Immune Parameters Correlate with Protection Against Ebola Virus Infection in Rodents and Nonhuman Primates

Abstract

Ebola virus causes severe hemorrhagic fever in susceptible hosts. Currently, no licensed vaccines or treatments are available; however, several experimental vaccines have been successful in protecting rodents and nonhuman primates (NHPs) from the lethal Zaire ebolavirus (ZEBOV) infection. The objective of this study was to evaluate immune responses correlating with survival in these animals after lethal challenge with ZEBOV. Knockout mice with impaired ability to generate normal T and/or B cell responses were vaccinated and challenged with ZEBOV. Vaccine-induced protection in mice was mainly mediated by B cells and CD4+ T cells. Vaccinated, outbred guinea pigs and NHPs demonstrated the highest correlation between survival and levels of total immunoglobulin G (IgG) specific to the ZEBOV glycoprotein (ZGP). These results highlight the relevance of total ZGP-specific IgG levels as a meaningful correlate of protection against ZEBOV exposure.

mAbs and Ad-Vectored IFN-α Therapy Rescue Ebola-Infected Nonhuman Primates When Administered After the Detection of Viremia and Symptoms

“…The strongest B cell responses were observed in animals receiving Ad-IFN and ZMAb starting at 3 dpi (Cyno72h and Rhesus72h groups) because IgG titers for these animals plateau by 14 dpi, compared to 28 dpi for the Cyno96h NHPs. High EBOV-specific IgG levels were shown to correlate with survival of lethally infected NHPs (21). An EBOV-GP-specific T cell response was observed at 21 dpi in both the IFN-g ELISpot and the intracellular cytokine flow cytometry assays.…”

Antibodies are necessary for rVSV/ZEBOV-GP–mediated protection against lethal Ebola virus challenge in nonhuman primates

“…Similarly, Geisbert et al (12) showed rVSV/ZEBOV-GP vaccination failed to protect SHIV-infected macaques that failed to generate a ZEBOV-GP-specific IgG response following vaccination. More recently, a study by Wong et al (20) showed that an adenovirus-based vaccine failed to protect mice genetically deficient in B or CD4+ T cells, whereas mice lacking CD8+ T cells were completely protected. Additional analyses of vaccinated guinea pigs and cynomolgus macaques revealed statistically higher antibody titers in survivors compared with nonsurvivors (20).…”

“…More recently, a study by Wong et al (20) showed that an adenovirus-based vaccine failed to protect mice genetically deficient in B or CD4+ T cells, whereas mice lacking CD8+ T cells were completely protected. Additional analyses of vaccinated guinea pigs and cynomolgus macaques revealed statistically higher antibody titers in survivors compared with nonsurvivors (20). These observations are in line with the results presented in this manuscript and strongly suggest that CD4+ T-cell help to B cells rather than CD4+ T-cell effector functions play a key role in protection.…”

Immunology of protection from Ebola virus infection

“…T ese data support a greater relative importance of humoral as compared with cellular response for this vaccine (8). Recent studies suggest that innate responses may aid the humoral immune response in VSV-vectored vaccine-induced protection (6,9).…”

“…Viral soluble glycoprotein (sGP), which is a nonstructural viral protein that shares features with GP and is secreted from infected cells, may inf uence (6). Moreover, NHP studies using VSVvectored vaccine reported protection from Ebola Zaire challenge in 4/4 animals, with antibody titer in the 1:100 to 1:1000 range (7).…”