Active vaccination with vaccinia virus A33 protects mice against lethal vaccinia and ectromelia viruses but not against cowpoxvirus; elucidation of the specific adaptive immune response

Paran, Nir; Lustig, Shlomo; Zvi, Anat; Erez, Noam; Israely, Tomer; Melamed, Sharon; Politi, Boaz; Ben‐Nathan, D.; Schneider, Paula A.; Lachmi, Bat-El; Israeli, Ofir; Stein, Dana; Levin, Reuven; Olshevsky, Udy

doi:10.1186/1743-422x-10-229

Cited by 29 publications

(21 citation statements)

References 45 publications

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“…All efforts were made to minimize animal suffering. The end-points were weight loss (25% of the initial weight in the infected untreated groups and 40% in the treated groups) and/or inability to respond to the righting reflex [39] . Animals that reached these predetermined end-points were humanely sacrificed by cervical dislocation.…”

Section: Methodsmentioning

confidence: 99%

TLR3 and TLR9 Agonists Improve Postexposure Vaccination Efficacy of Live Smallpox Vaccines

et al. 2014

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Eradication of smallpox and discontinuation of the vaccination campaign resulted in an increase in the percentage of unvaccinated individuals, highlighting the need for postexposure efficient countermeasures in case of accidental or deliberate viral release. Intranasal infection of mice with ectromelia virus (ECTV), a model for human smallpox, is curable by vaccination with a high vaccine dose given up to 3 days postexposure. To further extend this protective window and to reduce morbidity, mice were vaccinated postexposure with Vaccinia-Lister, the conventional smallpox vaccine or Modified Vaccinia Ankara, a highly attenuated vaccine in conjunction with TLR3 or TLR9 agonists. We show that co-administration of the TLR3 agonist poly(I:C) even 5 days postexposure conferred protection, avoiding the need to increase the vaccination dose. Efficacious treatments prevented death, ameliorated disease symptoms, reduced viral load and maintained tissue integrity of target organs. Protection was associated with significant elevation of serum IFNα and anti-vaccinia IgM antibodies, modulation of IFNγ response, and balanced activation of NK and T cells. TLR9 agonists (CpG ODNs) were less protective than the TLR3 agonist poly(I:C). We show that activation of type 1 IFN by poly(I:C) and protection is achievable even without co-vaccination, requiring sufficient amount of the viral antigens of the infective agent or the vaccine. This study demonstrated the therapeutic potential of postexposure immune modulation by TLR activation, allowing to alleviate the disease symptoms and to further extend the protective window of postexposure vaccination.

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Section: Methodsmentioning

confidence: 99%

TLR3 and TLR9 Agonists Improve Postexposure Vaccination Efficacy of Live Smallpox Vaccines

et al. 2014

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“…The data we obtained using single alanine scanning mutagenesis within the A27D7 antibody epitope may explain why a previous study observed that vaccination with recombinant Sindbis virus expressing A33 VACV conferred protection against ECTV but not CPXV [ 31 ]. In this case, vaccination might not have elicited anti-A33 antibodies that could bind the Gln173Arg variation found in cowpox.…”

Section: Discussionmentioning

confidence: 91%

“…A former study showed that VACV-A33 vaccination protected mice against ECTV but interestingly not against CPXV-Br [ 31 ]. The reason for the lack of protection remains unclear, because VACV is more closely related to CPXV-Br than to ECTV ( S4 Fig ).…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Characterization of Anti-A33 Antibodies Reveal a Potent Cross-Species Orthopoxviruses Neutralizer

