Combined vaccine composition comprising a herpes simplex virus (hsv) antigen and a human papillomavirus (hpv) antigen

摘要

A vaccine composition comprising a herpes simplex virus (HSV) antigen and a human papillomavirus (HPV) antigen in conjunction with an adjuvant which is a preferential stimulator of TH1 cell response, is new. ACTIVITY : Antiviral. MECHANISM OF ACTION : Vaccine. An immunogenicity study was performed in Balb/C mice using four different antigens: human papilloma virus (HPV)16 L1 Virus Like Particle (VLP-16), HPV 18 L1 Virus Like Particle (VLP-18), gD antigen of herpes simplex virus 2 (HSV-2) and hepatitis B surface antigen (HbsAg) formulated with Alum/3D-MPL (3 De-O-acylated monophosphoryl lipid A) (AS04) using pre-adsorbed monobulks of antigen or 3D-MPL on Al(OH) 3 or AlPO 4. 3D-MPL/Al(OH 3), formulations are referred to AS04D while 3D-MPL/AlPO4 based formulations are referred to AS04C. The following vaccines were assessed: VLP16 + VLP1 AS04D, gDAS04D, HbsAS04C, and the potential to combine these vaccines was evaluated. Groups of 10 mice were immunized intramuscularly twice at 3 week intervals with various antigen (Ag) based formulations, e.g. Group A (VLP16 2 micrograms/VLP18 2 micrograms/gD 2 micrograms/3D-MPL 5 micrograms/Al(OH) 3) 50 micrograms), Group B (VLP16 2 micrograms/VLP18 2 micrograms/HBs 2 micrograms/gD 2 micrograms/3D-MPL 5 micrograms/ Al(OH) 3) 40 micrograms/AlPO4 10 micrograms), Group C (gD 2 micrograms/3D-MPL 5 micrograms/ Al(OH) 3) 50 micrograms), Group D (VLP16 2 micrograms/VLP18 2 micrograms/3D-MPL 5 micrograms/Al(OH) 3) 50 micrograms), and Group E (HBs 2 micrograms/3D-MPL 5 micrograms/ AlPO 4 10 micrograms/ Al(OH) 3) 40 micrograms). Antibody response to VLPs, gD and HBs Ag and the isotypic profile induced by vaccination were monitored by ELISA (enzyme linked immunoabsorbant assay) at day 1 post II. At the same timepoint, the cytokine production (interferon-gamma (IFN-gamma)/interleukin-5 (IL-5)) was analyzed after in vitro restimulation of splenic cells with either VLPs, gD or HBs antigens. The anti-VLP16 titers obtained after immunization with the combination of VLPs, gD and HBs Ag (group B), were slightly lower than the one obtained with either the combination of VLPs and gD (group A) or the monovalent VLPs formulation (group D) (GMT respectively of 27578 versus 48105 EU/ml versus 44448 EU/ml). Before statistical analysis a T-Grubbs test was applied on each population for data exclusion. Two non-responder mice in groups A and D were eliminated for analysis. The differences observed between the groups were shown as statistically not significant using the Student Newman Keuls Test. The anti-VLP18 titers obtained after immunization with the combination of VLPs, gD and HBs Ag (group B), were in the same magnitude as the titers obtained with either the combination of VLPs and gD (group A) or the monovalent VLPs formulation (group D) (GMT respectively of 56078 versus 88786 EU/ml versus 76991 EU/ml). Before statistical analysis, a T-Grubbs test was applied on each population for data exclusion. Two non-responder mice in groups A and D were eliminated for analysis. The differences observed were shown as statistically not significant using one-way analysis of variance test. Regarding the anti-gD response, a slight decrease was observed in the GMT obtained with the VLPs/gD/HBs combination (group B) compared to gD alone (Group C) or VLPs/gD combination (Group A) (GMT respectively of 18631 versus 32675 versus 27058 EU/ml). Before statistical analysis a T-Grubbs test was applied on each population for data exclusion. Two non-responder mice in group A were eliminated for analysis. A one-way-analysis of variance was performed on anti-gD titers after log transformation of post II data. No statistically significant difference was observed between the three formulations (Group A, B and C). A slightly lower anti-HBs antibody response is observed in the combination group B containing the VLPs, gD and HBs antigens compared to HBs alone (group E) (GMT of 28996 EU/ml versus 20536 EU/ml). A one-way-analysis of variance was performed on anti-HBs titers after log transformation of post II data. No statistically significant difference was observed between the group B (VLP/HBs/gD) versus the group E (HBs AS04) using Student Newman Keuls test. The isotypic repartition analyzed on pooled sera showed no differences between the 2 groups (Group B and Group E) with a proportion of IgG2a preserved in the combination vaccine.