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Vaccination to prevent disease was first conceptualized in the late 18th century, and by the early 20th century vaccines for diseases including tuberculosis, yellow fever, and influenza had been developed (Plotkin, 2014). By 1980, vaccination had been used to eradicate smallpox globally — one of only two infectious diseases to date to be eliminated from the environment. Numerous vaccines are responsible for preventing millions of illnesses annually (Pardi, 2018).
Conventional vaccine types include the following:
- Live-attenuated vaccines, such as the measles-mumps-rubella vaccine, contain attenuated (weakened) forms of an organism that causes a disease. This attenuated organism acts as an antigen and stimulates the body to create a robust antibody response.
- Inactivated vaccines, including most influenza vaccines, contain a killed version of an organism that causes a disease. This killed form acts as an antigen and stimulates the body to create an antibody response.
- Subunit, recombinant, polysaccharide and conjugate vaccines, such as pneumococcal vaccines, contain components of an organism which act as antigens and stimulate an antibody response. They do not contain the organism itself.
- Toxoid vaccines, such as tetanus vaccine, contain a toxin made by an organism that causes a disease. The toxin acts as an antigen and stimulates an antibody response to specific parts of the organism, rather than the whole organism.
While conventional vaccines are critical in controlling disease, limitations include the time and materials required for production, difficulty with large-scale deployment and a reliance on the adaptive instead of innate immune response (which some infections may evade) (Pardi, 2018).
mRNA vaccines contain messenger RNA (mRNA), a single-stranded RNA molecule that complements DNA. It is created in the nucleus, when DNA is transcribed by RNA polymerase to create pre-mRNA (Zipursky, 2000). Pre-mRNA is then spliced into mRNA, which is exported from the nucleus to the cytoplasm and “read” by ribosomes (the translation machinery of cells). Ribosomes then make proteins.
mRNA vaccines use lab-created mRNA encapsulated within nanoparticles. Translation of the mRNA results in the development of a protein antigen that triggers an immune response (Schlake, 2012). mRNA vaccines deliver mRNA directly to the cytoplasm, where it is transcribed by ribosomes. The mRNA does not enter the nucleus and therefore cannot be incorporated into the genome. Its presence in the cell is transient, and it is quickly metabolized and eliminated via cellular processing mechanisms (Walsh, 2020). mRNA vaccines do not utilize any element of an organism.
Unlike conventional vaccines, which can take months to produce, mRNA vaccines can be created quickly and are more easily scaled because they use an organism’s genetic code.
The concept of mRNA vaccines was first developed in the early 1990s (Schlake, 2012). However, due to difficulty with the instability of mRNA, delivery challenges and other factors, the field did not make significant strides until the past decade, when technological advances and investment lead to significant development. Prior to the COVID-19 pandemic, mRNA vaccines targeting infectious diseases including HIV-1, rabies, Zika, and influenza were already in clinical trials, as were mRNA vaccines targeting multiple hematologic and solid organ malignancies (Pardi, 2018).
Soon after the COVID-19 pandemic emerged, Pfizer and BioNTech began to develop a mRNA vaccine against SARS-CoV-2, as did Moderna—the latter in partnership with the National Institute of Allergy and Infectious Diseases.
- The Pfizer-BioNTech vaccine, BNT162b2, uses mRNA to create the receptor binding domain of the spike protein of SARS-CoV-2 (Mulligan, August 2020). The spike protein is what SARS-CoV-2 uses to attach to host cells and enter them.
- The Moderna vaccine, mRNA-1273, uses mRNA to create the SARS-CoV-2 spike protein stabilized in its prefusion conformation (Jackson, 2020). Both vaccines are part of Operation Warp Speed, which allowed for rapid investment in the vaccines and their trials. Studies of these vaccines have shown them to be highly effective in preventing symptomatic COVID-19, and safe after several months of follow-up.
Vectored vaccines utilize either non-pathogenic organisms or plasmids (the vector) (Vrba, Nov 2020). Genes of a pathogen—most often proteins that code for specific antigens—are inserted into the genome of the vector. The vaccine delivers the vector, which infects host cells and then travels to the nucleus; there the genes of the pathogen are expressed, resulting in the creation of the antigen. The antigen is then expressed on the host cell surface, resulting in the induction of an immune response. This is both a cellular (T cell) and humoral (B cell) response.
Vectored vaccines can be replicating or non-replicating:
- Replicating viral vectored vaccines infect cells, resulting in the production of the vaccine antigen. The viral vector is also produced and is then able to infect new cells, which then create more viral antigen.
- Non-replicating viral vectored vaccines infect cells, resulting in the production of the vaccine antigen, but the viral vector cannot be reproduced (Riel, July 2020).
Soon after the COVID-19 pandemic emerged, AstraZeneca and Oxford University partnered to develop a viral vectored vaccine utilizing a modified replication-deficient chimp adenovirus vector, ChAdOx1. It contains a gene that encodes for the SARS-CoV-2 spike protein. The vaccine is part of HHS’s Operation Warp Speed, and is also funded by the U.K. Ministry of Health and the Biomedical Advanced Research and Development Authority. Studies have shown it effective in preventing symptomatic COVID-19 and safe after several months of follow-up.
Multiple viral vectored vaccines utilizing poxviruses, adenoviruses, and vesicular stomatitis virus are also in clinical trials for human use; the only FDA-approved viral vectored vaccine is the Ebola vaccine ERVEBO (Vrba, November 2020).