University of Liverpool-led Study Demonstrates in Mouse Model that Omicron Variant 100-Fold Less Severe than Delta
Just how severe of a SARS-CoV-2 strain is Omicron? The initial batch of research into the matter provides some insight, but much is still up to discover. Both are highly transmissible, and due to the many mutations involving spike glycoprotein substitutions, the pathogen’s ability to evade a spectrum of neutralizing antibodies emerges as distinct features of the variant of concern. Thus far the disease appears milder with initially less death and higher proportional hospitalization rates. Hospitalizations may rise regardless, due to the sheer number of cases. America has shattered pandemic records with new cases per day. On January 1, 2022, just under 400,000 cases were recorded, far exceeding infections during the worst surges. With 1,328 deaths per day based on a seven-day average and Omicron’s ability to infect the vaccinated, if this variant becomes more severe the pandemic crisis will intensify and worsen in the winter months. But just how severe is Omicron? This was a major question that a research team from a collection of academic medical centers in the United Kingdom sought to answer in a recent study. Led by James Stewart, corresponding author, and Chair of Molecular Biology at the University of Liverpool, the UK study team conducted a preclinical study based on a mouse model of SARS-CoV-2 infection. Based on a measurement of viral loads the team concluded that at various time points post-infection, Omicron is far less severe than both the Pango B and Delta variants of concern. While this represents good news, the authors remind all the mass number of infections represents real risks for a worsening widespread contagion, leading to a worsening pandemic—especially given the fact that this mutant can evade not only natural immunity but also vaccine-induced immunity.
Dr. Stewart, a trained molecular biologist, known internationally for his work in the field of virus-host interactions, and team members from Liverpool as well as Imperial College of London, and an immunologist from the University of Zurich constructed a mouse model of infection replicating severe disease in humans to better understand outcomes, at least, in the controlled lab environment. This study was made possible thanks to funds from UK’s Medical Research Council and a contract with the U.S. Food and Drug Administration (FDA).
The Study
Key to this experiment was what is known as K18-hACE2 mice which express human ACE2, the receptor used by the pathogen to penetrate the human host cell. These lab-engineered mice are susceptible to both SARS-CoV and SARS-CoV-2, so they are useful for investigations such as this one.
These preclinical animal models offer the opportunity to contribute to knowledge gaps for this evolving disease in humans, reported the authors in their preprint, yet to be reviewed in manuscript. This form of study both complements parallel longitudinal tissue sample studies and offers a controlled environment generating significant data for knowledge advancement.
The team infected some of the K18-hACE2 mice with either a Pango B, Delta, or Omicron variant of SARS-CoV-2, then compared relative pathogenesis, the process by which a disease or disorder develops. The team used stock viruses that matched non-synonymous and synonymous signatures associated with the respective variants. The investigators established three groups of mice (n=6 per group) for the study.
The Results
First and foremost, the authors noted expected weight loss manifests in the mice infected with Pango B and Delta variants of SARS-CoV-2. While the mice infected with Omicron also lost weight in the first five days after infection, by day six they exhibited a noticeable improvement, which the authors point out represented a “statistically significant recovery in weight loss as compared to other groups based on two way ANOVA with Bonferroni post-test which adjusts the data to ensure to check for false positives.
Importantly, the study team determined that mice infected with the Omicron variant had a lower viral load, significantly less, in fact. Team members extracted RNA via oral swabs at three intervals plus lung and tissue samples at the end of the experiment. Utilizing qRT-PCR to quantify viral loads, the study authors measured viral RNA as a proxy.
By day 2 post-infection, mice infected with Omicron exhibited 100-fold lower levels of viral RNA than Pango-B and Delta variant-infected animals (mean 2.5 x 103 vs 1 x 105 and 6 x 104 copies of N/µg of RNA respectively). Comparing the Omicron infected mice with each other, they found a statistically significant difference (p < 0.05) between the newest strain and Pango B. By day 4 post-infection, they found viral loads similar between all the study groups. On day 6 post-infection, they found that both the Pango B and Delta variant infected mice exhibited 10-fold higher viral loads than in the Omicron-infected mice subjects. The study authors verified the statistical significance which was included in the uploaded manuscript.
Additionally, the study authors identified that both Pango B and Delta-infected mice viral loads were approximately 100-fold greater in both nasal and lung tissue samples over a week post-infection.
Discussion
While more study and real-world evidence must be observed, the data points emerging from human observational research and this British study point to a less severe disease due to the mutant strain. Thus far this implies both good and bad news. On the positive side, this study introduces yet another important data point evidencing a milder strain.
On the other hand, news can turn negative fast in this pandemic. Given high transmissibility and the mutant’s seeming ability to evade, at least partially, pre-existing immunity (natural, monoclonal antibody and vaccine), the mass number of infections could lead to a dramatic increase in hospitalization and severe disease and death.
Public health systems undoubtedly emphasize the importance of protection, such as masks, not to mention social distancing, quarantining when infected, and of course, mass vaccination as primary methods for pathogen eradication. Of note, the study authors don’t recommend vaccination in their findings –this is because the current mutant can evade vaccine-induced antibodies, so undoubtedly, more research is necessary from industry, government, and academia, not to mention real-world observations for a more confident assessment as to the true protection levels presently existing.
TrialSite reminds us that this study hasn’t been peer-reviewed, thus shouldn’t be used for any decision-making until it’s properly validated. Moreover, the study authors represent their own opinions and not necessarily those of their employers—University of Liverpool, etc.
Lead Research/investigator
James Stewart, corresponding author and Chair of Molecular Biology at the University of Liverpool.
Steward is considered a global expert in virus-host interactions in the respiratory tract with an emphasis on respiratory pathogens from influenza to RSV and now of course SARS-CoV-2. He also teaches Veterinary, Medical, and Life Science students up to the Masters level. The Steward laboratory includes dozens of Ph.D. students.