Explainer: Covid-19 vaccine development – and why India has to be a player in this

As the novel coronavirus continues to devastate lives and livelihoods across the world, scientists are racing to find a vaccine that could stop its march.

On Monday, India announced its first experimental vaccine to go into human clinical trials in July. It has been jointly developed by a private firm Bharat Biotech and the Indian Council for Medical Research.

The World Health Organisation’s latest draft landscape of Covid-19 candidate vaccines shows 16 candidate vaccines in clinical trials and 125 candidate vaccines in preclinical evaluation.

One of the leading candidates in terms of timing is the University of Oxford-AstraZeneca Covid-19 experimental vaccine, which is already in the stage of human trials. Not far behind is the Moderna vaccine, said WHO chief scientist Soumya Swaminathan last week.

As cautious optimism builds over this global effort, unprecedented in scope, experts also caution that an effective vaccine could never be developed.

While vaccines have been acknowledged as among the greatest public health interventions, there has, arguably, never been so much focus on the development of a single vaccine.

Virologist and Chief Executive Officer of Wellcome Trust/DBT India Alliance, Dr Shahid Jameel, answers some of the most frequently asked questions on vaccine development.

We understand that the candidate vaccines are tested for their ‘immunogenicity’ and ‘protective efficacy’. What do these terms mean?
Immunogenicity means whether the vaccine candidate raises immune responses. Immune responses are mainly seen in terms of antibodies, does it raise antibody responses. Sometimes researchers also look at cellular response, but mainly it is antibody.

Protective efficacy means, does it protect from infection or disease. And all vaccines do not protect against infection but they do protect against disease. For example, take the influenza vaccine. The influenza vaccine does not prevent infection from the virus but it prevents the disease that develops and many people will feel very mild disease but it won’t become severe.

Everything that raises an immune response, does not necessarily have to be protective. People have been working on an AIDS vaccine for decades. And so far all the AIDS vaccine candidates have raised very robust immune responses but these responses are not protective.

In a clinical trial process, do researchers aim for diversity in age, gender, race, in the volunteer pool. Is that of consequence in testing the immunogenicity and protective efficacy of a candidate vaccine?
Yes, absolutely. It’s a critical thing. In a population, we have different protective genes and therefore we respond very differently to infection. Ideally a good vaccine has to be tested in multiple geographies. But the truth of the matter is that the testing is done in countries where it has been approved to be tested. For example, if the regulator in the US has given approval, the vaccine will be tested there, unless, simultaneously there is clearance from the regulator in India and the regulator in China. Ideally, it should be tested in multiple populations.

Even both genders, because sometimes you see that men and women respond differently to the same candidate. Different age groups sometimes respond differently. So, yes, all those things matter.

Can you explain what a typical phase-wise clinical trial process is?
I will tell you the traditional way of doing trial. But a lot of things have been turned on their head in the approvals that are required for the Covid-19 vaccine.

In a typical trial, the sequence is that you have to test the candidate in an animal. And in the animal you first do a toxicity study to make sure that the vaccine is not toxic. And then you also look at the immune response – whether it is raising antibodies, whether it is raising cellular immunity or not. It has to be proven to be both immunogenic and non-toxic in animals.

Once the candidate has gone through these phases, and there is approval to now test it in humans, the vaccine has to go through phases I, II and III.

Phase I is typically a small trial done in about 10-50 people. And that looks mainly at safety. Whether the vaccine candidate is safe in humans. In Phase I they also sometimes see if the vaccine makes the right kind of antibodies or not, but primarily it is a safety trial. That typically takes a few weeks.

Phase II is a larger trial. You go with more than 100 volunteers. You test dosage. You will figure out whether I should give, say, 1 injection of 20 micrograms or should I give two injections of 10 micrograms each. What should be the frequency with which I should give the vaccine? Usually a single injection doesn’t work, you have to give at least two to three shots. In phase II you also look at how the immune responses have developed in the various arms of the trail.

Phase III is basically a very large efficacy trial. Here you are asking whether those who get the vaccine are protected, compared to those who don’t get the vaccine. This is typically tested in thousands of volunteers. And they are usually done in an area where the infection is prevalent. Otherwise you will never have enough people getting naturally infected to be able to make a distinction between those who are protected versus those who are not.

(Cases in China are tapering off, which is why Chinese vaccine candidate Sinovac Biotech is now looking to test in Brazil, the epicentre of Latin America’s outbreak, for its final testing. )

In Phase III, let’s say you have 1,000 volunteers. You randomise and about 500 will get the vaccine and 500 will get the placebo. And after a few months you estimate, how many with the vaccine got infected versus how many people in the placebo arm got infected. And that is how you determine the efficacy of a vaccine. The entire process could take from 6 to 10 years.

Over 25,000 people have volunteered for human challenge trials for Covid-19. What does this mean and what are the ethical questions surrounding the use of this method?
In human challenge trials, instead of letting people get naturally infected, you purposely infect them and figure out how many of those were protected. It would be unethical to inject a known pathogen, knowingly into somebody. Normally human challenge trials are for those diseases for which there is a drug available. Human challenge trials have been done for example in a malaria vaccine, and that is mainly because there is no good animal model system to do trials for malaria. And there are good drugs to treat malaria.

