A novel replication-competent modified vaccinia Tian Tan (MVTT) as a mucosal vaccination vehicle

Abstract

BACKGROUND: Mucosal vaccination offers great advantage for inducing protective immune response at the sites of viral transmission. A novel replication-competent modified vaccinia Tian Tan (MVTT) is an attenuated variant of the wild-type VTT, which was historically used as a smallpox vaccine for millions of people in China. METHODS: MVTT was generated through genetic engineering and clonal selection of VTT. The spike glycoprotein (S) of SARS-CoV was used as the test antigen after the S gene was constructed in the identical genomic location of two live vectors to generate vaccine candidates MVTT-S and MVA-S. A head-to-head comparison has been conducted in mice for inducing neutralizing antibodies (Nabs) via mucosal vaccination. RESULTS: Using an identical dose, MVTT-S induced lower levels (2-fold) of Nabs than MVA-S after intramuscular (i.m.) inoculation. MVTT-S, however, was capable of inducing over 100-fold higher levels of Nabs than MVA-S when inoculated via either intranasal (i.n.) or intraoral (i.o.) routes. These levels of responses were higher (10-fold) than that induced via the i.m. route. Moreover, 2X10(6) PFU (20-fold) of MVA-S via i.n. or i.o. was required to achieve the level of Nab response induced by 105 PFU of MVTT-S via the same route. Pre-exposure to VTT via i.n. or i.o. route impaired the Nab response to S-glycoprotein through the same mucosal routes of MVTT-S vaccination. The impairment was likely due to the anti-vector Nab response inducied by VTT. CONCLUSION: Since the efficacy of mucosal vaccination was only slightly (2-fold) affected by pre-subcutaneous exposure of VTT, our findings have critical implications for people who maintain low levels of Nab after historical smallpox vaccination. MVTT is therefore an attractive vector for research of AIDS mucosal vaccination. The MVTT-SIVgpe vaccine is being studied in an SIV/macaque challenge model for inducing mucosal protection.