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Research Overview

Simon van Haren’s research is focused on better understanding the molecular basis of age-specific immune responses to vaccines. Understanding how the human immune system changes with age in how it responds to vaccination can ultimately inform the development of novel vaccines to provide early life protection against pathogens such as Respiratory Syncytial Virus (RSV).

  • A major area of his research is to dissect the molecular mechanism of adjuvant synergy. Adjuvants are key vaccine components capable of instructing different types of immune responses. Supported by an Early Career Award from the Thrasher Research Fund, he completed a project that aims to identify combinations of Toll-like receptor (TLR) and C-type lectin receptor (CLR) agonists that could overcome the classical impairment in CD4+ T cell-polarization seen in newborns. This study has identified novel age-dependent synergy between specific TLR and CLR adjuvant combinations, which are currently under evaluation for their ability to enhance early life immunity against RSV.
  • The second major area of Dr. van Haren’s research is the study of antigen presentation and the effect of vaccine adjuvants on this process. Dr. van Haren has developed a portfolio of mass-spectrometry techniques and cell culture platforms that can be used to study the ability of vaccine adjuvants, or combinations, to enhance the presentation of vaccine antigens on MHC class II or to induce antigen cross-presentation on MHC class I. The ability to induce cross-presentation and subsequently induce a CD8+ T cell response is key for developing immunity against intracellular pathogens such as RSV or Influenza.

Dr. van Haren has modeled the immune systems of newborns, 6-month old infants, adults, and elderly individuals in different in vitro settings, such as whole blood, monocytes, monocyte-derived DCs, B-and T-cells and a microphysiological tissue construct. Using state-of-the-art mass-spectrometry and cell biology techniques he aims to unravel the ontogeny of the human immune response to vaccines at the molecular level, with the goal to provide novel insights relevant to future vaccine development.

Research Background

Simon van Haren obtained his Ph.D at Utrecht University in The Netherlands, where he conducted immunological and biochemical research studying the formation of Factor VIII-neutralizing antibodies in patients with hemophilia A. His research project was focused on the mechanism of endocytosis of Factor VIII by human dendritic cells, the presentation of antigenic peptides on MHC class II and the identification of antigen-specific CD4+ T cells.

He undertook postdoctoral training in the lab of Dr. Ofer Levy in the Division of Infectious Diseases at Boston Children’s Hospital.

