Sabra L. Klein - US grants

DESCRIPTION Males are more susceptible to many parasite infections than females. The goal of this research proposal is to determine whether males are more susceptible to viruses, specifically hantaviruses, because androgens suppress immune function or because males engage in more androgen- dependent behaviors (e.g., aggression) that influence susceptibility to hantavirus. These studies are based on field observations of many species that report a high proportion of males being infected with hantavirus. The goal of this proposal will be met by examining: the role of sex steroid hormones in sex differences in immune responses to hantavirus infection; 2) how androgen metabolites influence the course of hantavirus infection; 3) when during ontogeny hormones influence adult susceptibility to infection; 4) whether aggressive males are more susceptible to hantavirus infection than less aggressive males. These studies represent a thorough examination of potential mechanisms that underlie population variation in hantavirus infection and serve to expand our knowledge of disease processes in general and, specifically, factors that affect susceptibility to hantavirus.

Hantaviruses are zoonotic agents that are carried by a wide range of rodent host species, are geographically diverse, and cause human disease for which there is currently no cure. The primary goal of this proposal is to better elucidate the cellular and molecular mechanisms mediating host responses to hantavirus infection. Because the CDC classifies hantaviruses as potential biological agents, studies that examine the mechanisms mediating host susceptibility to infectior are required for developing adequate therapies against infection. Sex differences in hantavirus infection are documented in humans and in several rodent reservoir species in which more males are infected than females. Although sex differences in hantavirus infection may reflect dimorphisms in behaviors, such as aggression in rodents or occupation in humans, recent data from our laboratory illustrate that immune responses against infection and virus replication differ between the sexes. After inoculation with Seoul virus (i.e., the naturally occurring hantavirus in Norway rats), male rats exhibit higher antibody responses, shed virus longer and through more routes, and have more viral RNA copies present in target organs, such as the lungs, than females. The expression of antiviral transcriptional factors (e.g., eIF-2alpha, NF-KappaB, IRF, and STAT) is higher in females than males. Upregulation of transcriptional factors, e.g. NF-KappaB, in females may underlie the elevated expression of genes that encode for proinflammatory, chemotactic, and antiviral proteins in females compared with males. Sex differences in hantavirus infection may reflect the effects of steroid receptor signaling pathways on NF-KappaB-mediated signal transduction. The primary aim of this research proposal is to test the hypothesis that steroid hormones, including androgens, estrogens, and glucocorticoids, mediate sex differences in Seoul virus infection through effects on cell signaling pathways. The aims of this proposal will be met by: 1) characterizing sex differences in the expression and translation of genes thal encode for proinflammatory, antiviral, and chemotactic proteins during the acute and persistent phases of infection; 2) manipulating sex steroids at different times during development, to determine if the expression and translation of genes that encode for proinflammatory, antiviral, and chemotactic proteins are influenced by sex steroids; and 3) assessing whether sex differences inthe expression and translation of genes that encode for proinflammatory, antiviral, and chemotactic proteins are mediated by dimorphisms in glucocorticoid receptor-mediated pathways. Taken together, these studies will provide a comprehensive analysis of how steroid hormones and genes that encode for immunoregulatory proteins interact to affect sex differences in phenotypic responses to infectious diseases and may assist in the development of treatments for qemorrhagic fever viruses that will be successful in both sexes.

