A nonreplicating subunit vaccine protects mice against lethal Ebola virus challenge

Abstract

Ebola hemorrhagic fever is an acute and often deadly disease caused by Ebola virus (EBOV). The possible intentional use of this virus against human populations has led to design of vaccines that could be incorporated into a national stockpile for biological threat reduction. We have evaluated the immunogenicity and efficacy of an EBOV vaccine candidate in which the viral surface glycoprotein is biomanufactured as a fusion to a monoclonal antibody that recognizes an epitope in glycoprotein, resulting in the production of Ebola immune complexes (EICs). Although antigen–antibody immune complexes are known to be efficiently processed and presented to immune effector cells, we found that codelivery of the EIC with Toll-like receptor agonists elicited a more robust antibody response in mice than did EIC alone. Among the compounds tested, polyinosinic:polycytidylic acid (PIC, a Toll-like receptor 3 agonist) was highly effective as an adjuvant agent. After vaccinating mice with EIC plus PIC, 80% of the animals were protected against a lethal challenge with live EBOV (30,000 LD 50 of mouse adapted virus). Surviving animals showed a mixed Th1/Th2 response to the antigen, suggesting this may be important for protection. Survival after vaccination with EIC plus PIC was statistically equivalent to that achieved with an alternative viral vector vaccine candidate reported in the literature. Because nonreplicating subunit vaccines offer the possibility of formulation for cost-effective, long-term storage in biothreat reduction repositories, EIC is an attractive option for public health defense measures.

Vesicular Stomatitis Virus Pseudotyped with Ebola Virus Glycoprotein Serves as a Protective, Noninfectious Vaccine against Ebola Virus Challenge in Mice

“…These results indicate that VSVΔG pseudovirion-based vaccines against EBOV elicit protective immune responses that can be independent of the production of antibodies that neutralize viral particles in cell culture assays. Consistent with our findings, protection conferred by other EBOV vaccines does not always correlate with the production of neutralizing antibodies (12,13,39,40).…”

Efficient Agroinfiltration of Plants for High-level Transient Expression of Recombinant Proteins

“…As discussed earlier, the most difficult parameter to control in this methodology is the plant material. We have expressed a variety of vaccines and therapeutic proteins using plants and the infiltration procedure we described here and obtained excellent results in all cases 4,8,14,18,[21][22][23] . These results demonstrated that the conditions we have developed are optimal for protein expression.…”

TLR7 and 9 agonists are highly effective mucosal adjuvants for norovirus virus-like particle vaccines

“…16,19,21,22,24 These TLR agonists, or PAMP, include bacterial ligands, virus-specific ribonucleotide motifs (i.e., dsRNA), and imidazoquinoline compounds and all are currently studied as adjuvants. [1][2][3][4]6,[14][15][16][17][18][19] We have previously published results demonstrating that intranasal co-delivery with gardiquimod (GARD; TLR7 agonist) and resiquimod (R848; TLR7/8 agonist) along with Norwalk virus (NV) VLPs can elicit equivalent immune responses relative to VLPs co-delivered with cholera toxin (CT).…”

“…In addition, we have demonstrated that a TLR3 agonist (polyinosinic:cytidylic acid (PIC)) co-delivered subcutaneously (s.c.) with Ebola immune complexes (EICs) can induce robust, systemic immunity and protection against lethal challenge with Ebola virus. 18 Recently, a TLR4 agonist (MPL, monophosphoryl lipid A) has successfully Virus-like particles (VLps) are an active area of vaccine research, development and commercialization. Mucosal administration of VLps provides an attractive avenue for delivery of vaccines with the potential to produce robust immune responses.…”

“…Poor immunogenicity of non-replicating subunit vaccines, however, can be overcome by the addition (or co-delivery) of potent adjuvants. [1][2][3][4]6,7,9,[13][14][15][16][17][18][19] One particularly potent group of molecules that can be exploited as mucosal adjuvants are toll-like receptor (TLR) agonists. 1,3,[14][15][16][17][19][20][21][22][23][24] TLRs are pattern recognition receptors (PRRs) of the innate immune system that have been shown to exhibit tissue or mucosa-specific expression patterns.…”