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Publications

  1. The BNT162b2 mRNA vaccine demonstrates reduced age-associated TH1 support in vitro and in vivo. iScience. 2024 Nov 15; 27(11):111055. View Abstract
  2. From hit to vial: Precision discovery and development of an imidazopyrimidine TLR7/8 agonist adjuvant formulation. Sci Adv. 2024 Jul 05; 10(27):eadg3747. View Abstract
  3. Respiratory infection- and asthma-prone, low vaccine responder children demonstrate distinct mononuclear cell DNA methylation pathways. Clin Epigenetics. 2024 Jul 03; 16(1):85. View Abstract
  4. Heterologous SARS-CoV-2 booster vaccine for individuals with hematological malignancies after a primary SARS-CoV-2 mRNA vaccine series. Vaccine. 2024 Sep 17; 42(22):126054. View Abstract
  5. Human In vitro Modeling Identifies Adjuvant Combinations that Unlock Antigen Cross-presentation and Promote T-helper 1 Development in Newborns, Adults and Elders. J Mol Biol. 2024 02 15; 436(4):168446. View Abstract
  6. Author Correction: Co-adjuvanting DDA/TDB liposomes with a TLR7 agonist allows for IgG2a/c class-switching in the absence of Th1 cells. NPJ Vaccines. 2024 Jan 11; 9(1):13. View Abstract
  7. Co-adjuvanting DDA/TDB liposomes with a TLR7 agonist allows for IgG2a/c class-switching in the absence of Th1 cells. NPJ Vaccines. 2023 Dec 22; 8(1):189. View Abstract
  8. Modeling human immune responses to vaccination in vitro. Trends Immunol. 2024 01; 45(1):32-47. View Abstract
  9. Human in vitro modeling of adjuvant formulations demonstrates enhancement of immune responses to SARS-CoV-2 antigen. NPJ Vaccines. 2023 Oct 26; 8(1):163. View Abstract
  10. A protocol for high-throughput screening for immunomodulatory compounds using human primary cells. STAR Protoc. 2023 Sep 15; 4(3):102405. View Abstract
  11. Integrative systems biology characterizes immune-mediated neurodevelopmental changes in murine Zika virus microcephaly. iScience. 2023 Jul 21; 26(7):106909. View Abstract
  12. The mRNA vaccine BNT162b2 demonstrates impaired TH1 immunogenicity in human elders in vitro and aged mice in vivo. Res Sq. 2022 Dec 21. View Abstract
  13. Shaping Neonatal Immunization by Tuning the Delivery of Synergistic Adjuvants via Nanocarriers. ACS Chem Biol. 2022 09 16; 17(9):2559-2571. View Abstract
  14. Immunogenicity of a Three-Dose Primary Series of mRNA COVID-19 Vaccines in Patients With Lymphoid Malignancies. Open Forum Infect Dis. 2022 Aug; 9(8):ofac417. View Abstract
  15. Precision Vaccines: Lessons Learned From the Coronavirus Pandemic. Clin Infect Dis. 2022 08 15; 75(Suppl 1):S1. View Abstract
  16. Implications of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Pandemic on the Epidemiology of Pediatric Respiratory Syncytial Virus Infection. Clin Infect Dis. 2022 08 15; 75(Suppl 1):S130-S135. View Abstract
  17. CAF08 adjuvant enables single dose protection against respiratory syncytial virus infection in murine newborns. Nat Commun. 2022 08 02; 13(1):4234. View Abstract
  18. Adjuvant Discovery via a High Throughput Screen using Human Primary Mononuclear Cells. bioRxiv. 2022 Jul 11. View Abstract
  19. Bacille Calmette-Guérin vaccine reprograms human neonatal lipid metabolism in vivo and in vitro. Cell Rep. 2022 05 03; 39(5):110772. View Abstract
  20. An aluminum hydroxide:CpG adjuvant enhances protection elicited by a SARS-CoV-2 receptor binding domain vaccine in aged mice. Sci Transl Med. 2022 Jan 26; 14(629):eabj5305. View Abstract
  21. Ontogeny of plasma cytokine and chemokine concentrations across the first week of human life. Cytokine. 2021 12; 148:155704. View Abstract
  22. Human Newborn Monocytes Demonstrate Distinct BCG-Induced Primary and Trained Innate Cytokine Production and Metabolic Activation In Vitro. Front Immunol. 2021; 12:674334. View Abstract
  23. Alum:CpG adjuvant enables SARS-CoV-2 RBD-induced protection in aged mice and synergistic activation of human elder type 1 immunity. bioRxiv. 2021 May 21. View Abstract
  24. Human Blood Plasma Shapes Distinct Neonatal TLR-Mediated Dendritic Cell Activation via Expression of the MicroRNA Let-7g. Immunohorizons. 2021 04 30; 5(4):246-256. View Abstract
  25. Vaccine-Induced CD8+ T Cell Responses in Children: A Review of Age-Specific Molecular Determinants Contributing to Antigen Cross-Presentation. Front Immunol. 2020; 11:607977. View Abstract
  26. Corrigendum: Clinical Protocol for a Longitudinal Cohort Study Employing Systems Biology to Identify Markers of Vaccine Immunogenicity in Newborn Infants in The Gambia and Papua New Guinea. Front Pediatr. 2020; 8:610461. View Abstract
