The First Next-Generation COVID-19 Vaccine Combines Three Technologies – Technology Networks

The first generation ofCOVID-19 vaccines have been highly effective, but also have limitations: their efficacy can wane without a booster shot, and they may be less effective against some variants. Now scientists atThe Wistar Institutehave developed a more targeted vaccine that, in animal studies, shows stronger, broader, and more durable protection in a single, lowdose.

The vaccine combines three technologies immune focusing, self-assembling nanoparticles, andDNAdelivery into a single platform for the first time. In addition to its other advantages, the vaccine could be stored at room temperature, making it potentially easier to transport to remote or developing locations than existing mRNA vaccines, which require specialized coldstorage.

This is among the first next-generation vaccines that will have more advanced features and broader protection, saidDaniel Kulp, Ph.D., associate professor in the Vaccine&Immunotherapy Center at The Wistar Institute and corresponding author of thestudy.

The paper, Nucleic acid delivery of immune-focusedSARS-CoV-2 nanoparticles drive rapid and potent immunogenicity capable of single-dose protection, was published in the journalCell Reports.

Existing vaccines include an unmodifided receptor binding domain ofSARS-CoV-2 spike protein. The new vaccine includes a rationally engineered receptor binding domain using computational and structure-based design methodologies. The engineered receptor binding domain blocks immune distracting sites and can therefore elicit stronger levels of protective, neutralizingantibodies.

Researchers then used naturally self-assembling proteins to form nanoparticles which display these highly engineered immunogens. By arranging themselves into structures that resemble an actual virus, the nanoparticles are more easily recognized by the immune system and transported to the germinal centers, where they activate B cells which produce protectiveantibodies.

Using nucleic acid vaccine delivery technology similar to mRNA, the nanoparticle vaccine is encoded inDNAand delivered into cells thereby giving genetic instructions for the body to build the immunogen internally. This is an advance over traditional vaccines that must be manufactured in specialized factories through complex vaccine production processes. In contrast to other vaccines, Dr. Kulp noted that one advantage of theDNAplatform is that it doesnt require refrigeration and it can also be quickly reformulated to target newvariants.

In animal models, researchers found that theDNAdelivered immune-focused nanoparticle vaccine produced much higher levels of neutralizing antibodies than the vaccine that wasntimmune-focused.

A difficulty with current vaccines is that neutralizing antibodies decline over time, Kulp said. The nanoparticle vaccine produced durable responses after a single immunization out to six months in mice, unlike what we are seeing with currentSARS-CoV-2 vaccines inpeople.

The ultimate test forSARS-CoV-2 vaccine candidates is protection from death inSARS-CoV-2 challenge experiments. The researchers found that in a lethal challenge model 100% of mice who received the immune-focused nanoparticle vaccine were protected from death with a single low dose. Most mice who received the standard, non-immune focused vaccine died within 10 days ofchallenge.

The vaccine assessment was conducted in both wild-type mice and mice that were genetically engineered to mimic human immune systems, henoted.

Even without being updated, the immune-focused vaccine showed a comparable level of antibody production to Delta, and other variants, Kulp said. Thats partly because of the immune focusing approach itself, he noted; in blocking parts of the receptive binding domain for the purpose of inhibiting non-neutralizing antibodies, it also blocks many of the areas affected by spike protein mutations. Studies on the Omicron variant areunderway.

Researchers are seeking funding to begin human trials of thevaccine.

Co-authorDavid B. Weiner, Ph.D., executive vice president, director of the Vaccine&Immunotherapy Center and theW.W.Smith Charitable Trust Professor in Cancer Research, at The Wistar Institute, said the vaccine could provide a needed step forward to improve protection againstCOVID-19.

Current vaccine effects on reducing transmission ofSARS-CoV-2 variants of concern including Delta and Omicron could be improved for their breadth of protection as well as their immune potency, Weiner said. This study demonstrates that using a nucleic acid approach combined with in vivo structural assembly of a glycan immune-focused nanoparticle drives single protection and neutralization against diverse variants of concern in a dose-sparing formulation. Additional studies of this vaccine approach forSARS-CoV-2 appear timely andimportant.

Reference: Konrath KM, Liaw K, Wu Y, et al. Nucleic acid delivery of immune-focused SARS-CoV-2 nanoparticles drives rapid and potent immunogenicity capable of single-dose protection. Cell Reports. 2022;38(5). doi: 10.1016/j.celrep.2022.110318.

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The First Next-Generation COVID-19 Vaccine Combines Three Technologies - Technology Networks