If you were to do a human challenge trial for Covid, for which there is no drug available, that would be hugely unethical. But some regulators will give permission for that because they have to weigh the public good against individual harm.

In the normal course if it takes nearly a decade for a vaccine to reach the market, what are researchers doing differently that is giving us hope of one or more vaccine candidates clearing regulatory approvals by early next year?
See, in a regular clinical trial, you do things sequentially. But what has happened now is, regulators have allowed the vaccine to go into humans, even before it has been tested in animals. So it is sort of like, animal and human running parallely, instead of serially. Also, they have allowed a combination of phase 1 and 2. So instead of doing it serially, you do it parallely. So that has really shortened the time. And they are also monitoring, following up the response in volunteers for a lesser amount of time. This is unprecedented. It has never happened before.

What are the different kinds of vaccines?
There are multiple types of vaccines that are in various stages of development right now.

You have the live vaccine, the killed or inactivated vaccine. The killed vaccine would be where the virus is produced in culture, large amounts of it, and the virus is inactivated using chemicals. An example of that is the injectable polio vaccine.

Another kind of vaccine is the live attenuated vaccine. Here you have somehow weakened the virus, so that when it infects, it replicates but it does not produce disease. And an example of that is the oral polio vaccine which has been a big part of our pulse polio programme.

We also have the replicating viral vector vaccine. Here, you would take another virus, and use that to deliver genes of the SARS-CoV-2 (the coronavirus causing the Covid-19 disease) into cells.

In this case the common cold virus, called the adenovirus. In the adenovirus you put in one of the genes of the SARS-CoV-2. The Covid-19 gene that is expressed, makes the spike protein, which triggers an immune response. Remember, the coronavirus used the spike protein to break into human cells.

The Oxford-Astrazeneca is the most advanced vaccine right now. And that vaccine is based on a chimpanzee adenovirus from which the spike protein of the SarsCoV2 Virus is expressed.

There are other vaccines based on human adenovirus that are in the pipeline. There is a vaccine based on a measles virus that is in development. There are multiple vaccines based on this platform.

Then there are what we call genetic vaccines. Genetic vaccines can be produced much faster than vaccines using traditional methods.

Genetic vaccines mean that instead of injecting the protein, you inject a genetic material which then makes the protein. As you know DNA makes RNA and RNA makes protein.

So researchers are injecting DNA directly and the idea is that the DNA will be taken up by the cells, the cells will make RNA and the RNA will make protein. There are a couple of vaccine candidates which are based on this platform.

And finally, for the first time we are seeing the RNA vaccines. The Moderna vaccine, which is the first one to go into trials, is a mRNA vaccine (messenger RNA). Here the RNA which expresses the Covid-19 spike protein is injected. Now the trouble is that the RNA is a very labile (susceptible to alteration or destruction) molecule. If it is given just by itself, it will degrade very quickly. So the RNA has to be packaged into a carrier and then given.

While the RNA technology is simple, it is not simple to develop the particle which will carry the RNA. Moderna has been using this platform for other vaccines and they quickly adapted it to make the Covid-19 vaccine candidate.

Is there, presently, any vaccine produced using this approach that has got regulatory approval?
Moderna has been working on this but no nMRNA vaccines have got approval yet. I don’t know if any of them have gone to human trials or not. Certainly they have developed the platform and if this Covid-19 vaccine candidate even raises immune responses, it’s going to be a very simple way of doing it and this could be the way vaccines will be made in the future. It will become very easy to make vaccines, if this technology is perfected.

Whether a person who has recovered from Covid-19 could be reinfected, is a question that doesn’t have a definite answer. So, is it possible to say, how long would vaccine induced immunity last?
That is very hard to predict. If you look at various vaccines that are in use, you will see that there are all kinds. The flu vaccine for example gives immunity only for about a year. So every year there is a new flu strain and you have to essentially get a new vaccine. On the other hand, polio vaccine gives you life long immunity. Hepatitis-B vaccine, which is the first recombinant vaccine to have been approved, gives you immunity which lasts about 5 years and every 5 years you need to get a booster shot.

Dr. William Haseltine, known for his groundbreaking work in fighting cancer and HIV/AIDS has said in interviews that it is not a question of when, but a question of if at all a vaccine would make it. He points out, for example, that it would be near impossible to vaccinate the most Covid-vulnerable population – the elderly.

It is true that the older you get, the more difficult it becomes to raise protective responses, your immune system starts slowing down. But the point is, if you were to successfully vaccinate the younger population, especially in countries like India, where the majority of the population is young, then you achieve what is called herd immunity.

Herd immunity will therefore protect even susceptible people from getting infected. So there is certainly value in vaccines, and vaccines have proven to be the most cost effective public health measure.

What about vaccine geopolitics? Some are fearing a repeat of the HIV/AIDS situation, when the world’s most infected areas were denied drugs.
Who will decide who gets the vaccine first. You know, countries which have developed and manufactured the vaccine will have the first claim on it. It is upto international agencies to ensure an equitable mechanism.

Sure, imbalance is there in medicines also. This is an unequal world. So to expect anything other than that would be foolish.

I think where India will really contribute is its manufacturing ability. India has some of the largest vaccine manufacturing capability in the world. And if you see some of the partnerships international vaccine developers have built with Indian companies is a testament to the manufacturing capabilities in India.

If the world has to be vaccinated, India has to be a player in this, there is no doubt about it.