Haralambieva, Iana H.

Abstract Background While immunologic aging impacts immune responses to vaccination, consistent biomarkers associated with aging of the immune system and suboptimal serologic response to influenza vaccination have not been well-studied. Identification of readily measurable biomarkers of immunosenescence may have predictive clinical utility and inform targeted influenza vaccination strategies and future research into aging of the immune system. Methods We quantified multiple serum/plasma and cell-based parameters related to immune aging (CMV serostatus, plasma cytokines/chemokines, TREC, TERT, NK cell functionality, and DNA methylation clock) at baseline in an adult (age range 18-85) cohort of 2019-2020 influenza vaccine recipients (n=337) and evaluated their associations with vaccine-induced HAI response to influenza A/H1N1, A/H3N2 and B/Victoria strains. Results CMV IgG titers were significantly positively correlated with vaccine-induced increases in HAI antibody titers to influenza A/H1N1 ( p= 0.02) and A/H3N2 ( p =0.014). CMV IgG titers ( p= 0.00096) and CMV seropositivity ( p= 0.003) were also associated with Day 28 HAI seropositivity against influenza A/H3N2 in subjects seronegative at baseline. Conversely, plasma MCP-1 levels were negatively associated with HAI responses to the A/H3N2 ( p= 0.04) strain. These findings were significant independent of age, sex or vaccine type received (high vs standard-dose seasonal influenza vaccine) Conclusions Our identification of significant relationships between easily quantifiable immune markers and HAI responses to influenza A vaccine strains across sex and age enhances our knowledge of specific links between immune aging and influenza vaccine-induced immunity. These markers could be leveraged for predicting response to influenza immunization.

Rubella is typically a mild viral illness, but it can lead to severe complications when contracted during pregnancy, such as pregnancy loss or developmental defects in the fetus (congenital rubella syndrome). Therefore, it is crucial to develop and maintain protective immunity in women of childbearing age. In this study, we assessed the transcriptional factors associated with rubella-specific immune outcomes (IgG binding antibody and avidity, neutralizing antibody, and memory B cell ELISpot response) following a third MMR vaccine dose in women of reproductive age to identify key factors/signatures impacting the immune response. We identified baseline (Day 0) and differentially expressed (Day 28–Day 0) genes associated with several RV-specific immune outcomes, including the transferrin receptor 2 (TFR2), which is an important factor regulating iron homeostasis and macrophage functional activity, and a close functional homolog of TFR1, the cellular receptor of the New World hemorrhagic fever arenaviruses. We also identified enriched KEGG pathways, “cell adhesion molecules”, “antigen processing and presentation”, “natural killer cell-mediated cytotoxicity”, and “immune network for IgA production”, relevant to immune response priming and immune activation to be associated with RV-specific immune outcomes. This study provides novel insights into potential biomarkers of rubella-specific immunity in women of childbearing age.

Older adults experience declining influenza vaccine-induced immunity and are at higher risk of influenza and its complications. For this reason, high dose (e.g., Fluzone) and adjuvanted (e.g., Fluad) vaccines are preferentially recommended for people age 65 years and older. However, T cell transcriptional activity shaping the humoral immune responses to Fluzone and Fluad vaccines in older adults is still poorly understood. We designed a study of 234 older adults (≥65 years old) who were randomly allocated to receive Fluzone or Fluad vaccine and provided blood samples at baseline and at Day 28 after immunization. We measured the humoral immune responses (hemagglutination inhibition/HAI antibody titer) to influenza A/H3N2 and performed mRNA-Seq transcriptional profiling in purified CD4+ T cells, in order to identify T cell signatures that might explain differences in humoral immune response by vaccine type. Given the large differences in formulation (higher antigen dose vs adjuvant), our hypothesis was that each vaccine elicited a distinct transcriptomic response after vaccination. Thus, the main focus of our study was to identify the differential gene expression influencing the antibody titer in the two vaccine groups. Our analyses identified three differentially expressed, functionally linked genes/proteins in CD4+ T cells: the calcium/calmodulin dependent serine/threonine kinase IV (CaMKIV); its regulator the TMEM38B/transmembrane protein 38B, involved in maintenance of intracellular Ca2+ release; and the transcriptional coactivator CBP/CREB binding protein, as regulators of transcriptional activity/function in CD4+ T cells that impact differences in immune response by vaccine type. Significantly enriched T cell-specific pathways/biological processes were also identified that point to the importance of genes/proteins involved in Th1/Th2 cell differentiation, IL-17 signaling, calcium signaling, Notch signaling, MAPK signaling, and regulation of TRP cation Ca2+ channels in humoral immunity after influenza vaccination. In summary, we identified the genes/proteins and pathways essential for cell activation and function in CD4+ T cells that are associated with differences in influenza vaccine-induced humoral immunity by vaccine type. These findings provide an additional mechanistic perspective for achieving protective immunity in older adults.