DESCRIPTION (provided by applicant): During a typical influenza season, influenza A viruses primarily cause mortality in the very young and old;conversely, pandemic influenza viruses, including the 1918 H1N1 subtype and avian H5N1 viruses, cause high rates of mortality in young adults (ages 18-40) in addition to children and the elderly. During the 1918 epidemic, death rates were significantly higher among men than women. Conversely, in 2006, human cases of H5N1 avian influenza were significantly higher among young women than men. Whether gender differences in mortality from influenza virus infection during pandemics are due to dimorphic exposure or susceptibility to infection has not been resolved. To date, there are no reports of systematic examination of gender differences in response to influenza A viruses in either humans or animal models. The overarching aim of this proposal is to develop an animal model that enables us to test the hypothesis that gender differences in susceptibility to influenza virus infection reflect differential regulation of inflammation and development of immunopathology. Preliminary data from my laboratory reveal that following intranasal inoculation with the virulent mouse-adapted influenza A virus A/PR/8/34 (PR8;H1N1), morbidity and mortality are higher in female than male C57BL/6 mice. Our data further indicate that this dimorphism is dependent on circulating sex steroid hormones. We hypothesize that induction of excessively high proinflammatory responses to influenza virus infection may lead to immunopathology and death in females. Specific Aim 1 will test the hypothesis that gender differences in the pathogenicity of influenza A viruses are associated with sex steroid hormones, production of pro- and anti- inflammatory cytokines/chemokines, and signaling through the Myd88 pathway. Specific Aim 2 will establish whether the balance between proinflammatory and anti-inflammatory T cell responses during infection, specifically responses of regulatory T cells and IL-17-producing T cells, differs between the sexes and is altered by sex steroids during influenza A virus infection. The studies proposed will provide a comprehensive examination of innate and adaptive immunological factors mediating gender differences in inflammatory responses to influenza which will serve as an important consideration for pandemic preparedness. Development of the proposed animal model for systematic examination of gender-specific responses to influenza also will translate into testable hypotheses for the determination of gender differences in responses to influenza A virus infection and vaccination in humans. PUBLIC HEALTH RELEVANCE: The burden of influenza as a global infectious disease is well recognized;missing from current initiatives is an understanding of the causes of gender differences in susceptibility to infection. Preliminary data from my laboratory reveal that following infection with virulent influenza A virus, morbidity and mortality are higher in female than male mice and we hypothesize that induction of excessively high proinflammatory responses to influenza virus may lead to immunopathology and death in females. The studies proposed will provide essential information about immune regulation in males and females, which may impact our understanding of infection as well as vaccine efficacy in different populations-a critical consideration for pandemic preparedness.

DESCRIPTION (provided by applicant): Sex differences in the incidence and severity of influenza A virus infection have been documented in humans. Although exposure rates are often higher in men, fatality following exposure to pathogenic influenza A viruses is reportedly higher in women. Sex differences also are reported in response to influenza virus vaccines, with women consistently mounting higher antibody responses and developing more frequent and severe side effects following vaccination than men. Small animal models are critical for establishing the mechanisms mediating why males and females respond differently to influenza virus infection and vaccination. Following primary inoculation with the mouse-adapted influenza A viruses A/PR/8/34 (PR8;H1N1) or A/HK/68 (HK68;H3N2), female mice mount higher inflammatory and humoral immune responses than males. Our preliminary data further reveal that elevated immunity in females against influenza A viruses represents a delicate balance between immune responses conferring protection or causing pathology. The goal of this proposal is to develop a small animal model to test the hypothesis that protective immunity to heterosubtypic influenza A virus challenge differs between the sexes and is modulated by sex steroid hormones. In Specific Aim 1, we will establish whether neutralizing antibody responses, virus-specific T cell responses, and protection against lethal influenza A virus challenge is greater among females than males. Whether males and females differentially rely on subsets of adaptive immune cells for protection against lethal influenza A virus infection has not been documented;thus, we also propose to compare heterosubtypic immune responses between male and female mice devoid of specific adaptive immune cell populations. If protective heterosubtypic immunity is elevated in females compared with males, then estrogens and/or progestins may enhance and androgens may suppress adaptive immunity against heterosubtypic influenza A virus challenge. In Specific Aim 2 we will test this hypothesis by manipulating sex steroid concentrations in vivo and establishing the effects on humoral and cell-mediated immunity as well as protection from lethal influenza A virus challenge. These are a series of high risk-high return experiments because there are no data to date assessing the sex-specific induction of heterosubtypic immunity in response to influenza A virus infection. Demonstrating that females mount a broadly protective immune response, however, will have important implications for dealing with annual epidemics of influenza, as this may explain why the attack rates for influenza are higher in men than in woman and influenced by pregnancy. PUBLIC HEALTH RELEVANCE: Sex differences in the incidence and severity of influenza A virus infection as well as in response to vaccination have been documented in humans. Small animal models are critical for establishing the mechanisms mediating why males and females respond differently to influenza virus infection and vaccination. We will evaluate whether higher humoral immune responses following sublethal infection confers greater protection from challenge with pathogenic influenza A viruses in females compared with males and the extent to which these differences are mediated sex steroids, which may provide clues into why responses to pandemic influenza A viruses differ between the sexes and during pregnancy.

