Ebolaviruses Zaire (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) cause human disease with high case fatality rates. Experimental monovalent
vaccines, which all utilize the sole envelope
glycoprotein (GP), do not protect against heterologous ebolaviruses. Human
parainfluenza virus type 3-vectored
vaccines offer benefits, including needle-free administration and induction of mucosal responses in the respiratory tract. Multiple approaches were taken to induce broad protection against the three ebolaviruses. While GP consensus-based
antigens failed to elicit
neutralizing antibodies,
polyvalent vaccine immunization induced neutralizing responses to all three ebolaviruses and protected animals from death and disease caused by EBOV, SUDV, and BDBV. As immunization with a cocktail of antigenically related
antigens can skew the responses and change the
epitope hierarchy, we performed comparative analysis of antibody repertoire and Fc-mediated protective mechanisms in animals immunized with monovalent versus
polyvalent vaccines. Compared to sera from guinea pigs receiving the monovalent
vaccines, sera from guinea pigs receiving the trivalent
vaccine bound and neutralized EBOV and SUDV at equivalent levels and BDBV at only a slightly reduced level.
Peptide microarrays revealed a preponderance of binding to
amino acids 389 to 403, 397 to 415, and 477 to 493, representing three linear
epitopes in the
mucin-like domain known to induce a protective antibody response. Competition binding assays with
monoclonal antibodies isolated from human
ebolavirus infection survivors demonstrated that the
immune sera block the binding of
antibodies specific for the GP
glycan cap, the GP1-GP2 interface, the
mucin-like domain, and the membrane-proximal external region. Thus, administration of a cocktail of three
ebolavirus vaccines induces a desirable broad antibody response, without skewing of the response toward preferential recognition of a single virus.IMPORTANCE The symptoms of the disease caused by the ebolaviruses Ebola, Bundibugyo, and Sudan are similar, and their areas of endemicity overlap. However, because of the limited antigenic relatedness of the ebolavirus
glycoprotein (GP) used in all candidate
vaccines against these viruses, they protect only against homologous and not against heterologous ebolaviruses. Therefore, a broadly specific pan-
ebolavirus vaccine is required, and this might be achieved by administration of a cocktail of
vaccines. The effects of cocktail administration of
ebolavirus vaccines on the antibody repertoire remain unknown. Here, an in-depth analysis of the antibody responses to administration of a cocktail of human
parainfluenza virus type 3-vectored
vaccines against individual ebolaviruses was performed, which included analysis of binding to GP, neutralization of individual ebolaviruses,
epitope specificity, Fc-mediated functions, and protection against the three ebolaviruses. The results demonstrated potent and balanced responses against individual ebolaviruses and no significant reduction of the responses compared to that induced by individual
vaccines.