SARS-CoV-2 UK variant shows low virulence and high shedding in hamster model

The emergence of new strains of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the ongoing coronavirus disease 2019 (COVID-19) pandemic, pose a serious potential challenge to attempts at curbing its spread.

A new preprint, released on the bioRxiv* server, compares the pathogenicity and infectiousness of one such variant, the VOC 202012/01 (B.1.1.7 lineage) from the United Kingdom, with the globally dominant D614G mutation-carrying strains.

The UK variant

The UK variant carries 23 defining mutations involving changes in the spike protein of the virus that interacts with the human host cell receptor, the angiotensin-converting enzyme 2 (ACE2). The spike mutations include the deletions (69/70,144Y) and substitutions (N501Y, A570D, D614G, and P681H).

The N501Y affects the receptor-binding domain (RBD) of the spike protein and has been estimated to increase the binding affinity of this protein for the ACE2 receptor ten-fold relative to the wildtype RBD. The implications for increased infectivity and transmissibility are clear.

Since 90% of neutralizing antibodies against SARS-CoV-2 are formed against the RBD, the immune evading effects of these mutations also deserve serious attention, particularly when they are found together. Preliminary research from the New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) suggests that this variant could be associated with a higher mortality rate.

The current study explores the ability of the UK variant to cause disease in the golden Syrian hamster and the viral shedding profile of this variant, compared to the D614G variant.

Infection leads to transient weight loss

The researchers found that VOC-202012/01 inoculated into hamsters intranasally produced weight loss but no clinical illness. The weight loss worsened over seven days from infection to a mean of 7% and then tended to reverse itself to the end of the study period, at day 14. Controls showed a loss of 3% and then a gain of 6% until the end of the study.

Immune response

The infected hamsters developed a predominant anti-SARS-CoV-2 immunoglobulin (Ig) G2 antibody response, observed on the seventh day from infection. This continued up to day 14. Neutralization titers remained similar against both variants, even though, on day 5, titers against VOC 202012/01 were higher.

Viral load

The researchers found high viral genomic RNA (gRNA) in the upper and lower respiratory tract, with the load being highest in the lungs and the lowest in the throat swabs. Nasal and tracheal samples were intermediate.

From day 3 to 14, the gRNA load in the nasal wash, tracheal, and throat swabs showed a decreasing trend. However, lung and nasal turbinate specimens showed a peak at day 5, but then went down until day 14.

Infectious virus was found in various tissues up to day 7, but on day 10 and day 14, infectious viral particles were not found.

Subgenomic (sg) RNA was found in the lungs and trachea of all hamsters on day 3, but not in the nasal wash or nasal turbinates at this point. By day 5, only lung samples were always positive.

Some animals showed the presence of gRNA in other tissues as well, but not sgRNA. The lack of the latter confirms that the virus targets the respiratory tract primarily.

Lung pathology

Infected hamsters showed signs of consolidation, exudation and other signs of pneumonia with both variants. Serum cytokine profiles were also comparable.

Viral shedding

Hamsters infected with VOC 202012/01 showed persistent gRNA in the throat, nasal wash and feces. Nasal wash levels were highest. All tissues showed decreasing levels until day 14. The peak levels were on days 4, 6 and 8 following infection. However, virus titers remained comparable between the two variants.

What are the implications?

The study confirmed the pathogenicity of the VOC 202012/01 variant, with a higher body weight loss caused by infection with this strain compared to the earlier D614G strain.

VOC 202012/01-infected hamsters showed the ability to produce antibodies that neutralized the earlier variant, indicating that this cluster of mutations did not produce significant immune escape from antibodies produced following either natural infection or vaccination.

The high gRNA load in the nasal turbinates and lungs on day 3 in hamsters infected with the D614G variant was not replicated here. Instead, the peak was observed on day 5 following infection with VOC 202012/01.

This may indicate delayed viral clearance with the newer strain. Viral clearance appeared to be correlated with increasing neutralizing antibody titer, from day 7 following infection.

Again, the D614G variant was associated with the live virus in the lungs and nasal turbinates only up to day 5 following infection, but with VOC 202012/01, up to day 7. This indicates that this variant may prolong virus persistence in the respiratory tract, perhaps accounting for its higher transmission.

Interestingly, the viral gRNA loads in the respiratory tract were higher with the newer variant, but the lungs showed signs of only mild pneumonia. This belied the more severe loss of body weight, and also disagrees with earlier findings of more severe human disease following infection with VOC 202012/01, as reported by NERVTAG.

Viral shedding was also high in nasal samples throughout the first week, but not higher than that observed with the earlier variant. The higher viral RNA loads may correlate with the higher transmissibility of the virus.

Overall, increased lung pathology was not observed despite the decrease in body weight. Further studies will be required to explore this seemingly paradoxical relationship.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.