DESCRIPTION (provided by applicant): Continued training in The Molecular and Cellular Bases of Infectious Diseases (MCBID) is proposed for 8 PhD students and 3 postdoctoral fellows selected from large pools of highly qualified applicants. The training program is uniquely situated in the Molecular Microbiology and Immunology Department (MMI) within the Johns Hopkins Bloomberg School of Public Health. The 29 training faculty have a wide range of experience and expertise in viruses, bacteria and parasites causing human disease and in the vectors and environmental factors associated with emergence and transmission of these pathogens. The training program has been funded since 1994 and has produced scientists working in many areas of academia and government on problems related to infectious diseases, vaccine development and the public's health. The goal of the MCBID training program is to provide students with both a firm foundation in the basic disciplines necessary for the study of infectious diseases and a perspective that will enable them to apply their knowledge creatively to public health problems. Each student is expected to complete 1) a series of required courses in the basic disciplines of cell and molecular biology, biochemistry, and immunology, 2) courses in virology, bacteriology, parasitology, and disease ecology, 3) courses in research ethics and public health perspectives, and 4) elective courses relevant to thesis topic and long-term career goals. Elective courses are chosen from among courses available in MMI, other departments in the School of Public Health, or in other Divisions of the University. Students will also complete 3 11-week laboratory rotations during the first year. Student progress is monitored by a Thesis Advisory Committee and the Graduate Program Committee. The goals of the postdoctoral training program are 1) to provide focused training in those areas of the molecular and cellular basis of infectious diseases in which program faculty have special expertise;2) to provide an opportunity for doctoral degree holders trained in more traditional environments to broaden their exposure to problems of public health importance and to evaluate their career goals in terms of public health issues;and 3) to prepare the PDF for an independent career in the biological sciences. RELEVANCE : This program is highly relevant to national interests in the areas of emerging infectious diseases, as it trains students and postdoctoral fellows broadly not only in both the molecular aspects of pathogen biology and disease pathogenesis, but also in the ecology of disease emergence and the role of vectors in pathogen transmission.

DESCRIPTION (provided by applicant): Continued training in The Molecular and Cellular Bases of Infectious Diseases (MCBID) is proposed for 8 PhD students and 3 postdoctoral fellows selected from large pools of highly qualified applicants. The training program is uniquely situated in the Molecular Microbiology and Immunology Department (MMI) within the Johns Hopkins Bloomberg School of Public Health. The 29 training faculty have a wide range of experience and expertise in viruses, bacteria and parasites causing human disease and in the vectors and environmental factors associated with emergence and transmission of these pathogens. The training program has been funded since 1994 and has produced scientists working in many areas of academia and government on problems related to infectious diseases, vaccine development and the public's health. The goal of the MCBID training program is to provide students with both a firm foundation in the basic disciplines necessary for the study of infectious diseases and a perspective that will enable them to apply their knowledge creatively to public health problems. Each student is expected to complete 1) a series of required courses in the basic disciplines of cell and molecular biology, biochemistry, and immunology, 2) courses in virology, bacteriology, parasitology, and disease ecology, 3) courses in research ethics and public health perspectives, and 4) elective courses relevant to thesis topic and long-term career goals. Elective courses are chosen from among courses available in MMI, other departments in the School of Public Health, or in other Divisions of the University. Students will also complete 3 11-week laboratory rotations during the first year. Student progress is monitored by a Thesis Advisory Committee and the Graduate Program Committee. The goals of the postdoctoral training program are 1) to provide focused training in those areas of the molecular and cellular basis of infectious diseases in which program faculty have special expertise; 2) to provide an opportunity for doctoral degree holders trained in more traditional environments to broaden their exposure to problems of public health importance and to evaluate their career goals in terms of public health issues; and 3) to prepare the PDF for an independent career in the biological sciences. RELEVANCE : This program is highly relevant to national interests in the areas of emerging infectious diseases, as it trains students and postdoctoral fellows broadly not only in both the molecular aspects of pathogen biology and disease pathogenesis, but also in the ecology of disease emergence and the role of vectors in pathogen transmission.

