Needle in a haystack

Complexities in Covid-19 vaccine pose many challenges to the researchers


As the world eagerly awaits a vaccine for SARS-CoV-2, those who are developing the shot face several challenges in making a safe and effective product in a short time. According to the World Health Organization’s draft landscape for Covid-19 vaccines, there are 133 candidates at different stages of development. Ten of these are in the clinical evaluation stage, while 123 are in pre-clinical stages. The Coalition for Epidemic Preparedness Innovations, the global body that is funding vaccine candidates, lists 224 candidates across the globe that are being worked on using diverse technologies. The sheer numbers, and the different technologies being used, mean that the chances of a successful candidate are high, say experts.

Here is the bitter truth, though. Experts also concede that given the complexities involved in building a vaccine, a majority of these candidates are bound to fail—one would be lucky if a couple of them succeeded. In India, some 30 groups are working on a vaccine; only two or three look promising, said some top government officials.

WHO vaccine landscape 133 candidates 10 in clinical evaluation
Coalition for Epidemic Preparedness Innovations 224 candidates, using diverse technology
Indian landscape At least 30 groups working on a vaccine Fewer than five look promising

Typically a vaccine takes 10-15 years to reach the market, and the process involves several stages where animals and humans are tested in large numbers to ensure that the shot is safe, it induces the right immune response and has a protective effect against the disease in a healthy person. But with Covid-19 spreading fast, researchers do not have the luxury of time. “To determine the efficacy of a vaccine, you need to test it on large numbers of healthy people who have not been exposed to the virus, or live in areas where few have been infected. In a pandemic where the disease footprint is increasing rapidly with time, such a population is hard to find,” said Dr Vineeta Bal, immunologist and visiting faculty at the Indian Institute of Science Education and Research, Pune.

Before the human trials begin, researchers test vaccines on animal models. The traditional mouse model is not the most appropriate one for SARS-CoV-2, and alternative models such as cats, ferrets and monkeys were being tried for the testing, said Bal.

Since this is a new virus for which specific animal models cannot be designed given the short window, researchers are testing with available models. “We are using rodents for the initial animal testing,” said Dr Prabuddha Kundu, co-founder of Manesar-based Premas Biotech. “The questions we are asking are, one, is the vaccine safe? Two, does it generate antibody response? The next step would then be to test if the antibody is protective against the disease.” Kundu’s team at Premas Biotech is working on a multicomponent recombinant protein vaccine against COVID-19. 

Researchers at Oxford University recently tested their vaccine candidate in monkeys, and the results showed that the animals were not protected against the virus, but they did not develop pneumonia. In China, too, researchers testing a vaccine candidate found that monkeys did not develop severe disease.

Primate studies cannot be a replacement for human trials, and were typically done to complement data gathered in humans, said Dr Gagandeep Kang, director, Translational Health Science and Technology Institute, an autonomous body under the Department of Biotechnology. She was speaking at a discussion organised by the Indian Scientists’ Response to Covid-19, a voluntary group of scientists.

“Primate models are not particularly great for SARS-CoV-2,” she said. “Therefore, the only option we have is to generate data in humans, which follow the phase 1, phase 2, phase 3 route.” she said. In these three phases, researchers start with a small group of people whom they test it on, and then increase the number, with phase 3 trials involving large numbers of people. In normal times, each of these phases take a lot of time, as each phase requires approval and people given the vaccine are followed up for a long time. Kang said that in case a rescue treatment was available, researchers might consider human challenge studies—where vaccinated people are challenged with the disease to test its efficacy—but these studies were still not considered equivalent to phase 3 trials. “If we do get to the point of human challenge studies, that might speed up our ability to develop new vaccines, and could lead to us discarding a lot of candidates that are likely to fail in phase 3,” she said.

Dr Vineeta Bal | Sanjay Ahlawat Dr Vineeta Bal | Sanjay Ahlawat

Finding a large number of people for phase 3 efficacy trials is not easy not only because the population should not have been exposed to the infection, but also because the cohort design has to be well thought out for the trials. “For instance, pregnant women and elderly people are a high risk population, to be part of such a cohort. So, for those who are going to do such studies, picking healthy people for the trial will be a huge issue,” said Kundu.

In India, however, there is access to only a limited number of animal models. Ferrets, which are widely used to study respiratory diseases, are currently not available in the country, said Raghavan Varadarajan, professor at Indian Institute of Science, Bengaluru, and cofounder of Mynvax, which is developing a vaccine candidate against SARS-CoV-2. Also, India does not have a non-human primate facility where viral challenge experiments can be conducted. Since it is difficult to get permission to euthanise non-human primates at the conclusion of study, carrying out vaccine studies with large numbers of animals has become difficult from a logistical point of view for the facility, said Varadarajan.

Fortunately, hamsters are emerging as a convenient animal model for SARS-CoV-2. At the moment, for the IISc-Mynvax candidates that are in early stages of development, a number of spike protein derivatives have been designed, characterised and tested in mice and guinea pigs with some promising initial results, Varadarajan said. The design which shows the best results in animals will be advanced to process development, safety, toxicity and subsequent clinical testing.

You need to test it (a vaccine) on large numbers of healthy people who have not been exposed to the virus. In a pandemic, such a population is hard to find—Dr Vineeta Bal, immunologist

Varadarajan said the true efficacy of the vaccine would only be established after post-marketing surveillance was done. “But since this is a difficult situation, researchers might target partial efficacy, or look for surrogate markers of immunity,” he said. Usually researchers measure the level of neutralising antibodies to determine vaccine efficacy.

Besides, there is the complex interaction of antibodies. In respiratory viruses and dengue virus, for instance, it has been found that the antibodies that develop in response to the disease enhance the entry of the virus, and in some cases, the replication of the virus. This phenomena is called antibody dependant enhancement (ADE), said Bal.

The ADE mechanism hampers vaccine development because the neutralising antibodies produced by the vaccine are insufficient to prevent this from happening. This was seen in SARS-CoV-2 in vitro (outside a living organism), but it is not known whether the same would show up in vivo (inside a living organism).

Even as complex questions of antibody response in animals and humans are being worked on, having a vaccine ready does not mean that everyone will have it. There are issues of scaling up. Varadarajan, for instance, pointed out that mRNA vaccines, such as the one the American biotech company Moderna was making, were difficult to manufacture in bulk. “For India, where routine immunisation is a challenge and public health cadres are not available, how will we deliver the vaccine to everyone?” asked Bal. Besides, she said, decisions would have to be made on what kind of vulnerable populations would be given the vaccine.

“The vaccine has to be safe, effective, scalable and cost-effective,” said Kundu. “In a situation such as the current pandemic, where things are being rushed through—take the case of Hydroxychloroquine, where the narrative has constantly been changing—it tells us that many of these complex questions need time to be solved. And responses may not always be right in the first instance.