May 05, 2020 By Team YoungWonks *
While a large part of the world stays hunkered down due to the Coronavirus outbreak and healthcare professionals struggle to cope with the outpouring of patients who need to be treated, there is yet another section out there that deserves our attention: the companies making vaccines.
One of the biggest problems with the outbreak of COVID-19 is the fact that not only is very little is known about how to treat / defeat this virus but also that there are no vaccines out there to build our immunity against future outbreaks as well.
And even as the world eagerly awaits the development of a Coronavirus vaccine - over 100 vaccines are currently under pre-clinical trials - there is also worry over a future with no Covid-19 vaccine, like in the case of HIV and dengue.
This blog then shall explain to you what a vaccine is, how it works, what it takes to build one and make it available to the public as also the leading names that are currently working on creating a vaccine to fight this dreaded pandemic.
What is a Vaccine?
First let us start with what is a vaccine. A vaccine is a biological preparation that offers active acquired immunity to an infectious disease. It contains an agent that is similar to the disease-causing microorganism as it is more often than not made from weaker or dead forms of the microbe, its toxins, or one of its surface proteins. This agent then activates the body’s immune system which goes on to identify it as a threat, destroy it and to further identify and destroy any of the microbes associated with that agent that it may encounter in the future. Vaccines can be prophylactic (used to prevent the occurence of a disease), or therapeutic (for instance, vaccines against cancer, which are used to treat existing cancer).
There are several types of vaccines out there and each type is different in terms of what it’s made up of, how it builds immunity and its advantages and disadvantages.
Below are a the main types of vaccines in production today:
Live attenuated vaccines
These vaccines entail introducing a live virus into the body, but one that has been attenuated or weakened. Live attenuated vaccines, such as those used for measles, mumps and rubella, create a strong immune response and are often the preferred type for healthy adults. That said, they take a long time to make and one cannot rule out the possibility of their mutating within the body to become more dangerous again.
Inactivated vaccines refer to those that are made with inactivated, but previously virulent microorganisms that have been destroyed with chemicals, heat, or radiation. So these vaccines contain the whole virus with all its components, which in turn causes the immune system to recognise and create a response against it but the virus itself can’t cause the disease. Vaccines for polio, hepatitis A, rabies and some influenza vaccines are key examples.
The disadvantage here is that while the virus is not a danger to the body, the body might not mount much of an immune response to it, and the vaccine might need a higher dose of virus in it so as to cause a stronger effect.
Subunit vaccines are ones where a fragment of the virus is introduced into the body to provoke an immune response. Examples include the subunit vaccine against Hepatitis B virus that is composed of only the surface proteins of the virus (the proteins were earlier extracted from the blood serum of chronically infected patients, but are now produced by recombination of the viral genes into yeast); as an edible algae vaccine; the virus-like particle (VLP) vaccine against human papillomavirus (HPV) that is composed of the viral major capsid protein; the hemagglutinin and neuraminidase subunits of the influenza virus and the spike protein that sticks out on the shell of a coronavirus. The spike protein is what actually binds to the receptors in your body and lets the virus enter one’s body cells.
The idea behind these vaccines is that when the body identifies the protein it produces special immune cells that block the receptors, which in turn ensures the virus can no longer cause the disease. In fact, quite a few subunit vaccines are currently being developed for COVID-19 since they can be produced relatively faster than live attenuated and inactivated virus vaccines. But it is also important to understand that getting the body to recognise the virus fragment as a threat and thus produce a strong immune response is more often than not a challenge.
While the vaccines mentioned so far include the actual virus or parts of it, genetic vaccines contain the DNA (Deoxyribonucleic acid) or RNA (Ribonucleic Acid) — the code that tells cells what to produce. These vaccines make the body’s cells create the protein of the virus that the vaccine is fighting. The body then recognises both the genetic material and new protein as foreign and launches an immune response against it. These types of vaccines are easier and cheaper to make, but they are new technology, especially RNA vaccines which explains why there aren’t any existing RNA vaccines as of now.
Viral vector vaccines
These are vaccines where a different type of virus - one that has been engineered to include proteins of the virus the vaccine is aimed to fight - is introduced into the body. Here too the virus can’t cause disease but it does bring about an immune response.
Here are some other terms related to vaccination:
Herd immunity: This term is used to refer to the indirect protection from a contagious infectious disease that occurs when a population becomes immune either through vaccination or immunity developed through previous infections. So even people who have not been vaccinated, or in whom the vaccine doesn’t trigger immunity, are safe because people around them are immune and thus act as buffers between them and an infected person. Once the spread of a disease has been arrested and herd immunity has been established for a while, the disease can eventually be eliminated. Smallpox, for instance, was eradicated in the world through herd immunity.
