It has been over a year since the World Health Organization declared COVID-19 a pandemic, shutting down any sense of normalcy in people’s daily lives. Despite causing considerable isolation, the pandemic has also fostered greater connections and collaborations among communities. One of the most unlikely partnerships was between the two research teams of in-state rivals U.Va. and Virginia Tech. U.Va. Health’s Dr. Steven L. Zeichner and Virginia Tech’s Dr. Xiang-Jin Meng worked together to develop a potential broad spectrum coronavirus vaccine, combining Zeichner’s innovative new vaccine platform with Meng’s research on zoonotic viruses.
Zeichner and Meng emphasized that their research does not take away from the current vaccines but rather they are looking more towards the future as a possible fourth wave of the virus approaches and new zoonotic diseases, which can spread from animals to humans, appear around the world.
“What we're trying to do is to make a vaccine that is going to be broadly protective against many, many different coronaviruses and against many different variants,” Zeichner said.
In order to create a more broad spectrum vaccine, the research team looked across many different coronavirus variants and isolated to find a highly conserved region — a section of identical amino acids that remain unchanged even as strains mutate and evolve — within the viral genome to target with the vaccine.
“There's been so much replication, so many new variants, so if something doesn't vary at all across all the thousands of sequences that have been obtained, then that's a pretty good indication that the virus for whatever reason cannot mutate that and maintain its viability,” Zeichner said.
The researchers discovered a highly conserved region within the fusion peptide of the spike protein, which is essential for the virus to insert its viral genome into the host’s cells for replication and infection. The region was about 23 amino acids long with a core six amino acid sequence that is identical in every single coronavirus that has ever been sequenced in animals ranging from whales to pigs to people.
Zeichner and Meng began working on implementing this targeted region of the genome into Zeichner’s new vaccine production platform with a kill-whole cell technique, an innovative process that synthesizes DNA to be inserted into bacteria with majority of its genes deleted to then instruct the immune system on how to mount a response against the virus.
Vignesh Rajasekaran, a University student who worked on the study before starting medical school in the fall, helped to design the new plasmids — the DNA that is given to bacteria to instruct it to make proteins that are put on its surface — as well as deliver the plasmids into the bacteria and test the vaccine in vitro to ensure the bacteria were expressing the right sequence on their surfaces.
“One of the unique aspects with this project is that we are using bacteria that have had major sections of their genome deleted,” Rajasekaran said in an email to The Cavalier Daily. “This reduces the amount of other surface proteins on the bacteria and thus [increases] the immune system’s ability in seeing the target antigen, in this case the fusion peptide of SARS-CoV-2.”
Next, the researchers set out to prove the effectiveness of their technique by using the platform in a model system. Meng suggested using pigs since they are the naturally occurring host for the coronavirus porcine epidemic diarrhoea virus.
“PEDV is a very devastating disease in pigs, and the virus originally emerged in the United States in 2013 and in our first years killed more than eight million pigs,” Meng said. “So we definitely see the devastation a coronavirus can cause in the animal population.”
The researchers immunized the pigs with two different vaccines, one developed from the PEDV fusion peptide sequence and the other from the SARS-CoV-2 fusion peptide sequence, then challenged them with the PED virus itself.
“What we found was a little bit unexpected,” Zeichner said. “We found that the PEDV vaccine protected the pigs against clinical disease. What we didn't expect was when we vaccinated the pigs with the SARS-CoV-2 vaccine that it also protected [the pigs from PEDV].”
The key to this experiment was that both were coronaviruses but only distantly related. PEDV is an alpha coronavirus while SARS-CoV-2 is a beta coronavirus, meaning they evolved into different strains so they have many differences in their genome but their similar fusion peptide sequences allowed for both vaccines to be successful.
“Both of those [vaccines] can protect the pigs against the PEDV,” Zeichner said. “If we make a vaccine against the SARS-CoV-2 fusion peptide, it is very likely to protect people against many different strains of SARS-CoV-2.”
This breakthrough presents great potential in providing a broad spectrum vaccine for COVID-19 and future coronavirus variants for both animals and humans. The study is currently in discussions with sponsors as the research team moves toward human trials and FDA approval.
“The next study that we need to do before a human trial would be to test the vaccine in a nonhuman primate model and then challenge the vaccinated nonhuman primates with the SARS-CoV-2 to see if we can confer protection,” Meng said, “If we can do that, then that will pave the road for human clinical trials.”
The inter-university team’s research was funded by several sources, including the Pendleton Pediatric Infectious Disease Laboratory, University of Virginia Manning Fund for COVID-19 Research and Virginia Tech internal funds.
Currently, the country is at a crossroads as vaccines roll out and restrictions loosen, but continual viral transmission can still lead to an increased risk of an evolving variant immunity, making this research integral to the fight against future viruses and mutations, like the South African and U.K. variants which emerged in early fall of 2020.
Both variants have spike protein mutations that make them more transmissible than the original coronavirus variant, and it is still unclear how much resistance the current vaccines have against these variants. Some studies have shown that mRNA vaccines — such as the Pfizer and Moderna shots — are effective against the B.1.1.7 or U.K. variant while others have shown that the Johnson & Johnson vaccine was 64 percent effective against the South African variant. Additional studies are underway to confirm the effectiveness of the vaccines against emerging variants.
With a predicted cost of $1 per dose compared to the $10 per dose of the current vaccines, this broad spectrum vaccine would be easily replicable since it could be produced in existing factories and facilities within three weeks, unlike some of the mRNA vaccines that require special containment at minus 70 degrees Celsius.
“We are at a plateau now and we're headed up in the incidence rate,” Zeichner said, “This plateau is at a higher level than the peak was last summer when everybody was panicking and with the new variants that are coming in that are more transmissible and more pathogenic.”
With hope on the horizon for a better year, health officials say it is important to stay vigilant and responsible, as the world looks now toward future vaccines and research in the fight against the pandemic.