Binding of the von Willebrand factor A domain of capillary morphogenesis protein 2 to anthrax protective antigen vaccine reduces immunogenicity in mice

Thumbnail Image
de Oliveira, Fabiana Freire Mendes
Mamillapalli, Sireesha
Gonti, Srinivas
Brey, Robert N.
Li, Han
Schiffer, Jarad M.
Casadevall, Arturo
Bann, James G.
Issue Date
Anthrax , Antigen processing , Immunization , Protein stability
Research Projects
Organizational Units
Journal Issue
Fabiana Freire Mendes de Oliveira, Sireesha Mamillapalli, Srinivas Gonti, Robert N. Brey, Han Li, Jarad Schiffer, Arturo Casadevall, James G. Bann. 2020. Binding of the von Willebrand Factor A Domain of Capillary Morphogenesis Protein 2 to Anthrax Protective Antigen Vaccine Reduces Immunogenicity in Mice. mSphere, vol. 5:no. 1

Protective antigen (PA) is a component of anthrax toxin that can elicit toxin-neutralizing antibody responses. PA is also the major antigen in the current vaccine to prevent anthrax, but stability problems with recombinant proteins have complicated the development of new vaccines containing recombinant PA. The relationship between antigen physical stability and immunogenicity is poorly understood, but there are theoretical reasons to think that this parameter can affect immune responses. We investigated the immunogenicity of anthrax PA, in the presence and absence of the soluble von Willebrand factor A domain of the human form of receptor capillary morphogenesis protein 2 (sCMG2), to elicit antibodies to PA in BALB/c mice. Prior studies showed that sCMG2 stabilizes the 83-kDa PA structure to pH, chemical denaturants, temperature, and proteolysis and slows the hydrogen-deuterium exchange rate of histidine residues far from the binding interface. In contrast to a vaccine containing PA without adjuvant, we found that mice immunized with PA in stable complex with sCMG2 showed markedly reduced antibody responses to PA, including toxin-neutralizing antibodies and antibodies to domain 4, which correlated with fewer toxin-neutralizing antibodies. In contrast, mice immunized with PA in concert with a nonbinding mutant of sCMG2 (D50A) showed anti-PA antibody responses similar to those observed with PA alone. Our results suggest that addition of sCMG2 to a PA vaccine formulation is likely to result in a significantly diminished immune response, but we discuss the multitude of factors that could contribute to reduced immunogenicity.

Table of Contents
© Authors. mSphere® is a multidisciplinary open-access journal that publishes high-quality work that makes fundamental contributions to any of the immense range of fields within the microbial sciences.
NLM (Medline)
Book Title
PubMed ID