- The document discusses animal models that are being used to test vaccines for COVID-19. It conducted a systematic review of studies published between January and August 2020. - The review identified 20 relevant studies examining nonhuman primates, mice, hamsters, ferrets, cats and dogs. These animal models show some similar responses to SARS-CoV-2 infection as humans such as respiratory symptoms. - However, the models do not fully mimic the severe complications seen in human COVID-19 patients such as acute respiratory distress syndrome and coagulopathy. While the models provide useful information, they have limitations in replicating the full disease severity in humans.

1. S31
© 2021 Journal of Pharmacy and Bioallied Sciences | Published by Wolters Kluwer - Medknow
Extensive work is being done to form targeted drugs against severe acute
respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection; however, it is
imperative to have a safe and effective vaccine against the same to win the war
against this pandemic. For creating an efficacious vaccine, a proper animal model
needs to be selected which can have an acceptable similarity of response as well
as effects when administered to humans. For the present research, extensive
search was conducted in MEDLINE and bioRxiv and medRxiv servers which
were published in the English language from January 1, 2020, to August 20,
2020. Search terms included animal models, SARS‑CoV‑2, COVID‑19, immune
response against coronavirus, nonhuman primates, mice, ferrets, and macaques. In
our study, creating an adequate immune response mimicking the response as in
humans, as the endpoint, was considered as inclusion criterion while assessment
of any additional therapies like safety as well as minimal tolerable dose using
animal models as well as formation of adequate sample size of these models
against COVID-19 was not considered. In our search, 163 articles were shortlisted,
of them only 20 articles were finally included in our study which addressed to
our inclusion and exclusion criterion. Our research articles focused on nonhuman
primates, mice, hamsters, ferrets, cats, and dogs, with the main goal to investigate
the role of animal models in the pathogenesis of COVID‑19. It was evident in our
research that animal models only mimic limited signs and symptoms experienced
in COVID infection as compared to infections in humans. However, they are still
essential to understand the pathogenesis, transmissibility of viral particles, and
vaccine testing.
Keywords: Animal models, COVID‑19, ferrets, hamster, nonhuman primate,
review, rodent, severe acute respiratory syndrome coronavirus 2
COVID and Animal Trials: A Systematic Review
Muhamood Moothedath, Muhaseena Muhamood1
, Yadnit S. Bhosale2
, Aseem Bhatia3
, Pranav Gupta4
,
Medapati Rama Haranadha Reddy5
, Rahul V. C. Tiwari6
Access this article online
Quick Response Code:
Website: www.jpbsonline.org
DOI: 10.4103/jpbs.JPBS_749_20
Address for correspondence: Dr. Muhamood Moothedath,
Department of Oral and Dental Health,
College of Applied Health Sciences in Ar Rass,
Qassim University, Buraydah, Saudi Arabia.
E‑mail: drmuhamoodmoothedath@gmail.com
coronavirus disease 2019 or COVID‑19.[1]
Older people
above 60–65 years and those having comorbidities are
Introduction
Coronavirus pandemic has affected more than 400
thousand people around the world and has been
causing severe respiratory syndromes, which also has
been a cause for the mortality of the people affected.
This disease has been commonly referred to as
Department of Oral and Dental
Health, College of Applied
Health Sciences in Ar Rass,
Qassim University, Buraydah,
Saudi Arabia, 1
Department of
Biomedical Dental Science,
College of Dentistry, Imam
Abdulrahman Bin Faisal
University, Dammam, Saudi
Arabia, 2
Department of
Prosthodontics and Crown and
Bridge, MGM Dental College
and Hospital, Navi Mumbai,
Maharashtra, 3
Bachelor of
Dental Surgery, Gian Sagar
Dental College and Hospital,
Baba Farid University of
Health Sciences, Faridkot,
Punjab, 4
Ex- Senior Resident,
Department of Conservative
Dentistry and Endodontics,
Himachal Institute of Dental
Sciences, Paonta Sahib,
Himachal Pradesh, 5
Department
Oral and Maxillofacial Surgery,
Panineeya Mahavidyalaya
Institute of Dental Sciences and
Research Center, Hyderabad,
Telangana, 6
Department of
OMFS, Narsinhbhai Patel
Dental College and Hospital,
Sankalchand Patel University,
Visnagar, Gujarat, India
Submitted: 20‑Nov‑2020
Revised: 21-Nov-2020
Accepted: 23‑Nov‑2020
Published: 05-Jun-2021.