DESCRIPTION (provided by applicant): With age, circulating testosterone levels decline in males, resulting in conditions ranging from decreased sexual function to cognitive decline, metabolic disorders, and increased cardiovascular disease risk. As a result, aged males, and in some cases young males with clinically low testosterone concentrations, are prescribed long-term testosterone replacement therapy. In preliminary studies, we found that the immune system also is a target of testosterone, affecting the outcome of infectious diseases, including influenza. Using a murine model, we show that low testosterone concentrations, either endogenously occurring in aged male or caused by surgical castration (i.e., hypogonadism) in young males, increase inflammation and result in greater morbidity and mortality following influenza virus infection as compared with young males that have high circulating concentrations of testosterone. In this R21 application, we propose to critically test the hypothesis that low circulating testosterone concentrations contribute to age-associated changes in susceptibility to influenza and in vaccine efficacy by altering immune responses in males. We further predict that testosterone replacement in either young or aged males with low testosterone levels will protect against influenza infection and improve the outcome of vaccination. In Aim 1, we will determine whether age-dependent reduced testosterone in males affects the kinetics and magnitude of virus replication as well as inflammatory, cell-mediated, and humeral immune responses to influenza infection. We will also establish whether treatment with testosterone protects against disease, particularly in older males. Vaccination against influenza is the most effective means for reducing influenza, yet the efficacy of vaccines declines with age, especially in males. Aim 2 will test the hypothesis that low testosterone levels reduce antibody responses to influenza vaccination and protection against lethal challenge with influenza viruses in males. Replacement of testosterone in either young or aged males with low testosterone levels should improve vaccine efficacy by directly altering humeral immune responses. During seasonal epidemics of influenza as well as during the recent H7N9 outbreak, a significant majority of the deaths occur in people over 65 years of age, with men being 2-times more likely to die than women. If testosterone replacement therapy provides significant protection for males against influenza, then this could provide an inexpensive supplemental therapeutic approach for saving lives and reducing disease burden during influenza epidemics and pandemics.

SADII RESEARCH PROJECT 3: Genetic and hormonal mechanisms of sex differences in immune responses and influenza vaccine efficacy in young and aged mice SUMMARY Using C57BL/6 mice and an inactivated 2009 H1N1 vaccine prime and boost strategy, we have shown that greater antibody in young adult females is sufficient for protection against influenza. Following influenza virus vaccination, young adult female mice have greater antibody responses and protection against challenge with an influenza drift variant virus than males. Antibody derived from vaccinated females is better at protecting both naïve males and females than antibody derived from males, and this protection is associated with increased antibody specificity and avidity to the influenza virus. We have identified two factors that reduce female-biased antibody responses and protection following influenza vaccination?old age and deletion of genes that control somatic hypermutation (activation-induced cytidine deaminase [Aicda]) and antibody class switching recombination in B cells (toll like receptor 7 [Tlr7]). Because secretion of sex steroids is reduced to a greater extent in females than males with older age, the age-associated reduction in female-biased immunity suggests a role for sex steroids. In contrast, because Tlr7 is on the X chromosome and escapes X inactivation in B cells, female-biased immunity to influenza may also reflect direct effects sex chromosomes. The overarching goal of SADII Research Project 3 is to analyze and manipulate the biological factors mediating the sex and age differences in immunity to influenza, through completion of three aims: Aim 1 will systematically evaluate how sex chromosome complement either directly through imbalanced expression of X and Y genes or indirectly via sex hormone concentrations cause sex differences in immunity and protection from influenza, using transgenic mice (i.e., Four Core Genotype); Aim 2 will tease apart the impact of chronological age versus reproductive senescence on reduced sex differences in humoral immunity and protection from influenza in aged as compared with young adult mice; and Aim 3 will characterize sex differences in transcriptional activity and B-cell influenza-specific receptor repertoire following vaccination, focusing initially on activation of pathways that we have shown to be differentially regulated between the sexes (e.g., TLR7 signaling) in mice, as well as novel pathways that are uncovered in the analyses of cells from Projects 1 and 2. Together, the studies in Research Project 3 will provide translational mechanistic insights that can be used test hypotheses derived from the human data from Research Projects 1 and 2.

