A vaccine for a new disease usually takes more than ten years before it can be given to humans. In the case of Ebola, which was gaining momentum, it took five years for a candidate vaccine to enter clinical trials. Vaccine development has been exceptionally fast since January, when the causative agent of 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 as the “2020 Breakthrough of the year
How was this even possible without cutting off?
Many of the traditional steps in vaccine development have been taken. Initially, many assumptions have been made in the development of a SARS-CoV-2 vaccine based on experience with other viruses. Vaccine makers have learned from the experience with Ebola. In many ways, the world was lucky that we were dealing with a coronavirus as there were plans to develop vaccines for MERS, another coronavirus.
In addition, many new technologies and platforms were used that accelerated the development of vaccines. This in contrast to the earliest generation of vaccines for other diseases that took a more passive approach. I will discuss these technologies later in this chapter.
By the end of 2020, multiple vaccines had passed the gauntlet of clinical trials and received preliminary approvals for use in many parts of the world. While these vaccines were still in clinical trials, the manufacturers had already started producing them in the hope that they would work. Two mainstream precursor vaccines showed similar efficacy (about 95 percent) in preventing disease after two doses – a prime and a booster shot.12 Other vaccines also showed slightly lower efficacy.
Essentially, COVID-19 vaccines try to do the same. They rely on the idea of preventing the spike protein from binding to the ACE2 receptor. This is the most important step in infection, and while antibodies can be formed against other viral proteins, the neutralizing antibodies we want target this interaction. The virus is also not completely defenseless against antibodies: it is covered in sugars and tries to hide the crucial part of the peak so that antibodies cannot access it.
Traditionally, a vaccine was made from a virus that had been isolated and attenuated or inactivated.
The whole virus (or part of it) was introduced into the body (producing neutralizing antibodies). This is the basis for most vaccines in use.
Within months of the identification of SARS-CoV-2, there were vaccine candidates using attenuated virus, killed (inactivated) virus, or pieces of virus to attempt to elicit an immune response. This is remarkable not only because of the speed with which the candidate vaccines were created, but also because they represent so many different strategies.
Without going into the question of whether viruses are alive at all, vaccines containing inactivated viruses are popularly “killed” by chemical treatment or heat. This means that after being injected into the body, they can activate the immune system, but cannot replicate in cells. Completely inactivated virus vaccines require an additional substance to enhance the immune response. This is called an adjuvant.
On the other hand, instead of inactivating the virus, a vaccine can also consist of an attenuated virus to the extent that it causes only a mild infection while losing all its pathogenic properties. Traditionally, attenuated viruses have been generated by passing through cell cultures repeatedly.
The safety of inactivated and live virus vaccines is extensively tested as they use real viruses.
Inactivated viruses require large amounts of virus. For weakened live viruses, we must ensure that they do not revert to their disease-causing ancestral strains. Again, because a live virus is injected, extensive testing is needed to make sure these are safe for people with compromised immune systems.
An example of an inactivated vaccine is Covaxin made in India by the National Institute of Virology of the Indian Council of Medical Research and Bharat Biotech. At the end of November 2020, thousands of participants were enrolled in a phase III clinical trial.
Other vaccines can be made from protein portions of viruses or virus-like particles, all of which are deficient in some key component present in an infectious virus. Some of these also require adjuvants to fuel the immune system.
A few vaccines consist of virus proteins that are packaged in nanoparticles and injected into the body. These virus proteins are recognized by the immune system as foreign, which begins to build up an appropriate response. By the end of 2020, Novavax had 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 contains no genetic material. These are expected to cause the body to build an immune response, but since they have no genetic material, they are not contagious. However, the vaccines approved in late 2020 and most other vaccine candidates use platforms that don’t need real virus or parts, but instead use genetic information to make human cells make the virus parts, just as the virus would.
These are fast and safe systems.
DNA or RNA is injected into the body, where it serves as a blueprint for the cellular machinery to make parts of a virus that adhere to antigen-presenting cells. The immune system recognizes these virus parts created by cells as “alien” and makes antibodies against them. Prior to this pandemic, there was limited experience working with these systems, although some of these platforms had reasonable success with cancer and other molecular diseases.
Some companies use the DNA vaccine route with genetic material in the form of a sling. Getting DNA into cells has been a bit of a problem. Thus, a technique called electroporation is used, which uses electricity to briefly make holes in the membrane of cells. Once inside the cell, the DNA is transcribed into RNA that is translated into the coronavirus spike protein that will hopefully cause humans to generate a strong immune response to it.
But by the end of 2020, the vaccines that generated the most excitement were using RNA.
An RNA vaccine completely skips the first few steps of a DNA vaccine and generates powerful immunity. Once in the cell, it is directly translated into the spike protein that is used by the host cell to build immune responses.
In late November, two leading vaccine candidates, made by Pfizer and BioNTech and by Moderna using RNA technology, were found to be effective after two doses. In December, these candidates were the first two mainstream vaccines to be approved in the world. The wide use of mRNA vaccines may indicate a paradigm shift in the way we try to prevent the spread of infectious diseases.
Why are the first approved RNA vaccines only now available? 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 get into cells. But by encapsulating it in molecules known as lipid nanoparticles, release and stability are improved. Second, ‘foreign’ RNA can trigger an immune response (instead of the protein the body helps make). But if the RNA is made chemically with synthetic nucleosides, the immune system will not respond to it. Third, RNA is “read” by the host cells to make viral proteins. But before it was adjusted and stable it was not read properly. The proverbial stars lined up just before the COVID-19 pandemic.
RNA vaccines are not without drawbacks, however. RNA is less stable than many other biological molecules.
Enzymes that can break down RNA are ubiquitous. Even with chemical changes that improve stability, the Pfizer vaccine should be stored at -70 ° C. The Moderna vaccine is more stable and can be stored in a regular 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 by the end of 2020, clinical trials and preliminary observations after weeks of wider rollout indicated that both approved RNA vaccines were generally well tolerated. Some side effects, such as injection site pain, fatigue, headache or mild fever, have been reported, but there were no overall safety concerns.20
The last class of vaccines that I want to discuss contains a DNA blueprint inserted into the shell of a harmless virus (usually an adenovirus vector). This is quite ingenious because it uses a faulty virus to deliver a message that will generate antibodies against SARS-CoV-2. These faulty viruses elicit immune responses but are either too weak to cause disease or lack the necessary components to fully multiply.
In 2020, AstraZeneca, in partnership with Oxford University, and Johnson & Johnson were two companies who had enrolled thousands of participants in trials of vaccines using adenovirus vectors. By the end of 2020, the AstraZeneca candidate vaccine had shown promising initial results and was ready for approval for use in 2021.
Reprinted with permission from Covid-19: Separating fact from fiction, Anirban Mahapatra, Penguin Books.