covaxin – OpenAxis

Covid-19 Vaccines: The Good, The Bad and The Ugly

The number of times a day that you encounter the word ‘vaccine’ has probably gone up a lot in the last five months. There is a barrage of news articles, viral videos and unverifiable claims from our family Whatsapp groups coming our way each day. In this moment, understanding how vaccines work and getting rid of misconceptions has a huge impact on our personal lives but can be frustratingly difficult. What are the differences between all the Covid-19 vaccines out there? Why does the Pfizer vaccine have to be stored at -70 degrees Celsius? Is it true that Covaxin can give you Covid? What are vaccines, anyway? This article explains how the immune system actually works, how vaccines confer immunity and why the new mRNA vaccine technology is important.

The Immune System is a Mad Genius

High school biology tells us of this supernatural-sounding, sophisticated defense mechanism residing in the body of each human being –– the immune system. Indeed, your immune system can fight against millions of pathogenic microorganisms that you constantly come in contact with. But how does it accomplish this feat? The immune system has two crucial abilities that protect you from diseases. First, it can recognize substances that are unwelcome in your body: pathogens such as bacteria and viruses. This is more complicated than it sounds, because our bodies are made up of cells that are similar in many respects to bacteria and viruses, and there are no well-defined rules that neatly separate healthy cells from pathogens. Second, the immune system can use biological pathways to destroy the recognized pathogens. The immune system can also recognize toxins such as dust particles –– the reason we sneeze and have a runny nose if it’s dusty or polluted. However, in this article we will focus on the interaction between the immune system and biological pathogens.

The first function of the immune system is like a text editor that recognizes incorrect grammar. We’ve all been caught red-handed while typing grammatically incorrect sentences in MS Word (quite literally –– MS Word informs us of this with a frustrating squiggly red underline). MS Word does this by using pre-defined grammar rules and checking whether sentences satisfy these rules. Now consider this. If the text editor in question operated like the immune system, it would literally construct every possible grammatically incorrect sentence, and then check each new sentence it encountered against this enormous library of incorrect sentences. Well, naturally, this system is much less efficient than verifying a few grammar rules. But remember, there aren’t any analogous rules that the immune system can use to distinguish pathogens from healthy tissue. So, it does what it can…

Right now, floating around in your body, are approximately one trillion immune cells, each sporting a unique ‘antibody’ (for context, the human body has roughly 30 trillion cells). These antibodies are made of small bits of protein, combined in arbitrary ways (the way our inefficient text editor would make up wrong sentences by combining random words). Each of these antibodies ‘fits’ a particular molecule that your body might encounter on a pathogen. If that pathogen molecule happens to enter your body and encounter the corresponding antibody, the antibody will lock into place and trigger an immune system cascade that will either neutralize (i.e., make unable to function) or destroy the pathogen. If you’re paying attention, you would have guessed by now that everyone in the world is currently walking around with a Covid-19 antibody in their system.

The natural question that follows is, why does anybody ever get sick? The answer is that it’s a numbers game. The likelihood that a single pathogen molecule will come into contact with its matching antibody in your body is very, very low. This likelihood gets higher as the pathogen replicates and produces copies of itself. Once the antibody-pathogen match occurs, your immune system starts producing many more of that particular antibody and starts destroying the pathogen copies. From there, it’s a race to see which group of cells (the pathogen or the antibody-containing immune cell) can replicate faster and conquer the other.

Vaccines: Leveraging the Fantastic Memory of the Mad Genius

Once your immune system has recognized a pathogen and raised antibodies against it, it does something amazing –– it memorizes the pathogen by always keeping a bunch of the relevant antibodies handy. So the next time you encounter that pathogen, the likelihood of it matching up with its antibody is much higher, the process of triggering the destructive immune system cascade is much faster and you are much less likely to fall sick. This is where vaccines come in. Vaccines are modified pathogens that don’t cause disease but are still recognized by the immune system as a foreign object. When the vaccine is injected into the body, the immune system generates and maintains an army of the relevant antibody; when the real pathogen shows up, these antibodies fight for you and you are immune to the disease. The commonly held notion that vaccines ‘trick’ the immune system into raising antibodies is subtly incorrect. The immune system is functioning as intended when it produces antibodies against a vaccine, but it’s simply getting a leg up because the vaccine can’t actually cause the disease.

How does one modify a virus to make a vaccine? The most commonly used and well-established technique is to inactivate it by heating it or exposing it to chemicals that denature the proteins that make up the virus (similar to what happens when you boil an egg). Covaxin, produced by Bharat Biotech, is an example of a whole-virion inactivated virus. Another common method is to take a different virus that is harmless to humans, and genetically modify it to produce a few proteins from the virus you want to vaccinate against. The harmless virus, when injected into the body, replicates and produces many copies of the proteins that were introduced into its genome. The immune system raises antibodies against these proteins that confer immunity against the harmful virus. Examples of such ‘viral vector’ vaccines are the Oxford-AstraZeneca Covid-19 vaccine and the Johnson & Johnson Covid-19 vaccine. The advantage of viral-vector vaccines over inactivated virus vaccines is that there is no chance of the vaccinated person contracting the disease due to incorrect inactivation of the virus.

