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India's Pipeline for Next-Gen Covid-19 Vaccines

India's Pipeline for Next-Gen Covid-19 Vaccines

Covid-19 inoculations have gathered pace in India. But with the virus mutating and new variants being discovered, next-generation vaccines may be the need of the hour. Where does India stand?

Photograph by Milind Shelte Photograph by Milind Shelte

When Vasant (Vas) Narasimhan, the global CEO of Novartis AG, met Business Today at the company's India office in Mumbai on February 17, 2020, India had already reported the first cases of the Coronavirus. They were three medical students who had returned to their native Kerala from Wuhan in the Hubei province of China. At that point, 1,523 people had died of the outbreak in Wuhan. For most Indians, the Coronavirus was just another curious case of a new virus surfacing in the Far East or Africa. A week before that, on February 11, the World Health Organization (WHO) had baptised 'Novel Coronavirus SARS-CoV2' with a new name — 'Covid-19' — and was yet to declare the outbreak a 'pandemic'.

Naturally, Covid-19 was also a point of discussion with Narasimhan. Replying to a question on why big multinational pharmaceutical companies were not researching on developing vaccines for such viruses, the US-born Indian executive said, "Right now, we don't have a great market for these antibiotics. Usually it doesn't make for a great business case, because you don't know whether the virus will remain or not." If a company takes the risk of researching a vaccine for a virus outbreak, the virus itself may disappear by the time the vaccine reaches the market, and it may or may not resurface again, he had explained. So, it is the job of governments to fund such public health concerns.

Covid-19 soon spread across the globe. As of September 14, 2021, the virus has infected over 220 million people and caused the death of 4.4 million people. Within weeks of that interview, Narasimhan had to take up additional responsibility to save humankind, as the co-chair of a consortium of leading global life sciences companies to find and supply vaccines, diagnostics, and treatments for Covid-19. That was the beginning of the biggest-ever hunt for a vaccine in human history.

While new drugs and vaccines historically took almost 8-12 years of development to reach the market, Covid-19 vaccines were developed within two years of the virus being discovered, through unprecedented concerted efforts of scientists, regulators and governments. So far, 117 vaccines are in clinical development worldwide, while another 185 are in pre-clinical development. According to data from GAVI, the Vaccine Alliance, 21 vaccines are already in the market, 34 are in final Phase 3 trials, and another 35 are in Phase 2. According to statistics from ourworldindata.org, which tracks the pandemic, 42.3 per cent of the world population has received at least one dose of a Covid-19 vaccine, as of September 14. So far, 5.76 billion doses have been administered globally and 33 million are now administered each day.

India has been at the forefront of fighting the virus. It has approved for use six Covid-19 vaccines, though only two-three of them — early ones like Covishield, Covaxin and Sputnik — account for the mega vaccination drive in India. As of September 16, India has vaccinated nearly 20 per cent of the adult population with two doses, while 62 per cent have got at least one dose. That is nearly 770 million vaccinations, including two doses for 190 million people, according to the Co-WIN dashboard. While India is vaccinating at a run rate of over 750,000 people a day, with vaccine production being augmented month after month, the government is hopeful of vaccinating the entire adult population by the end of the year.

However, the problem is mutation of the virus and 'breakthrough' infections, that is, the virus breaking through the protective barrier provided by the vaccine. A Council of Scientific & Industrial Research (CSIR)-Institute of Genomics and Integrative Biology-Max Hospitals study says one-fourth of 600 fully vaccinated healthcare workers were re-infected, though complications and hospitalisations were minimum. A similar study by the Christian Medical College (CMC), Vellore and Post Graduate Institute of Medical Education Research (PGIMER), Chandigarh, says about 1-10 per cent of fully vaccinated healthcare workers have been re-infected, but only 5 per cent of those required hospitalisation. So far, mutated variants recognised by the WHO are Alpha, Beta, Gamma, Delta, and Delta Plus. Studies say Delta and Delta Plus variants account for nearly 70 per cent of the infections currently in India.