SUMMARY Zika virus (ZIKV) infection of pregnant females results in congenital infection of offspring and long-term developmental birth defects. Using an immunocompetent mouse model that we developed (published in Nature Communications), we have shown that intrauterine infection with either African, American, or Asian strains of ZIKV during early, but not late, pregnancy causes infection of the placenta and fetuses, placental inflammation, neonatal cortical thinning, and short-term neurologic deficits in offspring. More recently, we have demonstrated that placental IL-1? concentrations are elevated in ZIKV-infected dams, and we can reverse the ZIKV-associated short-term neurobehavioral sequelae in offspring by blocking IL-1 receptor signaling during the infection. We hypothesize that placental inflammation following intrauterine ZIKV infection causes perinatal neurological injury, which can then be reversed by targeting maternal IL-1? signaling. While most ZIKV interventions focus on antivirals and vaccines to limit perinatal ZIKV infection, to date no studies have considered the role of maternal and placental inflammation as a mechanism mediating long-term adverse perinatal outcomes following ZIKV infection. Specific Aim 1 will assess the mechanisms mediating elevated IL- 1? signaling in the placenta at different gestational ages following ZIKV infection, the long-term downstream effects of the placental immunopathology and placental IL-1? signaling, and whether these effects are sex- specific. In particular, Aim 1 will determine how placental inflammasome activation, IL-1? release, or engagement of the IL-1 receptor lead to adverse perinatal outcomes. Specific Aim 2 will examine the importance of maternal as opposed to fetal IL-1? signaling in the pathogenesis of perinatal brain injury following ZIKV infection. Using embryo transfer of IL-1? signaling deficient and wild type mouse strains, Aim 2 will assess whether IL-1? activity of maternal origin is critical for sex-specific fetal brain injury. Our novel translational research proposal, utilizing a ZIKV model that we developed, will have a significant impact on perinatal medicine as it will lead to a better understanding of the role of placental inflammation in the pathogenesis of fetal congenital diseases caused by infection or other inflammatory states during pregnancy.

SEX AND AGE DIFFERENCES IN IMMUNITY TO INFLUENZA (SADII) IMMUNE RESPONSES RESOURCE CORE SUMMARY Under the leadership of Dr. Patricia Gearhart (Director) and Dr. Sabra Klein (Co-Director), the Immune Responses Core will provide the serological, cellular, and genetic assays that will be necessary for the accurate, and consistent measurement of sex and aged differences in immune responses to influenza vaccines and viral antigens. The Core will provide serological assessment of antibody responses to influenza vaccine and virus antigens for Research Projects 1, 2, and 3. The serological assessments will include microneutralization assays, hemagglutinin (HA) inhibition assays, and ELISAs to detect IgG that is specific for diverse influenza virus proteins, including HA, neuraminidase (NA), and the M2 protein as well as IgM and IgG isotypes to evaluate somatic hypermutation and class switching. The Core will also be responsible for conducting cellular analyses of antigen-specific (i.e., HA, NA, M2) B cells in humans and mice by flow cytometry using the MMI BD Immune Function Core facility. Particular attention will be paid to the quantification of plasmablasts and germinal center cells, including memory B cells and the recently characterized Age-associated B cells (ABCs). Finally, using the MMI Genomics and Analysis Sequencing Core, we will analyze the transcriptional variation associated with sex and age by transcriptional profiling antigen-specific B cells (i.e., plasmablasts) in humans and mice (Projects 1, 2, and 3). The transcriptional analyses will include using deep sequencing to quantify transcriptional activity in plasmablasts to evaluate the pathways differentially regulated by age and sex. Following repeated exposures to influenza antigens through infection and vaccination, an immune repertoire develops that reflects clonal selection during the primary response and recall and somatic rearrangement of VH genes following subsequent exposures, including following vaccination. V gene repertoires will be compared and analyzed for sex and age associated differences following vaccination. Together, the SADII Immune Responses Core will provide an in-depth analysis of how sex, age, and frailty alter antibody responses, B cell phenotypes, and B cell genotypes in response to influenza vaccination. With serological, cellular, and genomic assay capabilities, the SADII Immune Responses Resource Core can provide services to investigators interested in characterizing influenza virus-specific immune responses, which is currently not available at Johns Hopkins, and to SCOREs at other institutions that are seeking to measure inflammatory and immune markers of diverse diseases, beyond influenza.