Antibodies: This is a term one shall come across regularly in the field of medicines and vaccination and hence it is important to know what it means. An antibody (Ab), also known as an immunoglobulin (Ig), is basically a large, Y-shaped protein that is generated mainly by plasma cells. This protein is used by the body’s immune system to fight attacks by pathogens such as bacteria and viruses.
The latest news has it that the Israel Institute for Biological Research (IIBR), the country’s main biological research laboratory, has isolated a key coronavirus antibody. Israel’s defence minister Naftali Bennett has called it a significant breakthrough in the war against the coronavirus pandemic as it is a step closer to finding an antidote (a term typically used to refer to substances that can counteract poisoning). It is being said that the antibody developed has the capacity to neutralise the coronavirus inside bodies of carriers. Also, greater hopes are being pinned on it given that the antibody is monoclonal, or derived from a single recovered cell; such antibodies usually make for more potent treatments as compared to polyclonal antibodies that are or derived from two or more cells of different ancestry.
News reports also say that Italian scientists are claiming to have developed a vaccine that has successfully generated antibodies in mice that work on human cells. Tested in the Spallanzani Hospital hospital in Rome, the vaccine is said to be in an advanced stage of testing for potential vaccines in Italy.
There are many stages in vaccine production. It starts with the generation of the antigen aka the agent or the substance that helps induce an immune response in the body. Viruses are grown on primary cells such as chicken eggs (like in the case of influenza vaccine) or on continuous cell lines such as cultured human cells (for hepatitis A vaccine).
Bacteria, on the other hand, are grown in bioreactors. Similarly, a recombinant protein derived from the viruses or bacteria can be produced in yeast, bacteria, or cell cultures. After the antigen is generated, it is isolated from the cells used to generate it.
A virus may have to be inactivated, possibly with no further purification needed. Recombinant proteins require ultrafiltration.
The vaccine is finally formulated by adding adjuvants (which enhance the immune response of the antigen), stabilizers (that increase the shelf life) and preservatives (which allow the use of multidose vials) as needed.
Combination vaccines are harder to develop and produce, mainly due to the potential incompatibilities and interactions among the antigens and other ingredients involved. But they are expected to reduce the amount of antigens they contain, and thus decrease and slow down undesirable interactions.
Thanks to greater productivity and fewer problems with contamination, it is being said that cultured mammalian cells are more likely to be preferred over traditional options such as chicken eggs. Also showing a lot of promise is recombination technology that produces genetically detoxified vaccines, especially with regards to bacterial vaccines that use toxoids.
As the different types of vaccines shared above indicate, there are several potential avenues to explore. And given the urgency of the situation and the dire need of vaccines to protect the masses against COVID-19, it is not surprising to see that the World Health Organisation (WHO) and Coalition for Epidemic Preparedness Innovations (CEPI) are keeping all options / methods open.
The WHO has already shared a list of more than 60 vaccines in development all around the world. Not only do we need a vaccine that will work, but we need a vaccine to speed past all the stages that are involved in the production and the rollout processes. Vaccines cannot possibly be made available for the public until they have cleared all stages of their trials.
Here we take a quick look at what these stages are:
1. Preclinical: At this stage, the vaccine is tested in animals. And the following aspects are studied in the course of testing: Is the vaccine producing antibodies, if so how much of it and is it protecting the animal against the illness and lastly, what dose is needed?
2. Phase I: Here the vaccine is tested in a small number of humans. This phase is aimed at ensuring that the vaccine is safe for humans.
3. Phase II: This stage also involves testing in humans but here the group is a bigger one and this is when it is checked if the vaccine actually works or not.
4. Phase III: This is when a larger number of people are roped in to test the effectiveness of the vaccine.
5. Phase IV: At this stage the vaccine has been made available to the public, but the long term effects of the vaccine are studied through ongoing surveillance. This is an equally crucial stage as it helps make sure that the vaccine doesn’t have long-term adverse effects.
It is important to note that this potential vaccine also needs to be approved for use by relevant regulatory bodies. Then comes another significant phase, where enough quantities need to be manufactured and distributed in time across the world. All of this typically takes time and normally, vaccines take years to be developed, let alone ramp up production and that too for the world’s population. This is why billionaire Bill Gates has stepped forward to do his bit. Through his Bill and Melinda Gates Foundation, the Microsoft founder and philanthropist has decided to help fund factories for not one but a whopping seven promising vaccines and all this even before seeing any conclusive data.
