsets, including B cells and regulatory T cells, were able to partially explain variation in memory B‐cell ELISPOT results. Increased expression of HLA‐DR on plasmacytoid dendritic cells after vaccination was correlated with increased HAI and VNA responses. Our data suggest that the expression of activation markers (HLA‐DR and CD86) on various immune cell subsets, as well as the relative distribution of cell subsets, both have value in predicting immune responses to influenza vaccination in older individuals.

ABSTRACT Protective antigen (PA)-specific antibody and cell-mediated immune (CMI) responses to annual and alternate booster schedules of anthrax vaccine adsorbed (AVA; BioThrax) were characterized in humans over 43 months. Study participants received 1 of 6 vaccination schedules: a 3-dose intramuscular (IM) priming series (0, 1, and 6 months) with a single booster at 42 months (4-IM); 3-dose IM priming with boosters at 18 and 42 months (5-IM); 3-dose IM priming with boosters at 12, 18, 30, and 42 months (7-IM); the 1970 licensed priming series of 6 doses (0, 0.5, 1, 6, 12, and 18 months) and two annual boosters (30 and 42 months) administered either subcutaneously (SQ) (8-SQ) or IM (8-IM); or saline placebo control at all eight time points. Antibody response profiles included serum anti-PA IgG levels, subclass distributions, avidity, and lethal toxin neutralization activity (TNA). CMI profiles included frequencies of gamma interferon (IFN-γ)- and interleukin 4 (IL-4)-secreting cells and memory B cells (MBCs), lymphocyte stimulation indices (SI), and induction of IFN-γ, IL-2, IL-4, IL-6, IL-1β, and tumor necrosis factor alpha (TNF-α) mRNA. All active schedules elicited high-avidity PA-specific IgG, TNA, MBCs, and T cell responses with a mixed Th1-Th2 profile and Th2 dominance. Anti-PA IgG and TNA were highly correlated (e.g., month 7, r 2 = 0.86, P < 0.0001, log 10 transformed) and declined in the absence of boosters. Boosters administered IM generated the highest antibody responses. Increasing time intervals between boosters generated antibody responses that were faster than and superior to those obtained with the final month 42 vaccination. CMI responses to the 3-dose IM priming remained elevated up to 43 months. (This study has been registered at ClinicalTrials.gov under registration no. NCT00119067.)

AbstractAutoimmune bullous diseases, such as pemphigus, pemphigoid, and dermatitis herpetiformis, are uniquely associated with vulnerability in the mucocutaneous barrier against infection. The management of immunobullous diseases is complex and may at times require immunosuppressive medications. Iatrogenic immunosuppression may increase susceptibility to vaccine‐preventable illnesses. Currently, there are no guidelines to assist the clinician treating patients with immunobullous disease regarding the delivery of various vaccinations. The aim of this review is to provide recommendations for immunization in the unique setting of immunobullous disease. Recommendations are based on careful review of the literature in other conditions requiring iatrogenic immunosuppression, as well as the most recent Centers for Disease Control and Prevention guidelines. Immunization with nonlive vaccines appears to be a safe and effective strategy for preventing infection in the particularly susceptible patient with immunobullous disease. Opportunities for live vaccine administration may become available at lower levels of immune suppression or during clinical remission when immunosuppressive regimens can be reduced. Anticipatory vaccination before the initiation of iatrogenic immunosuppression is ideal. Although immunologic response to vaccination may be suboptimal during immunosuppression, nonlive vaccination is strongly recommended for this patient population.

AbstractTwo recently developed fine-mapping methods, CAVIAR and PAINTOR, demonstrate better performance over other fine-mapping methods. They also have the advantage of using only the marginal test statistics and the correlation among SNPs. Both methods leverage the fact that the marginal test statistics asymptotically follow a multivariate normal distribution and are likelihood based. However, their relationship with Bayesian fine mapping, such as BIMBAM, is not clear. In this study, we first show that CAVIAR and BIMBAM are actually approximately equivalent to each other. This leads to a fine-mapping method using marginal test statistics in the Bayesian framework, which we call CAVIAR Bayes factor (CAVIARBF). Another advantage of the Bayesian framework is that it can answer both association and fine-mapping questions. We also used simulations to compare CAVIARBF with other methods under different numbers of causal variants. The results showed that both CAVIARBF and BIMBAM have better performance than PAINTOR and other methods. Compared to BIMBAM, CAVIARBF has the advantage of using only marginal test statistics and takes about one-quarter to one-fifth of the running time. We applied different methods on two independent cohorts of the same phenotype. Results showed that CAVIARBF, BIMBAM, and PAINTOR selected the same top 3 SNPs; however, CAVIARBF and BIMBAM had better consistency in selecting the top 10 ranked SNPs between the two cohorts. Software is available at https://bitbucket.org/Wenan/caviarbf.

Introduction: Comprehensive evaluation of measles-specific humoral immunity after vaccination is important for determining new and/or additional correlates of vaccine immunogenicity and efficacy. Methods: We used a novel proteome microarray technology and statistical modeling to identify factors and models associated with measles-specific functional protective immunity in 150 measles vaccine recipients representing the extremes of neutralizing antibody response after two vaccine doses. Results: Our findings demonstrate a high seroprevalence of antibodies directed to the measles virus (MV) phosphoprotein (P), nucleoprotein (N), as well as antibodies to the large polymerase (L) protein (fragment 1234 to 1900 AA). Antibodies to these proteins, in addition to anti-F antibodies (and, to a lesser extent, anti-H antibodies), were correlated with neutralizing antibody titer and/or were associated with and predictive of neutralizing antibody response. Conclusion: Our results identify antibodies to specific measles virus proteins and statistical models for monitoring and assessment of measles-specific functional protective immunity in vaccinated individuals.

For influenza hemagglutination inhibition (HAI) assays, species selection of red blood cells (RBCs) is critical to determine antibody titers to influenza viruses reliably. We compared pandemic influenza virus A/H1N1 (pdH1N1) HAI titers using turkey or guinea pig RBCs. Turkey RBCs appear to be the more appropriate species choice for influenza A/pH1N1 HAI assays.