Just when life was returning to normal with the U.S. Food and Drug Administration’s (FDA) Emergency Use Approval (EUA) for three different SARS-CoV-2 vaccines, the virus had another trick up its sleeve: a spike (S) protein capable of binding to the human angiotensin-converting enzyme 2 (ACE2) receptor with even greater affinity than the original Wuhan strain.[1]
The emergence of the Delta variant (B.1.617.2) as the predominant SARS-CoV-2 variant in the United States[2] is a stark reminder that the virus responsible for the COVID-19 pandemic doesn’t just passively wait by the sidelines while modern medicine mounts an appropriate defense. SARS-CoV-2, with its +ssRNA genome, is constantly mutating and evolving new ways to evade our immunity. This necessitates constant vigilance on the part of scientific and medical communities to stay one step ahead of an increasingly transmissible and virulent virus.
The Pfizer-BioNTech SARS-CoV-2 mRNA vaccine just recently received full FDA approval.[3] Additionally, the Centers for Disease Control and Prevention (CDC) currently recommends booster vaccines for moderately to severely immunocompromised individuals that may be more susceptible to breakthrough infections[4] and may have difficulty fully recovering from SARS-CoV-2 infection, providing a greater opportunity for the virus to mutate and evolve within a single host.[5] Pending FDA approval and CDC Advisory Committee on Immunization Practices (ACIP) recommendation, individuals that are not immunocompromised and received the Pfizer-BioNTech or Moderna vaccines will likely require booster shots eight months after they received their second shot to boost protection against the Delta variant.[6]
As new SARS-CoV-2 variants continue to emerge, new vaccines will likely need to be developed to provide sufficient immunity against the virus. Transgenic animal models expressing the human ACE2 (hACE2) receptor are critical research tools in preclinical SARS-CoV-2 vaccine development studies, none more so than human ACE2 transgenic mice.
A recent preclinical research study vaccinated hACE2 transgenic mice with a modified, recombinant vaccinia virus Ankara (MVA) vaccine vector expressing a modified SARS-CoV-2 spike (S) protein—the protein that binds to the human ACE2 receptor to gain entry into the cell. The vaccine produced sufficient immunity in the vaccinated mice to decrease virus replication and prevent severe respiratory disease. Importantly, the ability to use transgenic mice in this preclinical study allowed researchers to better characterize the production of neutralizing antibodies and S protein-specific T cells after immunization, SARS-CoV-2 challenge, or the administration of a second vaccine dose.[7]
Likewise, another study using humanized ACE2 mice characterized the duration of immune protection conferred by mRNA vaccines of the SARS-CoV-2 receptor binding domain (RBD) of the S protein. The study found high levels of neutralizing antibodies capable of near-complete SARS-CoV-2 infection protection present in the vaccinated human ACE2 mice for 6.5 months, providing preclinical evidence of potential long-term immunity in humans administered a similar mRNA RBD vaccine.[8]
hACE2 transgenic mouse models are an invaluable preclinical research tool that can be used to establish SARS-CoV-2 vaccine efficacy, safety, host immune response, and protection duration. Importantly, the hACE2 mouse model can also be used in a variety of other research studies aimed at characterizing SARS-CoV-2 infectivity, life cycle, and COVID-19 disease progression. ingenious has developed an exclusive human ACE2 transgenic model, huACE2-ingenL, that expresses a human/mouse hybrid ACE2 transgene developed to bind SARS-CoV-2 and maintain downstream intracellular signalling in the mouse. This innovation will maximize the likelihood that experimental results in the model organism will translate to humans and inform future SARS-CoV-2 studies and clinical trials.
A great deal more research is required to eliminate COVID-19 fatalities, and the hACE2 transgenic mouse model will play a critical role in preclinical studies. Currently, only one antiviral agent, remdesivir, has been granted EUA by the FDA for use in some COVID-19 patients, and the antiparasitic drugs ivermectin and nitazoxanide are currently being evaluated for use in individuals with COVID-19.[9] Additional research into new or existing drugs that can treat and/or prevent SARS-CoV-2 infection is necessary to provide additional protection for the immunocompromised and against new virus variants.[10]
Very little is also known about COVID-19 pathogenesis, and future studies will be designed to characterize the disease mechanisms. Ideally, we’ll soon understand why some people develop severe COVID-19 while others remain asymptomatic and why children are generally less affected by COVID-19 compared to adults. Several humanized ACE2 mouse models currently show differences in their susceptibility to severe COVID-19.[11] Additionally, research into the multisystem inflammatory syndrome observed in a small percentage of adults and children and post-COVID-19 syndrome (COVID-19 “long haulers”) is also necessary to understand, prevent, and potentially reverse complications of the disease.[12]
Studies into SARS-CoV-2 stability and life cycle can additionally improve society’s first line of defense against COVID-19 through basic infection control measures. Fortunately, the Environmental Protection Agency (EPA) has established that SARS-CoV-2 can be neutralized with a variety of disinfectants and effectively removed with soaps.[13] Future well-designed, controlled studies investigating the infectivity of exhaled, virus-contaminated microdroplets over time can inform future infection control measures and reduce disease transmission.
[1] How dangerous is the delta variant (B.1.617.2)? – American Society for Microbiology
[2] Delta variant: what we know about the science – Centers for Disease Control and Prevention
[3] FDA approves first COVID-19 Vaccine – U.S. Food and Drug Administration
[4] COVID-19 vaccines for moderately to severely immunocompromised people – Centers for Disease Control and Prevention
[5] Lynch M, Macori G, Fanning S, et al. 2021. Genomic Evolution of SARS-CoV-2 Virus in Immunocompromised Patient, Ireland. Emerg Infect Dis 27(9): 2499-2501.
[6] COVID-19 vaccine booster shot – Centers for Disease Control and Prevention
[7] Liu R, Americo JL, Cotter CA, Earl PL, Erez N, Peng C, Moss B. 2021. One or two injections of MVA-vectored vaccine shields hACE2 transgenic mice from SARS-CoV-2 upper and lower respiratory tract infection. Proc Natl Acad Sci U S A 118(12): e2026785118.
[8] Huang, Q., Ji, K., Tian, S. et al. 2021. A single-dose mRNA vaccine provides a long-term protection for hACE2 transgenic mice from SARS-CoV-2. Nat Commun 12(1): 776.
[9] Antiviral Therapy – National Institutes of Health
[10] COVID-19 vaccines and immunocompromised people: fully vaccinated and not protected – Johns Hopkins Bloomberg School of Public Health
[11] Lutz C, Maher L, Lee C, Kang W. 2020. COVID-19 preclinical models: human angiotensin-converting enzyme 2 transgenic mice. Hum Genomics 14(1): 20.
[12] COVID-19 (coronavirus): long-term effects – Mayo Clinic
[13] Cleaning and disinfecting best practices during the COVID-19 pandemic – U.S. Environmental Protection Agency
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