With the fear of mutated variants increasing and experts of the opinion that the virus is likely to stay with us longer, people are already demanding booster doses to boost their immunity.

"Studies on booster doses have been on overseas and at least seven different vaccines have been tried out for booster doses. When more countries catch up with vaccination, recommendations for boosters will definitely come," said Dr Priya Abraham, Director of the National Institute of Virology (NIV), Pune, at a recent interaction on India Science, the OTT channel of the Department of Science and Technology. Booster doses are not a priority for the government at present and the focus is to vaccinate the entire adult population, according to Dr Balram Bhargava, Director General, Indian Council of Medical Research (ICMR), who says the antibody level in the human body is not a measurement of one's immunity. "As the government rightly says, now the priority should be to vaccinate all than allowing boosters," Adar Poonawalla, CEO, Serum Institute of India (SII), said at a press briefing recently.  

That's why next-generation vaccines are important. At least half a dozen such vaccines are being readied to be introduced in India in the coming months.  

From the initial case samples from India, scientists at NIV, Pune, which is under ICMR, were able to isolate about 11 strains of the Wuhan virus. Soon, India developed an indigenous vaccine, Covaxin, one among the first-generation vaccines globally to fight Covid-19. ICMR transferred the technology to Bharat Biotech and by early January, Covaxin got emergency use authorisation (EUA) in India.

But the main problem with Covaxin is its complexity. It has a difficult manufacturing process, and so it is tough to scale up production. Of the total vaccinations done in India so far, Covaxin accounts for less than 15 per cent, though most experts do not doubt its efficacy and some reckon it to be the best to fight the Delta variants. By the end of the first week of September, India could administer less than 80-85 million doses of Covaxin, compared to 610-616 million doses of Covishield and 700,000-800,000 doses of the Russian-made Sputnik V. The government was expecting supply of 60-70 million Covaxin doses by July-August, though supplies were less than half. Bharat Biotech says it requires a 120-day timeline from lab to vaccination centre for manufacturing, testing, release, regulatory approvals, and distribution. The whole-virion inactivated vero cell vaccines — the platform used to make Covaxin — are highly complex to manufacture as the critical ingredient is based on live viruses, which require highly sophisticated, multiple-level containment and purification methods. Such extensive, high standards of purification naturally lead to significant process losses and low yields, resulting in a highly purified and safe vaccine. Bharat Biotech is trying to scale up capacities. Since early June, manufacturing has commenced at its new sites at Malur in Karnataka and Ankleshwar in Gujarat, and three more public sector undertakings are also going to make the vaccine.

However, Bharat Biotech's biggest bet is going to be a nasal vaccine, in partnership with Washington University in St Louis, US. "If the government can develop a total protocol for [all phases of] clinical trials now itself, we can get the nasal vaccine into the market by June 2021. Its production is very easy and the facility is in place already and I can make more than one billion doses, if successful in trials," Krishna Ella, Chairman and Managing Director of Bharat Biotech, had told Business Today in October last year. The vaccine candidate, BBV154 — a novel adenovirus vectored, intranasal vaccine — can be a next-gen vaccine as it can create an immune response in the nose, which is the point of entry for the virus, thereby protecting against disease, infection, and transmission. Based on pre-clinical trials in mice and Rhesus macaques, a recent report published in Cell Reports Medicine says, "A single intranasal dose of ChAd-SARS-CoV-2-S induced neutralising antibodies and T cell responses and limited or prevented infection in the upper and lower respiratory tract after SARS-CoV-2 challenge. As this single intranasal dose vaccine confers protection against SARS-CoV-2 in non-human primates, it is a promising candidate for limiting SARS-CoV-2 infection and transmission in humans."

BBV154 has become the front runner globally among intranasal vaccines for Covid-19. In August, the government gave the green signal to conduct combined Phase 2 and 3 final clinical trials in India; trials have already started. At present, of the 117 vaccines under clinical development globally, only eight are intranasal vaccines and three are oral vaccines. So far, none of these vaccines have entered the final phase of trials. Bharat Biotech is also working on a deactivated rabies vaccine, in collaboration with the US-based Thomas Jefferson University, and with funding support from India's Department of Biotechnology (DBT).

