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Research Models
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Regina Kelder, Steve Festin, PhD

Syrian Hamster’s Starring Role in COVID-19 Research

The model has become a ‘golden’ standard’ in researching the pandemic.

In 2005, scientists first discovered that the Golden Syrian Hamster could be infected with a coronavirus, in this case the Severe Acute Respiratory Syndrome or SARS that sparked a global outbreak in the early 2000s. Flash forward 15 years, and the hamsters have emerged as a leading light, helping us to understand the SARS-CoV-2 virus—a cousin to SARS—during the early months of the pandemic. While some scientists were forced to shut down their labs due to lockdowns, others were working the problem, increasing both the scientific field and the public’s understanding of the virus and how it reacts to emerging treatments. This unprecedented global effort has unearthed an unprecedented volume of research that is helping us find new treatments and drugs in record time. In the midst of all of this has been the hamster.

Just a few months after the global pandemic struck, a team of scientists from the University of Hong Kong published a paper in Clinical Infectious Diseases documenting the utility of the Syrian golden hamster as an important tool for studying transmission, pathogenesis, treatment and vaccination against SARS-CoV-2 virus. The research, led by lead author Jasper Fuk-Woo Chan, showed what happened to eight hamsters infected with SARS-CoV-2. The animals lost weight, became lethargic, and developed ruffled fur, a hunched posture and rapid breathing. High levels of SARS-Cov-2 were found in the hamsters’ lungs and intestines, and the tissues were covered with the protein receptor, angiotensin-converting enzyme 2 (ACE2), which provides an entry point for the virus.

Another study during the early stages of the pandemic further establishing the validity of the model, also from the University of Hong Kong, again showed comparable disease patterns in Syrian hamsters compared to humans. Viral antigens were found in the nasal mucus, bronchial epithelial cells, and in areas of lung consolidation 2-5 days post-inoculation of the virus. SARS-CoV-2 transmitted efficiently between hamsters via aerosols or direct contact, though transmission via fomites in soiled cages was less so. The findings were published in Nature .

This would not be the last time that Syrian hamsters helped inform our understanding of the deadly virus sparking a global pandemic. In study after study, the hard-working Syrian hamster has enlightened scientists about the efficacy of vaccines and drugs, viral genetics, mask effectiveness, aging, convalescent plasma, side effects of COVID-19 and ever-important question of how neutralizing antibodies might work against the virus. To date there have been at least 50 published studies using Syrian hamsters, and while there are many other animal models also being deployed, the Syrian hamster has proven to be among the FIRST most useful in probing all aspects of COVID-19. Here is a glimpse of some of those studies and how they are informing COVID-19 research.

Looking for the Perfect Challenge

Hamster modelIt is necessary to test a novel drug or vaccines in humans without first gathering sufficient data that the product is safe and effective in preclinical models. Finding the perfect infection model to test these vaccines and drugs is tricky, particularly considering our limited understanding of SARS-CoV-2. Findings from the US Rocky Mountain Laboratory in Montana , the same site that helped to develop an Ebola vaccine, found that the Syrian hamster is highly susceptible to SARS-CoV-2, making it an ideal infection model for COVID-19 countermeasure development. They were able to reach this conclusion by determining the correct dose of virus to infect the hamster. Another study, led by the United States Army Research Institute of Infectious Diseases, developed a novel severe disease hamster model that disrupts their adaptive immunity, and their research suggests that both B and T cells—twin arms of the adaptive system—are important for both clearing the virus and early protection following exposure. And an Indian study used bioinformatics tools —ACE2 protein sequence homology—to rank the susceptibility of multiple animal models, including the Syrian hamster.

Meanwhile, scientists at the University of Essex , in the UK, looked at how the virus interacts with proteins present on the surface of lung cells and found that the hamster was one of the most similar models to humans, making them a useful model for researchers looking into COVID-19 therapies, particularly ones targeting the respiratory tract.

Another study out of the University of Hong Kong used the Syrian hamster model to demonstrate that the severity of pneumonia induced by the intranasal inhalation of SARS-CoV-2 increases with virus inoculum.

And Syrian hamsters weren’t the only hamster evaluated. A study conducted by the Institut für Virologie in Berlin found that SARS-CoV-2 infection of Chinese hamsters caused pneumonia in the animals.

Vaccine and drug studies

COVID vaccineArguably, one of the most robust areas of research has been the hunt for antiviral drugs and vaccines to treat and prevent SARS-CoV-2. There are close to three dozen clinical trials underway for antiviral drugs and more than 100 clinical trials for vaccines. On the vaccine front , several candidates have reached late-stage efficacy studies and one antiviral drug, previously developed for Ebola, is now being distributed on an emergency use basis.

