title: Concurrent influenza vaccination reduces anti-FVIII antibody responses in murine hemophilia A.
abstract: Inflammatory signals such as pathogen- and danger-associated molecular patterns have been hypothesized as risk factors for the initiation of the anti-factor VIII (FVIII) immune response seen in 25% to 30% of patients with severe hemophilia A (HA). In these young patients, vaccines may be coincidentally administered in close proximity with initial exposure to FVIII, thereby providing a source of such stimuli. Here, we investigated the effects of 3 vaccines commonly used in pediatric patients on FVIII immunogenicity in a humanized HA murine model with variable tolerance to recombinant human FVIII (rhFVIII). Mice vaccinated intramuscularly against the influenza vaccine prior to multiple infusions of rhFVIII exhibited a decreased incidence of rhFVIII-specific neutralizing and nonneutralizing antibodies. Similar findings were observed with the addition of an adjuvant. Upon exposure to media from influenza- or FVIII-stimulated lymph node or splenic lymphocytes, naïve CD4(+) lymphocytes preferentially migrated toward media from influenza-stimulated cells, indicating that antigen competition, by means of lymphocyte recruitment to the immunization site, is a potential mechanism for the observed decrease in FVIII immunogenicity. We also observed no differences in incidence or titer of rhFVIII-specific antibodies and inhibitors in mice exposed to the live-attenuated measles-mumps-rubella vaccine regardless of route of administration. Together, our results suggest that concomitant FVIII exposure and vaccination against influenza does not increase the risk of inhibitor formation and may in fact decrease anti-FVIII immune responses.
authors.affiliation: Department of Pathology & Molecular Medicine, Queen's University, Kingston, ON, Canada;
authors.forename: Jesse D
authors.identifier: 0000-0003-2916-2954
authors.initials: JD
authors.lastname: Lai
authors.affiliation: Discipline of Pediatrics, Faculty of Medicine, Memorial University, St. John's, NL, Canada; Section of Pediatric Hematology/Oncology, Janeway Children's Health and Rehabilitation Centre, St. John's, NL, Canada; and.
authors.forename: Paul C
authors.identifier: 0000-0001-8711-0445
authors.initials: PC
authors.lastname: Moorehead
authors.affiliation: Department of Pathology & Molecular Medicine, Queen's University, Kingston, ON, Canada;
authors.forename: Kate
authors.initials: K
authors.lastname: Sponagle
authors.affiliation: Baxalta Innovation GmbH, Vienna, Austria.
authors.forename: Katharina N
authors.initials: KN
authors.lastname: Steinitz
authors.affiliation: Baxalta Innovation GmbH, Vienna, Austria.
authors.forename: Birgit M
authors.initials: BM
authors.lastname: Reipert
authors.affiliation: Department of Pathology & Molecular Medicine, Queen's University, Kingston, ON, Canada;
authors.forename: Christine
authors.initials: C
authors.lastname: Hough
authors.affiliation: Department of Pathology & Molecular Medicine, Queen's University, Kingston, ON, Canada;
authors.forename: David
authors.initials: D
authors.lastname: Lillicrap
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D001323:Autoantibodies / Q000276:immunology*; D019774:Blood Coagulation Factor Inhibitors / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D005169:Factor VIII / Q000037:antagonists & inhibitors* / Q000276:immunology; D005260:Female; D006467:Hemophilia A / Q000276:immunology*; D006801:Humans; D007252:Influenza Vaccines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014611:Vaccination
chemical_list: D001323:Autoantibodies; D019774:Blood Coagulation Factor Inhibitors; D007252:Influenza Vaccines; D005169:Factor VIII