Commentary: As COVID-19 research evolves, so too will animal models
Infectious disease researchers must expand the repertoire of animal models to advance their research
As the first COVID-19 vaccines began to roll out in December, there was a much-needed glimmer of hope—both in the research community and the public. The fact that the earliest vaccines far surpassed the 50-percent efficacy benchmark was a huge win. Notwithstanding the challenges of ramping up manufacturing on a massive scale and safely transporting vaccines with cold chain requirements, the race to stem the tide of the pandemic was finally paying off.
But no matter how many COVID-19 vaccines reach the market, the drug discovery work on this novel coronavirus is far from over. Investigators who focus on infectious disease will maintain or accelerate their work on a variety of fronts, relying on an evolving repertoire of animal models to advance their research.
No single magic bullet
History has shown that not all vaccines are effective for all people, in part due to variations in the technologies used to develop them.
In mRNA-based COVID-19 vaccines—like those developed by Pfizer/BioNTech and Moderna—a small portion of the gene that produces the coronavirus spike protein is placed into a nanoparticle that is then taken up by a human’s cells, spurring them to produce the protein and elicit an immune response. It’s a fast and relatively easy approach to vaccine development. However, it can result in a somewhat unstable formulation requiring storage at deep-frozen temperatures, making distribution challenging.
In protein-based COVID-19 vaccines—like the AstraZeneca/Oxford and Johnson & Johnson formulations —the coronavirus spike protein is created artificially and packaged into a vector known to infect humans (e.g., the adenovirus that causes the common cold). The vector provides entry into a person’s cells, which generate more of the protein to initiate an immune response. Protein-based vaccines are inexpensive to produce, easy to scale up, and refrigerator-stable for long periods, which is why they represent many of the vaccines we’re accustomed to getting.
Inherent differences in technologies make it inevitable that a given vaccine may work better in one individual vs. another or may be more feasible for certain groups vs. others, with concomitant divergent side effect profiles.
For instance, people with a history of anaphylaxis are cautioned about the chance of a reaction to the Pfizer/BioNTech vaccine and are advised to take precautionary measures. We’re learning that blood type may impact infection susceptibility, raising questions about whether it could also affect vaccine response. In some parts of the world, a vaccine with cold chain requirements may be impractical to deploy. Those that require two doses present adherence risks (will everyone return for the second dose?) and could create a false sense of immunity between doses—two factors that make the single-dose Johnson & Johnson vaccine all the more significant.
Complicating all of this is the inevitable emergence of SARS-CoV-2 mutations, including the novel South African variant, which possesses a mutation in the spike protein not found in the UK variant. Investigators are still determining to what degree, if any, this new mutation will interfere with the efficacy of currently approved COVID-19 vaccines and those in clinical trials, and whether those vaccines would need modifications in response.
Even as more COVID-19 vaccines receive approval, it will take many months—potentially years—to produce and distribute enough doses of enough varieties to protect the global population. Many more people will become infected in the meantime. As a result, there is an urgent need for targeted, efficacious, non-vaccine countermeasures designed specifically for SARS-CoV-2.
Addressing the full spectrum
Given the likely timeline to vaccinate a global, mobile population, improved COVID-19 therapeutics are needed, beyond the repurposed drugs the medical community has turned to so far. Investigators will need specialized animal models to support this work.
Initially researchers have leaned on existing models for their COVID-19 studies, including the transgenic mouse models expressing human ACE2 which were used in SARS-CoV-1 research in the early 2000s.
Since the mouse ACE2 receptor differs from the human version, but both SARS-CoV-1 and SARS-CoV-2 bind to the human version, hACE2 models have proven invaluable in studying the mechanisms of COVID-19 and testing vaccine candidates. ACE2 knockout models also are being used to study the mechanisms of acute lung injury after infection with COVID-19. And with reports that severe COVID-19 infection may be associated with the presence of the human apolipoprotein E4 allele, mouse models that express human ApoE alleles may support investigatory work in this arena.
While this approach provided access to relevant models for studying SARS-CoV-2 out of the gate, it is just the first step. Much work is underway to bring next-generation SARS-CoV-2 models to the research community.
These could include models that develop a mouse-acquired version of the virus, or models designed to assess genetic drivers of infection susceptibility (beyond the known comorbidities), or those with a humanized immune system, helping to elucidate how the virus and the immune system interact.
Other models will be needed to unravel the mechanisms at work in COVID-19 “long haulers” (those who experience long-term health effects) or for use in mechanistic studies on the effects of blood type on virus susceptibility or treatment response. As more vaccines reach the market, relevant models may be needed to study any adverse effects that emerge, to assess how virus mutations may alter vaccine response, or to test novel vaccine candidates better suited to emerging variants. And with more pharmaceutical and biotech companies taking a rational design approach—developing small molecules that bind to and disrupt the coronavirus spike protein target—they will need relevant tools to support their work.
Beyond COVID-19, mouse models will play an integral role in the evolving landscape of infectious disease research. We already know of seven unique coronaviruses that infect humans, three of which cause severe respiratory disease, and yet a coronavirus is just one type of virus with the potential to be deadly.
No one can be certain what the next pathogen will be, or what preventive measures or therapies will be needed. But we do know that committing to the necessary research tools and infrastructure will enable investigators to move fast the next time. If we have learned anything from this pandemic, it’s that there is no substitute for preparedness.
Terina Martinez, Ph.D., is a field applications scientist with Taconic Biosciences.