BackgroundHow infection shapes recall responses in the setting of preexisting influenza virus hemagglutinin (HA) stem-focused immunity has important implications given the known impact of imprinting on future immune responses. Adoption of an HA-based universal stem vaccine approach for young infants would likely result in stem-specific imprinting. Understanding how imprinting programs memory B cell recall and early antibody responses to HA stem and head in newborns is therefore essential.MethodsAfrican green monkeys vaccinated with a A/New Caledonia/20/1999 (NC99) hemagglutinin stem-bearing nanoparticle (H1ssF) adjuvanted with R848+AddaVax as newborns were challenged with H1N1 A/California/07/2009 (Ca09). Antibody and draining lymph node cellular responses were analyzed on d7 following challenge. Both quantitative and qualitative aspects of the antibody response were assessed.ResultsOur previous studies showed newborn African green monkeys vaccinated with an R848+AddaVax dual adjuvanted H1ssF nanoparticle exhibited a robust stem-specific antibody response that had broad reactivity and enhanced functional activity. In the present study, we investigated how the response elicited by this vaccine was recalled following infection, evaluating both antibody and cellular responses. While challenge resulted in increases in recognition of many heterologous HA molecules, not all responses showed evidence of boosting at this timepoint. Control (Ctrl) animals had limited neutralizing activity to Ca09 at d7 following infection, whereas challenge resulted in significant increases in neutralizing antibody to the challenge virus. Compared to Ctrl animals, vaccinated infants exhibited lower germinal center B cell responses and IFNγ-producing T follicular helper (Tfh) responses. However, vaccinated infants exhibited a significant increase in HA stem-specific plasmablasts and plasma cells in the lung-draining tracheobronchial lymph nodes together with similar head-specific responses.ConclusionCollectively, these findings are consistent with efficient recall of stem-specific responses generated by vaccination with dual adjuvanted H1ssF administered to newborn African green monkeys in response to influenza virus challenge. Interestingly, challenge with the heterologous virus appears to reshape the reactivity profile of the stem-specific response. Further, vaccinated animals exhibit robust early antibody-secreting cell responses, including increased numbers of stem-specific cells, without an apparent reduction in the generation of head-specific cells.

The absence of an approved influenza vaccine for young infants, combined with the annual requirement for updates, underscores the urgent need for a universal vaccine that is effective in newborns. The H1ssF vaccine, an influenza hemagglutinin stem-bearing nanoparticle, generates broadly protective responses in adult animal models and humans. Here, we use a nonhuman primate model to explore the ability of H1ssF, adjuvanted with R848 and AddaVax, to induce a protective response in the altered immune setting of newborns. We find that the vaccine induces strong stem-specific IgG responses that are broadly reactive. Notably, the vaccine promotes antibodies with neutralizing activity and broad Fc effector functions in all newborns. Finally, administration of this vaccine confers improved viral clearance after challenge. These findings demonstrate the potential of this dual-adjuvanted stem nanoparticle to serve as an effective vaccine approach that can elicit protective responses in newborns against influenza A virus infection.

There is an urgent need for strategies that can improve vaccine immunogenicity, especially for vulnerable populations such as newborns and young infants. Growing evidence supports Toll-Like Receptor agonists (TLRa) as potent stimulatory molecules to increase vaccine efficacy. We have previously demonstrated that the inclusion of either flagellin (TLR5a) or R848 (TLR7/8a) in an inactivated influenza virus vaccine can improve responses in newborn NHP, with R848 being superior at providing protection upon challenge. This study aimed to identify early immune events triggered by either inactivated virus alone or in combination with R848 or flagellin using scRNA-seq analysis of draining lymph nodes (dLN) collected 24 h after vaccination. Our study reveals that globally, R848 enhanced gene expression associated with B cell activation, while flagellin was a stronger modulator of T cells. Analysis of distinct lymph node populations showed that surprisingly, while APCs had a potent transcriptional response to inactivated virus, we observed minimal additional changes in transcriptional activity with addition of a TLRa. In contrast, R848 had a potent effect on cellular translation, while flagellin resulted in increased expression of type I interferon genes in B cells. All vaccines resulted in a population of T cells bearing an interferon response signature that was further modified by TLRa inclusion. R848 uniquely increased the expression of genes involved with cellular migration and inflammation in this population, while flagellin increased genes involved in vesicular trafficking, cAMP responsiveness, and calcium signaling. Together, these results suggest R848 promotes newborn B cell activation and enhanced migration/retention in the dLN. In contrast, flagellin amplifies the type I interferon signature of B cells and had broad impacts on the responding T cell population. Our findings provide new insights into the modulation of early vaccine responses in newborns following administration of inactivated influenza virus, R848 and flagellin.

