Comparison of Antibody Responses in Mice Generated by Different Multivalent Filovirus Vaccines Based on Recombinant Glycoprotein Subunits

Tashiro, Taylor Emi
Lehrer, Axel T.
Biomed Science (Tropical Medicine)
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Filoviruses cause fulminant hemorrhagic fevers with case-fatality rates up to 90%. The objective of this research is to achieve a multivalent filovirus vaccine that can be thermostabilized and used to prevent the spread of lethal filovirus disease. The central hypothesis is that since each immunogen was found to elicit a strong antibody response on its own, it should be possible to optimize the formulation dosages of each immunogen to generate a combination vaccine that induces a balanced, robust antibody response and neutralizing antibody titers against the most pathogenic filovirus species, EBOV. Recombinant glycoprotein (GP) derived from Ebola virus (EBOV), Sudan virus (SUDV) and Marburg virus (MARV) have been expressed from stably transformed Drosophila S2 cells and used to formulate recombinant subunit vaccine candidates showing efficacy in rodents and non-human primates. Immunogenicity of 12 different formulations of our trivalent subunit vaccine with adjuvant was tested in Swiss Webster mice, and serum antibody concentration and neutralization of rVSV-EBOV GP was measured and compared to responses from monovalent formulations. The 12 formulations were categorized into three sets of four groups of increasing dosage – The first set being formulations of equal antigen, the second being equal EBOV and MARV antigen with less SUDV antigen, and the third being equal amounts of Ebolavirus to Marburgvirus antigen. These formulations were determined in order to set up assays for potency testing of the vaccine and to understand antibody responses to different formulations. When quantifying antibody concentration, the results were as expected as trivalent formulations induced high antibody concentrations for all antigens at higher dosages. Also, the trivalent vaccine is able to produce comparable antibody concentrations to being vaccinated with monovalent formulations which suggests that trivalent formulations can still elicit antibodies that are specific for each antigen. It was observed that higher dosages of antigen elicit higher antibody concentrations against EBOV and SUDV GP, but a dose-response was not detected for antibody concentrations against MARV GP suggesting that it may be the most immunogenic antigen. Ultimately, the formulation that was able to elicit the highest, and balanced antibody concentration against EBOV, SUDV, and MARV GP was the formulation of equal antigens at the highest dosage. Results from the neutralization tests against rVSV-EBOV GP show that higher neutralization titers are achieved with increased dosages. Neutralization titers were also increased with inclusion of SUDV GP antigen as compared to monovalent vaccination and further increases when there is less SUDV GP present compared to the EBOV and MARV antigens, suggesting SUDV GP interference. This led to highest neutralization observed from groups containing less SUDV GP as compared to EBOV and MARV GP. From these findings, we have shown that trivalent formulations can be balanced to both optimize total antigen-binding IgG and neutralizing responses. This data will be used to formulate the next vaccines for testing in NHP’s and to develop potency tests for antigen- and batch-release testing.
Immunology, Virology, Biology, Antibody, Ebola, Glycoprotein, Multivalent, Subunit, Vaccine
69 pages
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