NIAID Now | August 18, 2021
As the global COVID-19 pandemic continues, safe and effective vaccines are playing a pivotal role in preventing severe disease and death and limiting the spread of SARS-CoV-2, the virus that causes COVID-19. The urgency of the COVID-19 pandemic necessitated rapid vaccine development and testing. Fortunately, NIAID’s decades-long support and conduct of coronavirus and vaccine research laid the groundwork for helping to develop a safe and effective COVID-19 vaccine in record speed.
COVID-19 Animal Models
Animal research plays a key role in developing successful vaccines for humans. Before promising vaccine candidates can be tested in humans, they must first be tested for safety and effectiveness in animals as required by the U.S. Food and Drug Administration. To do this, scientists first determine whether a vaccine candidate can stimulate an adequate and safe immune response. This important step is often conducted using small and then, potentially, larger animal models of disease. Mice are frequently used because they reproduce rapidly, have a well-characterized immune system and a defined genome. Some labs turned to mouse models of infection early in the COVID-19 pandemic only to find that mice don’t get infected with SARS-CoV-2. In order to infect cells, SARS-CoV-2 must bind to a human protein called ACE2. The human and mouse ACE2 proteins are different, and SARS-CoV-2 does not bind to mouse cells. Scientists overcame this problem by generating mice that can express the human version of ACE2 and can therefore be infected with SARS-CoV-2. When these genetically modified mice are infected by the virus, they lose weight and become sick in ways that are similar to what happens when people are infected with the virus. Mouse models provided vital information about COVID-19 symptoms and its disease course and continues to be used by researchers to understand COVID-19 disease.
Syrian hamsters are another important animal model for COVID-19 because disease in those animals closely resembles the disease in humans. Additionally, older male hamsters develop more severe disease than young female hamsters, which reflects some of the differences seen in humans infected by SARS-CoV-2. Hamster models have contributed to the evaluation of investigational COVID-19 vaccine candidates, immunotherapies, and antiviral drugs.
Vaccine development for COVID-19 also benefitted from nonhuman primate studies. In assessing immunogenicity and protection of vaccines in pre-clinical animal models, nonhuman primates provide several advantages for clinical translation. They are outbred, have greater similarity to humans than rodents in innate immune responses and B- and T-cell repertoires, and allow use of clinically-relevant vaccine doses. Recent studies in nonhuman primates show that SARS-CoV-2 targets similar replication sites and recapitulates some aspects of COVID-19 disease. Nonhuman primates are used during the later stages of vaccine development and typically build upon the knowledge accumulated in earlier small animal studies.
A New Type of Vaccine
The biopharmaceutical companies Moderna, Inc., based in Cambridge, Mass., and Pfizer, Inc., based in New York City, developed a new type of nucleic acid vaccine called an mRNA vaccine that when tested in clinical trials, proved to be more than 90 percent effective at preventing COVID-19. Animal studies contributed to the scientific understanding of how these new types of mRNA vaccines work. For example, when the 2016 Zika virus outbreak occurred, researchers developed a nucleic acid vaccine that protected against Zika virus infection in mice and nonhuman primates. The Moderna and Pfizer COVID-19 vaccines use the nucleic acid, messenger RNA (mRNA) to produce the viral spike protein found on the surface of SARS-CoV-2. Because mRNA is unstable, it is enclosed in lipid nanoparticles to prevent it from degrading following injection. Cells then produce the viral spike protein and display it on their surfaces. In this form, the viral spike protein is recognized by the body and triggers an immune response. This response includes the production of antiviral antibodies and T- cell responses that allow the body to remember how to fight off SARS-CoV-2 if infected in the future.
Preclinical data with Moderna’s mRNA vaccine produced promising results in animal models. Mouse experiments demonstrated that a low dose of the vaccine induced a robust neutralizing antibody response and a high-level protection against SARS-CoV-2. Moreover, vaccination of nonhuman primates with the mRNA vaccine induced robust SARS-CoV-2 neutralizing activity and notably, rapid protection in the upper and lower airways, similar to safety and immunogenicity results subsequently observed in a phase I human clinical study.
Looking to the Future
Biomedical studies involving animal models have greatly contributed to the public health response to SARS-CoV-2 by assisting in the development of COVID-19 vaccines and treatments. Animal studies will continue to provide vital information as new SARS-CoV-2 variants emerge and new questions arise as to the transmissibility of these variants, whether they are more harmful to people, and if they remain sensitive to available vaccines. Animal models play a critical role in pandemic response efforts as they are necessary for evaluating the safety and effectiveness of new vaccines and therapeutics. Scientists will continue building on the lessons learned from COVID to develop animal models as part of our pandemic preparedness efforts to target other emerging or re-emerging infectious diseases.