SEX AND AGE DIFFERENCES IN IMMUNITY TO INFLUENZA (SADII) LEADERSHIP ADMINISTRATIVE CORE SUMMARY The primary goal of the SCORE on Sex and Age Differences in Immunity to Influenza (SADII) is to systematically evaluate sex differences in vaccine-induced immune responses across the life course, with consideration of the role that hormones, genes, age, and frailty play as independent and combined mediating factors. The primary objective of the SADII Leadership Administrative Core (LAC) is to provide centralized management, leadership, rigor, sharing, and dissemination of the data from the proposed Research Projects and Cores in the SADII SCORE. This objective will be met by accomplishing three specific aims. Aim 1 will be to provide a centralized, structured administration for all SADII SCORE investigators. The SADII SCORE will be physically housed within the Department of Molecular Microbiology and Immunology (MMI) at the Johns Hopkins Bloomberg School of Public Health and through the SADII Career Enhancement Core, will be integrated with the Johns Hopkins BIRCWH program and the Johns Hopkins Center for Women?s Health, Sex, and Gender Research (JH-CWHSGR). Aim 2 will be to provide scientific leadership for the SADII SCORE program. The SADII LAC will ensure rigor in the research conducted, dissemination of the research results to the greater scientific community, mentoring of junior faculty new to the study of sex as a biological variable, and integration of the SADII SCORE into the conceptual framework and teachings at Johns Hopkins University. Aim 3 of the SADII LAC will seek to enhance dissemination of research findings from the SADII SCORE to the Johns Hopkins research community, broader scientific community, and governmental decision bodies determining influenza vaccine strains and platforms. Dissemination of research findings from the SADII SCORE will involve diverse platforms, including, but not limited to: 1) presentation and dissemination of results at the annual JH-CWHSGR symposium, national and international meetings of professional societies, and the annual meeting of the Organization for the Study of Sex Differences, which is an international research society, for which Dr. Sabra Klein is President (2018-2020); 2) embedding the concept of sex as a biological variable into the Johns Hopkins graduate and medical school curriculum; 3) establishment of a rigorous publication plan that will ensure that publications of research, ideas, and information derived from the SADII SCORE will appropriately acknowledge SADII for its contribution; 4) development of an informational website for the SADII SCORE that links to other related websites both within and outside of Johns Hopkins; and 5) social media engagement for immediate dissemination of SADII research, presentations, and activities. The Program Director (Dr. Sabra Klein) and Co-Director (Dr. Patricia Gearhart) have the research expertise and leadership skills to ensure that the overarching goals of the SADII SCORE are met and exceeded.