AbstractBackgroundA third dose of measles-mumps-rubella vaccine (MMR3) is recommended in mumps outbreak scenarios, but the immune response and the need for widespread use of MMR3 remain uncertain. Herein, we characterized measles-specific immune responses to MMR3 in a cohort of 232 healthy subjects.MethodsSerum and peripheral blood mononuclear cells (PBMCs) were sampled at day 0 and day 28 after MMR3. Measles-specific binding and neutralizing antibodies were quantified in sera by enzyme-linked immunosorbent assay and a microneutralization assay, respectively. PBMCs were stimulated with inactivated measles virus, and the release of cytokines/chemokines was assessed by a multiplex assay. Demographic variables of subjects were examined for potential correlations with immune outcomes.ResultsOf the study participants, 95.69% and 100% were seropositive at day 0 and day 28, respectively. Antibody avidity significantly increased from 38.08% at day 0 to 42.8% at day 28 (P = .00026). Neutralizing antibodies were significantly enhanced, from 928.7 at day 0 to 1289.64 mIU/mL at day 28 (P = .0001). Meanwhile, cytokine/chemokine responses remained largely unchanged. Body mass index was significantly correlated with the levels of inflammatory cytokines/chemokines.ConclusionsMeasles-specific humoral immune responses, but not cellular responses, were enhanced after MMR3 receipt, extending current understanding of immune responses to MMR3 and supporting MMR3 administration to seronegative or high-risk individuals.

Abstract The durability of protective humoral immunity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and infection is largely dependent on the generation and persistence of antigen-specific isotype-switched memory B cells (MBCs) and long-lived plasma cells that reside in the bone marrow and secrete high-affinity neutralizing antibodies. The reactivity of vaccine-induced MBCs to emerging clinically significant SARS-CoV-2 variants of concern (VoCs) is largely unknown. In a longitudinal cohort study (up to 6 months following coronavirus disease 2019 messenger RNA vaccination), we measured MBCs in concert with other functional antibody measures. We found statistically significant differences between the frequencies of MBCs responding to homologous and VoC (Beta, Gamma, and Delta) receptor-binding domains after vaccination that persisted over time. In concert with a waning antibody response, the reduced MBC response to VoCs could translate to a weaker subsequent recall immune response and increased susceptibility to the emerging SARS-CoV-2 variant strains after vaccination.

Abstract Multiple factors linked to host genetics/inherent biology play a role in interindividual variability in immune response outcomes after rubella vaccination. In order to identify these factors, we conducted a study of rubella‐specific humoral immunity before (Baseline) and after (Day 28) a third dose of MMR‐II vaccine in a cohort of 109 women of childbearing age. We performed mRNA‐Seq profiling of PBMCs after rubella virus in vitro stimulation to delineate genes associated with post‐vaccination rubella humoral immunity and to define genes mediating the association between prior immune response status (high or low antibody) and subsequent immune response outcome. Our study identified novel genes that mediated the association between prior immune response and neutralizing antibody titer after a third MMR vaccine dose. These genes included the following: CDC34 ; CSNK1D ; APOBEC3F ; RAD18 ; AAAS ; SLC37A1 ; FAS ; and JAK2 . The encoded proteins are involved in innate antiviral response, IFN/cytokine signaling, B cell repertoire generation, the clonal selection of B lymphocytes in germinal centers, and somatic hypermutation/antibody affinity maturation to promote optimal antigen‐specific B cell immune function. These data advance our understanding of how subjects’ prior immune status and/or genetic propensity to respond to rubella/MMR vaccination ultimately affects innate immunity and humoral immune outcomes after vaccination.

AbstractThis article provides a review of studies evaluating the role of host (and viral) genetics (including variation in HLA genes) in the immune response to coronaviruses, as well as the clinical outcome of coronavirus‐mediated disease. The initial sections focus on seasonal coronaviruses, SARS‐CoV, and MERS‐CoV. We then examine the state of the knowledge regarding genetic polymorphisms and SARS‐CoV‐2 and COVID‐19. The article concludes by discussing research areas with current knowledge gaps and proposes several avenues for future scientific exploration in order to develop new insights into the immunology of SARS‐CoV‐2.