Researchers at the University of California, San Diego School of Medicine, with colleagues elsewhere, describe a different way to build a vaccine against COVID-19, one that would, in theory, remain effective against new variants and emerging and that could be taken like a pill. inhalation or other delivery methods.
Their findings are published in the July 21, 2022 online issue of PLOS Pathogens.
The research involved constructing plasmids genetically altered to contain pieces of genetic material specifically intended to target a vulnerability in the spike protein of the SARS-CoV-2 virus, a part of the virus critical for attaching to and infecting cells. Plasmids are small, circular DNA molecules from bacteria that are physically separate from chromosomal DNA and can replicate independently. Scientists can use them to transfer genetic material from one cell to another, after which the introduced genetic material can be replicated in the recipient cell.
The approach, said lead author Maurizio Zanetti, MD, professor of medicine at the UC San Diego School of Medicine and chief of the Immunology Laboratory at the UC San Diego Moores Cancer Center, points to the possibility of a more durable and more effective system. Vaccine against covid19.
“The details are complicated, but the fundamentals are simple,” Zanetti said. “They are based on known and proven principles and methods.”
mRNA vaccines for COVID-19, such as those from Pfizer and Moderna, are the result of decades of previous research and development. The pandemic added new urgency, focus and resources. These vaccines promised a faster way for people, although not without significant challenges, such as the need for an ultra-low temperature cold chain.
The resulting mRNA vaccines have fundamentally altered the course of the pandemic, dramatically mitigating disease severity, hospitalizations, and deaths. But mostly, Zanetti said, they do little to block the transmission of the virus. Case rates still rise and fall with the emergence of viral variants.
“The goal in the beginning was not to stop the disease,” Zanetti said. “It was to mitigate the consequences, to reduce the severity and outcomes of COVID. Vaccines have done that. People who are vaccinated tend not to get as sick. They don’t require hospitalization as often. The death rates have gone down. All of that is it has greatly reduced pressures on health systems and society, which is a good thing.”
But the constantly evolving nature of the SARS-CoV-2 virus has revealed that the effectiveness of vaccines varies, depending on the variant, often decreasing. The Alpha variant, for example, proved more contagious than the “wild-type” strain originating in Wuhan, China. The Delta variant was more transmissible than Alpha and Omicron more than Delta. Although vaccines continue to provide substantial protection against severe disease, the antibodies they induce are consistently less potent at neutralizing the virus, thus increasing transmission. SARS-CoV-2 remains an unrelenting threat to global public health.
Zanetti said the most recent work emphasizes “quality over quantity,” looking for the induction of antibodies that preferentially block the binding of the virus to its cellular receptor and its transmission. This results in a more focused antibody response with the vaccine.
“In the early days of COVID vaccine development, it was all about generating a broad and robust immune response,” Zanetti said. “But it was a scattered approach. The vaccine response targeted many epitopes (parts of the virus that the host’s immune system recognizes) and resulted in an immune response that was largely noisy. most of the antibodies produced did not affect the virus’ ability to infect.”
“The new research narrows the focus to a part of the viral spike specifically involved in the ability of the virus to infect that appears to be evolutionarily conserved,” said co-senior author Aaron F. Carlin, MD, PhD, assistant professor in the Division of Infectious Diseases and Global Public Health at UC San Diego Health. In other words, the site does not change with new variants and represents a persistent site of vulnerability and a reliable vaccine target.
How it works
Zanetti and his colleagues constructed plasmids containing immunogens -; molecules that cause B lymphocytes to create antibodies -; which were specifically designed to display a spike protein knob that is part of the receptor binding motif or RBM. Specifically, these were amino acid residues that act as keys to open the cell door. The keys and lock do not change.
B lymphocytes are part of the immune system. They are prodigious producers of antibodies created to respond and protect against specific antigens or unwanted substances in the body, such as viruses. The average B lymphocyte can spit out 1,000 antibody molecules per second, an incredibly robust output if it’s the right antibody for the job.
Zanetti and colleagues cloned selected spike protein amino acids into a plasmid DNA so that when injected into the spleens of mice, the introduced immunogen molecules would trigger the production of specifically tailored neutralizing antibodies to the RBM target nob of the spike protein of the virus. . The researchers then tested their approach in mice with variants of the original SARS-CoV-2 strain (Beta, Delta and Omicron) and found that the immune response was similar in all variants.
“We were a little lucky in picking our target on the spike,” Zanetti said, “although it was also a result of experience and intuition. I’ve been doing this for 30 years. Previous experiments d ‘others had suggested this might be a ‘supersite’. I followed my instincts.”
Zanetti said translating these findings into a vaccine suitable for clinical trials will be “an uphill battle.” A lot is 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. New ideas for delivery include a pill that survives the digestive system and releases the plasmid DNA to be taken up by B lymphocytes that appear to possess an ancestral property to take up plasmid DNA. Alternatively, the “DNA can be formulated for delivery to the upper respiratory tract using a formulation suitable for inhalation. Many other researchers and I have investigated and pursued this basic idea before in other ways. It’s time to try it with COVID” .
Source:
University of California – San Diego
Journal reference:
10.1371/journal.ppat.1010686