Immune Requirements of Post-Exposure Immunization with Modified Vaccinia Ankara of Lethally Infected Mice

Abstract

Current prophylactic vaccines work via the induction of B and T cell mediated memory that effectively control further replication of the pathogen after entry. In the case of therapeutic or post-exposure vaccinations the situation is far more complex, because the pathogen has time to establish itself in the host, start producing immune-inhibitory molecules and spread into distant organs. So far it is unclear which immune parameters have to be activated in order to thwart an existing lethal infection. Using the mousepox model, we investigated the immunological mechanisms responsible for a successful post-exposure immunization with modified vaccinia Ankara (MVA). In contrast to intranasal application of MVA, we found that intravenous immunization fully protected mice infected with ectromelia virus (ECTV) when applied three days after infection. Intravenous MVA immunization induced strong innate and adaptive immune responses in lethally infected mice. By using various gene-targeted and transgenic mouse strains we show that NK cells, CD4 T cells, CD8 T cells and antibodies are essential for the clearance of ECTV after post-exposure immunization. Post-exposure immunization with MVA is an effective measure in a murine model of human smallpox. MVA activates innate and adaptive immune parameters and only a combination thereof is able to purge ECTV from its host. These data not only provide a basis for therapeutic vaccinations in the case of the deliberate release of pathogenic poxviruses but possibly also for the treatment of chronic infections and cancer.

The effects of post-exposure smallpox vaccination on clinical disease presentation: Addressing the data gaps between historical epidemiology and modern surrogate model data

“…Only one study has directly compared differences between failed post-exposure vaccination protection (MVA-intranasal) and successful post-exposure vaccination protection (MVA-intravenous) in the ECTV model. Results of that study indicate that activation of innate and adaptive immunity shown by increased cytokine and neutralizing antibody production as well as activation of NK and T cells is important for post-exposure vaccination protection [52]. However, a more recent study in the ECTV model indicates that B cells, but not T cells, are dispensable in protecting animals vaccinated with MVA (intranasal) and then challenged 2 days later with a 3× LD 50 dose of ECTV [85].…”

“…Mice that are incapable of producing poxvirus specific IgG and IgM are not protected by post-exposure MVA vaccination (intravenous) at day 3 post-exposure whereas wild type mice are which indicates the importance of neutralizing antibodies [52]. The time it takes a virus to spread to the point where post-exposure vaccination is not beneficial will depend in part on the incubation period of the virus and the kinetics of the immune response.…”

“…The survival benefit was 30% for day 2 vaccination and 0% for day 3 and 5 vaccination. However, 100% survival was seen with 5 × 10 7 TCID 50 MVA (intravenous) vaccination on day 2 and day 3 and 20% survival was seen with vaccination on day 5 [52]. In the final study reviewed here, mice with a deficient innate immune response (TLR9 −/− ) were lethally challenged with 100 TCID50 ECTV (respiratory) and received 1 × 10 8 TCID 50 MVA (intranasal) 24 h and 48 h post-exposure with 100% survival benefit.…”

“…In animals with intravenous vaccination IgG neutralizing titers could be detected earlier (day 6) and had higher titers (~10 3 ) than in intranasally vaccinated animals (day 9) and (~10 2 ). The similarity of results between unvaccinated and intranasally vaccinated animals indicates that the immune response (both innate and adaptive) to the original ECTV challenge was not enhanced by intranasal vaccination [52]. …”

CD70 encoded by modified vaccinia virus Ankara enhances CD8 T‐cell‐dependent protective immunity in MHC class II‐deficient mice

“…injection of MVA induces strong systemic cytokine responses and DC activation35, 59 and induces stronger CD8 T‐cell responses than immunization via peripheral routes (see ref. 59 and HL, unpublished observation), we speculate that systemic delivery of MVA renders it more immunogenic. This is in line with enhanced therapeutic anti‐tumour effects after i.v.…”