Despite the lockdown, Dr Amol D. Raut, CEO at Pune's Genetic Healing and Director at GeneOmbio Technologies, has not slept for days. That's also the case with his 50-odd colleagues, mainly scientists. Dr. Raut is using his nearly two decades of experience in infectious diseases, molecular diagnostics and human genome sequencing to study the structure and characteristics of the four-month-old SARS-CoV-2 virus gene. Soon, his team will launch a genetic study to develop diets suitable to Indians that can improve immunity against the disease. Another study with the 70-year-old Kaivalyadham Yoga Research Institute at Lonavala near Pune will map genes of a sample pool in Maharashtra to learn how Yoga can improve immunity against the coronavirus.
If Dr. Raut's studies to fight coronavirus are looking for allied solutions based on traditional knowledge, cutting- edge genome research is also on across the world to find drugs or vaccines or other possible ways to control coronavirus. MedGenome, a market leader in genetic diagnostic testing in India, has found out why some people are more susceptible to the SARS-CoV-2 virus. MedGenome, along with Chennai-based SciGenom Research Foundation (SGRF), analysed DNA sequence and variation data from over three lakh individuals across the world for its study. They found out variations in ACE2 protein as the reason for the spread of the pandemic. The job of ACE2 - an enzyme created by the ACE2 protein and seen on cell surface - is to maintain blood pressure in the body. The SARS-CoV-2 virus fools ACE2 and binds itself to it to enter human cells.
"We have found variants that are predicted to bind to the virus less tightly and make individuals less susceptible," says Dr. Sekar Seshagiri, President, SGRF, and lead study author. He says the study can lead to a rationally engineered soluble ACE2 that can be quickly developed as a therapeutic against the deadly virus. "I think we have a potential drug solution that should work. It can be developed quickly with the right pharma or biotech partner," says Sam Santhosh, Chairman, MedGenome. The Centre for Cellular and Molecular Biology (CCMB), Hyderabad, the Institute of Genomic and Integrated Biology (IGIB), New Delhi, and Chandigarh-based Institute of Microbial Technology (IMTech) have taken up the task of large-scale genome sequencing of the Covid-19 virus to study its behaviour on the Indian population.
It is a desperate rush globally to find a cure for coronavirus. More than two lakh people have died of the disease but science is yet to develop a vaccine or proven drug. Thousands of research papers and results of brief studies have been out in the last three-four months. Based on data from Wuhan, experts say 79 per cent of the virus has the same genetic material as Severe Acute Respiratory Syndrome (SARS) and 50 per cent of the same material as Middle East Respiratory Syndrome (MERS). But a confirmed treatment is still not on the horizon. Only a frantic hunt is on.
The best solution is a vaccine. Another option is re-purposing of old molecules against infections like fevers, leprosy or malaria as drugs for coronavirus. Many respiratory drugs are also being looked at. All known vector platforms are being used to develop new vaccines, be it dengue, influenza, HIV, SARS or Ebola, or a mix of many or new platforms.
At least seven out of 78-plus ongoing known vaccine projects are from India. From malaria drugs to BCG vaccines and innovated medical devices, almost all public and pure research private R&D laboratories are working on one or the other project to fight the virus.
Indian Baby Steps
Adar Poonawalla, CEO of Pune-based Serum Institute of India, was among the first to initiate attempts to make a Covid-19 vaccine in India. Serum, the world's largest vaccine maker in volume terms, roped in US-based biotech Codagenix, which is developing a Covid-19 vaccine similar to the one for measles. "By 2021, we should have a vaccine from Serum. We will not patent it and will make it available to as many people as we can to manufacture it. Profits are not the focus at this point," he announced this week. Codagenix plans to move into human trials by September and recombinant BCG vaccine trials in April.
Pankaj R. Patel, Chairman, Zydus Cadila, has to his credit development of a couple of new chemical drugs and creation of a robust vaccine portfolio and infrastructure. When coronavirus was spreading in Wuhan, in mid-February, Zydus initiated Covid-19 vaccine development in India and Europe. One attempt is to develop a DNA platform vaccine to stop entry of Covid-19 virus into human cells. Simply put, it is a process that involves using the DNA with the genetic code of certain parts of the virus injected into the body to trigger the body's immune system to fight the virus. The second approach is with a recombinant measles virus (rMV) vectored vaccine against Covid-19. The rMV, produced by reverse genetics to protect from infection, is currently in animal testing, and if all goes well, clinical trials can start in the second half of FY21. It involves using the measles virus vaccine as a carrier to make the body produce antibodies against the Covid-19 virus. "Our manufacturing facilities for producing recombinant antigens and measles containing vaccines will enable rapid ramping up of production for both vaccine candidates once the proof-of-concept is established, " says Patel.
