A Novel Replication-Competent Vaccinia Vector MVTT Is Superior to MVA for Inducing High Levels of Neutralizing Antibody via Mucosal Vaccination

Abstract

Mucosal vaccination offers great advantage for inducing protective immune response to prevent viral transmission and dissemination. Here, we report our findings of a head-to-head comparison of two viral vectors modified vaccinia Ankara (MVA) and a novel replication-competent modified vaccinia Tian Tan (MVTT) for inducing neutralizing antibodies (Nabs) via intramuscular and mucosal vaccinations in mice. MVTT is an attenuated variant of the wild-type VTT, which was historically used as a smallpox vaccine for millions of Chinese people. 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 vectors to generate vaccine candidates MVTT-S and MVA-S. Using identical doses, MVTT-S induced lower levels (∼2-3-fold) of anti- SARS-CoV neutralizing antibodies (Nabs) than MVA-S through intramuscular inoculation. MVTT-S, however, was capable of inducing consistently 20-to-100-fold higher levels of Nabs than MVA-S when inoculated via either intranasal or intraoral routes. These levels of MVTT-S-induced Nab responses were substantially (∼10-fold) higher than that induced via the intramuscular route in the same experiments. Moreover, pre-exposure to the wild-type VTT via intranasal or intraoral route impaired the Nab response via the same routes of MVTT-S vaccination probably due to the pre-existing anti-VTT Nab response. The efficacy of intranasal or intraoral vaccination, however, was still 20-to-50-fold better than intramuscular inoculation despite the subcutaneous pre-exposure to wild-type VTT. Our data have implications for people who maintain low levels of anti-VTT Nabs after historical smallpox vaccination. MVTT is therefore an attractive live viral vector for mucosal vaccination.

HIV/AIDS Vaccine Candidates Based on Replication-Competent Recombinant Poxvirus NYVAC-C-KC Expressing Trimeric gp140 and Gag-Derived Virus-Like Particles or Lacking the Viral Molecule B19 That Inhibits Type I Interferon Activate Relevant HIV-1-Specific B and T Cell Immune Functions in Nonhuman Primates

“…Another strategy is the generation of new vectors with replication competence in human cells in order to increase the timing and levels of expression of the heterologous antigen in the host. To date, some replication-competent recombinant VACV-based vaccines have been used for various infectious diseases, demonstrating that they are able to elicit potent humoral and cell-mediated immune responses and to confer long-lasting protection while maintaining a safety phenotype (23,(45)(46)(47).…”

Establishment of functional influenza virus-specific CD8+ T cell memory pools after intramuscular immunization

“…While one inoculation route may be efficacious for a particular vaccine, such route may not be as effective for vaccine-induced protection in a different disease context [34,35]. This notion holds true for the use of live-virus vaccines, where different inoculation routes not only affect the overall protective effect of the vaccine but also the type, range and localization of ensuing responses [36][37][38].…”

Enhancing poxvirus vectors vaccine immunogenicity

“…To date, some replication-competent recombinant VACV-based vaccines have been used for various infectious diseases, demonstrating that they are able to elicit potent humoral and cellular immune responses and to confer long-lasting protection while maintaining a safety profile. [110][111][112][113] We have previously reported that insertion of the host range C7L gene into NYVAC recombinant vectors expressing HIV-1 antigens significantly improved the magnitude and quality of the HIV-specific immune responses in mice. 112 Moreover, restoration of replication competence in human cells of a NYVAC recombinant expressing HIV-1 antigens from clade C (NYVAC-C) by re-incorporation of the K1L and C7L host range VACV genes (NYVAC-C-KC) or combination of restoration of replication competence with removal of the immunomodulatory viral molecule B19 protein (NYVAC-C-KC-ΔB19R) increased the expression of the heterologous antigen in infected human cells.…”

“…114,115 Other attenuated replication competent vectors are M65 and M101, derived from the Western Reserve (WR) strain after multiple passages in Friend erytroleukemia cells, that have been shown to contain mutations in multiple gene sequences but with the capacity to trigger immunogenicity and protection against leishmania parasitic infection. 116 Another replication-competent and attenuated smallpox-derived vaccines, such as the Japanese LC16m8 (derived from the Lister vaccinia strain), [117][118][119] and the Chinese Tian-Tan strains 111,120,121 are also being investigated as vaccines for other diseases. Moreover, myxomavirus have been used as a promising vaccine candidate against several types of cancer, due to the oncolytic ability of this poxvirus to specifically infect various classes of human cancer cells.…”