The Syrian hamster proved to be a useful animal model in the evaluation of some of these therapies. A study published recently in PNAS by a collaborative team of researchers from Japan and the US found that SARS-CoV-2 isolates replicate efficiently in the lungs of Syrian hamsters and cause severe pathological lesions in the lungs of these animals similar to what we find in the images of human COVID-19 patients with pneumonia. In the study, SARS-CoV-2−infected hamsters mounted neutralizing antibody responses and were protected against re-challenge with SARS-CoV-2. Moreover, passive transfer of convalescent serum—antibodies drawn from the blood of recovered patients—inhibited virus replication in their lungs. Hamsters were used to demonstrate the safety and of a cheaper viral vector model that relies on a Newcastle virus (NDV-S) to shuttle the vaccine into cells intramuscularly . A pilot study found that the inactivated NDV-S vaccine was immunogenic, inducing high titers of spike-specific antibodies, conferring protection and attenuating the symptoms of SARS-CoV-2 induced diseases in hamsters.

The Syrian hamster also helped advance our understanding of the use of hydroxychloroquine, an immunosuppressant touted as a potential treatment in the early days of the pandemic but which has since been shown to be ineffective in the treatment of critically ill COVID-19 patients. A study led by the US National Institutes of Health found that the drug, typically prescribed for the treatment of malaria, did not have any beneficial effect on clinical disease or replication/shedding in the Syrian hamster. These findings were encompassed in a commentary published in August in Nature Communications that found that an international collaboration of independent scientists reached the same conclusion. Also, a study from the Rega Institute for Medical Research in Belgium used the Syrian hamster model to show that an antiviral influenza drug had a marked protective effect against SARS-CoV-2, while hydroxychloroquine did not.

And last month, Nature Medicine published findings from a study led by Beth Israel Deaconess Medical Center that found that an optimal Ad26-based SARS-CoV-2 viral vector vaccine elicited robust immune responses in Syrian golden hamsters and prevented severe clinical disease, including weight loss, pneumonia and death. The vaccine candidate is currently being evaluated in humans.

Syrian hamsters were also used to test a therapeutic antibody cocktail designed to treat critically-ill COVID-19 patients and to prevent infection. And lastly, a drug commonly used to treat the bacterial infection Helicobacter pylori was found to be a potent SARS-CoV-2 agent. In Syrian hamsters , the drug suppressed SARS-CoV-2 replication, leading to decreased viral loads in both upper and lower respiratory tracts. It also relieved virus-associated pneumonia.

Viral fitness and genetics

Viral DNANot surprisingly, some of the earliest studies of SARS-Cov-2 involved viral genetics. After all, understanding how the genes of SARS-CoV-2 function will go a long way toward developing ways of treating and preventing the virus from spreading. One study showed why some SARS-CoV-2 viruses are more transmissible than others by underscoring the importance of the furin site—which contains a cleavage site that is thought to help the SARS-CoV-2 virus enter cells. The study found that a deletion of the furin site in the hamsters, due to a mutation, greatly reduced the ability of the virus to replicate. A similar study conducted in hamsters showed marked attenuated disease and viral replication when the furin cleavage was missing, underscoring how central the cleavage site is to understanding SARS-CoV-2 pathogenesis.

Syrian hamsters also proved useful in the testing of an infectious clone of SARS-CoV generated by Texas Medical Center . Such clones are essential for studying a virus’s method of infection, its replication, drugs that might work against it, and potential vaccines. The Texas study showed similar levels of replication to that of the natural isolate in nasal turbinates and lungs of infected hamsters. Lastly, the hamster model was useful in determining the relative replication fitness of variants compared to wild-type SARS-CoV-2 in a study using a sensitive assay developed by the University of Hong Kong.

Viral fitness was also looked at to determine which SARS-CoV-2 viruses are “fitter” than others, i.e. more capable of adapting to a host environment. A Syrian hamster study led by the University of Texas Medical Branch confirmed that the SARS-CoV-2 spike protein mutation D614G enhances viral loads in the upper respiratory tract of COVID-19 patients, and may increase transmission. And a study conducted by a hospital in Shandong Province, China suggested that the reason why Syrian hamsters might be more susceptible to SARS-CoV-2 than other animals is due to ACE2 isoform diversity—different versions of the cell-surface receptor that have behave differently. The ACE2 isoforms found in hamsters make then more susceptible to SARS-CoV-2 unique functions.

A University of California-San Diego study sought to define the cytokine storm—the extreme and abnormal immune assault in response to the virus—and again the Syrian hamster helped in this study. Using machine learning, techniques, over 45,000 transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature using ACE2 as a ‘seed’ gene. The signature was then exploited as a predictive model to navigate COVID-19. Findings pinpointed the precise nature of the cytokine storm, the culprit cell types and the organs. Key findings were validated in Syrian hamsters and in patients.