Zydus Cadila, among the largest integrated manufacturers of malaria drug Hydroxychloroquine (HCQ), which is now in demand as a drug to treat Covid-19 patients, is also going to experiment with its biological therapy Pegylated Interferon Alpha-2b, 'PegiHep'. Recent studies in the US suggest Interferon Alpha has positive effects on Covid-19 patients. Zydus has approached the Department of Biotechnology (DBT) for permission to start clinical trials. It is also working with the USFDA to open an Investigational New Drug filing for PegiHep.
CCMB-Hyderabad is developing an inactivated virus vaccine, which is in the lab stage. Here, viruses are inactivated with heat or chemical process to stop reproduction. When injected, the body recognises the proteins of the virus and starts making antibodies against it. "If we can grow a large amount of virus and then inactivate it, it will become material for a candidate vaccine," says Dr. Rakesh K. Mishra, Director, CCMB. For that, he says, "We will need a company that can take it forward. We are currently at a discussion stage on this."
Hyderabad-based Bharat Biotech has collaborated with University of Wisconsin-Madison and US-based vaccine company FluGen, which will transfer technology to the Indian company. Bharat Biotech founder Dr. Krishna M. Ella says, "We can bring the vaccine into market in eight months though globally experts talk of 12 to 18 months." He is optimistic. "Because this platform (M2SR) is proven in Phase II human challenge studies, we can fast-track the project," he says.
Indian Immunologicals, another Hyderabad company, has joined hands with Australia's Griffith University to develop a live attenuated vaccine using a faster process called 'codon optimization technology'. "This will be a single dose with long-term protection and a safety profile similar to other vaccines used in active immunisation," says K. Anand Kumar, Managing Director, IIL. Scientists with Indian Institute of Science, Bangalore, are also developing virus spike proteins controlling vaccine and have tied up with local biotech R&D start-up Mynvax to explore a vaccine cure for coronavirus.
"Immune boosting vaccines such as Recombinant BCG (bacillus of Calmette and Guerin) and Mw (Mycobacterium Indicus) strains are in the works in India. Convalescent plasma therapy has also been initiated in some sites (Kerala and New Delhi)," Lav Agarwal, Joint Secretary, Ministry of Health & Family Welfare, said during a recent press briefing on Covid-19.
India, which is working with the World Health Organization (WHO) for a 'Solidarity Trial' - a concerted effort to develop vaccines and drugs for coronavirus - has formed a high-level task force for vaccine development and related research. If Indian vaccine dreams are in nascent stages, global firms have advanced a lot in a short time frame.
The Global Hunt
In mid-January, when the virus was spreading in Wuhan, Chinese authorities asked Major General Chen Wei, the military's top epidemiologist and virologist, to go there. The 54-year-old and her team had in 2002/03 developed a vaccine for Ebola and suppressed SARS. Chen Wei's team set up a makeshift laboratory at a tent in Wuhan. The initial attempts were to try plasma therapy. They also tried a nasal spray they had developed during SARS. That was effective but high costs of development, inability to mass produce and side effects were roadblocks. One vaccine they developed has entered second phase of clinical trials and could be among the first vaccines for coronavirus, by early next year.
The Institute of Biotechnology of the Academy of Military Medical Sciences along with Tianjin-based CanSino Biologics will test candidate vaccine on 500 people in the second phase at two Wuhan military hospitals till January 31, 2021, says data available in the Chinese Clinical Trial Registry. That vaccine attempt, named as Ad5-nCoV, is based on a known route - from inactivated viruses, using the platform that developed an Ebola vaccine.
Another vaccine candidate - a recombinant novel coronavirus vaccine, aAPC, from Shenzhen Geno-Immune Medical Institute, has also moved to Phase I. While Sinovac and China National Pharmaceutical Group are testing vaccines using inactivated SARS-CoV-2, Shenzhen Genoimmune has begun clinical trials of two vaccines (LV-SMENP-DC and aAPC), genetically modified to target the SARS-CoV-2 spike protein, say sources.
US-based Moderna is the first to test a Covid-19 vaccine (mRNA-1273) on humans after record development in 66 days. "Plans are to start Phase II study in the second quarter, with a Phase III study by fall 2020," says Moderna. mRNA vaccine alters the genetic code in DNA of human cells to develop immunity against the virus. It has high potency, low cost of production and is safer than conventional vaccines. But the issue is that so far no biotech company has commercialised an mRNA vaccine. (CureVac and BioNTech are two other companies trying the same route).