The Covid-19 pandemic has fueled advances in a new type of vaccine that does not require a virus at all. You may remember from high school biology that proteins are made from mRNA, which is made from DNA (the genetic code in your body’s cells). These non-viral vaccine delivery systems make use of DNA or mRNA fragments that encode proteins from the virus that you want to vaccinate against. The DNA or mRNA fragments are packaged in such a way that makes them appear non-foreign (basically, they are coated with the same oily molecules – lipids – that form the surface of our healthy cells). When the lipid-coated genetic material is injected into the body, it is taken up by immune cells which use it to produce the virus’ proteins. In this case, you actually are tricking the immune system into doing something it ordinarily isn’t supposed to. Once there are enough of the virus’ proteins floating around, the normal function of the immune system kicks in and it starts making antibodies against the virus.

Both the Pfizer and Moderna vaccines are mRNA vaccines. Their advantages are that they are more amenable to quality control and can be designed and manufactured in a short time scale. However, mRNA is much more chemically unstable than protein or whole virus, and so it needs to be stored at much lower temperatures. Another disadvantage is that since these mRNA vaccines have not been around for long, there is no data on potential long-term side effects.

There are currently 12 different Covid-19 vaccines that have been approved, with loads more in the pipeline. As we race to get enough people vaccinated in time to achieve herd immunity, it is vital that we all participate in the effort by getting vaccinated ourselves and encouraging our close friends and family to do the same. I hope this article will help you navigate the debates and discussions with more confidence.

Amrita Singh has a B. Tech in Biological Sciences and Bio-Engineering. She is currently pursuing a PhD in neuroscience at Janelia Research Campus in Virginia, USA.

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Road to Recovery: A Conversation on Covaxin with Prof. Gautam Menon

What exactly do clinical trials for a new vaccine involve?

The first step after a potential vaccine is developed is to try it out on animals to check that it is not toxic and that it leads to an immune response. If this step is successful, the next stage is to move to human trials, where these preliminary trials are called phase 1 trials.

In such trials, healthy volunteers (typically 20-50 in number) are injected with one of a range of possible doses of the vaccine, to determine the optimal and safe dose, starting from very small doses. Whether the vaccine elicits an immune response is also verified. In phase 2 trials, the immune response is examined further, and questions of side effects and safety are also explored in a larger group of volunteers, typically more than 100.

Finally, phase 3 trials involve administering the vaccine to a much larger group, often tens of thousands of people, selected to be representative of the population. These trials are called “randomized control trials”. In these trials, about half the participants enrolled are given a placebo, something that is harmless to the body, while the other half is given the vaccine. No one knows, not even the doctors administering it, whether the injection contains a placebo or the real thing.

In India, emergency use authorization has been granted to two vaccines: Covishield, made by the Serum Institute of India and Covaxin, made by Bharat Biotech.

Since Covaxin didn’t complete its phase 3 trials and publish them, what can we confidently say about its efficacy?

At the moment we can say little since there simply is no data yet. In the much smaller phase-1 and phase-2 trials, the vaccine elicited a robust immune response, making antibodies against the virus. The vaccine was also shown to be safe in appropriate doses. It is based on an inactivated whole-virus vaccine platform which is well-understood. However, it is important to understand that efficacy—whether a vaccine works well at preventing you from getting the disease under ideal conditions—is not a simple and immediate consequence of immunogenicity, the ability of a vaccine to provoke an immune response. That is why we need phase 3 trials in the first place.

Is there a broader misunderstanding of immunogenicity and efficacy? What is the difference and why is it important?

A vaccine should certainly provoke a response from the immune system. That’s central to how vaccines function. But whether it works in preventing people from getting the disease – protective immunity – is a harder question and there are a few things that could go wrong. One extreme case is that getting vaccinated might, paradoxically, increase your chances of severe disease, through what is called ADE or antibody-dependent enhancement. Another possibility is a vaccine-associated enhanced respiratory disease, in which antibodies induced by the vaccine bind with viruses and form immune complexes that clog the lungs. These are possibilities that a phase-3 trial should rule out.

How is Covaxin going to complete phase 3 trials?

What should happen, in principle, is the following: The scientists running the trial will wait till a certain number of people, a number pre-approved in the trial protocol, within the group that received an injection, are diagnosed with COVID-19. They then go back and check whether these people belonged to the group that was administered the placebo or the actual vaccine. If there are many more cases in the placebo group than the vaccine group than can be accounted for by chance, that suggests that the vaccine works in protecting against developing the actual disease.

