Vaccines: A Brief Overview
By: Curran Shah
Tags: Covid 19, Vaccines, Coronavirus, Biotechnology, Pharmaceutical

Let’s talk about vaccines. For all of the controversy surrounding them, vaccines have undoubtedly been a boon for society. Children no longer routinely die of smallpox or are paralyzed due to polio. A small cough in an infant these days is simply a small cough and not a deadly bout of pertussis. Vaccines work, but often the underlying mechanisms of their efficacy remain mysterious to the general public. Especially with the speed of approval and distribution of the recent COVID-19 vaccines, the hesitancy to be in the initial groups to receive these vaccines is understandable. But an understanding of the basic principles of vaccination could help alleviate any tension and lead to a realization that the mRNA vaccination technology behind the Pfizer-BioNTech and Moderna vaccines is far “safer” than many of the vaccines most of us have taken as children.

To understand how vaccination works, one must first understand the immune response. Our immune systems are wonderfully complex and have the capability to deal with not only external pathogens but also work to clear cancer cells, cell debris, and maintain a homeostatic balance with the gut microbiome. The true response is immensely complicated, and our knowledge remains superficial. However, the general response follows a response similar to a 911 call. A bystander or someone involved would see an emergency situation and respond by dialing 911. The 911 operator would then dispatch the appropriate first responder based on the type of emergency. The first responder would then arrive on the scene and begin to deal with the emergency. Likewise, in the body, a cell type known as an antigen presenting cell (dendritic cell, macrophage, B-cell) will respond to inflammatory markers indicating an emergency and begin to internalize an extracellular antigen (a molecule indicating what to target). It will then travel to the lymph nodes where it will activate a helper T cell (CD4+ T cells). Helper T cells function similar to a 911 operator and work to coordinate the immune response. These activated helper T cells will begin to activate B-cells as a part of the humoral response (antibody response) and cytotoxic T cells (CD8+ T cells) as a part of the cell-mediated response. These activated B-cells and cytotoxic T cells function similar to a first responder once they arrive at the site of and set about to clear the infection before differentiating into immune memory cells. It is these memory cells which allow rapid response to subsequent infection and are the goal for a vaccine.

Vaccination works using the same infection response pathway described above, but rather than exposing the body to a full version of the infection, vaccination works by exposure to a milder version of the disease in order to spur the development of immunological memory. These memory T and B cells can rapidly mount an adaptive immune response during subsequent infection. The principles of vaccination have been around since the 1500s when variolation (the practice of scratching scabs from smallpox lesions into healthy individuals) was used to inoculate against smallpox. Vaccine technology as we know it begins to take shape in the 1900s with the development of live and non-live vaccines. Live vaccines contain attenuated versions of the pathogen meaning that the pathogen has reduced virulence than its unmodified counterpart but maintains the capability to replicate within the vaccine recipient. Non-live vaccines on the other hand can either be whole-killed pathogens that do not have the ability to replicate or a highly purified antigen which is a marker of the pathogen but not the entire pathogen (think of the coronavirus spike protein). Examples of live attenuated vaccines would be the measles, mumps, and rubella vaccine (MMR), and an example of a whole killed vaccine would be polio vaccine. The choice between live and non-live construction is dependent on the efficacy vs. the safety of the vaccine. A live vaccine will be able to produce a more robust immune response, but safety could be a concern as the pathogen could mutate in a way that it reverts to a more virulent state. Even a whole killed pathogen could still produce a dangerous level of immune response. Conversely, while purified antigen vaccines tend to be safer, they often do not produce as strong of an immune response due to a lack of pathogen associated molecular patterns (PAMPs). PAMPs bind to pattern recognition receptors (PRRs) on antigen presenting cells in order to alert the body to a state of infection and spur the antigen presenting cells to action. In order to address the issues with lackluster immune responses, vaccines often contain compounds known as adjuvants which work to mimic PAMPs and boost the immune response. Adjuvants can consist of a variety of materials from aluminum salts to lipids with the end result being the body being better primed to the vaccination.

While mRNA vaccines are relatively novel, they build upon the previously discussed techniques. mRNA serves as the intermediate molecule between DNA and the protein product specified by a certain gene (genes are specific segments of DNA). This allows for the ability to specify what antigen is to be presented by our antigen presenting cells. Additionally, recent technological advances have made the production of mRNA more rapid and often a cheaper alternative to conventional vaccine methods. Furthermore, the inherent aspect of the vaccine being mRNA makes it safer than many of the traditional technologies. The mRNA is neither a weakened version of the pathogen nor is it a molecule from the pathogen. Rather the mRNA “codes” for a specific antigen of the pathogen. This subtle difference makes a tremendous difference when it comes to safety. In these vaccines, the mRNA molecule is delivered to antigen presenting cells, often a dendritic cell, where the innate cell machinery will begin to produce the antigen specified by the transcript. The inclusion of adjuvants will signal to the cell to begin the process of spurring the adaptive immune response against the antigen specified by the mRNA. In this way, immunity will be developed against a tightly controlled aspect of a pathogen in a safer and more efficacious manner.

While what has been described is in many ways an oversimplification, the basic tenets remain true. It is in some of these more specific and complicated aspects that the differences between companies and their technologies lie (for example delivery of mRNA). On those aspects I hope to write more later.