The lack of an approved influenza vaccine for infants <6 months, coupled with the requirement for annual updates of current vaccines, warrants the development of a universal vaccine that can confer protection in young infants. Here we test the ability of a ferritin nanoparticle universal influenza vaccine (H1ssF) containing the stem region of hemagglutinin (HA) adjuvanted with AddaVax to elicit responses in newborn African green monkeys (AGM). Vaccinated newborns show robust HA stem-specific IgG responses but, despite the high antibody levels, viral load in the lung following H1N1 Ca09 challenge is variable among animals. Further analysis indicates that viral clearance is correlated with the presence of antibodies with neutralizing and antibody-dependent cellular phagocytosis activity. Our findings show that newborn AGM can generate functional HA stem-specific antibodies for viral clearance following vaccination with H1ssF+AddaVax and support further investigation of H1ssF as a universal vaccine for this vulnerable human population.

Influenza virus infection poses a significant health risk to newborns, with this population experiencing higher hospitalization and mortality rates compared to older children. The heightened vulnerability of this age group results from a combination of an altered immune system and lack of a licensed vaccine for children under six months of age. mRNA-LNP vaccines have shown remarkable efficacy, including the capacity to induce antibodies in poorly responding populations. This makes them a promising candidate for addressing the unique immunological environment of newborns. Here, we leveraged the close immunological and physiological similarity of NHP to evaluate the efficacy of an influenza hemagglutinin mRNA-LNP vaccine in newborns. Our findings show the HA mRNA-LNP vaccine elicits robust, multi-functional antibody responses in newborn NHP that result in significantly reduced viral load and disease severity following challenge. These results highlight the potential of mRNA-based vaccines as a transformative approach to protect the vulnerable newborn population against influenza. Continued development and optimization of this platform could address the critical gap in influenza virus and other pathogen vaccine coverage for infants under six months of age.

A number of studies have demonstrated the role of sex in regulating immune responses to vaccination. However, these findings have been limited to adults for both human and animal models. As a result, our understanding of the impact of sex on vaccine responses in the newborn is highly limited. Here, we probe this important question using a newborn non-human primate model. We leveraged our prior analysis of two cohorts of newborns, with one being mother-reared and one nursery-reared. This provided adequate numbers of males and females to interrogate the impact of sex on the response to inactivated influenza vaccines alone or adjuvanted with R848, flagellin, or both. We found that, in contrast to what has been reported in adults, the non-adjuvanted inactivated influenza virus vaccine induced similar levels of virus-specific IgG in male and female newborns. However, the inclusion of R848, either alone or in combination with flagellin, resulted in higher antibody titers in females compared to males. Sex-specific increases in the neutralizing antibody were only observed when both R848 and flagellin were present. These data, generated in the highly translational NHP newborn model, provide novel insights into the role of sex in the immune response of newborns.

The objective of this study was to evaluate hemagglutinin stem‐specific antibody response to the influenza vaccine during pregnancy and its transfer to the infant.