  27. Preparing for Life: Plasma Proteome Changes and Immune System Development During the First Week of Human Life. Front Immunol. 2020; 11:578505. View Abstract
  28. Towards Precision Vaccines: Lessons From the Second International Precision Vaccines Conference. Front Immunol. 2020; 11:590373. View Abstract
  29. Clinical Protocol for a Longitudinal Cohort Study Employing Systems Biology to Identify Markers of Vaccine Immunogenicity in Newborn Infants in The Gambia and Papua New Guinea. Front Pediatr. 2020; 8:197. View Abstract
  30. BCG as a Case Study for Precision Vaccine Development: Lessons From Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny. Front Microbiol. 2020; 11:332. View Abstract
  31. Licensed Bacille Calmette-Guérin (BCG) formulations differ markedly in bacterial viability, RNA content and innate immune activation. Vaccine. 2020 02 24; 38(9):2229-2240. View Abstract
  32. Cyclic AMP in human preterm infant blood is associated with increased TLR-mediated production of acute-phase and anti-inflammatory cytokines in vitro. Pediatr Res. 2020 11; 88(5):717-725. View Abstract
  33. Dynamic molecular changes during the first week of human life follow a robust developmental trajectory. Nat Commun. 2019 03 12; 10(1):1092. View Abstract
  34. First International Precision Vaccines Conference: Multidisciplinary Approaches to Next-Generation Vaccines. mSphere. 2018 08 01; 3(4). View Abstract
  35. Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses. J Allergy Clin Immunol. 2017 Nov; 140(5):1339-1350. View Abstract
  36. TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth. JCI Insight. 2017 03 23; 2(6):e91020. View Abstract
  37. A Meningococcal Outer Membrane Vesicle Vaccine Incorporating Genetically Attenuated Endotoxin Dissociates Inflammation from Immunogenicity. Front Immunol. 2016; 7:562. View Abstract
  38. Age-Specific Adjuvant Synergy: Dual TLR7/8 and Mincle Activation of Human Newborn Dendritic Cells Enables Th1 Polarization. J Immunol. 2016 12 01; 197(11):4413-4424. View Abstract
  39. Distinct TLR-mediated cytokine production and immunoglobulin secretion in human newborn naïve B cells. Innate Immun. 2016 08; 22(6):433-43. View Abstract
  40. In vitro cytokine induction by TLR-activating vaccine adjuvants in human blood varies by age and adjuvant. Cytokine. 2016 07; 83:99-109. View Abstract
  41. The Imidazoquinoline Toll-Like Receptor-7/8 Agonist Hybrid-2 Potently Induces Cytokine Production by Human Newborn and Adult Leukocytes. PLoS One. 2015; 10(8):e0134640. View Abstract
  42. Soluble mediators regulating immunity in early life. Front Immunol. 2014; 5:457. View Abstract
  43. Limited promiscuity of HLA-DRB1 presented peptides derived of blood coagulation factor VIII. PLoS One. 2013; 8(11):e80239. View Abstract
  44. Preferential HLA-DRB1*11-dependent presentation of CUB2-derived peptides by ADAMTS13-pulsed dendritic cells. Blood. 2013 Apr 25; 121(17):3502-10. View Abstract
  45. Modification of an exposed loop in the C1 domain reduces immune responses to factor VIII in hemophilia A mice. Blood. 2012 May 31; 119(22):5294-300. View Abstract
  46. Requirements for immune recognition and processing of factor VIII by antigen-presenting cells. Blood Rev. 2012 Jan; 26(1):43-9. View Abstract
  47. Uptake of blood coagulation factor VIII by dendritic cells is mediated via its C1 domain. J Allergy Clin Immunol. 2012 Feb; 129(2):501-9, 509.e1-5. View Abstract
  48. HLA-DR-presented peptide repertoires derived from human monocyte-derived dendritic cells pulsed with blood coagulation factor VIII. Mol Cell Proteomics. 2011 Jun; 10(6):M110.002246. View Abstract
  49. T-cell responses in two unrelated hemophilia A inhibitor subjects include an epitope at the factor VIII R593C missense site. J Thromb Haemost. 2011 Apr; 9(4):689-99. View Abstract
  50. The Peroxisomal Targeting Signal 1 in sterol carrier protein 2 is autonomous and essential for receptor recognition. BMC Biochem. 2011 Mar 04; 12:12. View Abstract
  51. Getting rid of bad memory. Blood. 2011 Jan 06; 117(1):7-8. View Abstract
  52. Factor VIII-specific B cell responses in haemophilia A patients with inhibitors. Haemophilia. 2010 May; 16(102):35-43. View Abstract
  53. STAT3-mediated up-regulation of BLIMP1 Is coordinated with BCL6 down-regulation to control human plasma cell differentiation. J Immunol. 2008 Apr 01; 180(7):4805-15. View Abstract

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