US-listed Inovio Pharmaceutical, with Beijing Advaccine Biotechnology, is developing vaccine candidate INO-4800. It has started Phase I clinical trials and will start a Phase I/II clinical trial in South Korea soon with International Vaccine Institute, supported by a $6.9 million grant from the Coalition for Epidemic Preparedness Innovations. Moderna and Inovio are yet to commercialise any vaccines.
Although many large multinational vaccine developers - Janssen, Sanofi, Pfizer and GlaxoSmithKline (GSK) - are also making attempts, most lead developers so far are small or inexperienced biotech firms. Therefore, multinationals are teaming up with them, with funds and expertise.
GSK and Sanofi joined hands to develop a vaccine by the second half of 2021 and shared potential molecules that excite the immune system and boost vaccine potency. GSK is also working with Vir Biotech, the University of Queensland in Australia, Chinese biotech company Clover Biopharmaceuticals and five other partner companies and research groups to develop vaccines based on its own compounds that enhance the effectiveness of vaccines.
Sanofi and US-based Translate Bio are researching on many potential vaccines. Sanofi also has collaborated with BARDA and US Health and Human Services (HHS) to advance a SARS vaccine candidate using Sanofi's recombinant DNA technology, besides sharing its vaccine R&D experience with others. The Australia-based Commonwealth Serum Laboratories (CSL) and German influenza vaccine major Seqirus are trying a novel molecular-clamp technology to fast-track the development of a vaccine.
The world's largest drug company Pfizer has teamed up with BioNTech to jointly develop BioNTech's mRNA-based vaccine candidate BNT162. The vaccine will soon enter human trial stage. Johnson & Johnson's unit Janssen Pharmaceutical and Beth Israel Deaconess Medical Center are trying a vaccine from candidates for Ebola and HIV, and plan to start Phase 1 trials by end of 2020. Australia's national science agency CSIRO has begun pre-clinical tests of a vaccine developed by the Oxford University in the UK.
Funds and Approaches
Sir Andrew Witty, former global CEO, GSK, has taken leave from his current employer, US-based UnitedHealth Group, where he is president and CEO of group firm Optum. Witty, who transformed GSK as a vaccine specialist's mission, is to co-lead a global effort of the WHO to accelerate development of Covid-19 vaccines. Other experts reportedly include Moderna's Tal Zaks, CanSino Biologics' Xuefeng Yu and Sanofi's John Shiver. This group is expected to coordinate and design common trials instead of independent trial designs and studies. On April 9, the WHO announced it is planning an international study, the Solidarity vaccine trial, to compare and assess various vaccines under development. India has also joined.
There are broadly six-eight approaches to develop vaccines. Normally, it takes two-three years of pre-clinical and animal studies and three phases of human trials with 2,000-5,000 people over five-six years before the product is commercialised. Now, regulators are ready to compromise on trial rules and have fast-tracked promising molecules. According to CEPI, a global alliance financing and coordinating development of vaccines against emerging infectious diseases, the global Covid-19 vaccine R&D landscape includes 115 candidates. Of this, 78 are confirmed as active and 37 are unconfirmed and in exploratory stages.
Fifty-six of the confirmed 78 are being developed by private or industry developers and 22 are led by academic, public sector and not-for-profit organisations. Of that, 36 developers are in North America, 14 each in China, Asia excluding China and Australia, and Europe.
Another vaccine into human clinical trials is ChAdOx1 from University of Oxford, based on a non-replicating viral platform that attempted cures for MERS, influenza, TB, Chikungunya, Zika, MenB, plague, etc. According to WHO and clinicaltrials.gov details, the vaccine will go through Phase I and 2 trials together in 510 volunteers in the UK from this month, with a target of trial completion by May 2021. However, the university has started production at seven sites so that time is not lost after completion of trials.
The world is pooling resources to fund vaccine development. The World Bank has announced a $6 billion support for disease control and related developments. Re-allocations are expected from the Global Fund to Fight AIDS, Tuberculosis and Malaria, Gavi, an international alliance to improve access to vaccines, and Global Financing Facility grants for service delivery. UK's Wellcome Trust is looking to raise $8 billion to eliminate Covid-19. It plans to spend $2 billion on vaccine development and $1.5 billion on advancing therapeutics. WHO, CEPI and Covid-19 Therapeutics Accelerator have already committed more than $1 billion. Biomedical Advanced Research and Development Authority (BARDA) of the US government has committed $483 million for development of Moderna's vaccine. Inovio has got a $6.9 million grant from CEPI. BARDA is also part funding J&J in its Covid-19 vaccine quest, a $1 billion affair. BioNTech's partner Pfizer will give $185 million upfront payments, with $563 million on the table in the form of biobucks. J&J is investing $1 billion on its vaccine candidate, with half the funding promise from BARDA.
But, most know it is a risky, unsure path ahead to come up with a vaccine this year.