Scientists at Scripps Research have unveiled a new vaccine design against Ebola, which they say has several advantages over standard vaccine approaches against Ebola and related viruses that continue to threaten global health.
In the new design, described in an article in Nature communications, copies of the Ebola virus outer spike protein, known as the glycoprotein, are attached to the surface of a spherical carrier particle. The resulting structure resembles the spherical appearance of common RNA viruses that infect humans – and is radically different from the snake-like shape of the Ebola virus.
Scientists say the design aims to boost a better protective immune response than standard vaccine approaches, which often expose the immune system to individual glycoproteins rather than realistic-looking viral particles.
When designing the vaccine, the researchers also modified the outer spike protein to be more stable than the normal “wild-type” version found in Ebola virus. In tests on mice and rabbits, they have shown that this stabilized version elicits more strongly neutralizing antibodies than the wild-type glycoprotein used in previous vaccine approaches against Ebola.
“Here, we did a step-by-step investigation into the stability of glycoproteins and how this affects the vaccine’s ability to produce antibodies,” says Jiang Zhu, PhD, associate professor in the Department of Integrative and Computational Structural Biology at Scripps Research and inventor of the vaccine. “In the end, we were able to develop a really promising vaccine design.”
Continuing viral threat
The Ebola virus is endemic in various species of African bats and can reach humans, causing outbreaks of hemorrhagic fever with high death rates. The largest known epidemic occurred in West Africa between 2013 and 2016, killing over 11,000 people.
About two decades ago, Canadian researchers developed a vaccine against the Zaire Ebola virus, better known as the Ebola virus. The vaccine, which was later licensed to a large pharmaceutical company and is called rVSV-ZEBOV, uses a live virus – the vesicular stomatitis virus – which has been modified to include the glycoprotein gene from the Ebola virus.
When injected, the rVSV-ZEBOV vaccine infects cells and makes copies of the glycoprotein, eliciting an immune response to protect against future exposure to the Ebola virus. Tests in Africa amid the aforementioned outbreak suggested it was working well and it was approved by the Food and Drug Administration at the end of 2019. However, these tests lacked placebo groups and other standard features of the trials. typical large-scale phase III. Thus, questions remain about true effectiveness.
In developing their new vaccine design against Ebolavirus, Zhu and his team focused on the relative instability of glycoprotein structure as a potential factor in vaccine efficacy. They studied the molecular sources of this instability in detail and finally came up with a set of modifications that greatly stabilize the glycoprotein. In mice and rabbits, their modified glycoprotein elicited a more potent neutralizing antibody response against two different ebolaviruses – the Makona strain of Ebola virus and the Ugandan strain of Bundibugyo ebolavirus – and compared those with the wild-type glycoprotein.
The team’s design also included special protein segments that tightly self-assemble into a ball-shaped “nanoparticle” that supports multiple glycoproteins on their surface. This nanoparticle-based structure presents glycoproteins to the immune system like common human viruses, and so the body has learned to recognize spherical particles.
“Think of our nanoparticles as your sports vehicle, with a roof rack that carries a mountain bike and a trunk where you store your clothes, gear and food,” Zhu explains. “The only difference here is that the Ebola peak is your mountain bike, and the lock domains and T cell epitopes are your stuff in the trunk. We call it a multi-layered design.”
A new approach
This nanoparticle design is distinctly different from other nanoparticle platforms. Zhu explains that in his team’s design, the genetic codes for the optimized glycoprotein, nanoparticle-forming unit, locking domain, and T-cell epitope are all contained in a single piece of DNA. In cells, this DNA generates a single protein chain that can self-assemble, form the right structure, and combine with other identical chains to create a virus-like protein ball with multiple layers.
“The idea is that the all-in-one design simplifies the manufacturing process and lowers the cost of the vaccine,” Zhu says.
His team has previously used the nanoparticle platform to create a COVID-19 vaccine candidate, which has shown in animal models that it can induce a potent antibody response to both SARS-CoV-1 and SARS-CoV -2. It has also been shown to be effective against variants.
For Ebola virus, nanoparticle-based vaccines have shown much better results in mouse and rabbit virus neutralization tests which only use glycoproteins to stimulate the immune response. Inoculation of animals with the wild-type glycoprotein Ebola, which tends to disintegrate, has led to signs suggesting a vaccine phenomenon known as antibody-dependent boosting – in which a vaccine not only triggers neutralizing antibodies. the virus, but also antibodies which paradoxically increase the capacity of the virus to infect cells. The researchers found that their best nanoparticle-based designs elicit very little of these bad antibodies.
“There is a lot in the area of the Ebola vaccine that still needs to be carefully considered, but in this study we ended up with two nanoparticle-based designs that seem very suitable for further optimization and testing. Zhu said.
He says the vaccine approach can be extended to other members of the same virus family, such as the Marburg virus, which is also a major threat. Both Ebolaviruses and Marburgviruses belong to a group of viruses, called filoviruses, which have a strange, thread-like shape when viewed under a microscope.
The study also included atomic-level crystal structures on modified glycoproteins, which was carried out in collaboration with the lab of Ian Wilson, DPhil, Hansen Professor of Structural Biology and Head of the Department of Integrative and Computational Structural Biology.
This work was funded in part by the National Institutes of Health (AI129698, AI140844) and Uvax Bio LLC.