Immune responses to COVID-19 mRNA vaccines have not been well characterized in frail older adults. We postulated that frailty is associated with impaired antibody and cellular mRNA vaccine responses. We followed older adults in a retirement facility with longitudinal clinical and serological samples from the first Moderna mRNA-1273 vaccine dose starting in February 2021 through their 3rd (booster) vaccine dose. Outcomes were antibody titers, antibody avidity, and AIM+ T cell function and phenotype. Statistical analysis used linear regression with clustered error for antibody titers over multiple timepoints with clinical predictors including, age, sex, prior infection status, and clinical frailty scale (CFS) score. T cell function analysis used linear regression models with clinical predictors and cellular memory phenotype variables. Participants (n = 15) had median age of 90 years and mild, moderate, or severe frailty scores (n = 3, 7, or 5 respectively). Over the study time course, anti-spike antibody titers were 10-fold higher in individuals with lower frailty status (p = 0.001 and p = 0.005, unadjusted and adjusted for prior COVID-19 infection). Following the booster, titers to spike protein improved regardless of COVID-19 infection or degree of frailty (p = 0.82 and p = 0.29, respectively). Antibody avidity significantly declined over 6 months in all participants following 2 vaccine doses (p < 0.001), which was further impaired with higher frailty (p = 0.001). Notably, avidity increased to peak levels after the booster (p < 0.001). Overall antibody response was inversely correlated with a phenotype of immune-senescent T cells, CD8 + CD28- TEMRA cells (p = 0.036, adjusted for COVID-19 infection). Furthermore, there was increased detection of CD8 + CD28- TEMRA cells in individuals with greater frailty (p = 0.056, adjusted for COVID-19). We evaluated the immune responses to the Moderna COVID-19 mRNA vaccine in frail older adults in a retirement community. A higher degree of frailty was associated with diminished antibody quantity and quality. However, a booster vaccine dose at 6 months overcame these effects. Frailty was associated with an increased immune-senescence phenotype that may contribute to the observed changes in the vaccine response. While the strength of our conclusions was limited by a small cohort, these results are important for guiding further investigation of vaccine responses in frail older adults.

Supplementary Figure from Circulating Immune Bioenergetic, Metabolic, and Genetic Signatures Predict Melanoma Patients' Response to Anti–PD-1 Immune Checkpoint Blockade

Subunit or inactivated vaccines comprise the majority of vaccines used against viral and bacterial pathogens. However, compared to their live/attenuated counterparts, these vaccines often demonstrate reduced immunogenicity, requiring multiple boosters and or adjuvants to elicit protective immune responses. For this reason, studies of adjuvants and the mechanism through which they can improve inactivated vaccine responses are critical for the development of vaccines with increased efficacy. Studies have shown that the direct conjugation of adjuvant to antigen promotes vaccine immunogenicity, with the advantage of both the adjuvant and antigen targeting the same cell. Using this strategy of direct linkage, we developed an inactivated influenza A (IAV) vaccine that is directly conjugated with the Toll-like receptor 7/8 agonist resiquimod (R848) through a heterobifunctional crosslinker. Previously, we showed that this vaccine resulted in improved protection and viral clearance in newborn nonhuman primates compared to a non-adjuvanted vaccine. We subsequently discovered that the choice of linker used to conjugate R848 to the virus alters the stimulatory activity of the vaccine, promoting increased maturation and proinflammatory cytokine production from DC differentiated in vitro. With this knowledge, we explored how the choice of crosslinker impacts the stimulatory activity of these vaccines. We found that the linker choice alters signaling through the NF-κB pathway in human monocyte-derived dendritic cells (moDCs). Further, we extended our analyses to in vivo differentiated APC present in human peripheral blood, replicating the linker-dependent differences found in in vitro differentiated cells. Finally, we demonstrated in a mouse model that the choice of linker impacts the amount of IAV-specific IgG antibody produced in response to vaccination. These data enhance our understanding of conjugation approaches for improving vaccine immunogenicity.

Background CD47 is an integral membrane protein that alters adaptive immunosurveillance when bound to the matricellular glycoprotein thrombospondin-1 (TSP1). We examined the impact of the CD47/TSP1 signaling axis on melanoma patient response to anti-PD-1 therapy due to alterations in T cell activation, proliferation, effector function, and bioenergetics. Methods A syngeneic B16 mouse melanoma model was performed to determine if targeting CD47 as monotherapy or in combination with anti-PD-1 impacted tumor burden. Cytotoxic (CD8+) T cells from Pmel-1 transgenic mice were used for T cell activation, cytotoxic T lymphocyte, and cellular bioenergetic assays. Single-cell RNA-sequencing, ELISA, and flow cytometry was performed on peripheral blood mononuclear cells and plasma of melanoma patients receiving anti-PD-1 therapy to examine CD47/TSP1 expression. Results Human malignant melanoma tissue had increased CD47 and TSP1 expression within the tumor microenvironment compared with benign tissue. Due to the negative implications CD47/TSP1 can have on antitumor immune responses, we targeted CD47 in a melanoma model and observed a decrease in tumor burden due to increased tumor oxygen saturation and granzyme B secreting CD8+ T cells compared with wild-type tumors. Additionally, Pmel-1 CD8+ T cells exposed to TSP1 had reduced activation, proliferation, and effector function against B16 melanoma cells. Targeting CD47 allowed CD8+ T cells to overcome this TSP1 interaction to sustain these functions. TSP1 exposed CD8+ T cells have a decreased rate of glycolysis; however, targeting CD47 restored glycolysis when CD8+ T cells were exposed to TSP1, suggesting CD47 mediated metabolic reprogramming of T cells. Additionally, non-responding patients to anti-PD-1 therapy had increased T cells expressing CD47 and circulating levels of TSP1 compared with responding patients. Since CD47/TSP1 signaling axis negatively impacts CD8+ T cells and non-responding patients to anti-PD-1 therapy have increased CD47/TSP1 expression, we targeted CD47 in combination with anti-PD-1 in a melanoma model. Targeting CD47 in combination with anti-PD-1 treatment further decreased tumor burden compared with monotherapy and control. Conclusion CD47/TSP1 expression could serve as a marker to predict patient response to immune checkpoint blockade treatment, and targeting this pathway may preserve T cell activation, proliferation, effector function, and bioenergetics to reduce tumor burden as a monotherapy or in combination with anti-PD-1.