et al. 2015

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Vaccinia virus A33 is an extracellular enveloped virus (EEV)-specific type II membrane glycoprotein that is essential for efficient EEV formation and long-range viral spread within the host. A33 is a target for neutralizing antibody responses against EEV. In this study, we produced seven murine anti-A33 monoclonal antibodies (MAbs) by immunizing mice with live VACV, followed by boosting with the soluble A33 homodimeric ectodomain. Five A33 specific MAbs were capable of neutralizing EEV in the presence of complement. All MAbs bind to conformational epitopes on A33 but not to linear peptides. To identify the epitopes, we have adetermined the crystal structures of three representative neutralizing MAbs in complex with A33. We have further determined the binding kinetics for each of the three antibodies to wild-type A33, as well as to engineered A33 that contained single alanine substitutions within the epitopes of the three crystallized antibodies. While the Fab of both MAbs A2C7 and A20G2 binds to a single A33 subunit, the Fab from MAb A27D7 binds to both A33 subunits simultaneously. A27D7 binding is resistant to single alanine substitutions within the A33 epitope. A27D7 also demonstrated high-affinity binding with recombinant A33 protein that mimics other orthopoxvirus strains in the A27D7 epitope, such as ectromelia, monkeypox, and cowpox virus, suggesting that A27D7 is a potent cross-neutralizer. Finally, we confirmed that A27D7 protects mice against a lethal challenge with ectromelia virus.

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“…Similarly, ectromelia virus (an othropoxvirus that causes mousepox) is lethal in B cell deficient mice despite mounting a CD8 T cell response, while passive transfer of immune serum allows such mice to clear an established infection and fully recover (45). The expectation that antibodies to VACV membrane proteins could mediate protection has been confirmed by virus neutralizing studies in vitro (39, 46-62), and several purified membrane proteins, including WR101/H3L (39), WR187/B5R (51), WR156/A33R (51, 63, 64), WR151/A28L (59), WR132/A13L (60), and WR150/A27L (65) have been shown to protect animals against challenge in vivo . Proteome-wide screening by microarray for antibody targets in sera confirmed the response is heavily skewed towards recognition of virion-associated targets (29, 39, 41, 66).…”

Section: Discussionmentioning

confidence: 92%

T Cell Antigen Discovery Using Soluble Vaccinia Proteome Reveals Recognition of Antigens with Both Virion and Nonvirion Association

Davies

Chun

Hermanson

et al. 2014

The Journal of Immunology

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Vaccinia virus (VACV) is a useful model system for understanding the immune response to a complex pathogen. Proteome-wide antibody profiling studies reveal the humoral response to be strongly biased towards virion associated antigens, and several membrane proteins induce antibody-mediated protection against VACV challenge in mice. Some studies have indicated the CD4 response is also skewed toward proteins with virion association, whereas the CD8 response is more biased toward proteins with early expression. In this study, we have leveraged a VACV-WR plasmid expression library, produced previously for proteome microarrays for antibody profiling, to make a solubilized full VACV-WR proteome for T cell antigen profiling. Splenocytes from VACV-WR-infected mice were assayed without prior expansion against the soluble proteome in assays for Th1 and Th2 signature cytokines. The response to infection was polarized toward a Th1 response, with the distribution of reactive T cell antigens comprising both early and late VACV proteins. Interestingly, the proportions of different functional subsets were similar to that present in the whole proteome. In contrast, the targets of antibodies from the same mice were enriched for membrane and other virion components, as described previously. We conclude that a ‘non-biasing’ approach to T cell antigen discovery reveals a T cell antigen profile in VACV that is broader and less skewed to virion-association than the antibody profile. The T cell antigen mapping method developed here should be applicable to other organisms where expressible ‘ORFeome’ libraries are also available, and is readily scalable for larger pathogens.

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Active vaccination with vaccinia virus A33 protects mice against lethal vaccinia and ectromelia viruses but not against cowpoxvirus; elucidation of the specific adaptive immune response

Cited by 29 publications

References 45 publications

TLR3 and TLR9 Agonists Improve Postexposure Vaccination Efficacy of Live Smallpox Vaccines

TLR3 and TLR9 Agonists Improve Postexposure Vaccination Efficacy of Live Smallpox Vaccines

Structural and Functional Characterization of Anti-A33 Antibodies Reveal a Potent Cross-Species Orthopoxviruses Neutralizer

T Cell Antigen Discovery Using Soluble Vaccinia Proteome Reveals Recognition of Antigens with Both Virion and Nonvirion Association

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