title: Intranasal vaccination with AAV5 and 9 vectors against human papillomavirus type 16 in rhesus macaques.
abstract: Cervical cancer is the second most common cancer in women worldwide. Persistent high-risk human papillomavirus (HPV) infection has been identified as the causative event for the development of this type of cancer. Recombinant adeno-associated viruses (rAAVs) are currently being developed and evaluated as vaccine vector. In previous work, we demonstrated that rAAVs administered intranasally in mice induced high titers and long-lasting neutralizing antibodies against HPV type 16 (HPV16). To extend this approach to a more human-related species, we immunized rhesus macaques (Macaca mulatta) with AAVs expressing an HPV16 L1 protein using rAAV5 and 9 vectors in an intranasal prophylactic setting. An rAAV5-L1 vector followed by a boost with rAAV9-L1 induced higher titers of L1-specific serum antibodies than a single rAAV5-L1 immunization. L1-specific antibodies elicited by AAV9 vector neutralized HPV16 pseudovirions and persisted for at least 7 months post immunization. Interestingly, nasal application of rAAV9 was immunogenic even in the presence of high AAV9 antibody titers, allowing reimmunization with the same serotype without prevention of the transgene expression. Two of six animals did not respond to AAV-mediated intranasal vaccination, although they were not tolerant, as both developed antibodies after intramuscular vaccination with HPV16 virus-like particles. These data clearly show the efficacy of an intranasal immunization using rAAV9-L1 vectors without the need of an adjuvant. We conclude from our results that rAAV9 vector is a promising candidate for a noninvasive nasal vaccination strategy.
authors.affiliation: Research Program Infection and Cancer, German Cancer Research Center, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Nieto
authors.forename: Christiane
authors.initials: C
authors.lastname: Stahl-Hennig
authors.forename: Barbara
authors.initials: B
authors.lastname: Leuchs
authors.forename: Martin
authors.initials: M
authors.lastname: Müller
authors.forename: Lutz
authors.initials: L
authors.lastname: Gissmann
authors.forename: Jürgen A
authors.initials: JA
authors.lastname: Kleinschmidt
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology; D005260:Female; D005822:Genetic Vectors; D057809:HEK293 Cells; D006367:HeLa Cells; D052162:Human papillomavirus 16 / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral; D008253:Macaca mulatta; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology; D030361:Papillomavirus Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D053918:Papillomavirus Vaccines / Q000008:administration & dosage / Q000235:genetics*; D014611:Vaccination
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D036022:Capsid Proteins; D009856:Oncogene Proteins, Viral; D053918:Papillomavirus Vaccines; C063317:L1 protein, Human papillomavirus type 16