Researchers at the University of California San Diego School of Medicine, in collaboration with colleagues elsewhere, describe a novel approach to developing a COVID-19 vaccine that, in theory, would remain effective against new and emerging variants and could be administered as a pill, by inhalation, or through other means.
Their findings were published online in the journal PLOS Pathogens.
The researchers created plasmids that were genetically modified to contain bits of genetic material that were specifically designed to target a vulnerability in the SARS-CoV-2 virus’s spike protein, a component of the virus that is essential for binding and infecting cells. Plasmids are small, circular DNA molecules found in bacteria that can replicate independently of chromosomal DNA. They can be used by scientists to transfer genetic material from one cell to another, after which the introduced genetic material can replicate in the receiving cell.
According to senior author Maurizio Zanetti, MD, professor of medicine at UC San Diego School of Medicine and director of the Laboratory of Immunology at UC San Diego Moores Cancer Center, the approach points to the possibility of a more durable and broadly effective COVID-19 vaccine.
“The details are complicated, but the fundamentals are straightforward,” Zanetti explained. “They are founded on well-known and time-tested principles and methods.”
The new research narrows the focus to a part of the viral spike specifically involved in the virus’s ability to infect that appears to be evolutionarily conserved. The goal at the beginning wasn’t to stop the disease. It was to mitigate the consequences, to reduce COVID’s severity and outcomes
Aaron F. Carlin
COVID-19 mRNA vaccines from Pfizer and Moderna are the result of decades of research and development. The pandemic heightened the urgency, focus, and resources. These vaccines promised people a faster path, but not without significant challenges, such as the need for an ultralow temperature cold chain.
The resulting mRNA vaccines have fundamentally altered the course of the pandemic, dramatically mitigating the severity of disease, hospitalizations, and deaths. But notably, said Zanetti, they do little at blocking transmission of the virus. Case rates still rise and fall with the emergence of viral variants.
“The goal at the beginning wasn’t to stop the disease,” said Zanetti. “It was to mitigate the consequences, to reduce COVID’s severity and outcomes. The vaccines have done that. Vaccinated persons tend not to get as sick. They don’t require hospitalization as often. Death rates are down. All of this has greatly reduced pressures on health systems and society, which is a good thing.”
However, due to the ever-changing nature of the SARS-CoV-2 virus, the vaccines’ efficacy varies depending on variant, often diminishing. The Alpha variant, for example, was found to be more contagious than the “wild-type” strain from Wuhan, China. Delta was more transmissible than Alpha, and Omicron was more transmissible than Delta. Though vaccines continue to provide significant protection against severe disease, the antibodies produced are consistently less effective at neutralizing the virus, resulting in increased transmission. SARS-CoV-2 remains a persistent global public health threat.
According to Zanetti, the new research emphasizes “quality over quantity,” with the goal of inducing antibodies that preferentially block virus binding to its cell receptor and transmission. As a result, the vaccine elicits a more focused antibody response.
“It was all about generating a broad, robust immune response in the early days of COVID vaccine development,” Zanetti explained. “But it was a haphazard approach. The vaccine response targeted many epitopes (parts of the virus recognized by the host’s immune system), resulting in a largely ineffective immune response. The majority of the antibodies produced had no effect on the virus’s ability to infect.”
“The new research narrows the focus to a part of the viral spike specifically involved in the virus’s ability to infect that appears to be evolutionarily conserved,” said co-senior author Aaron F. Carlin, MD, Ph.D., assistant professor in the Division of Infectious Diseases and Global Public Health at UC San Diego Health. In other words, the site doesn’t change with new variants, and represents a persisting site of vulnerability and a reliable vaccine target.
How it works
Zanetti and colleagues created plasmids that contained immunogens (molecules that cause B lymphocytes to produce antibodies) that were specifically designed to display a knob of the spike protein that is part of the receptor binding motif, or RBM. These were amino acid residues that served as keys to open the cell door. The keys and lock remain the same.
The immune system includes B lymphocytes. They are prolific producers of antibodies designed to respond to and protect the body against specific antigens or foreign substances such as viruses. The average B lymphocyte can produce 1,000 antibody molecules per second, which is incredible if the antibody is the right one for the job.
The selected spike protein amino acids were cloned into plasmid DNA by Zanetti and colleagues so that when injected into the spleens of mice, the introduced immunogen molecules would induce the production of neutralizing antibodies specifically tuned to the targeted nob on the RBM of the virus protein spike. The researchers then tested their method on mice infected with SARS-CoV-2 variants (Beta, Delta, and Omicron) and discovered that the immune response was consistent across all variants.
“We were a little lucky in picking our target on the spike,” Zanetti explained, “but it was also a result of experience and intuition.” This is something I’ve been doing for 30 years. Earlier experiments by others had suggested that this could be a’supersite,’ so I trusted my instincts.”
Zanetti said translating these findings into a vaccine suitable for clinical trials will be “an uphill battle.” There is much invested in current approaches, and it’s a considerable leap from mouse studies to human clinical trials. But the promise of a consistently effective and easy to administer vaccine is irresistible.
“DNA is very stable. The new delivery ideas include a pill that survives the digestive system and releases the plasmid DNA to be picked up by B lymphocytes that appear to possess an ancestral property for taking up plasmid DNA. Alternatively, the DNA can be formulated for delivery to the upper airways by a suitable formulation for inhalation. Many other researchers and I have investigated and pursued this basic idea in other ways before. It’s time to try it with COVID.”
