Indian scientists now face one less hurdle for research into the SARS-CoV-2 virus, thanks to a new government memorandum giving them access to blood, nasal and throat samples from COVID-19-infected people – a crucial precondition for vaccine development, genetic sequencing and the development of diagnostic kits.
On March 21, the government’s Empowered Committee on COVID-19 Response said in a memorandum that not only could national labs use clinical samples for research but also culture the virus themselves if they had Biosafety Level 3 facilities. This announcement has spurred several COVID-19-related research projects that would otherwise have been infeasible.
“This move is overdue, because if we want to do anything, we need patient samples. If the institute is equipped, I don’t see why it should not be allowed,” said Radhakrishna Pillai, director of the Rajiv Gandhi Centre Biotechnology (RGCB), Thiruvananthapuram, which is funded by the Department of Biotechnology.
Constituted by the government after the COVID-19 outbreak began, the Empowered Committee is co-chaired by India’s Principal Scientific Advisor K. VijayRaghavan and NITI Aayog member Vinod Paul; and includes representatives from multiple scientific agencies such as the Indian Council of Medical Research (ICMR), the Department of Science and Technology (DST) and the Department of Biotechnology (DBT). In a text, VijayRaghavan told The Wire Science that the decision was meant to open up clinical research to a wider group of scientists. While these scientists would still have to follow all ethical and safety regulations, any permissions required from bodies like ICMR would be given in a “time-bound manner,” he said.
The memo could jumpstart COVID-19 research in India because until now, anyone wanting to work with clinical samples has had to jump through several hoops. For one, Indian diagnostic labs currently testing for SARS-CoV-2 – chiefly a network of 89 facilities coordinated by the ICMR – had to send all positive samples to Pune’s National Institute of Virology (NIV), an ICMR institution. Anyone else wishing to use these samples then had to request NIV for these samples, precipitating delays. But the memo now asks all diagnostic facilities as well as hospitals treating COVID-19 patients to cooperate with national labs that want samples.
National labs have been defined in the memo as institutions under the DST, DBT, the Council for Scientific and Industrial Research (CSIR), the Department of Atomic Energy (DAE) and the Defence Research and Development Organisation (DRDO). Researchers at many of these institutions had commenced SARS-CoV-2-related research soon after the first few Indian cases were detected in February.
For example, Anurag Agarwal, a scientist at the Institute of Genomics and Integrative Biology, a CSIR lab in New Delhi, began exploring applications of next-generation sequencing, a set of methods to obtain the genetic codes of viruses from many patients quickly. He said the memo could now help him access the clinical samples he needs to test his application.
The memorandum also boosts potential drug development for COVID-19. Pillai said his team has applied for permission from RGCB’s ethics committee to collect blood samples from recovered patients, and use immune cells from these samples to develop a type of treatment called humanised monoclonal antibodies.
Monoclonal antibodies are antibodies that recognise only specific proteins, called antigens, on the surface of specific bacteria or viruses. To deploy them as treatment, scientists take monoclonal antibodies produced by mice and change their protein sequences to resemble those of humans. These “humanised” monoclonal antibodies have a lower chance of being rejected by the patient’s body as well as can be mass produced in mouse cell lines. Pillai said RGCB had a technology transfer agreement with the Oklahoma Medical Research Foundation to develop such humanised monoclonal antibodies.
Meanwhile, another group at the Indian Institute of Science, Bengaluru, led by Rahul Roy, an associate professor of chemical engineering, is considering a collaboration with the St John’s Research Institute (SJRI) in the same city for a clinical trial of the drug hydroxychloroquine. Hydroxychloroquine has shown some efficacy against COVID-19 in small, inconclusive studies, and larger studies are currently ongoing. Roy said his team was putting together a proposal for a trial to the DST.
