title: Intranasal seasonal influenza vaccine and a TLR-3 agonist, rintatolimod, induced cross-reactive IgA antibody formation against avian H5N1 and H7N9 influenza HA in humans.
abstract: The intranasal use of rintatolimod, a specific TLR-3 agonist, combined with trivalent seasonal influenza vaccine generated cross-protection against highly pathogenic H5N1 avian influenza in mice. The purpose of this clinical trial is to assess the safety and impact of rintatolimod on intranasal influenza vaccine in healthy adults. During Stage I of this Phase I/II clinical trial, 12 volunteers were immunized intranasally with 3 doses of FluMist seasonal influenza vaccine on Days 0, 28, and 56 followed by intranasal rintatolimod (50 μg, 200 μg, or 500 μg) 3 days later. Parotid saliva and nasal wash samples were collected at baseline and on Days 25, 53, 84, and 417. The samples were tested for IgA and IgG specific antibodies (Ab) directed against the homologous FluMist viral hemagglutinins (HAs). In addition, viral specific responses against influenza A HAs were tested for IgA Ab cross-reactivity against 3 H5 clades: HA (H5N1) A/Indonesia/5/2005, HA (H5N1) A/Hong Kong/483/97 and HA (H5N1) A/Vietnam/1194/2004, as well as, two H7 strains, HA (H7N9) A/Shanghai/2/2013 and HA (H7N3) A/chicken/Jalisco/CPA1. The combination of the intranasal FluMist along with the rintatolimod generated specific secretory IgA responses of at least 4-fold over baseline against at least one of the homologous vaccine strains included in the vaccine in 92% of the vaccinees. Additionally, this vaccination strategy induced cross-reactive secretory IgA against highly pathogenic avian influenza virus strains H5N1, H7N9, and H7N3 with pandemic potential for humans. The combination of rintatolimod and FluMist was well-tolerated.
authors.affiliation: University of Alabama at Birmingham, 908 20th Street South, Birmingham, AL 35294, United States. Electronic address: toverton@uab.edu.
authors.forename: Edgar Turner
authors.initials: ET
authors.lastname: Overton
authors.affiliation: University of Alabama at Birmingham, 908 20th Street South, Birmingham, AL 35294, United States. Electronic address: paulg@uab.edu.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Goepfert
authors.affiliation: University of Alabama at Birmingham, 908 20th Street South, Birmingham, AL 35294, United States. Electronic address: pelliott@uab.edu.
authors.forename: Pamela
authors.initials: P
authors.lastname: Cunningham
authors.affiliation: Hemispherx Biopharma, Inc., One Penn Center, 1617 JFK Boulevard, Suite 500, Philadelphia, PA 19103, United States. Electronic address: annmarie.coverly@hemispherx.net.
authors.forename: William A
authors.initials: WA
authors.lastname: Carter
authors.affiliation: Hemispherx Biopharma, Inc., One Penn Center, 1617 JFK Boulevard, Suite 500, Philadelphia, PA 19103, United States. Electronic address: Joseph.Horvath@Hemispherx.net.
authors.forename: Joseph
authors.initials: J
authors.lastname: Horvath
authors.affiliation: Hemispherx Biopharma, Inc., One Penn Center, 1617 JFK Boulevard, Suite 500, Philadelphia, PA 19103, United States. Electronic address: Diane.Young@Hemispherx.net.
authors.forename: Diane
authors.initials: D
authors.lastname: Young
authors.affiliation: Hemispherx Biopharma, Inc., One Penn Center, 1617 JFK Boulevard, Suite 500, Philadelphia, PA 19103, United States. Electronic address: David.Strayer@Hemispherx.net.
authors.forename: David R
authors.initials: DR
authors.lastname: Strayer
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000281:Administration, Intranasal; D000328:Adult; D000914:Antibodies, Viral / Q000276:immunology*; D000917:Antibody Formation; D003429:Cross Reactions; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D018928:Immunity, Mucosal; D007070:Immunoglobulin A / Q000276:immunology*; D053124:Influenza A Virus, H5N1 Subtype; D057920:Influenza A Virus, H7N3 Subtype; D064766:Influenza A Virus, H7N9 Subtype; D007252:Influenza Vaccines / Q000627:therapeutic use*; D007251:Influenza, Human / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D011070:Poly I-C / Q000494:pharmacology*; D011072:Poly U / Q000494:pharmacology*; D051196:Toll-Like Receptor 3 / Q000819:agonists*; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D007070:Immunoglobulin A; D007252:Influenza Vaccines; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D011072:Poly U; C047490:poly(I).poly(c12,U); D011070:Poly I-C
keywords: Adjuvant; Influenza; LAIV; Live attenuated influenza vaccine; Mucosal IgA; TLR-3