Abtract
How to cite this article: Moothedath M, Muhamood M, Bhosale YS,
Bhatia A, Gupta P, Haranadha Reddy MR, et al. COVID and animal trials:
A systematic review. J Pharm Bioall Sci 2021;13:S31-5.
This is an open access journal, and articles are distributed under the terms of the Creative
Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to
remix, tweak, and build upon the work non-commercially, as long as appropriate credit is
given and the new creations are licensed under the identical terms.
For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com
Review Article
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2. S32 Journal of Pharmacy and Bioallied Sciences ¦ Volume 13 ¦ Supplement 1 ¦ June 2021
Moothedath, et al.: COVID and animal trails
seriously affected and thus end up with multi‑organ
failure leading to death of the patient.[2]
Spike protein
binding is the main aspect which hastens the entry of
virus particle inside human cells, which is facilitated by
binding with angiotensin‑converting enzyme‑2 (ACE 2)
protein on the host cell.[3]
This increases the propensity
of the infection, with mortality rate up to 5.8% with
an average of 3.4% and covering almost 210 countries
worldwide.[4,5]
Hence, it is a matter of great concern that
progress in the field of drug and vaccine development
is increased at a breakneck speed. Pharmaceutical
companies are trying to manufacture a potent vaccine
by either using a weakened virus/or viral particle,
viral RNA, or utilizing the target mechanism of spike
protein, which allows entry of virus inside host cells.[6]
An effective and prompt immune response against this
virus is the endpoint considered in vaccine studies.
Hence, to generate a high‑level immune response,
certain specific antigens are considered as the ideal
candidate for vaccine production, but it requires host as
well. This is where animal models come into the picture
so that testing can be done easily without harming
human lives.[7]
However, currently, the animal models
used for production of vaccines against severe acute
respiratory syndrome coronavirus 2 (SARS‑CoV‑2) are
still under testing phase for many vaccine candidates,
and more so the virus should induce similar pattern of
disease and pathogenesis, as in humans, for successful
vaccine generation.[8]
Therefore, it is important to
summarize if any of the animal models which are
being currently used are turning out to be effective host
reservoir.
Methods
Search strategy and selection criteria
A systematic review was hence conducted according to
the Preferred Reporting Items for Systematic Reviews
and Meta‑analysis guidelines[9]
where studies which
had laid emphasis on the generation of animal models
against coronavirus infection were considered as the
endpoint [Table 1].
Included studies
Researches where animal models were used for vaccine
generation against COVID‑19 infection were considered.
Articles which were between January 1, 2020, and
August 20, 2020 were included in the review.
Excluded studies
During the course of searching articles for our systematic
review, the articles where only abstracts were available
and the ones which were based on SARS and Middle
East respiratory syndrome (MERS) as primary infection
were excluded from our search criteria. Articles which
were published in languages other than English were
also excluded.
Data extraction
Data from articles were extracted individually by two
reviewers, which were used to construct the tables.
Quality assessment
Quality of each publication was evaluated by two
independent reviewers. This review addressed various
domains: vaccine production, quality of immune
response, active immunity, dose of administration, and
pathogenesis of the disease in animal models.
Assessment of risk of bias and applicability in
included studies
Assessment of risk of bias and its inclusion in the
studies were comprehended by reviewers independently.
SYRCLE’s risk of bias tool was used for quality
evaluation of animal studies and Nature Publication
Quality Improvement Project score sheet was used to
assess in vitro studies.[10,11]
Results
During our search on MEDLINE and various other
Internet platforms and servers, we identified 69 studies
and 94 preprints, of which 143 articles were excluded
as many were not original articles, not related to
COVID‑19 infection. Only 20 articles were consistent
with our inclusion and exclusion criterion. Our research
64 articles identified in
Pubmed
94 reprints identified in
BioRxiv and MedRxiv
163 preprint articles screened
123 articles excluded
following abstract screening
40 articles read in full
20 articles included
7 preprints
76 unrelated to animal models
35 not original research
12 animal models without
SARS-COV-2 inoculation
20 articles excluded with no
SARS-CoV-2 or missing data
13 peer-reviewed articles
Table 1: Flow diagram illustrating the process of study selection. A
systematic review was conducted according to the Preferred Reporting
Items for Systematic Reviews and Meta- analysis
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Journal of Pharmacy and Bioallied Sciences ¦ Volume 13 ¦ Supplement 1 ¦ June 2021
Moothedath, et al.: COVID and animal trails
articles focused on nonhuman primates, mice, hamsters,
ferrets, cats, and dogs, with the main goal to investigate
the role of animal models in pathogenesis of COVID‑19
infection, risk of transmission, rate of infectivity,
and inoculation with SARS‑CoV‑2 viral strains
with ascending doses and studying the therapeutic
effects [Table 2].
