Attenuation and immunogenicity of host-range extended modified vaccinia virus Ankara recombinants

Abstract

Modified vaccinia virus Ankara (MVA) is being widely investigated as a safe smallpox vaccine and as an expression vector to produce vaccines against other infectious diseases and cancer. MVA was isolated following more than 500 passages in chick embryo fibroblasts and suffered several major deletions and numerous small mutations resulting in replication defects in human and most other mammalian cells as well as severe attenuation of pathogenicity. Due to the host range restriction, primary chick embryo fibroblasts are routinely used for production of MVA-based vaccines. While a replication defect undoubtedly contributes to safety of MVA, it is worth considering whether host range and attenuation are partially separable properties. Marker rescue transfection experiments resulted in the creation of recombinant MVAs with extended mammalian cell host range. Here, we characterize two host-range extended rMVAs and show that they (i) have acquired the ability to stably replicate in Vero cells, which are frequently used as a cell substrate for vaccine manufacture (ii) are severely attenuated in immunocompetent and immunodeficient mouse strains following intranasal infection, (iii) are more pathogenic than MVA but less pathogenic than the ACAM2000 vaccine strain at high intracranial doses, (iv) do not form lesions upon tail scratch in mice in contrast to ACAM2000 and (v) induce protective humoral and cell-mediated immune responses similar to MVA. The extended host range of rMVAs may be useful for vaccine production.

Identification of Vaccinia Virus Inhibitors and Cellular Functions Necessary for Efficient Viral Replication by Screening Bioactives and FDA-Approved Drugs

“…Secondly, the prior study used the ACAM2000 strain of VACV, a clone derived from Dryvax [ 77 ]. ACAM2000 is a live attenuated strain approved as a smallpox vaccine [ 78 ]. VACV-WR, the virus used in our study, is, on the other hand, one of the most virulent VACV strains tested in animal models and was considered unsuitable to be used as a vaccine due to its high neuropathogenicity in mice models [ 79 ].…”

Percutaneous Vaccination as an Effective Method of Delivery of MVA and MVA-Vectored Vaccines

“…In subsequent experiments, antibody responses and protection of mice that were vaccinated with MVA subcutaneously or by tail scarification were higher than in those vaccinated via the intramuscular route. Melamed et al [47] compared the antibody response elicited in response to MVA and two recombinant MVAs that had been genetically modified to replicate in Vero and BSC-1 cells, after inoculating mice by intramuscular injection or tail scarification. Their data indicate that tail scarification was efficient at inducing an antibody response, although the intramuscular route elicited higher geometric mean titers of antibody and conferred higher survival rates.…”

“…The difference between their observation and the one reported here may be due to differences in experimental procedures and/or assay methods. For instance, in our work, MVA for tail scarification is typically in 2 μL volume per dose, making it easier to handle than the 10μL used by Melamed et al [47]. In subsequent experiments, the route comparison was limited to subcutaneous versus percutaneous routes, since the subcutaneous route is more commonly used in vaccination studies of MVA vectors.…”

“…During the course of the work above [46], antibody [47] and robust cell-mediated immune responses after the inoculation of recombinant MVA vectors through the skin, were also reported [48,49,50], suggesting that percutaneous inoculation of MVA may elicit equivalent or higher immune responses than subcutaneous injection. In the work described here, we demonstrate in mouse models that percutaneous inoculation of MVA elicited protective immune responses against lethal intranasal challenge with the Western Reserve (WR) strain of vaccinia virus, and at low doses of MVA, lower morbidity was recorded in mice that were vaccinated via the percutaneous route than in those immunized via the intramuscular or subcutaneous routes.…”

The contribution of biotechnology toward progress in diagnosis, management, and treatment of allergic diseases

“…Regarding allergies, genetically modified VA was used to prevent the onset of intestinal allergy to ovalbumin (OVA) in a murine model of food allergy by vaccination of the mice with MVA expressing OVA on the surface. This vaccination induced a strong OVA‐specific Th1 immune response mediated by the induction of IFN‐γ, and protective OVA‐specific IgG2a antibody responses, highlighting the potential of older vaccination concepts and the need for further research of these type of vaccines in allergy .…”