Induction of Humoral and CD8+ T Cell Responses Are Required for Protection against Lethal Ebola Virus Infection

Abstract

Ebola virus (EBOV)-like particles (eVLP), composed of the EBOV glycoprotein and matrix viral protein (VP)40 with a lipid membrane, are a highly efficacious method of immunization against EBOV infection. The exact requirements for immunity against EBOV infection are poorly defined at this time. The goal of this work was to determine the requirements for EBOV immunity following eVLP vaccination. Vaccination of BALB/c or C57BL/6 mice with eVLPs in conjunction with QS-21 adjuvant resulted in mixed IgG subclass responses, a Th1-like memory cytokine response, and protection from lethal EBOV challenge. Further, this vaccination schedule led to the generation of both CD4+ and CD8+ IFN-γ+ T cells recognizing specific peptides within glycoprotein and VP40. The transfer of both serum and splenocytes, but not serum or splenocytes alone, from eVLP-vaccinated mice conferred protection against lethal EBOV infection in these studies. B cells were required for eVLP-mediated immunity to EBOV because B cell-deficient mice vaccinated with eVLPs were not protected from lethal EBOV challenge. We also found that CD8+, but not CD4+, T cells are absolutely required for eVLP-mediated protection against EBOV infection. Further, eVLP-induced protective mechanisms were perforin-independent, but IFN-γ-dependent. Taken together, both EBOV-specific humoral and cytotoxic CD8+ T cell responses are critical to mediate protection against filoviruses following eVLP vaccination.

Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques

“…In the second experiment, MB-003 from the CHO and RAMP system were compared, using a more rigorous challenge of 1,000 pfu. Results from this experiment are confounded by the survival of the control, which has occurred one other time in the last 2 y with this viral stock (of 15 animals total; given the likely genetic diversity of these wild-caught macaques, it is not entirely surprising that controls occasionally can survive, as do humans, perhaps due to differences in CD4+, CD8+, or IFN-γ responses) (30). Nevertheless, the control did show symptoms of infection and viremia.…”

A nonreplicating subunit vaccine protects mice against lethal Ebola virus challenge

“…In fatal cases, EBOV-specific IgG and T cell-related mRNA cannot be detected. This suggests that a combination of antibody and cell-mediated immune responses to an EBOV vaccine candidate are important for generating the appropriate and protective immune response (3,4). mAbs were shown to be effective postexposure therapeutics in a mouse model using lethal EBOV challenge (5).…”

Status and challenges of filovirus vaccines

“…and vaccinated mice were fully protected against challenge with mouse-adapted ZEBOV [57]. Further study in mice suggests that a Th1-type immune response with CD8 + T lymphocytes is critical to the protection against ZEBOV challenge [55].…”

“…inoculation of the virus, the mouse model is not considered ideal for studies of the human disease. Mice have, however, been used as a tool for studying innate immunity, screening vaccine candidates, and elucidating protective epitopes for humoral and cellular immunity to ZEBOV [49][50][51][52][53][54][55][56][57][58].…”

“…Nevertheless, in mice, CD8 + T lymphocytes are important for protection against ZEBOV [55,58]. NHP studies with the adenovirus and VSV-vectored vaccines have also found the presence of CD8+ T lymphocytes in vaccinated macaques by ICS before challenge [87,96].…”