Gates has cited the importance of shunning traditional vaccine deployment timelines by helping scale up manufacturing during testing instead of after, as it would help accelerate vaccine production once they are developed and approved. In a bid to ensure safety, efficacy and building manufacturing simultaneously in these factories, Gates is going ahead with a plan that is likely to result in the loss of a few billion dollars on the projects that fail to take off.
Vaccines under development
Below are some of the other leading COVID-19 vaccines that are currently under development (in addition to the instances of antibody isolation shared above):
1. mRNA-1273: Funded by CEPI, mRNA-1273 is being worked on by the biotech company Moderna and the National Institute of Allergy and Infectious Diseases (NIAID). mRNA stands for messenger ribonucleic acid, where the molecules get the cells to produce certain proteins. This technology involves injecting genetic code into the body muscle so the muscle cells can start making the viral proteins on their own. After this is done, the immune system kicks in and fights the disease. Currently, the phase 1 clinical trial is underway for this vaccine.
2. INO-4800: This COVID-19 vaccine is being produced by biotech company Inovio Pharmaceuticals and its partner Beijing Advaccine Biotechnology who are recipients of a CEPI grant. Inovio might just have the edge because it has produced a CEPI-supported vaccine for MERS — a coronavirus closely related to COVID-19 — that is currently going through human trials. Meanwhile, INO-4800 - a genetic vaccine using the DNA code approach - is still in the preclinical phase and is looking to test on humans by the end of this year.
3. CureVac’s mRNA vaccine: Another CEPI-funded mRNA vaccine is the mRNA vaccine by the biotech firm CureVac, which is looking to unveil a vaccine candidate within a few months. It helps that they have already tried a rabies mRNA vaccine in humans and are hoping to develop a mRNA vaccine for COVID-19 of which only a low dose would be needed for immunization. However, this vaccine too is in the preclinical phase of testing.
4. Johnson & Johnson’s vector-based vaccine: Johnson & Johnson’s Janssen is developing a vector-based vaccine, much like the approach that led to the development of the effective Ebola vaccine. In this non-experimental approach, the vaccine is made using a non-replicating virus (or viral vector) with coronavirus genetics thrown in. The resulting vaccine is then injected into a person’s muscle, where the virus produces a protein, which in turn induces an immune response. While the virus being used as a vector cannot get humans sick, the fact remains that it has not yet been tested on humans. Being made with help from the U.S. Biomedical Advanced Research and Development Authority (BARDA), Janssen is looking to start human trials by autumn this year.
5. Sanofi vaccine: Another company working with BARDA to produce a vaccine is Sanofi Pasteur. Instead of taking a viral protein generated in the human body and injecting it, Sanofi is working on producing a version of the protein. Sanofi already makes flu vaccines in this fashion, so it might be in a position to scale up production of their vaccine in a relatively shorter period of time. But like most vaccines in development, it too has to be tested in people first and this could happen within a year.
6. GSK vaccine: Another product of a collaboration with CEPI is the vaccine being worked upon by GlaxoSmithKline (GSK). GSK is sharing its proprietary adjuvants with Clover Biopharmaceuticals, a Chinese biotech company, and the University of Queensland. They are yet to go into clinical testing.
7. Baylor’s vaccine: A few years ago, the vaccine research center at Baylor College of Medicine developed a potential vaccine for SARS, another coronavirus that’s closely related to the COVID-19 virus. In 2016, the Walter Reed Army Institute of Research manufactured the shot only for work on it to get stopped due to lack of interest in developing such a vaccine. As a result, the vaccine - which was made with the help of a National Institutes for Health (NIH) grant - never underwent clinical trials to make it to the market. But now with the pandemic underway, Baylor has realised that there are around 80 percent similarities between SARS and the COVID-19 virus, especially their amino acid and genetic codes. This has prompted them to appeal for fresh funding to revive their testing and move their vaccine into phase 1 trial.
8. Oxford trial vaccine: Oxford University has already started phase-1 human clinical trial of its vaccine on April 23, where two volunteers have been injected with the vaccine. The vaccine -ChAdOx1 nCoV-19- has been developed within a record three months by the University’s Jenner Institute using a weakened strain of common cold virus (adenovirus) that causes infections in chimpanzees.
According to the World Health Organization (WHO), eight COVID-19 vaccines have entered the human trial phase. In the US, pharmaceutical companies Pfizer and BioNtech have teamed up to start the clinical trials of their BNT162 vaccine programme. Both the companies are working on four RNA vaccine candidates and they have already injected 12 healthy adults with the mRNA vaccine candidate.
*Contributors: Written by Vidya Prabhu; Lead image by: Leonel Cruz