Replicating RNA vaccine rebuffs COVID-19

The vaccine’s design has advantages of safety, cost, scalability and storage

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SEATTLE—Researchers have discovered that a replicating RNA vaccine produces antibodies against the COVID-19 coronavirus with a single immunization, in both mice and primates. These antibodies potently neutralize the virus.
The vaccine is designed to avoid immune responses that could enhance a respiratory disease induced by the coronavirus. Instead, it directs the immune response toward more protective antiviral measures. In addition to antibody production, which can block the infection, the vaccine induces T cells. The methods and results of animal tests of the replicating RNA coronavirus vaccine candidate vaccine were published today in an article in Science Translational Medicine.
The lead author of the paper is Jesse H. Erasmus, a Washington Research Foundation postdoctoral fellow in the laboratory of Dr. Deborah Heydenburg Fuller. Fuller is a professor of microbiology at the University of Washington School of Medicine and division chief of Infectious Diseases and Translational Medicine at the Washington National Primate Research Center.
“A vaccine that can stop COVID-19 will ideally induce protective immunity after only a single immunization, avoid immune responses that could exacerbate virus-induced pathology, be amenable to rapid and cost-effective scale-up and manufacturing, and be capable of inducing immunity in all populations — including the elderly, who typically respond poorly to vaccines,” wrote Fuller. “That's a tall order.”
Fuller sees conventional nucleic acid vaccines as promising, but at least two immunizations are needed to instill immunity in people. Most DNA vaccines require high doses to achieve protective levels of immunity in humans. Traditional messenger RNA vaccines, which are formulated with lipid nanoparticles to increase their effectiveness, may face obstacles of mass-production and shelf life.
To try and overcome these limitations, the labs of Fuller and her collaborators at the National Institutes of Health Rocky Mountain Laboratories and HDT Bio Corp. have developed a replicating RNA version of a coronavirus vaccine. Replicating RNA expresses a greater amount of protein, and also triggers a virus-sensing stress response that encourages other immune activation.
In the case of the COVID-19 vaccine candidate, the RNA enters cells and instructs them to produce proteins that teach the body to recognize coronaviruses and attack them with antibodies and T cells. These antibodies induced by the vaccine provide protection by interfering with the protein machinery on the spikes of the coronavirus. This might keep the viruses from fusing to cells and injecting their genetic code.
Antibodies were produced within two weeks after vaccine administration. The level of antibodies generated was comparable to people who are recovering from COVID-19. The vaccine robustly induced coronavirus-neutralizing antibodies in both younger and older mice.
This hopeful finding was well-received by the researchers. A major concern of COVID-19 is that older patients are less likely to respond to vaccination, due to their aging immune systems. Vulnerability to severe COVID-19 increases with age, and a vaccination suitable for high-risk populations is a key goal.
This replicating RNA vaccine contains the novel Lipid InOrganic Nanoparticle (LION) developed by Seattle-based biotechnology company HDT Bio Corp. HDT is advancing the replicon RNA with LION vaccine toward clinical development under the name HDT-301.
“We are pleased with the collaboration with UW to move our RNA vaccine platform forward,” said Steve Reed, chief executive officer of HDT Bio.
The nanoparticle reportedly enhances the vaccine’s ability to provoke the desired immune reaction, and its stability. This vaccine is stable at room temperature for at least one week. Its components would allow it to be rapidly manufactured in large quantities, should it prove safe and effective in human trials. The scientists believe that lower and fewer doses would need to be made to immunize a population.
“RNA molecules are highly susceptible to degradation by enzymes,” added Amit P. Khandhar, the lead formulation developer at HDT Bio. “LION is a next-generation nanoparticle formulation that protects the RNA molecule and enables in vivo delivery of the vaccine after a simple mixing step at the pharmacy.”
The ability of LION to be formulated with mRNA by simple mixing at the bedside is a key differentiating factor between it and  the lipid nanoparticle delivery vehicle used in other mRNA COVID-19 vaccines. The two-vial approach enabled by LION allows for manufacturing of the formulation independently from the mRNA component. The research team is now working to advance the vaccine to Phase 1 testing in human subjects.

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