The problem is that it may take some time to reach this stage of having a predetermined number infected with the disease. Since most people develop no or only mild symptoms of the disease, they may not notice they have been infected.

A second problem is that phase-3 trials are being done in a background where a good number of people have already been infected in the past, so are immune to the disease for at least some time, as far as we know. These people won’t develop the disease even if they encounter an infected person.

Finally, currently in India, all this is happening in the background of a steadily decreasing number of new cases. This makes it harder to have new infections in the trial group.

Why aren’t people given a choice on which vaccine they would prefer?

The government, which is, after all, making these vaccines available for free at this point, may have wanted to ensure that they did not appear to be favouring one over the other when granting emergency-use approval. Perhaps there is also an element of national pride in this, in that Covaxin is a fully indigenous vaccine while Covishield is the result of a collaboration with international groups, at Oxford University and the pharmaceutical giant AstraZeneca.

What, according to you, is the biggest health concern with not having any efficacy data on Covaxin?

Whenever one is administering a vaccine to a healthy person, one would like to know that it has been worth it. Does the vaccine, for example, provide protection against the disease to more than 50% of the population it is administered to? A phase-3 trial, precisely because it is so large and planned as a randomised control trial, is a good way to ask this question as well as to look out for possible rare but serious side-effects of being vaccinated.

Would it have been a better move to rollout Covaxin after phase 3 clinical trial data was published? Why do you think it was encouraged over other alternatives?

It would have been better to rollout Covaxin after the efficacy data became available, in my opinion. Data demonstrating good efficacy and safety, which could have taken another month or so to obtain, would have spoken for itself.

Of course, these decisions have to be made based on available information as well as projections for what might happen in the future, such as new variants that are more transmissible. There are certainly cases where granting emergency use authorisation might have been justified. This is why scientists as well as the lay public need to understand the basis on which these decisions were made.

The committee that approved Covaxin distribution may have had data that was shown to it that suggested that it was efficacious. We don’t know because neither the names of the committee members nor the minutes of their deliberations are available to us.

Transparency should always be a central consideration in such matters, especially since you will be vaccinating people who are healthy and you don’t want to compromise on safety.

Considering how the vaccination drive is going right now, do you think vaccine hesitancy is slowly eroding and that target numbers will be met?

Yes, the numbers of those getting vaccinated each day are steadily increasing. That is a good sign. Unlike in the USA and some other developed countries, there is no strong anti-vaccination movement in this country and people are accustomed to large-scale immunization programs, such as the pulse polio campaign.

Do you think the vaccine rollout should’ve been critiqued more or less than it was by the Indian scientific community? What could have been different?

I think the sections of the scientific community that critiqued the Covaxin rollout did the right thing. Prof. Shahid Jameel of Ashoka University and Prof. Gagandeep Kang of the CMC Vellore, in particular, were sane voices in this, pointing out gently, but firmly, the need to stick to established procedure. One has to ensure that the public does not feel that they would be guinea pigs. Several fellows of the Indian Academy of Science also signed a document expressing their concern.

I was dismayed at the counter signature campaign, supporting the Covaxin rollout, from a group of 49 medical doctors and scientists. Their arguments made little sense to me.

Can anything be said about whether the current vaccine candidates can be effectively used for the new strains of the virus?

There is some encouraging news of the effectiveness of some of the international vaccines against the new strains, although perhaps not at the same level. Bharat Biotech has claimed very recently that its Covaxin was effective against the UK variant of the virus. Our understanding is rapidly evolving.

Do you think that the overall vaccine development process has changed in the course of the global effort in formulating a COVID-19 vaccine?

Absolutely. I thought, as many others did, that a period of 18 months to two years would be the minimum time required for a vaccine to be distributed. That we managed to do this in less than a year is a remarkable achievement. Without our ever-improving knowledge of both basic and applied science, this would simply have been impossible. Indeed, it would have been impossible even a decade ago.

I am, in many ways, proud of what India has achieved. The Serum Institute of India, located in Pune, is the world’s largest vaccine manufacturer. Bharat Biotech, the manufacturers of Covaxin, has a manufacturing plant that is the largest of its kind in the Asia-Pacific region. It is a respected company which exports therapeutics and vaccines across the world. India itself produces 60% of global vaccines. The Director-General of the WHO commented recently that “…the production capacity of India is one of the best assets the world has today”.

As an Indian, this does make me very happy.

Gautam Menon is Professor of Physics and Biology at Ashoka University as well as Professor of Theoretical Physics and Computational Biology at the Institute of Mathematical Sciences in Chennai. He works in biophysics as well as in, more recently, the modelling of infectious disease.