A vaccine for a new disease usually takes more than ten years to be ready to be given to people. In the case of Ebola, which was accelerated, it took five years for a vaccine candidate to enter clinical trials. Vaccine development has advanced exceptionally fast since January, when the causative agent for COVID-19 was identified. The first vaccines for COVID-19 were created and underwent clinical trials in less than a year. This was a record and was recognized by Science While the “Discovery of the year in 2020”.
How was that possible without cutting shortcuts?
Many of the traditional stages of vaccine development have been contracted. Initially, many assumptions were made in the development of a vaccine against SARS-CoV-2 based on experience with other viruses. Vaccine manufacturers have learned from experience with Ebola. In many ways, the world was lucky that we were dealing with a coronavirus, because there were vaccine development plans underway for MERS, another coronavirus.
In addition, many new technologies and platforms have been used, which has increased the speed of vaccine development. This is in contrast to the first generation of vaccines for other diseases, which used a more passive approach. I will discuss these technologies later in this chapter.
By the end of 2020, there were several vaccines that had passed the challenge of clinical trials and received provisional approvals for use in many parts of the world. While these vaccines were still in clinical trials, manufacturers had already started the process of producing them in the hope that they would work. Two traditional pioneer vaccines have shown similar efficacy (about 95 percent) in disease prevention after two doses – an initial dose and a booster dose.12 Other vaccines have also been shown to work with slightly lower efficacy.
Fundamentally, the COVID-19 vaccines are trying to do the same thing. They depend on the idea of preventing the spike protein from binding to the ACE2 receptor. This is the main stage of infection and, although antibodies can be formed against other viral proteins, the neutralizing antibodies we want are aimed at this interaction. The virus is also not completely defenseless against antibodies: it is coated with sugars and tries to keep the crucial part of the peak covered so that the antibodies cannot access it.
Traditionally, a vaccine was created from isolated and weakened or inactivated viruses.
The entire virus (or part of it) was inserted into the body (which produced neutralizing antibodies). This is the basis for most vaccines in use.
Months after the identification of SARS-CoV-2, there were vaccine candidates that used weakened viruses, killed (inactivated) viruses or bits of the virus to try to generate an immune response. This is notable not only for the speed with which the vaccine candidates were created, but also because they represent many different strategies.
Without getting into the debate about whether viruses are alive in the first place, colloquially inactivated virus vaccines are “killed” by chemical treatment or heat. What this means is that, once injected into the body, they can activate the immune system, but they cannot replicate within the cells. Fully inactivated virus vaccines require an additional substance to increase the immune response. This is called an adjuvant.
On the other hand, instead of inactivating the virus, a vaccine can also consist of viruses weakened to the point of causing only a mild infection, while losing all of their disease-causing properties. Traditionally, weakened viruses were generated by repeatedly culturing cells.
The safety of live and inactivated virus vaccines is tested extensively, as they use real viruses.
Large amounts of viruses are required for inactivated viruses. For weakened live viruses, we must make sure that they do not revert to their ancestral disease-causing strains. Again, as a live virus is being injected, extensive testing is needed to ensure that it is safe for those with compromised immune systems.
An example of an inactivated vaccine is Covaxin, created in India by the National Institute of Virology of the Indian Medical Research Council and Bharat Biotech. Thousands of participants were being registered for a Phase III clinical trial in late November 2020.
Other vaccines can be made from parts of virus proteins or virus-like particles, all of which are deficient in some key component present in an infectious virus. Some of them also require adjuvants to activate the immune system.
Some vaccines consist of viral proteins packaged in nanoparticles and injected into the body. These viral proteins are recognized as foreign by the immune system, which begins to mount an appropriate response. In late 2020, Novavax enrolled patients in Phase III clinical trials for their version of this type of vaccine.
Another approach is based on creating a “virus-like particle” that mimics SARS-CoV-2, but does not contain any genetic material. They are expected to cause the body to create an immune response, but since they have no genetic material, they are not infectious. However, vaccines approved by the end of 2020 and most other candidate vaccines are using platforms that do not require viruses or real parts, but use genetic information to make human cells create parts of the virus in a very similar way to viruses. .
They are fast and safe systems.
The DNA or RNA is injected into the body, where it serves as a model for cellular machinery to make parts of a virus that are trapped in antigen-presenting cells. The immune system recognizes these parts of the virus created by cells as being “foreign” and makes antibodies against them. Prior to this pandemic, experience with working with these systems was limited, although some of these platforms were reasonably successful with cancer and other molecular diseases.
Some companies are using the route of a DNA vaccine with genetic material in the form of a garland. Putting DNA inside cells has been a problem. Thus, a technique called electroporation, which uses electricity to create holes in the cell membrane, is being used. Once inside the cell, the DNA is transcribed into RNA, which is translated into the coronavirus spike protein that can cause people to generate a strong immune response to it.
But by the end of 2020, the vaccines that generated the most enthusiasm used RNA.
An RNA vaccine completely skips the first steps of a DNA vaccine and induces potent immunity. Once inside the cell, it is translated directly into the spike protein that is used by the host cell to build immune responses.
In late November, two leading candidate vaccines created by Pfizer and BioNTech and Moderna that used RNA technology proved effective after two doses. In December, these candidates were the first two conventional vaccines approved in the world. The widespread use of mRNA vaccines may signal a paradigm shift in how we try to prevent the spread of infectious diseases.
Why are the first approved RNA vaccines available only now? After all, they could have helped us fight other infectious diseases in the past. Three recent technical advances make these vaccines possible. First, RNA is unstable and difficult to enter cells. But by wrapping it in molecules known as lipid nanoparticles, delivery and stability have been improved. Second, the “foreign” RNA can trigger an immune response (instead of the protein that helps the body produce). But if the RNA is chemically made with synthetic nucleosides, the immune system does not react against it. Third, RNA is “read” by host cells to produce viral proteins. But before it was modified and stable, it was not well read. The proverbial stars lined up just before the COVID-19 pandemic.
RNA vaccines have disadvantages. RNA is less stable than many other biological molecules.
Enzymes that can degrade RNA are ubiquitous. Even with chemical changes that improve stability, the Pfizer vaccine should be kept at -70 ° C. Moderna’s vaccine is more stable and can be kept in a normal freezer at -20 ° C for six months.
The ability to produce and distribute hundreds of millions of doses of RNA vaccines during an active pandemic remains a challenge. But the good news is that, at the end of 2020, clinical trials and preliminary observations after weeks of broader implementation indicated that both approved RNA vaccines were generally well tolerated. Some adverse effects, such as pain at the injection site, tiredness, headaches or low fever, have been reported, but there have been no widespread safety concerns20.
The last class of vaccines I want to discuss contains a DNA project inserted into the shell of a harmless virus (usually an adenovirus vector). This is quite ingenious, as it uses a defective virus to deliver a message that will generate antibodies against SARS-CoV-2. These defective viruses generate immune responses, but are either too weak to cause disease or lack the components necessary to replicate completely.
In 2020, AstraZeneca, in conjunction with Oxford University, and Johnson & Johnson were two companies that enrolled thousands of participants in trials of vaccines that use adenovirus vectors. In late 2020, the AstraZeneca candidate vaccine showed promising initial results and was ready to be approved for use in 2021.
Extracted with permission from Covid-19: Separating fact from fiction, Anirban Mahapatra, Penguin Books.