The vaccine race

The unprecedented pace at which a vaccine is being developed to combat COVID-19 offers a ray of hope. How prepared is India in the race to obtain a vaccine?

Britain’s William, Duke of Cambridge, during a visit to the laboratory where a vaccine against COVID-19 has been produced at the Oxford Vaccine Group’s facility at the Churchill Hospital in Oxford on June 24.

ON January 11, the genetic sequence of the virus causing the outbreak of the respiratory disease in Wuhan, China, was posted by a team at Fudan University in Shanghai on GenBank, a global online database maintained by the United States’ National Institutes of Health (NIH).

No one knew how far the disease would spread or how serious it would be, but the genomic information was seized upon almost immediately by laboratories across the world for a variety of purposes. Some used it to create tests that would detect the virus in infected people. Others worked on trying to decipher the genetic origins of the virus and understand how it had passed from animal to man. And some seized on the virus’ genetic structure as a way to start developing a vaccine.

Among the early vaccine developers was a team at Oxford University led by Sarah Gilbert, a professor of vaccinology, who had recently developed a prototype vaccine against another coronavirus, Middle East Respiratory Syndrome (MERS). She decided to develop a vaccine for this new coronavirus using the same technique used for the MERS vaccine. Without any inkling of how the coronavirus pandemic would explode, she saw this more as an experiment or, as she described it to The New York Times , an interesting laboratory project to demonstrate the versatility of the recombinant viral vector vaccine platform that had been used for the MERS vaccine.

Within three months, a period equivalent to travelling at the speed of light for vaccine development (which is typically measured in years and decades), the Oxford SARS-CoV-2 vaccine was in the first stage of human clinical trials.

And it was not the first: two other vaccine developers: Moderna, a U.S.-based biotechnology company, and CanSino, a Chinese biotech, had begun trials slightly earlier. And by July all these vaccines are expected to be in the third and final stages of clinical trials, opening prospects for limited supplies of vaccine for those at the greatest risk from the disease by the last quarter of the year.

Stages of development

Vaccines pass through several stages of development. Once a prototype vaccine is developed in a laboratory , it is first tested on animals, typically mice, ferrets, guinea pigs or hamsters. These laboratory animals are bred with genetic mutations that allow researchers to test the vaccine better. In the case of a vaccine for COVID-19, laboratories have used mice bred to express a receptor known as ACE2 in their cells, as these are the receptors that the SARS-CoV-2 virus uses to enter human cells. If the vaccine has few side effects and creates antibodies in the mice, then its development moves to the NHP , or non-human primate , stage, when the vaccine is tested on monkey species such as macaques.

If the monkeys tolerate the vaccine and are also protected against challenge doses of the virus, the vaccine moves from the lab to human, or clinical , trials. This happens in three stages: phase 1 focusses on testing vaccine safety, and to a lesser extent on the immune response the vaccine produces. Typically , around 50 to 100 healthy adults are vaccinated at this stage, any aches, pains, fevers and other reactions are noted, and blood samples are tested for the presence of antibodies and other proteins indicating an immune response. The vaccine then goes into phase 2 trials, in a slightly larger group representing a wider demography. Different doses of vaccine are also tried to assess adverse reactions as well as immune response. If the vaccine is thought safe and effective enough , it goes into phase 3 trials and is tested on several thousands of people across a variety of age groups.

Besides collecting more data on safety, the aim of phase 3 trials is to see how the vaccine works in the real world: how much protection it provides in a situation when the disease is circulating actively? To do this, some of those in the trial are given a placebo, and the number of those who get the disease among the vaccinated group is compared to those who received a placebo and the effectiveness of the vaccine is calculated. After phase 3 trials, the manufacturer can apply to regulatory authorities to license the vaccine for public use.

The whole process, from laboratory to market, can take five to 10 years. Funding is usually a major constraint, particularly in moving from the laboratory to clinical trials. But the pandemic has released a floodgate of funding for vaccine development, largely from the U.S. The money, along with an eagerness on the part of the regulatory authorities to get a safe and effective vaccine out as quickly as possible, has speeded up the process in a way that would have been unimaginable in normal circumstances.

New vaccine technologies, too, have helped speed up development, particularly the use of generic vaccine platforms that can be repurposed for different vaccines. The Oxford vaccine, for example, is based on the platform of chimpanzee adenovirus, which has been engineered to express the spike protein of the coronavirus.

The same platform was used for an MERS vaccine, and so researchers were able to replace relatively quickly the genetic code for the MERS spike protein with that of the SARS-CoV-2 virus spike protein on the same chimp adenovirus platform.

Neither the spike protein nor the platform alone can cause disease, so recombinant technology is generally regarded as safer than traditional vaccine techniques which use live weakened viruses.

Moderna, a Boston-based biotechnology company that is trying to carve a niche for itself in the new but rapidly developing field of messenger RNA-based vaccines, saw an opportunity to put its existing vaccine platform to quick use in a COVID-19 vaccine.