Rhesus macaques
In case of rhesus species, they have a similar amount of
ACE‑2‑binding receptor proteins on their cells. Hence,
they turn out to be near ideal choice for testing of
vaccines.[12]
In their case, pulmonary infection is present
when inoculated with SARS‑CoV‑2 virus and can be
verified with the help of radiographs. They also have an
increased number of viral particles that can be extracted
from their nose and throat samples.[13]
Ferrets
Ferret models are similar to human lungs as they are
susceptible to coughing and sneezing reflexes, so they
can be used to test COVID‑19 infection also.[14]
They
also have high transmissibility rates, as ferrets can
spread the virus with the help of direct contact and/or
aerosols.[15]
Mice
Laboratory mice is always an effective and much more
cost‑effective and easy to handle animals for vaccine
testing. Recently, humanized mice versions which
have similar ACE2 numbers have also been created to
successfully test SARS‑CoV‑2 infection.[16]
Syrian hamster
This animal model can also be used for testing as they
have similar phenotypic alterations in ACE‑2‑binding
mechanisms as and when compared to human binding
sites on the cell membrane, which is an essential
requisite for the pathogenesis of COVID infection.
Discussion
Many animal models have recently been included in
various studies which have proved to be hopeful for
effective vaccine generation. Moderna, a USA‑based
company, has already completed its phase I trials
successfully which helps in safety as well as toxicity
of these vaccine targets in humans.[6]
Pfizer is already
in phase III trials and according to some, the vaccine
generated by them is around 90% effective. Many studies
of animal models have been reviewed in connection
with SARS and MERS infection, these models usually
Table 2: Summary of studies using nonhuman primate models of COVID‑19
Species and concerned studies Number of samples (n) Outcome measures
Rhesus macaques
Munster et al. (2020) 8 Pathogenesis of COVID‑19
Yu et al. (2020) 2 Pathogenesis of COVID‑19 in aging animals
Van Doremalen et al. (2020) 6 Evaluation of DNA vaccine
Gao et al. (2020) 4 Evaluation of an inactivated vaccine
Williamson, B.N. et al. (2020) 6 Testing of antiviral therapy
Chandrashekar et al. (2020) 9 Immune protection after a second exposure
Bao et al. (2020) 7 Immune protection after a second exposure
Deng, W. et al. (2020) 5 Viral infection routes
Mice
Boudewijns et al. (2020) 20 Interferon response to SARS‑CoV‑2 Infection
Bao et al. (2020) 15 Pathogenesis of COVID‑19
Lv et al. (2020) 10 Cross‑reactivity of antibodies against SARS‑CoV and SARS‑CoV‑2
Pruijssers et al. (2020) 10 Establishment of mouse‑adapted SARS CoV‑2 model of COVID19
Dinnon et al. (2020) 33 Evaluation of vaccine and therapy in mouse‑adapted SARS‑CoV‑2 model
Ferret
Kim et al. (2020) 6 Viral infection and transmission
Golden Syrian Hamster
Chan et al. (2020) 10 Study of pathogenesis, therapeutics, and vaccines
Sia et al. (2020) 6 Immunological studies for vaccine development
Cynomolgus macaques
Lu et al. (2020) 6 Comparisons of pathogenesis between COVID‑19, SARS‑CoV, and MERS CoV
Rockx et al. (2020) 10 Comparisons of pathogenesis between COVID‑19, SARS‑CoV, and MERS CoV
Finch et al. (2020) 6 Evaluation of medical interventions
African green Monkey
Woolsey et al. (2020) 6 Pathogenesis of COVID‑19
SARS‑CoV‑2: Severe acute respiratory syndrome coronavirus 2, MERS CoV: Middle East respiratory syndrome coronavirus
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4. S34 Journal of Pharmacy and Bioallied Sciences ¦ Volume 13 ¦ Supplement 1 ¦ June 2021
Moothedath, et al.: COVID and animal trails
failed to replicate the conditions which are similar to
the human environment for trail and testing of vaccines.
