title: Identification of GLA/SE as an effective adjuvant for the induction of robust humoral and cell-mediated immune responses to EBV-gp350 in mice and rabbits.
abstract: Childhood infection with Epstein-Barr virus (EBV) is often asymptomatic and may result in mild flu-like symptoms, but exposure during adolescence and young adulthood can lead to acute infectious mononucleosis (AIM) with a pathology characterized by swollen lymph nodes, sore throat, and severe fatigue lasting weeks or months. A vaccine targeting the envelope glycoprotein gp350 adjuvanted with aluminum hydroxide complexed with the TLR4 agonist monophosphoryl lipid A (MPLA) achieved a 78% reduction in AIM incidence in a small phase II trial of college-age individuals, but development of this vaccine was halted by the manufacturer. Here, we report the evaluation in mice and rabbits of an EBV-gp350 vaccine combined with an adjuvant composed of the synthetic TLR4 agonist glucopyranosyl lipid A (GLA) integrated into stable emulsion (SE). In mice, GLA/SE-adjuvanted gp350 generated high IgG titers (both IgG1 and IgG2a/c subtypes), elevated EBV-neutralizing antibody titers, and robust poly-functional anti-gp350 CD4(+) T cell responses. In addition, GLA/SE routinely demonstrated superior performance over aluminum hydroxide in all immunological readouts, including induction of durable neutralizing antibody titers out to at least 1 year post-vaccination. Both components of the GLA/SE adjuvant were found to be required to get optimal responses in both arms of the immune response: specifically, SE for neutralizing antibodies and GLA for induction of T cell responses. Furthermore, this vaccine also elicited high neutralizing antibody titers in a second species, rabbit. These promising results suggest that clinical development of a vaccine comprised of EBV-gp350 plus GLA/SE has the potential to prevent AIM in post-adolescents.
authors.affiliation: Applied Immunology and Microbiology Group, MedImmune, Mountain View, CA, USA.
authors.forename: Darren S
authors.initials: DS
authors.lastname: Heeke
authors.affiliation: Applied Immunology and Microbiology Group, MedImmune, Mountain View, CA, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Lin
authors.affiliation: Translational Biology Group, MedImmune, Mountain View, CA, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Rao
authors.affiliation: Translational Biology Group, MedImmune, Mountain View, CA, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Woo
authors.affiliation: Vaccine Platform Group, MedImmune, Gaithersburg, MD, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: McCarthy
authors.affiliation: Vaccine Platform Group, MedImmune, Gaithersburg, MD, USA. Electronic address: marshallj@medimmune.com.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Marshall
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005960:Glucosides / Q000008:administration & dosage; D004854:Herpesvirus 4, Human; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007074:Immunoglobulin G / Q000097:blood; D008050:Lipid A / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D011817:Rabbits; D051197:Toll-Like Receptor 4 / Q000819:agonists; D014763:Viral Matrix Proteins / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D005960:Glucosides; D007074:Immunoglobulin G; D008050:Lipid A; D051197:Toll-Like Receptor 4; D014763:Viral Matrix Proteins; D014765:Viral Vaccines; C000608161:glucopyranosyl lipid-A
keywords: Adjuvants; Epstein–Barr virus; GLA; Gp350; Infectious mononucleosis