The newborn immune system is characterized by diminished immune responses that leave infants vulnerable to virus-mediated disease and make vaccination more challenging. Optimal vaccination strategies for influenza A virus (IAV) in newborns should result in robust levels of protective antibodies, including those with broad reactivity to combat the variability in IAV strains across seasons. The stem region of the hemagglutinin (HA) molecule is a target of such antibodies. Using a nonhuman primate model, we investigate the capacity of newborns to generate and maintain antibodies to the conserved stem region following vaccination. We find adjuvanting an inactivated vaccine with the TLR7/8 agonist R848 is effective in promoting sustained HA stem-specific IgG. Unexpectedly, HA stem-specific antibodies were generated with a distinct kinetic pattern compared to the overall response. Administration of R848 was associated with increased influenza-specific T follicular helper cells as well as Tregs with a less suppressive phenotype, suggesting adjuvant impacts multiple cell types that have the potential to contribute to the HA-stem response.

Elderly individuals are highly susceptible to developing severe outcomes as a result of influenza A virus (IAV) infection. This can be attributed to alterations that span the aged immune system, which also result in reduced responsiveness to the seasonal inactivated vaccine. Given the rapidly increasing number of individuals in this age group, it is imperative that we develop strategies that can better protect this population from IAV-associated disease. Based on our previous findings that the TLR7/8 agonist resiquimod (R848) could efficiently boost responses in the newborn, another population with decreased vaccine responsiveness, we evaluated this adjuvant in an elderly African green monkey (AGM) model. AGM aged 16–24 years old (equivalent to 64–96 in human years) were primed and boosted with inactivated A/PuertoRico/8/1934 (H1N1) (IPR8) alone or directly linked to R848 (IPR8-R848). We observed increases in the level of circulating virus-specific IgM antibody 10 days following primary vaccination in AGM that were vaccinated with IPR8-R848, but not IPR8 alone. In addition, there were significant increases in virus-specific IgG after boosting selectively in the IPR8-R848 vaccinated animals. These findings provide insights into the ability of R848 to modulate the aged immune system in the context of IAV vaccination.

BACKGROUND:COVID-19 has disproportionately affected older adults. Frailty has been associated with impaired vaccine response in other vaccine types, but the impact of frailty on mRNA vaccine response is undefined. METHODS:Observational study of adults aged 55 and older from 1 U.S. health care system between January 22, 2021 and September 16, 2021 with self-reported Moderna or Pfizer COVID-19 mRNA vaccine and an electronic frailty index (eFI) score from their medical record (n = 1 677). Participants' frailty status was compared with positive antibody detection (seroconversion) following full vaccination and subsequent loss of positive antibody detection (seroreversion) using logistic regression models. RESULTS:Of 1 677 older adults with median (interquartile range) age, 67 (62 and 72) years, and frailty status (nonfrail: 879 [52%], prefrail: 678 [40%], and frail: 120 [7.2%]), seroconversion was not detected in 23 (1.4%) over 60 days following full vaccination. Frail individuals were less likely to seroconvert than nonfrail individuals, adjusted odds ratio (OR) 3.75, 95% confidence interval (CI; 1.04, 13.5). Seroreversion was detected in 50/1 631 individuals (3.1%) over 6 months of median follow-up antibody testing. Frail individuals were more likely to serorevert than nonfrail individuals, adjusted OR 3.02, 95% CI (1.17, 7.33). CONCLUSION:Overall antibody response to COVID-19 mRNA vaccination was high across age and frailty categories. While antibody detection is an incomplete descriptor of vaccine response, the high sensitivity of this antibody combined with health-system data reinforce our conclusions that frailty is an independent predictor of impaired antibody response to the COVID-19 mRNA vaccines. Frailty should be considered in vaccine studies and prevention strategies.