Neutralizing antibodies

Neutralizing antibodiesLastly, researchers have used the Syrian hamster model to isolate potential neutralizing antibodies (nAbs) against SARS-CoV-2. Among many virologists, finding good nAbs that can be used to prevent and treat the virus is the gold standard in beating COVID-19. In fact, convalescent plasma comprised of antibodies rescued from recovered COVID-19 patients has become a strategy that many doctors are exploring with critically ill patients, and that the FDA is allowing as an investigational product based on recent data.

But how well does it really work? Researchers from The Scripps Research Institute and the International AIDS Vaccine Initiative recruited a cohort of naturally-infected individuals who had recovered from COVID-19. In less than seven weeks, they collected blood samples, developed functional assays to rapidly screen and sort antibodies from these samples, and set up cell and animals to evaluate the antibodies for protection against SARS-CoV-2. The scientists characterized more than 2,000 antibodies overall. The most potent ones, based on human tests, were evaluated in the Syrian hamster animal model for protection against SARS-CoV-2. Animals that received the most potent nAbs were protected, the study found. The findings were published in Science .

Other studies also showed the benefit of the hamster in isolating and testing neutralizing antibodies. A Japanese team determined that the hamster’s ability to mount potent neutralizing antibodies against SARS-CoV-2 and not being re-infected through challenge made it a useful model to test vaccines, antiviral drugs and immunotherapies. A study led by the German Center for Neurodegenerative Diseases found that a prophylactic and therapeutic application of a highly potent neutralizing antibody obtained from the blood of a COVID-19 patient protected hamsters from SARS-CoV-2 infection, weight loss and lung pathology. And researchers from the University of Pittsburgh used a hamster model to test a high-affinity antibody that they identified from a phage display library . The authors of the study suggested that it was the first report of a high-affinity antibody that binds to a variable region of the SARS-CoV-2 virus.

A study in China created a crystallized structure of a high-infinity neutralizing antibody binding to the SARS-CoV-2 surface protein to determine its neutralization mechanism, then treated infected hamsters with a sequential low dose of the antibody therapy. The study found high efficacy among the hamsters compared to a control group of untreated infected hamsters. Another study in China reported this summer described the rescue of a SARS-CoV-2 strain circulating in the US derived from an artificial bacterial chromosome—a miniature version of the real chromosome that can replicate alongside its natural counterpart in host cells. Syrian hamsters were then infected intra-nasally with the clone virus to see if it behaved the same as a naturally occurring virus strain. Lastly, a Colorado State University team identified a panel of human monoclonal antibody clones from a yeast display library with specificity to the SARS-CoV-2 spike protein binding domain. Their study found that administration of the lead antibody clone to Syrian hamsters challenged with SARS-CoV-2 significantly reduced viral load and histopathology score in the lungs.

Public Health Research

Face masksSyrian hamsters were not just useful in studying the biology of the virus. They also were used to study critical public health concerns, such as do masks help prevent transmission and how effective are they, why is COVID-19 so hard on the elderly and why do people infected with SARS-CoV-2 lose their sense of smell? These were among the many questions that consumed the scientific community, and which the hamster, once again, helped to inform.

The Syrian hamster model has been used to show that non-contact transmission of SARS-CoV-2 could be prevented by wearing surgical masks. To prove this, a control group of hamsters were artificially infected with SARS-CoV-2, and placed next to healthy hamsters whose cage contained a fully-knitted layer of partition made of surgical mask material. The use of masks in such a way reduced non-contact transmission of the virus by more than 60% whereas two thirds of the healthy hamsters got infected within a week when no masks were used. The findings appeared in Clinical Infectious Diseases , and are an important reminder of how important masks are at a time when this preventive measure has become politicized.

Virologists from the Freie Universität Berlin also used aged and young Syrian hamsters to demonstrate how the impact of the virus is more severe the older you are. The study found that young hamsters launched much stronger immune responses to SARS-CoV-2, and recovered lung capacity faster than their older relatives, who instead developed conspicuous alveolar and perivascular edema, indicating vascular leakage.

One of the surprising symptoms of COVID-19 has been the temporary loss of taste or smell. But why? A Hong Kong study in hamsters found that SARS-Cov-2 directly infected olfactory neurons of hamsters and induced cell death. It also provoked inflammatory responses in neighboring cells that may adverse impact the function of the olfactory neurons. A separate hamster study conducted in France found that massive shedding of olfactory epithelium that led to a loss of smell was triggered by COVID-19 infection of the cells supporting the olfactory epithelia as well as recruitment of immune cells to the nose’s sensory system.

Conclusion

Of course, we are learning a lot about the pandemic from other animal models, large and small; none of them are identical matches to the human virus, which prevents us from seeing the full picture in the preclinical setting. And 10 months into the pandemic, we are starting to see the emergence of other COVID-19 animal models, based on specific genetic targeting techniques including CRISPR. Yet were it not for the amazing Golden Syrian hamster, we would not have learned as much as we did, on so many different fronts, during the early black box months of the pandemic.

A sincere thank you to these hamsters.