Poonawalla of SII — the world's largest vaccine maker by volume — was among the first to get in touch with Oxford University's Jenner Institute and the Oxford Vaccine Group, led by Sarah Gilbert and Adrian Hill, who had started work on a Covid-19 vaccine in January 2020. That research led to the development of the first of the vaccines — Covishield — which Oxford gave to Anglo-Swedish drug maker Astra Zeneca. Soon, SII got the licence to manufacture and sell it in India and in 120-plus poor and emerging countries. SII also got at-risk pre-funding of $300 million from the Melinda and Bill Gates Foundation and the GAVI Alliance to scale up production.

In an exclusive interview with Business Today on October 22 last year, Poonawalla broke the news. "I am floating a new pandemic vaccine company — Serum Institute Life Sciences (SILS) — with a base in London and plans are to launch at least one new Covid-19 vaccine every quarter in the next 1-2 years so that Serum can make at least a billion doses of Covid-19 vaccines a year." He also said that five new Covid-19 vaccines were already in the pipeline.

Now, SILS is teaming up with Biocon Biologics (BBL), another leading Indian biotech company spearheaded by Kiran Mazumdar-Shaw, to create a combined global vaccine and biotech research and manufacturing powerhouse. Covidshield Technologies Private Limited — a wholly-owned subsidiary of SILS — will merge into BBL, in a deal valued at about $700 million. SILS will get a 15 per cent stake in BBL, valued at about $4.9 billion. Under the alliance, BBL will have access to 100 million doses of vaccines annually for 15 years and commercialisation rights of the SILS vaccine portfolio in global markets. The partners will also team up for manufacturing and research of other vaccines for viral diseases such as dengue, HIV, etc.

"Normally such partnerships happen between foreign companies and Indian partners, but here the two leading Indian biotech companies are teaming up with a vision to build a global biotech company of global impact," said Mazumdar-Shaw, Executive Chairperson, Biocon and Biocon Biologics, while announcing the alliance.

The second Covid-19 vaccine from SILS is likely to be Covovax, with US biotech firm Novavax. The Nasdaq-listed vaccine research company is using its recombinant nanoparticle technology to generate the antigen derived from the Coronavirus spike protein. Novavax has an arrangement with SII and plans to produce one billion doses of the vaccine, including at a facility called Praha Vaccines at Bohumil in Czech Republic, which it bought from SII in May 2020. Final trials are on in India for the 2-17 age group and the vaccine is likely to be ready for launch by December. "We have started stockpiling in a small way and can finalise production plans in a few months as per the directions of the government," Poonawalla said recently.

SII is also working with Codagenix (a US-based biotech backed by private equity), on an intranasal live-attenuated vaccine candidate, COVI-VAC. "We look forward to the anticipated immunogenicity data from our Phase 1 clinical trial (in the UK) later this year and continued clinical development," J. Robert Coleman, Co-founder and CEO of Codagenix, said in a recent update on the vaccine's development. Phase 1 clinical trials began in January and multiple Phase 2 or 2/3 trials are planned in South America, Europe and Asia based on soon-to-be-out initial study data.

Meanwhile, the UK-based SpyBiotech and SII are currently developing a novel virus-like particle (VLP) vaccine targeting Covid-19. SpyBiotech has an exclusive global licensing agreement with SII for the development of the vaccine candidate. It uses SpyBiotech's proprietary SpyCatcher/SpyTag protein "superglue" technology to display the Coronavirus spike protein on the surface of Hepatitis B surface antigen (HBsAg) VLPs. Named CYVAC, the vaccine candidate is undergoing Phase-1/2 human trials since September last year. SII is also trying to develop a measles virus-based vaccine with the University of Pittsburgh, US.

