When I was a graduate student studying HIV-1 encapsidation, I encountered an unusually enthusiastic virologist-to-be. As a prospective graduate researcher in my lab, he described his fascination with the Ebola virus, how he wanted to do research on it, how it affected human beings, and how he desired to be part of a team that would be sent to areas of Africa to learn from the Ebola virus outbreaks in hopes that a treatment or vaccine could be developed. I realized I was perfectly fine working with my env– HIV-1 in cell culture, thank you very much. Jumping into a situation with a hemorrhagic virus was too dangerous for my sensibilities even though I admired my peer’s enthusiasm. However, the devastation of Ebola infection remained imprinted on my brain. Therefore, I was excited to read that a vaccine had been developed against Ebola and was in clinical trials. Even more fascinating was a recent paper by Hensley et al. that demonstrated a vaccine developed for two Ebola virus species was able to protect against a third novel species.
The candidate Ebola virus vaccines were designed against the glycoprotein (GP) of two of the four known species: ZEBOV and SEBOV. These two species were the most commonly associated with Ebola virus outbreaks. However, a fifth species called Bundibugyo (BEBOV) was discovered after an outbreak of Ebola virus hemorrhagic fever (EHF) in 2007. The amino acid composition of BEBOV GP differed from ZEBOV and SEBOV GP by 38–47%. The authors decided to try a prime-boost vaccine strategy; that is priming with DNA vectors and using recombinant Adenovirus (rAd5) vectors to boost and generating a broad immune response in T- and B-cells and hopefully, inducing cross-protection against BEBOV.
This experiment was performed in eight cynomolgus macaques. Four were subjected to the vaccine regimen: injected with GP DNA four times at 4–6 week intervals with a year-long rest period before a boost with rAd5 vectors. To determine the immune response to the GP antigen, an ELISA was used to assess the plasma IgG antibody levels and intracellular cytokine staining (ICS) was used for T cells three weeks after the rAd5-GP boost immunization. While the ELISA test showed greater titers of IgG reacting to the ZEBOV GP compared to before rAd5 boost, there was little crossreactivity to BEBOV GP.
To evaluate memory and effector CD4+ and CD8+ T-cell function, PBMC samples collected from vaccinated animals four weeks after the rAd5 GP boost were stimulated with peptides spanning the GP open reading frame of two species Ebola virus. Expression of the cytokines TNFα, IFNγ, and IL-2 were assessed in the CD4+ and CD8+ memory T cells, demonstrating a crossreactive cellular immunity against both ZEBOV and BEBOV, in contrast to the antibody evaluation.
These tests of antibody reactivity and cellular cytokine secretion when challenged with GP peptides are all in vitro tests with intriguing results. The next step was to ask how would an animal vaccinated against ZEBOV and SEBOV stand up to the challenge of an Ebola virus infection with the new species BEBOV? Four control unvaccinated animals and the four vaccinated animals were challenged with a lethal dose of BEBOV. All four control animals exhibited symptoms of the hemorrhagic fever (presence of maculopapular rash, viral load in blood, and hepatocyte damage as assessed by liver enzymes AST and ALT); three died by day 13. The vaccinated animals all survived and the liver enzyme levels showed little to no change during the same time points tested. The control animal that survived BEBOV infection seemed to resolve it without vaccination, but showed all the symptoms of infection. One of the vaccinated animals did have a viral titer six days postinfection that became undetectable when tested four days later and a mild if transient increase in ALT serum levels.
Although only a small number of subjects was used in this experiment, the in vitro and in vivo tests demonstrated the efficacy of the ZEBOV/SEBOV DNA/rAd5 boost vaccine against a third species of Ebola virus, BEBOV. All four vaccinated subjects survived with little sign of infection; three of the four unvaccinated control animals died after showing multiple symptoms of Ebola virus infection. This immunity was surprising in the face of the 38–47% difference in the BEBOV GP amino acid composition compared to the ZEBOV and SEBOV GPs. The researchers demonstrated cellular immunity not antibody immunity protected the vaccinated animals from Ebola virus infection. This strategy has implications for future vaccine development, and gives hope that one vaccine may help prevent viral outbreaks even in the face of an unexpected novel Ebola species for which the vaccine was not explicitly designed.
Hensley, L.E., Mulangu, S., Asiedu, C., Johnson, J., Honko, A.N., Stanley, D., Fabozzi, G., Nichol, S.T., Ksiazek, T.G., Rollin, P.E., Wahl-Jensen, V., Bailey, M., Jahrling, P.B., Roederer, M., Koup, R.A., & Sullivan, N.J. (2010). Demonstration of cross-protective vaccine immunity against an emerging pathogenic Ebolavirus Species. PLoS pathogens, 6 (5) PMID: 20502688
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