Live Attenuated Measles Virus Vaccine Expressing Helicobacter pylori Heat Shock Protein A

Abstract

Measles virus (MV) Edmonston derivative strains are attractive vector platforms in vaccine development and oncolytic virotherapy. Helicobacter pylori heat shock protein A (HspA) is a bacterial heat shock chaperone with essential function as a Ni-ion scavenging protein. We generated and characterized the immunogenicity of an attenuated MV strain encoding the HspA transgene (MV-HspA). MV-HspA showed faster replication within 48 h of infection with >10-fold higher titers and faster accumulation of the MV proteins. It also demonstrated a superior tumor-killing effect in vitro against a variety of human solid tumor cell lines, including sarcoma, ovarian and breast cancer. Two intraperitoneal (i.p.) doses of 10 6 50% tissue culture infectious dose (TCID 50 ) MV-HspA significantly improved survival in an ovarian cancer xenograft model: 63.5 days versus 27 days for the control group. The HspA transgene induced a humoral immune response in measles-permissive Ifnarko-CD46Ge transgenic mice. Eight of nine animals developed a long-term anti-HspA antibody response with titers of 1:400 to 1:12,800 without any negative impact on development of protective anti-MV immune memory. MV-HspA triggered an immunogenic cytopathic effect as measured by an HMGB1 assay. The absence of significant elevation of PD-L1 expression indicated that vector-encoded HspA could act as an immunomodulator on the immune check point axis. These data demonstrate that MV-HspA is a potent oncolytic agent and vaccine candidate for clinical translation in cancer treatment and immunoprophylaxis against H. pylori .

Effect ofHelicobacter pylorion immunotherapy is gaining more attention

“…Helicobacter pylori heat shock protein A (HspA) is a bacterial heat shock chaperone. Recombinant MV‐HspA showed a superior tumor‐killing effect in vitro against human solid tumor cell lines, including sarcoma, ovarian and breast cancer, implying that MV‐HspA is a potent oncolytic agent and vaccine candidate for cancer treatment 38 …”

“…Recombinant MV-HspA showed a superior tumor-killing effect in vitro against human solid tumor cell lines, including sarcoma, ovarian and breast cancer, implying that MV-HspA is a potent oncolytic agent and vaccine candidate for cancer treatment. 38 While on the other hand, recent evidence suggests that H. pylori infection appears to have a detrimental effect on immunotherapy. By using mouse colon adenocarcinoma and melanoma model and two clinical cohort study of non-small-cell lung cancer, it is proven that H. pylori infection significantly reduced the antitumor efficacy of ICI or anti-cancer vaccine treatments and H. pylori seropositivity was found to be associated with a decreased NSCLC patient survival on anti-PD-1 therapy.…”

Perspectives from recent advances of Helicobacter pylori vaccines research

“…The MV can be used as a vector to present pathogens subunits to the host and induce humoral and cellular immunity, and it has a potential application in cancer treatment as oncolytic virotherapy. 123 Iankov et al 124 established recombinant MV-HspA, which expresses HspA from H. pylori. After immunization, 8 of 9 measlespermissive transgenic mice had a long-term anti-HspA antibody response.…”

“…Iankov et al 124 established recombinant MV‐HspA, which expresses HspA from H. pylori . After immunization, 8 of 9 measles‐permissive transgenic mice had a long‐term anti‐HspA antibody response.…”

Versatility of live-attenuated measles viruses as platform technology for recombinant vaccines

“… Target Antigen ATU a Strain b CD46-mice c ELISA d FACS e CDC f ELISpot g Cytokines h Efficacy i Clinical trial Refs. Carcinomas (melanoma) CLDN6 P Moraten X X X X X 89 Helicobacter pylori HspA (α-tumor) pre-N Edm-B X X X 103 >85% human cancers TERT P Schwarz X neg X X 90 Listed are all MeV-derived experimental vaccines that target cancer. Described are the vaccine properties; depicted by “X” is the animal model those have been tested in, positive immune responses detected in those models directed against the additional antigen, and efficacy in animal challenge models or clinical trials.…”