Objectives This study aimed to determine antibody responses in healthcare workers who receive the BNT162b2 mRNA COVID-19 vaccine and identify factors that predict the response. Methods We recruited healthcare workers receiving the BNT162b2 mRNA COVID-19 vaccine at the Chiba University Hospital COVID-19 Vaccine Center. Blood samples were obtained before the 1 st dose and after the 2 nd dose vaccination, and serum antibody titers were determined using Elecsys® Anti-SARS-CoV-2S, an electrochemiluminescence immunoassay. We established a model to identify the baseline factors predicting post-vaccine antibody titers using univariate and multivariate linear regression analyses. Results Two thousand fifteen individuals (median age 37-year-old, 64.3% female) were enrolled in this study, of which 10 had a history of COVID-19. Before vaccination, 21 participants (1.1%) had a detectable antibody titer (≥0.4 U/mL) with a median titer of 35.9 U/mL (interquartile range [IQR] 7.8 – 65.7). After vaccination, serum anti-SARS-CoV-2S antibodies (≥0.4 U/mL) were detected in all 1,774 participants who received the 2 nd dose with a median titer of 2,060.0 U/mL (IQR 1,250.0 – 2,650.0). Immunosuppressive medication (p<0.001), age (p<0.001), time from 2 nd dose to sample collection (p<0.001), glucocorticoids (p=0.020), and drinking alcohol (p=0.037) were identified as factors predicting lower antibody titers after vaccination, whereas previous COVID-19 (p<0.001), female (p<0.001), time between 2 doses (p<0.001), and medication for allergy (p=0.024) were identified as factors predicting higher serum antibody titers. Conclusions Our data demonstrate that healthcare workers universally have good antibody responses to the BNT162b2 mRNA COVID-19 vaccine. The predictive factors identified in our study may help optimize the vaccination strategy.

Rationale: The transcriptional networks guiding heart development remain poorly understood, despite the identification of several essential cardiac transcription factors. Objective: To isolate novel cardiac transcription factors, we performed gene chip analysis and found that Zac1, a zinc finger-type transcription factor, was strongly expressed in the developing heart. This study was designed to investigate the molecular and functional role of Zac1 as a cardiac transcription factor. Methods and Results: Zac1 was strongly expressed in the heart from cardiac crescent stages and in the looping heart showed a chamber-restricted pattern. Zac1 stimulated luciferase reporter constructs driven by ANF, BNP, or ␣MHC promoters. Strong functional synergy was seen between Zac1 and Nkx2-5 on the ANF promoter, which carries adjacent Zac1 and Nkx2-5 DNA-binding sites. Zac1 directly associated with the ANF promoter in vitro and in vivo, and Zac1 and Nkx2-5 physically associated through zinc fingers 5 and 6 in Zac1, and the homeodomain in Nkx2-5. Zac1 is a maternally imprinted gene and is the first such gene found to be involved in heart development. Homozygous and paternally derived heterozygous mice carrying an interruption in the Zac1 locus showed decreased levels of chamber and myofilament genes, increased apoptotic cells, partially penetrant lethality and morphological defects including atrial and ventricular septal defects, and thin ventricular walls. Conclusions: Zac1 plays an essential role in the cardiac gene regulatory network. Our data provide a potential mechanistic link between Zac1 in cardiogenesis and congenital heart disease manifestations associated with genetic or epigenetic defects in an imprinted gene network. (Circ Res. 2010;106:1083-1091.)

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Interleukin-4 (IL-4) suppresses the development of multiple sclerosis in a murine model of experimental autoimmune encephalomyelitis (EAE). Here, we show in mice with EAE that, compared with the administration of wild-type IL-4 or of the clinically approved drug fingolimod, the systemic injection of serum albumin (SA) fused to IL-4 better accumulates and persists in lymph nodes and in the spleen, leading to higher therapeutic efficacy and to the prevention of disease development in the majority of the mice. We also show that the SA-IL-4 fusion protein prevented immune-cell infiltration in the spinal cord, decreased integrin expression in antigen-specific CD4 + T cells, increased the number of granulocyte-like myeloid-derived suppressor cells (and their expression of programmed-death-ligand-1) in spinal-cord-draining lymph nodes, and decreased the number of T helper 17 cells, a pathogenic cell population in EAE. In mice with chronic EAE, SA-IL-4 inhibited immune-cell infiltration into the spinal cord and completely abrogated immune responses to myelin antigen in the spleen. The SA-IL-4 fusion protein may be prophylactically and therapeutically advantageous in the treatment of multiple sclerosis. Multiple sclerosis (MS) is a potentially disabling autoimmune disease that affects millions globally. Autoreactive immune cells home to the central nervous system (CNS) and cause demyelination and consequently focal damage to white matter 1 . Lymphocytes and macrophages that have infiltrated into the CNS cause axonal damage. Recent studies have shown that Th17 cells, activated in the secondary lymphoid organs (SLOs), migrate to the spinal cord and brain and play a crucial role in the disease development and severity of MS 2, 3 . Thus, inhibition of lymphocyte migration to the CNS and inducing an immune-suppressive microenvironment in the SLOs would provide an effective therapy for MS. FTY720 (fingolimod) and anti-integrin α4 antibody (natalizumab) are used in the clinic for treating MS 4, 5 , sequestering lymphocytes in the LNs and preventing them from reacting with autoantigens in target tissues. Experimental autoimmune encephalomyelitis (EAE) is a widely accepted murine model of MS, reflecting many features of disease progression and developmental mechanism, including lymphocyte migration to the CNS and demyelination.Interleukin (IL)-4 is a pleiotropic anti-inflammatory cytokine that differentiates naïve CD4 + T cells into a Th2 phenotype and results in decreased differentiation into Th1 and Th17 6 . IL-4 suppresses re-activation of committed Th17 cells 6 . Moreover, IL-4 polarizes macrophages toward the M2 phenotype, an antiinflammatory phenotype 7 . IL-4 has been reported to suppress EAE disease incidence and severity 8,9 ; this occurs not only through direct immuno-modulation, as a recent study has shown that intranasally administered IL-4 improved disease outcomes of EAE through IL-4 directly binding to neurons to promote regeneration 10 .Although IL-4 stimulates multiple pathways to suppress EAE, it has yet to be tr...