Does Omicron Cause Less Damage to the Lungs?

• Cell culture and animal studies, comparing the Delta variant with the Omicron variant, suggest that the latter may have a reduced ability to infect the lungs.
• This may explain why Omicron causes milder disease than Delta.
• These studies showed that the Omicron variant's ability to infect the upper airways may be greater than that of the Delta variant, potentially explaining its increased transmissibility.
• The Omicron variant's ability to evade neutralizing antibodies may be associated with its increased transmissibility.
• Previous COVID-19 infection or, more importantly, coronavirus vaccination, may be one reason why disease caused by Omicron is less severe.

Does Omicron Cause Less Harm?

Early reports following Omicron's emergence suggest that, compared with earlier SARS-CoV-2 (the novel coronavirus that caused the COVID-19 Pandemic) variants, less severe disease is likely to be caused by Omicron.

Genetic analysis of Omicron showed that this variant carries a large number of mutations, including in its spike protein. These numerous mutations may be a potential reason for reduced disease severity. However, milder disease caused by Omicron infection may result from a person's increased immunity acquired through SARS-CoV-2 infection or vaccination (it is now an established fact that vaccinated people have milder infections).

Although increased immunity can influence disease severity, animal and cell culture studies show that the mutations carried by Omicron are less effective at infecting the lungs than the Delta variant. This may explain why Omicron reduces disease severity.

Studies

The SARS-CoV-2 virus can affect both the upper and lower respiratory tract. The upper respiratory tract comprises the nose, sinuses and throat, while the lower respiratory tract includes the trachea and lungs.

Mild disease or early SARS-CoV-2 infections mostly involve upper respiratory symptoms such as a runny nose and sore throat. Severe disease caused by the original SARS-CoV-2 and other variants involves lung infection and inflammation. Inflammation can cause fluid to accumulate in the air sacs, or alveoli, reducing the lungs' capacity to deliver oxygen to the blood.

Scientists performed experiments using animal models and laboratory cultures of lung cells to characterize Omicron's ability to infect the respiratory tract and cause severe disease.

At the University of Hong Kong, cells taken from lung tissue during lung treatment were cultured. In the study, Omicron was observed to replicate in human bronchi, which connect the trachea to the lungs, 70 times faster than Delta. However, replication in lung tissue was less effective than that of Delta and the original SARS-CoV-2. Other research groups also compared the ability of Omicron, Delta and other SARS-CoV-2 variants to cause disease in animal models such as hamsters and mice.

After one week, weight loss in hamsters and mice is associated with infection by Delta and other variants. Some data suggest a correlation between increased virus levels in the respiratory tract and weight loss. However, various research groups independently showed no such weight loss in hamsters and mice after Omicron infection. These studies also found that hamsters with Omicron infection had higher and similar virus levels in the upper airways compared with the original SARS-CoV-2 and Delta. In contrast, researchers observed lower virus levels in the lower respiratory tract after Omicron infection than after Delta infection.

In summary, these studies indicate that Omicron may be less effective at infecting the lungs. These animal studies importantly show that Omicron infection results in less inflammation and lung destruction.

Consistent with this, growing evidence indicates that people infected with Omicron are likely to be hospitalized less often or less likely to need intensive care or intubation. The evidence for this continues to grow.

Dr. Scott Roberts, Professor of Infectious Diseases at Yale School of Medicine in New Haven, “Numerous laboratory-based studies show that Omicron is less able to infect the lungs than other variants, resulting in fewer pneumonia patients presenting to hospital needing oxygen and ventilators,” said.

Prof. Roberts continued: ”We see that the vast majority of patients infected with Omicron have mild disease located mainly in the upper respiratory tract, and hospitalizations are not increasing as quickly as with previous variants. However, hospitalizations and deaths are also lower than overall case numbers, and as our cases continue to rise and set daily records, we ultimately need to wait a few weeks to get the full picture of disease severity in the United States.“

Changes in Omicron's Route of Cell Entry

A potential reason for the lower level of lower respiratory tract infection caused by Omicron in current studies may be changes in this variant's ability to enter cells there. Omicron carries numerous mutations in the gene encoding the spike protein expressed on the surface of SARS-CoV-2.

The SARS-CoV-2 spike protein binds to the ACE2 receptor expressed in lung cells and helps the virus enter the cell. Cleavage of the spike protein by an enzyme called TMPRSS2 on human cell surfaces is required before the viral membrane fuses with the human cell membrane.

SARS-CoV-2 can also enter human cells by an alternative route. This involves the virus being engulfed by endosomes, membrane-bound sacs inside cells. Studies using laboratory-cultured cells suggest that mutations in Omicron's spike protein have changed the virus's ability to enter human cells with the help of TMPRSS2. These studies found Omicron less effective than Delta at infecting laboratory-cultured lung cells expressing TMPRSS2. In contrast, Omicron is more effective than Delta at infecting cells that allow entry through the endosomal route.

The ACE2 receptor and TMPRSS2 are expressed at higher levels in cells from the lower respiratory tract than in cells from the upper respiratory tract. This may potentially explain why Omicron is less effective at infecting the lower respiratory tract and causes mild disease. In addition, interaction between the SARS-CoV-2 spike protein and TMPRSS2 mediates fusion of infected human cells with uninfected neighboring cells.

The reduced ability of Omicron's spike protein to use TMPRSS2 also limits its ability to infect neighboring cells. This may contribute to the milder lower respiratory tract infection caused by Covid-19.

Because these results come from cell culture and animal experiments, human studies are needed to identify such a change responsible for Omicron's reduced ability to infect lung cells.

Prof. Peter Kasson of the University of Virginia said, “Omicron is interesting because it seems to change its preferred entry route compared with Delta and other earlier variants. As a result, it is less effective at infecting most upper respiratory tract cells.”

Why Is Omicron More Transmissible?

Besides causing less severe disease, Omicron has become more transmissible. Studies early in the pandemic showed a positive association between SARS-CoV-2 in the upper airways and increased transmissibility. Omicron's faster replication in the upper airways may explain its increased transmissibility.

Dr. Kasson “(These studies) lead to the appealing speculation that increased replication in upper respiratory tissues may contribute to increased transmissibility, potentially both by increasing the inhaled viral load and by reducing the number of viral particles needed to infect. However, this has not been conclusively proven,” said.

Omicron's increased transmissibility may also result from its ability to avoid detection by antibodies. Immunity provided by previous SARS-CoV-2 infection and Covid-19 vaccination enables production of antibodies that neutralize the virus. These neutralizing antibodies tend to predict the level of protection against SARS-CoV-2 infection.

Covid-19 vaccines were designed to induce an immune reaction against the spike protein of the original SARS-CoV-2 strain. Mutations in Omicron's spike protein suggest that this variant may be able to escape antibody neutralization.

A study led by researchers at the MRC-University of Glasgow Centre for Virus Research in the United Kingdom shows that Omicron can evade antibody neutralization in people immunized with the AstraZeneca Covid-19 vaccine. This may be another reason for Omicron's high transmissibility.

Although scientists need more research before drawing firm conclusions, the characteristics of this new variant are gradually emerging.