When Ahmedabad-based Zydus Cadila got the nod for launching ZyCoV-D in August, India not only got its first Covid-19 vaccine for adolescents (12-18 age group), but also the world's first plasmid DNA vaccine for Covid-19.

At least 10 DNA vaccines are under development globally. The three-dose ZyCoV-D will be administered using 'PharmaJet', a needle-free applicator, which ensures painless intradermal vaccine delivery. That is also a first of its kind in the world for delivery of vaccines. Zydus is also working on a two-dose vaccine. The plasmid DNA platform provides ease of manufacturing with minimal biosafety requirements and production can be easily scaled up. "The plasmid DNA platform also allows generating new constructs quickly to deal with mutations in the virus," Sharvil Patel, Managing Director, Zydus Cadila, said recently. Zydus is gearing up to produce of 100-120 million doses a month.

The DNA Covid-19 vaccine was developed by scientists at Zydus's Vaccine Technology Centre at Ahmedabad, in co-ordination with Etna Biotech in Italy, an acquired research facility. The team in Italy was also pursuing a live attenuated recombinant measles virus vectored vaccine against Covid-19. "We have stalled that project for now and all our focus currently is on rolling out ZyCoV-D," Patel had said .

Meanwhile, not many had heard about Moderna or BioNTech before Covid-19. mRNA-based vaccines got global focus following the success of Pfizer-BioNTech's Covid-19 vaccine Comirnaty (BNT162b2) and US-based biotech Moderna's Covid-19 vaccine mRNA-1273. It was the first time mRNA platform-based vaccines were developed for human use. Pune-based Emcure Pharmaceuticals' subsidiary Gennova Biopharmaceuticals started experimenting with mRNA to develop a Covid-19 vaccine. The development programme was partly funded by DBT, since June 2020. Later, the DBT further supported the programme under the Mission COVID Suraksha-The Indian COVID-19 Vaccine Development Mission implemented by BIRAC, and helped the project advance to human trials. In early August, the Drug Controller General of India approved Phase 2 and 3 study protocols for the candidate HGCO19, after interim Phase 1 data showed it was safe, tolerable, and immunogenic in the participants of the study. Gennova has now started the final trials among 4,000 subjects at approximately 10-15 sites in Phase 2 and will do trials at 22-27 sites in Phase 3.

"The approval for Phase 2 and 3 protocols for what could be the country's first mRNA platform-based Covid-19 vaccine brings us immense satisfaction and highlights the grit of scientists unified for a common cause," Sanjay Singh, CEO, Gennova Biopharmaceuticals, said at a recent briefing.

"The mRNA technology-based vaccines need to be fine-tuned to bring storage conditions suitable for use in countries like India at normal 2-8° Celsius storage from the current -2° to -20° C for mRNA vaccines. Our collaboration with Biocon will also aim to research and address such issues," SII's Poonawalla said recently.

Hyderabad-based Biological E's Corbevax is likely to be another vaccine to soon debut in India. The receptor binding protein technology-based vaccine, developed with a technical licence from the Houston-based health sciences university Baylor College of Medicine, has now entered Phase 3 trials following approval in September. The government has already placed orders and advance payment for 300 million doses of Corbevax. According to sources, the government is unlikely to wait for the final data and may give EUA for the vaccine once dosing and initial results are available. Biological E is the only Indian vaccine maker other than SII with a capacity to make over a billion doses a year. In August last year, it had acquired Akorn India, a subsidiary of the US-based Akorn Inc, primarily to access the facilities at Akorn India's Paonta Sahib plant in Himachal Pradesh. Biological E also has a contract to manufacture about 600 million doses of Johnson and Johnson's unit Janssen's single-dose Covid-19 vaccine, which was recently approved by India.

"India and the government can be proud of the fact that we are fast developing more and more vaccines and administering vaccines at a quick pace. We are moving towards vaccine adequacy to inoculate our entire population," Mazumdar-Shaw said at a recent press briefing. As newer variants of the virus emerge, next-gen vaccines are being readied, and the pace of inoculation is picking up in India. Vaccinating the entire population doesn't seem that distant anymore.

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