Introduction The COVID-19 Community Research Partnership is a population-based longitudinal syndromic and sero-surveillance study. The study includes over 17,000 participants from six healthcare systems in North Carolina who submitted over 49,000 serology results. The purpose of this study is to use these serology data to estimate the cumulative proportion of the North Carolina population that has either been infected with SARS-CoV-2 or developed a measurable humoral response to vaccination. Methods Adult community residents were invited to participate in the study between April 2020 and February 2021. Demographic information was collected and daily symptom screen was completed using a secure, HIPAA-compliant, online portal. A portion of participants were mailed kits containing a lateral flow assay to be used in-home to test for presence of anti-SARS-CoV-2 IgM or IgG antibodies. The cumulative proportion of participants who tested positive at least once during the study was estimated. A standard Cox proportional hazards model was constructed to illustrate the probability of seroconversion over time up to December 20, 2020 (before vaccines available). A separate analysis was performed to describe the influence of vaccines through February 15, 2021. Results 17,688 participants contributed at least one serology result. 68.7% of the population were female, and 72.2% were between 18 and 59 years of age. The average number of serology results submitted per participant was 3.0 (±1.9). By December 20, 2020, the overall probability of seropositivity in the CCRP population was 32.6%. By February 15, 2021 the probability among healthcare workers and non-healthcare workers was 83% and 49%, respectively. An inflection upward in the probability of seropositivity was demonstrated around the end of December, suggesting an influence of vaccinations, especially for healthcare workers. Among healthcare workers, those in the oldest age category (60+ years) were 38% less likely to have seroconverted by February 15, 2021. Conclusions Results of this study suggest more North Carolina residents may have been infected with SARS-CoV-2 than the number of documented cases as determined by positive RNA or antigen tests. The influence of vaccinations on seropositivity among North Carolina residents is also demonstrated. Additional research is needed to fully characterize the impact of seropositivity on immunity and the ultimate course of the pandemic.

Hemagglutinin (HA) glycoprotein is the dominant antigen of current influenza vaccines and antigenic drift requires a seasonal vaccine. The stem region of HA is conserved and is therefore a promising target for a universal vaccine. Understanding HA stem specific response is crucial in universal vaccine development. We hypothesize that maternal vaccination with influenza vaccine would result in a boost of HA stem antibodies and higher concentrations in neonatal cord blood.

Abstract Purpose: Immunotherapy with checkpoint inhibitors is improving the outcomes of several cancers. However, only a subset of patients respond. Therefore, predictive biomarkers are critically needed to guide treatment decisions and develop approaches to the treatment of therapeutic resistance. Experimental Design: We compared bioenergetics of circulating immune cells and metabolomic profiles of plasma obtained at baseline from patients with melanoma treated with anti–PD-1 therapy. We also performed single-cell RNA sequencing (scRNAseq) to correlate transcriptional changes associated with metabolic changes observed in peripheral blood mononuclear cells (PBMC) and patient plasma. Results: Pretreatment PBMC from responders had a higher reserve respiratory capacity and higher basal glycolytic activity compared with nonresponders. Metabolomic analysis revealed that responder and nonresponder patient samples cluster differently, suggesting differences in metabolic signatures at baseline. Differential levels of specific lipid, amino acid, and glycolytic pathway metabolites were observed by response. Further, scRNAseq analysis revealed upregulation of T-cell genes regulating glycolysis. Our analysis showed that SLC2A14 (Glut-14; a glucose transporter) was the most significant gene upregulated in responder patients' T-cell population. Flow cytometry analysis confirmed significantly elevated cell surface expression of the Glut-14 in CD3+, CD8+, and CD4+ circulating populations in responder patients. Moreover, LDHC was also upregulated in the responder population. Conclusions: Our results suggest a glycolytic signature characterizes checkpoint inhibitor responders; consistently, both ECAR and lactate-to-pyruvate ratio were significantly associated with overall survival. Together, these findings support the use of blood bioenergetics and metabolomics as predictive biomarkers of patient response to immune checkpoint inhibitor therapy.