SEX AND AGE DIFFERENCES IN IMMUNITY TO INFLUENZA (SADII) SUMMARY The NIH Office of Research on Women?s Health (ORWH) should support a Specialized Center of Research Excellence (SCORE) on sex differences in influenza immunity because despite having antivirals and vaccines, influenza remains a significant public health threat, causing approximately 100,000 hospitalizations, 30,000 deaths, and approximately $7 billion in lost productivity in the United States, alone. Sex and age are emerging as two host variables that significantly impact the pathogenesis of influenza virus infection and responses to influenza vaccines. The Sex and Age Differences in Immunity to Influenza (SADII, pronounced s?d?) SCORE will leverage the internationally recognized research, resources, and educational opportunities at Johns Hopkins University to transform women?s health and impact the development of and policy decisions about influenza vaccine programs, including universal influenza vaccines. The overarching hypothesis being tested through the SADII SCORE Research Projects is that female-biased vaccine-induced immunity to influenza viruses is age-dependent and reflects both hormonal and genetic differences between the sexes that impact immune responses (i.e., both effector and memory) to influenza vaccine antigens. SADII will bring together investigators focused on 1) seasonal influenza vaccination in an existing age and sex stratified human population; 2) animal models that can test hypotheses and mechanisms of action that are inferred from studies in human populations; and 3) the contributions of age, frailty, sex, and gender to vaccine outcomes using quantitative and qualitative statistical models. By using the combined expertise in our research groups, SADII is uniquely positioned to identify the biological basis behind sex and age differences in immune responses to influenza vaccination and disseminate those findings to the broader research, clinical, and public health communities. The overarching mission of the SADII SCORE will be achieved through the following Specific Aims: 1) To provide leadership and oversight of the SADII SCORE and collaboration with other entities at Johns Hopkins and elsewhere to develop a translational research program focused on sex and age differences in immunology and infectious diseases; 2) To systematically evaluate sex differences in vaccine-induced immune responses across the life course using translational approaches involving human studies and mechanistic animal models; and 3) To meet the career enhancement needs of diverse translational scientists studying sex differences at Johns Hopkins and beyond. We are prepared to transform women?s health, sex, and gender research into a signature initiative at Johns Hopkins and in the fields of microbiology and immunology.

SEX AND AGE DIFFERENCES IN IMMUNITY TO INFLUENZA (SADII) SUMMARY The NIH Office of Research on Women?s Health (ORWH) should support a Specialized Center of Research Excellence (SCORE) on sex differences in influenza immunity because despite having antivirals and vaccines, influenza remains a significant public health threat, causing approximately 100,000 hospitalizations, 30,000 deaths, and approximately $7 billion in lost productivity in the United States, alone. Sex and age are emerging as two host variables that significantly impact the pathogenesis of influenza virus infection and responses to influenza vaccines. The Sex and Age Differences in Immunity to Influenza (SADII, pronounced s?d?) SCORE will leverage the internationally recognized research, resources, and educational opportunities at Johns Hopkins University to transform women?s health and impact the development of and policy decisions about influenza vaccine programs, including universal influenza vaccines. The overarching hypothesis being tested through the SADII SCORE Research Projects is that female-biased vaccine-induced immunity to influenza viruses is age-dependent and reflects both hormonal and genetic differences between the sexes that impact immune responses (i.e., both effector and memory) to influenza vaccine antigens. SADII will bring together investigators focused on 1) seasonal influenza vaccination in an existing age and sex stratified human population; 2) animal models that can test hypotheses and mechanisms of action that are inferred from studies in human populations; and 3) the contributions of age, frailty, sex, and gender to vaccine outcomes using quantitative and qualitative statistical models. By using the combined expertise in our research groups, SADII is uniquely positioned to identify the biological basis behind sex and age differences in immune responses to influenza vaccination and disseminate those findings to the broader research, clinical, and public health communities. The overarching mission of the SADII SCORE will be achieved through the following Specific Aims: 1) To provide leadership and oversight of the SADII SCORE and collaboration with other entities at Johns Hopkins and elsewhere to develop a translational research program focused on sex and age differences in immunology and infectious diseases; 2) To systematically evaluate sex differences in vaccine-induced immune responses across the life course using translational approaches involving human studies and mechanistic animal models; and 3) To meet the career enhancement needs of diverse translational scientists studying sex differences at Johns Hopkins and beyond. We are prepared to transform women?s health, sex, and gender research into a signature initiative at Johns Hopkins and in the fields of microbiology and immunology.