In addition, the results of this systematic review are also
consistent with the above findings when COVID‑19
infection is considered.[17]
However, viral titers which
were high in number were discovered in the respiratory
passage, and many mild symptoms were similar to the
symptoms that humans experience. Unfortunately, the
common complications like acute respiratory distress
syndrome (ARDS) and coagulopathy, which is common
in human COVID patients, were not replicated in
any of these animal models.[18]
Most cases that end
up in intensive care units have hypoxemia which is
caused due to ARDS and coagulopathy leads to severe
thrombo‑embolic complications in humans, even in the
young age population.[19,20]
The postmortem studies of
the individuals who died of these complications revealed
extensive hyalinization and inflammatory cell damage
leading to destruction of the alveolar air spaces which
are essential,[21]
further supported by the fact that in
these individuals, many micro‑ and macrothrombi were
noted in the lung tissue which compromised their lung
perfusion leading to higher mortality.[22]
A full‑blown
COVID infection in humans significantly differs from
these animal models, as the severity of respiratory
as well as thrombo‑embolic manifestations is not
simulated to near ideal situations. However, mechanism
of respiratory symptoms as well as pathogenesis is not
fully clear as many pathways may lead to an increase
of tissue factor which will cause endothelial injury and
hence thrombotic episodes with complement activation,
which further compromises the vascular system,
especially in the pulmonary area which further worsens
the symptoms by activating the clotting cascade and
subsequent formation of thromboemboli. Hence,
animal models which can simulate these conditions
will help in understanding the pathogenesis better.[23‑27]
Rhesus macaques and mice were used to test both the
antiviral medications and vaccine candidates where
the medication stopped viral replication leading to a
recovery in case of pneumonitis.[28]
In case of vaccine
candidates, there was an increase in titer of anti‑COVID
antibodies as well as a decrease in the viral load which
helped in preventing respiratory infection significantly.
[29]
This leads to a promising outcome for vaccine
efficacy as well as antiviral medication effectiveness
against SARS‑CoV‑2. Unfortunately, even after the
epidemics such as SARS and MERS, scientists have not
been able to form an effective animal model to create
conditions appropriate for the spread of COVID‑19
in animals.[30,31]
Primates have similar binding affinity
to COVID‑19 virus as when related to humans,[32]
which differs in stark contrast to other animals such as
hamsters and mice, which have low‑to‑medium affinity.
This issue has been seen in many studies where mice
does not support increased SARS‑CoV‑2 replication as
compared to a chimera as the former does not have more
amount of ACE‑2‑binding protein receptors on their
cells.[33]
Recently, complex phenotype of COVID‑19
was found with the help of single‑cell RNA genomic
sequence technology which might help us to decide
on the dissimilarities between primate and nonprimate
species‑specific infections.[34]
For proper entry of
viral particles inside the host cell, it is imperative to
study the variations encountered in the distribution of
ACE‑2‑binding protein and TMPRSS2, as the amount
of these receptors as well as their surface configuration
varies in different organs as well as between two
species also. In the primate lung when compared with
human pneumocytes, ACE‑2 expression was lower
in the animals, especially in type II pneumocytes.[35]
During the course of evolution, lot of modifications
have happened, which has led to the limitation of this
viral infection in only the respiratory system of these
animals.[36]
This explains that animal models show less
of symptoms as compared to humans, which poses a
practical challenge in vaccine development for humans
in case of COVID‑19 infection. Our systematic review
did have its share of limitations, as we had included
preprints in the studies which were not peer‑reviewed
as yet. We also did have less number of articles studied,
and thus, the scope of this study needs to be widened.
Conclusion
Through this systemic review, we were able to find
out that animal models only mimic limited signs and
symptoms experienced in COVID infection as compared
to infections in humans. However, they are still essential
to understand the pathogenesis, transmissibility of viral
particles, and vaccine testing. Hence, an animal model
should be selected carefully, which can help outlining
the vaccine testing strategy effectively.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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