Abstract Prior COVID-19 mRNA vaccine trials included healthy older adults, but mRNA vaccine responses were not studied in frail older adults. We postulated that frailty was associated with immune responses of reduced quality and quantity following mRNA vaccination. A cohort of 15 older adults in a retirement facility were followed from the first Moderna mRNA-1273 vaccine dose in February 2021 with blood collections at baseline and weeks 4 (boost), 6, 18 and 28. Outcomes were IgG titers to SARS-CoV-2 Spike protein with secondary outcomes of T cell responses. Statistical analysis used log transformed geometric mean antibody titers in multivariable regression models with clinical predictors including, age, sex, prior infection status, and clinical frailty scale (CFS) score. Cellular immune response analysis used multivariable regression for function and phenotyping of T cell subsets. All participants with median (IQR) age: 90 years (84, 96) and CFS score: moderately frail 6 (5, 7) generated robust antibody responses with mean peak titer levels 10-fold higher than baseline. In the adjusted model, individuals with severely frail scores CFS=7 had lower antibody levels compared to mildly frail CFS=5, OR: 0.55 (0.35, 0.87) p=0.017. Both chronological age and sex had non-significant relationships with antibody titers. Spike peptide specific CD4 cells and T follicular helper cells were significantly decreased in more frail individuals (p=0.011 and p=0.008 respectively), though the relationship with antibody titers was non-significant. Frailty scores were a better predictor than age for serologic and cellular immune responses to COVID-19 mRNA vaccination in very old adults.

The immune system of young infants is both quantitatively and qualitatively distinct from that of adults, with diminished responsiveness leaving these individuals vulnerable to infection. Because of this, young infants suffer increased morbidity and mortality from respiratory pathogens such as influenza viruses. The impaired generation of robust and persistent antibody responses in these individuals makes overcoming this increased vulnerability through vaccination challenging. Because of this, an effective vaccine against influenza viruses in infants under 6 months is not available. Furthermore, vaccination against influenza viruses is challenging even in adults due to the high antigenic variability across viral strains, allowing immune evasion even after induction of robust immune responses. This has led to substantial interest in understanding how specific antibody responses are formed to variable and conserved components of influenza viruses, as immune responses tend to strongly favor recognition of variable epitopes. Elicitation of broadly protective antibody in young infants, therefore, requires that both the unique characteristics of young infant immunity as well as the antibody immunodominance present among epitopes be effectively addressed. Here, we review our current understanding of the antibody response in newborns and young infants and discuss recent developments in vaccination strategies that can modulate both magnitude and epitope specificity of IAV-specific antibody.

Spontaneous intracerebral hemorrhage (ICH) is a catastrophic illness causing significant morbidity and mortality. Despite advances in surgical technique addressing primary brain injury caused by ICH, little progress has been made treating the subsequent inflammatory cascade. Pre-clinical studies have made advancements identifying components of neuroinflammation, including microglia, astrocytes, and T lymphocytes. After cerebral insult, inflammation is initially driven by the M1 microglia, secreting cytokines (e.g., interleukin-1β [IL-1β] and tumor necrosis factor-α) that are involved in the breakdown of the extracellular matrix, cellular integrity, and the blood brain barrier. Additionally, inflammatory factors recruit and induce differentiation of A1 reactive astrocytes and T helper 1 (Th1) cells, which contribute to the secretion of inflammatory cytokines, augmenting M1 polarization and potentiating inflammation. Within 7 days of ICH ictus, the M1 phenotype coverts to a M2 phenotype, key for hematoma removal, tissue healing, and overall resolution of inflammation. The secretion of anti-inflammatory cytokines (e.g., IL-4, IL-10) can drive Th2 cell differentiation. M2 polarization is maintained by the secretion of additional anti-inflammatory cytokines by the Th2 cells, suppressing M1 and Th1 phenotypes. Elucidating the timing and trigger of the anti-inflammatory phenotype may be integral in improving clinical outcomes. A challenge in current translational research is the absence of an equivalent disease animal model mirroring the patient population and comorbid pathophysiologic state. We review existing data and describe potential therapeutic targets around which we are creating a bench to bedside translational research model that better reflects the pathophysiology of ICH patients.