Moderna had been working on vaccines for a variety of diseases, which include Zika and H7N9 influenza, using a technique that inserted the genetic sequence of target viruses expressed in messenger RNA form, into human cells so that the cells themselves produce the viral proteins that the immune system would recognise and produce antibodies against. As Tal Zaks, Moderna’s chief medical officer, put it in a recent webinar, this method taught “the body to make a vaccine in its own cells”.

The spike proteins of coronaviruses, whether it is SARS, MERS, or SARS-CoV-2, have been the main focus of vaccine developers, as this is the part of the virus that the immune system recognises. So Moderna’s team took the sequence of the spike protein, translated it into messenger RNA, the form of RNA that the cells use to create proteins from DNA and RNA. They enclosed this genetic information in a minuscule lipid, or fat, envelope to create a vaccine.

When this RNA vaccine is injected into a muscle or any other body tissue, it enters the cells, and makes them produce the coronavirus spike protein. These spike proteins are displayed on the surface of the cells, where the immune system detects it, and creates antibodies as well as a cellular immune response.

One of the advantages of RNA and other nucleic-based vaccines is that they are quick to produce as they do not require a virus to be cultured in cells. Tal Zaks claimed in the webinar that it took only two days from the time the genome was published to produce a candidate vaccine.

The speed was partly possible because Moderna, like the Oxford team, had been developing a vaccine for MERS and was able to switch the MERS spike protein with the SARS-CoV-2 virus protein.

Chinese efforts

Chinese researchers were, not surprisingly, amongst the first to get off the mark, with early results coming from three vaccine developers. One of them, CanSino, a Tianjin-based company, like the Oxford team, used recombinant viral vector technology to create a vaccine which had its first human trials in mid March as well and is now undergoing phase 2 clinical trials. CanSino has applied to hold phase 3 trials in Canada.

The two other Chinese companies that were quickly off the mark used traditional but tried and tested vaccine making techniques, which involve taking the SARS-CoV-2 virus and inactivating it so that it can no longer replicate and create disease but can still be recognised by the immune system to create antibodies.

SinoVac, a Beijing-based company, rapidly created an inactivated vaccine which, after mouse and macaque monkey trials, has completed phase 1 and phase 2 trials and will begin final phase 3 trials in Brazil, probably in July. Sinopharm, a government entity, also has begun phase 2 trials with an inactivated vaccine.

Other major vaccine developers are trying new DNA and protein-based vaccine platforms, most of which are in the pre-clinical stage of laboratory and animal tests.

Indian efforts

Compared to the work that has been done in the U.S., China, Europe and Australia, India has been a laggard in developing a COVID-19 vaccine despite having a globally competitive vaccine manufacturing industry.

In May, Prime Minister Narendra Modi held a well-publicised meeting to take stock of vaccine as well as diagnostic development in the country. A government release said Indian vaccine companies, academia and start-ups had “pioneered” work in the field of vaccine development. More than 30 Indian vaccines “are in different stages of corona vaccine development, with a few going on to the trial stages,” it said.

The government has not made the list of these developers public, but major vaccine manufacturers, including the Serum Institute of India, Bharat Biotech and Zydus Cadilla, and a handful of biotech companies such as the Bengaluru-based Mynvax, have started laboratory work which might bear fruit in a year or more.

The big manufacturers have tied up with laboratories abroad for the initial development work. The Serum Institute has an agreement with Astra Zeneca to manufacture 300 million doses of the Oxford vaccine under licence by the end of this year, and a billion doses by the end of 2021, provided the vaccine succeeds in phase 3 clinical trials. This is likely to be the first vaccine available in India, though it is not clear how many doses will be for domestic use, and how many for the rest of the world.

The Hyderabad-based Bharat Biotech is working with the Indian Council of Medical research (ICMR) to develop a vaccine, though there are no details of the technology that will be used or a timeline. More is known about Biotech’s two overseas collaborations. One is with scientists at the University of Wisconsin, who are using an influenza virus platform to develop a nasal vaccine to protect against COVID-19. If the candidate vaccine is successful in the laboratory, Bharat Biotech will produce the vaccine and conduct clinical trials.

Bharat Biotech has also teamed up with a research group at Thomas Jefferson University in Philadelphia, which is developing a coronavirus vaccine based on a rabies virus vector. The candidate vaccine is still at the mice trial stage, but if it proceeds further, Bharat Biotech will conduct the human trials as well as manufacture and distribute the vaccine globally in the developing world.

If successful, these vaccines could be available in 2021.

Ahmedabad-based Zydus Cadilla said in February that it was working on two different vaccine platforms: one DNA based and the other using a measles virus to carry the SARS-CoV-2 spike protein. Nothing has been heard from the company about the progress made since the announcement.

Since the Prime Minister’s meeting in May, little is known about the efforts towards developing an indigenous vaccine, or what kind of funding the cash-strapped government has provided to support them.

Vaccine development is expensive. The rapid advances made in other countries are due to the financial muscle of the home governments as well as funding from private organisations such as the Bill and Melinda Gates Foundation.

