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The goal of a vaccine is to trigger a response that safely protects against infection and / or the burden of disease. While this is true for all vaccines, the steps that lead to a safe and effective product may be different for each infection. In the case of COVID-19, caused by the SARS-CoV-2 virus, researchers at Baylor College of Medicine and Texas Children’s Hospital have found that vaccine design can face specific challenges and that approaches to developing the vaccine Vaccines require an understanding of how the immune system naturally responds to a specific infection, as well as how vaccines can trigger specific protective responses.
The Baylor National School of Tropical Medicine and the Texas Children’s Vaccine Development Center, co-chaired by Dr. Maria Elena Bottazzi and Dr. Peter Hotez, are currently developing vaccines against the coronavirus. The researchers are applying their years of experience in developing vaccines for emerging emerging tropical infectious diseases such as SARS and MERS to develop a safe and effective vaccine for COVID-19.
“As we move forward in the design and testing of vaccine candidates, we feel the need to collaborate with a clinical immunologist, who is also engaged in basic and translational research, so that together we can inform our vaccine development efforts and We want to make sure we assess both the protect mechanisms and avoid inducing undesirable immune responses that have been associated with some respiratory viruses, “said Bottazzi, professor of pediatrics and molecular virology and microbiology and associate dean of the Baylor National School of Tropical Medicine.
Bottazzi and Hotez approached Baylor’s pulmonologist, Dr. David Corry, professor of immunology, allergy, and rheumatology, and the Fulbright Chair of Pathology in the Department of Pathology and Immunology. He is also a member of the Dan L Duncan Comprehensive Cancer Center.
One of the results of their collaboration is the recent publication of two articles, one in Microbes and Infections and the other in Nature Reviews Immunology.
“These publications are the result of an in-depth search and analysis of the literature that has informed our vaccine development strategy. We highlight the experimental and clinical evidence that shows some of the challenges for the development of COVID-19 vaccines: what we know. and what we know I don’t know, and the critical points that we need to pay close attention to as we go forward and evaluate our vaccine candidates, “said Bottazzi.
What does a protective response against COVID-19 look like?
COVID-19 is a new disease, and while most evidence points to a natural infection with the virus that generates protective immunity, important gaps remain. Researchers know, for example, that the protective mechanism will likely depend on a robust antibody response with neutralizing capacity, along with a balanced cellular response and cytokines or immune proteins. In recent studies, SARS-CoV-2 infected rhesus macaques have been shown to develop protective antibodies and resistance to reinfection. Previous studies of SARS-CoV in 2003 also showed that persistent antibody responses against the virus’s spike protein, the protein that the virus uses to bind and invade a cell, and specifically against a part of the spike protein known as the binding domain to the recipient, compatible immunity.
“We are encouraged by the evidence supporting the likelihood that immunization against the spike protein receptor binding domain represents a realistic and viable vaccination strategy. However, many questions remain.” said Hotez, who serves as dean of the Baylor National School of Tropical Medicine as well as the Texas Children’s Hospital Gifted Chair in Tropical Pediatrics.
“Studying the immune responses triggered in people infected with the virus is one way that researchers can select which viral components or antigens are promising candidates to use when designing the vaccine,” said Bottazzi. “That, along with studies using laboratory disease models, is the way scientists are trying to predict what the ideal protective mechanisms activated by vaccines are.”
On that basis, teams from Baylor and Texas Children’s, in collaboration with the New York Blood Center, developed a vaccine strategy based on this fragment of the viral protein, the receptor binding domain.
How to design a vaccine that safely protects against COVID-19
Preclinical and experimental observations made during previous attempts to develop respiratory virus vaccines suggest that some vaccine formulations may trigger unwanted responses. Some of these responses may be cell-mediated, while others may be activated by antibodies.
Cell-mediated responses
Preclinical tests of some experimental vaccines followed by viral infection in animal models showed tissue damage caused by cellular infiltrates after induction of an immune response.
“Some experimental animals developed an inflammatory response in the lung or liver characterized by significant infiltration of immune cells: lymphocytes, monocytes, and eosinophils,” said Corry. “Our literature search suggests that this cellular infiltration may be associated with IL-6, a cytokine or immune protein that is greatly increased in COVID-19 patients experiencing a cytokine storm, overproduction of cytokines that can be life-threatening.” . “
“We also found studies showing that Th17-type immune responses could probably explain cell infiltrates, including eosinophils, seen in animal models,” said Hotez.
This immune infiltration was observed with experimental vaccines with viral vectors. Viral vector vaccines use a different chemically weakened virus to transport components or antigens of the COVID-19 virus to the body to stimulate an immune response.
Although more research is needed to understand the mechanisms of cell-mediated responses and their relevance to clinical outcomes, the potential for significant immune cell infiltration has important implications for the development of the COVID-19 vaccine.
Research has also suggested that the selection of adjuvants, agents that are traditionally added to vaccines to stimulate a positive immune response, may affect the type of immune response triggered. For example, in SARS vaccines, the use of alum reduces cell infiltration, indicating that this adjuvant could minimize these undesirable responses.
“Based on previous evidence, we also chose to test and use alum in our COVID-19 vaccine formulation as our goal is to make sure we reduce the chance of inducing an undesirable immune response,” said Bottazzi.
Antibody-mediated responses
Called antibody-dependent enhancement, this response has previously been observed in dengue and other viral infections.
“Antibody-dependent improvement in dengue occurs when the antibodies bind to the virus and transport it within the infection-fighting cells called macrophages. Once the virus covered with an antibody is inside the macrophages, it does not die. It replicates, “Corry said. “Macrophages end up spreading the infection within the body as macrophages move.”
It is unclear whether this phenomenon is relevant to human coronavirus infection. In laboratory experiments, antibody dependent improvement appears to occur with both non-neutralizing and neutralizing antibodies.
“For this reason, we select the virus receptor binding domain. It excludes epitopes or sections of viral proteins that could induce antibody-dependent potentiation,” said Hotez.
“We have found no evidence that our vaccine triggers an antibody dependent enhancement in preclinical laboratory experiments. Experimental evidence suggests that our vaccine against the receptor binding domain leads to neutralization of the virus,” said Bottazzi. “Preclinical studies conducted with our partners at the University of Texas Medical Branch show that the receptor binding domain in alum is indeed a promising vaccine candidate. It can trigger an immune response that is protective and does not induce responses undesirable cellular immune. We are working to advance this approach in the clinic for phase 1 studies. “
“There are many challenges to overcome, but like never before, scientists around the world are working together to develop effective and affordable vaccines,” said Corry. “We will get there, it will only take time to get it right.”
“We believe we need to have as many candidate vaccines, platforms, and trials, in order to evaluate as many vaccine options as possible to select the most appropriate and demonstrate that they are the most effective and safest,” said Hotez.
“We have invested nearly a decade of research to maximize immune protection and minimize or prevent immune enhancement. Ultimately, our goal is to make these vaccines for the world population, accessible and affordable for everyone.”
