Vaccine Development
- Teen Medical Research Club
- Feb 13, 2021
- 6 min read
By: Julie Wu
Developing a successful vaccine is an arduous undertaking typically spanning ten to fifteen years of research and testing. In light of the Covid-19 pandemic, scientists from around the world are speeding through this lengthy process in hopes that one of more than 160 vaccines can be safe and effective.
Vaccine Development
Vaccine development can be split into three main stages: lab studies, clinical trials, and approval and licensure. This first stage is the most flexible in terms of time as it involves basic research and testing with the pathogen. Scientists try to find a way to introduce the body to a pathogen in a safe manner so that it will be ready for an actual infection. Depending on the type of pathogen, scientists will decide on what antigen (a foreign substance that triggers an immune response) to use and how the immune system will be exposed to it. Vaccines subtypes are differentiated by these two conditions. After a potential vaccine is settled on, development moves into preclinical trials with animal testing. It is during these tests where many vaccines are unable to continue in the development process, being found unable to produce an immune response or deemed unsafe. If the vaccine can continue to progress, a baseline dosage for the human clinical trials is also established.
Clinical trials involve three phases of human testing with progressively larger amounts of volunteers and varied demographics. In the Phase 1 trials, the vaccine is evaluated in twenty to eighty adults. Scientists prioritize assessing safety, dosage and resulting side effects, and the extent of an immune response in the human body. The Phase 2 trials involve several hundred people, including children and the elderly. The immune response in different age groups and short-term side effects in a larger group of people is studied. Also, methods of delivering the vaccine along with a schedule for delivery are proposed. Thousands to tens of thousands of people are tested in the Phase 3 trials. This phase focuses on identifying rare side-effects and determines if the vaccine can protect against disease—typically in a double-blind, placebo-controlled test. If Phase 3 is successful, regulators, like the FDA in the US or the EMA in Europe, review the results from the clinical trials to determine if the vaccine is safe and effective. The manufacturer of the vaccine is also inspected to make sure each batch, called “lot,” and its production will hold up to standards. Once licensed, the vaccine will be available for use with the public.
Under normal circumstances, lab research takes two to four years while preclinical testing takes one to two. Research on SARS-CoV-2 (the virus responsible for Covid-19) has been accelerated as study has been done on previously occurring coronaviruses like SARS-CoV. The two viruses share about 80% of their genome and use similar ways to gain entry to human lung cells. The speed and likelihood of a vaccine making it through this first stage is also increased by having many different types of vaccines being worked on concurrently. There are currently thirty two vaccines for Covid-19 in human trials with the first batch of testable vaccine developed by Moderna completed in just forty two days. The second stage, clinical trials, can take anywhere from four to ten years and cannot be expedited as easily due to safety. Months are spent between phases reviewing data and getting approval before progressing. The phases themself also have to provide the necessary data, like how the vaccine fares against an actual infection. Scientists have been hastening the trials by combining or running phases simultaneously. Even if a vaccine pulls through the trials, there is the matter of approving and manufacturing the vaccines. After a new vaccine passes clinical trials, factories specifically designed for that vaccine have to be built and the vaccine and facilities have to be reviewed for safety. Construction can take from two to five years with approval lasting a year after which mass production can take up to another two years. To combat this problem, manufacturers can start construction then production before licensing or even the trials have been completed. Existing facilities can also be repurposed for the new vaccine. In extreme cases, a vaccine can even be approved before the clinical trials finish as in the case with CanSino Biologics’ vaccine approved for use in the Chinese military and the Gamaleya Research Institute’s Sputnik 5 vaccine approved in Russia, both after finishing Phase 2 trials.
Types of Vaccines
Vaccines are generally split into two types: live attenuated and inactivated vaccines. Live attenuated vaccines, or LAVs, contain live viruses or bacteria that have been weakened and cannot cause disease. This type of vaccine typically imparts lifelong protection because of how well it simulates an actual infection. However, LAVs take the longest to make as the pathogen has to be weakened through repeated culturing in labs. These vaccines also can cause severe reactions in people with compromised immune systems like the elderly. In exceptionally rare cases, a pathogen may even revert back to its original harmful state.