The Coalition for Epidemic Preparedness Innovations (CEPI), a public private partnership that includes the Gates Foundation and the Wellcome Trust, estimates that for a vaccine that is required urgently, pre-clinical development and phase 1 trials could cost up to $10 million, and accelerated phase 2/3 trials would cost around $210 million. This is without taking into account the cost of manufacturing and distributing a successful vaccine.

Without this kind of investment, vaccines cannot be developed at the rapid speed at which this pandemic requires it to be done, which is one reason Indian developers have been left trailing in the global race. Powered largely by a $10 billion war chest that the Donald Trump administration is investing in vaccine developers and manufacturers in this race, the U.S. aim is to ensure that it gets the first several hundred million doses of vaccine, perhaps towards the end of this year or early next year.

The U.S. government has invested $1.2 billion in the vaccine that Oxford University is developing, an amount that will pay for the remaining costs of developing the vaccine, manufacturing enough doses for clinical trials in the U.S., as well as at least part of the cost of “at risk manufacturing”, or beginning to manufacture hundreds of thousands of doses of a candidate vaccine before clinical trials are completed, so that if the trials are successful the vaccine will be available immediately to the public. The risk the manufacturer takes is that if the trials are unsuccessful, the money that has been invested in manufacturing advance doses is lost. In the case of Moderna, the NIH conducted phase 1 and phase 2 clinical trials and have been active in speeding regulatory approval for rapid testing. The U.S. government has been willing to pump in and potentially lose money on vaccines that do not eventually make it past clinical trials. As Anthony Fauci, a senior figure in the NIH put it in a recent webinar, “we may be investing in things that we never use, that to the tune of half a billion dollars right off the bat”.

It is not only the U.S. that has been throwing money and resources at the vaccines. The Chinese efforts have strong government support. CanSino has partnered with the military medical scientists, while other vaccine manufacturers are either government owned or have teamed up with government research and public health agencies.

The United Kingdom government got into the act and encouraged a deal for Oxford University to give the global manufacturing rights for its vaccine to AstraZeneca, a pharmaceutical major headquartered in the U.K.

The government injected £65.5 million into the deal to help manufacturing and developing costs, but also to assure the U.K. of 100 million doses, 30 million of which would be delivered by September if clinical trials were successful and would be reserved for people in the U.K.

The $1.2 billion that the U.S. government has invested in the Oxford-AstraZeneca deal assures it of 300 million doses if the vaccine proves successful.

The U.S. has invested $480 million in Moderna, in addition to the support Moderna has received from the NIH.

The pay-off will be rapid access to the Moderna vaccine if it is successful. There is a limit to how far this pandemic can be controlled through lockdowns and physical distancing, the only methods that have been available so far to slow down the spread of the virus.

The economic costs and social disruptions of extended lockdowns cause more harm than the virus itself, which is why major countries in the world are investing so heavily in vaccine development, which is the only way to build immunity at the population level and slowly allow the world to get back to normal life.

The AstraZeneca/Oxford and the Moderna vaccines expect to be going into phase 3 clinical trials in July. A vaccine developed by CanSino could also be testing in phase 3 trials around the same time. If the vaccines are tested in places where the number of cases is rising (Brazil is becoming a favoured location for phase 3 trials for this reason), an indication of how protective a vaccine is could be available in a couple of months. Both the Oxford group and Moderna have talked of possible results by August or September.

But this short space of time is not enough to give a complete profile of the safety and efficacy of a vaccine. As larger numbers of people are vaccinated over a longer period, rarer side effects could emerge. As different age groups, including the very young and the very old, or those with chronic conditions are included in long-term trials, new findings of safety and efficacy could emerge. At the same time though, once one or more vaccines that provide a degree of protection against COVID-19 emerge, pressure will also increase on regulators to allow limited or emergency use for groups of people at the highest risk such as health care workers. On the basis of a risk-benefit analysis, regulatory authorities in different countries could allow limited vaccine use for a variety of high-risk groups. The U.S. Food and Drug Adminstration (FDA) is de facto the most influential regulatory authority in the world, and once the FDA licenses a vaccine for limited or emergency use other countries tend to follow suit.

Of the three or four vaccines that are likely to begin phase 3 trials in July, the AstraZeneca/Oxford vaccine, the Moderna vaccine, the Sinopharm vaccine and the CanSino vaccine, at least one or two if not all are likely to show some protective effect against COVID infection.

It may not protect perfectly and it may not work in all age groups, but as long as it is judged to be as safe as other vaccines in current use, it is quite possible that those at highest risk of being exposed to COVID-19 such as frontline workers or those at highest risk of death from it, such as elderly people with other health problems, might have early access, at least in some countries, to one of the fastest-ever vaccines the world has developed.

Thomas Abraham is author of Twentieth Century Plague: The Story of SARS, and Polio: The Odyssey of Eradication. He is adjunct professor at the University of Hong Kong and a former consultant to the World Health Organisation.