Inactivated vaccines are vaccines that contain an inactivated or killed pathogen. Inactivated vaccines are easier to produce than live attenuated vaccines and cannot cause disease. However, the immunity derived from these vaccines weakens over time; long-lasting immunity requires periodically getting additional doses. Many inactivated vaccines have to include an adjuvant, or a substance that helps create a stronger immune response. Immunity from a response against inactivated vaccines is mostly humoral unlike immunity from LAVs. Because the pathogens in LAVs are still alive, they retain the ability to enter and replicate in the body’s cells. The antigens produced by the cells activate a humoral response while presentation of parts of the pathogen triggers a cellular response. Whole inactivated vaccines contain entire chemically inactivated viruses or bacteria. Fractional vaccines are another subset of inactivated vaccines. Unlike whole-pathogen vaccines, the antigens found in fractional vaccines are small components of a pathogen rather than the entire unit. Upon an actual infection, the immune system will have the means to dispatch those antigens, disabling the pathogen. Some fractional vaccines, called polysaccharide vaccines, use sugars that form the capsules of bacteria as their primary antigen. Others are instead protein-based, like protein-subunit and toxoid vaccines. The former are based on viral proteins while the latter are based on deactivated protein toxins produced by harmful bacteria. Scientists are harnessing gene editing to make what are called recombinant vaccines. Recombinant DNA, which is DNA created by combining genetic material from two different organisms, is used to genetically modify bacteria. The bacteria can be induced to assemble synthetic antigens after insertion of recombinant DNA. The resulting antigens are harvested and purified to be used in vaccines that work similarly to inactivated fractional vaccines. There are other types of vaccines that do not fit into the categories of live attenuated and inactivated vaccines, some experimental.
Nucleic acid vaccines are a much newer type of vaccine that does not directly bring antigens into the human body. Instead, it contains genetic material coding for those antigens. The genetic material is taken in by a cell, and the coded protein antigen is produced. DNA vaccines contain plasmids with pathogenic genes. The plasmid enters the cell’s nucleus and undergoes transcription; then the corresponding mRNA is transported to ribosomes for translation and protein synthesis. RNA vaccines were made to bypass the transcription process, preventing any chance of implementation into the genome. There is no risk of infection with nucleic acid vaccines, both the humoral and cellular response are activated, and the manufacturing process is well established, safe, and efficient. A DNA vaccine for the Zika virus was testable in three months, and the vaccine developed by Moderna was a RNA vaccine. Another type of vaccine that works similarly to nucleic acid vaccines is the viral vector vaccine. Genes coding for antigens are inserted into a vector virus’ genome. These viruses are either modified so they cannot replicate or attenuated. After introduction to the body, the viruses inject their genome into cells and the following events are similar to those with nucleic acid vaccines.
Vaccines being developed for Covid-19 can also be split. Some labs are focusing on making LAVs using SARS-CoV-2. A massive obstacle that has to be overcome with an attenuated Covid-19 vaccine is that this type of vaccine is notoriously unpredictable when used by people with immunodeficiencies. Yet, the elderly and people with pre-existing health problems are the hardest hit demographic by this disease. Thus, whole inactivated, protein sub-unit, nucleic acid, or viral vector vaccines seem to be promising with no risk of infection. Many of these vaccines target a part of the SARS-CoV-2 anatomy called a spike protein. These protein complexes stud the surface of the virus and are what it uses to identify and attach to human angiotensin-converting enzyme 2 or hACE2, a cell receptor found only on human epithelial cells lining the lungs. Once they attach to hACE2, the virus gains entry to the cell where it starts replicating. In various protein-subunit and recombinant DNA vaccines, parts of the spike protein are being used as the primary antigen while nucleic acid and viral vector vaccines are using sequences of genes coding for those proteins. These newer vaccines have found the most success, with three inactivated, two viral vector, and two nucleic acid vaccines in Phase 3 of clinical trials. Both approved Covid-19 vaccines are viral vector vaccines, and the fastest testable vaccine was a nucleic acid type.
With the ongoing Covid-19 pandemic, various parties like researchers, manufacturers, and health organizations all over the world have to collaborate to speed up the vaccine development process. The various types of vaccines each have their own unique characteristics and new innovative methods of using these vaccines as well their potential are being discovered.
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