Both short term and long-term COVID-19 research projects stand to benefit from the Empowered Committee’s move, according to experts. In the longer term, if labs develop vaccine candidates, the memo will ease their attempts to evaluate the vaccines’ efficacy. Without access to live virus from clinical samples, scientists can only test a candidate vaccine’s ability to trigger antibody production (immunogenicity) in lab animals, Satyajit Rath, an immunologist who was with New Delhi’s National Institute of Immunology before he retired, told The Wire Science.
However, to test whether such antibodies can protect against disease, animals have to be exposed to the virus. “The absence of clarity regarding permissions to culture SARS-CoV-2 and to access clinical samples for analyses would mean that most research groups would so far have been doing indirect and preliminary work,” he said.
Chipping in with diagnostics
The memo has prompted efforts to plug imminent shortfalls in India’s COVID-19 diagnostic capacity. As of today, 89 government labs and 12 private lab chains are testing for the virus’s presence in patient samples. But these numbers may soon become inadequate. The number of confirmed COVID-19 cases in India, at 468 today, are expected to rise exponentially as they did in other countries. One estimate from China suggests that the total number of infections doubled every 6.4 days during January 2020 while in the US, the case load doubled in just two days last week.
To prepare for such an event, several national labs are planning to chip in with the testing, Satyajit Mayor, the director of National Centre for Biological Sciences (NCBS), a DAE-funded institution in Bengaluru, told The Wire Science. These labs are taking advantage of the fact that the reverse-transcriptase polymerase chain reaction (RT-PCR), the technology used to identify telltale SARS-CoV-2 genetic material in patient samples, is also used by scientists for other studies. For example, an ecologist may use RT-PCR to identify the genetic material from phytoplankton species that trigger algal blooms in sea-water. Given this expertise, researchers at NCBS, who span disciplines such as ecology and neurobiology, are “ready and able to” offer RT-PCR testing even for COVID-19, Mayor said.
Apart from testing samples, NCBS plans to train researchers from other labs to do the same should the need arise. “Ideally, one would want a medical diagnostic lab to do this. But diagnostic labs may run out of capacity,” Mayor said.
Meanwhile, the Translational Health Sciences and Technology (THSTI), in Faridabad, is developing its own diagnostic kit for COVID-19, said its executive director Gagandeep Kang. While the kit currently used by most testing labs in India today is developed by the NIV, the NIV is also validating nine alternative kits from private firms. Such validation involves running clinical samples through the kits and measuring the rates of false-positive and false-negative results. THSTI’s diagnostic kit is still some time away from being ready to use.
But when it happens, the memo will make it easier to validate the test with human samples at THSTI itself, Kang told The Wire Science. “It makes a huge difference to us. Now we can think about diagnostics. We can think about clinical trials. We can think about anything to do with patients.”
Testing for immunity to SARS-CoV-2
A final crucial component of outbreak response that the Empowered Committee’s memo may help with is to estimate the number of Indians already infected by SARS-CoV-2. RT-PCR can only detect the virus in a patient who is currently infected but is of no use once the patient has recovered. For such recovered patients, India needs a test capable of detecting antibodies in the blood, which last for a longer time than the virus itself.
Such a test could yield an estimate of how many people are immune to the infection, according to Pillai. Most people who recover from viral infections become immune, at least for a short time. However, we don’t yet know how long the immunity against SARS-CoV-2 would last or even if such immunity exists at all. Antibody tests could help answer these questions, and help identify healthcare workers in whom such immunity could mean lower risk of infection, Roy said. Finally, such a test could help estimate the true COVID-19 case-fatality rate – the number of deaths per number of infected people – given that many people are asymptomatic and aren’t accounted for in current calculations.
Both THSTI and RCGB are working to develop such antibody tests and which they plan to use in large population surveys. And the removal of impediments in accessing clinical samples, Kang and Pillai agree, helps with this too.
A key stipulation in the Empowered Committee’s memo is that all data generated by national labs on COVID-19 has to be published in open formats. This is the biggest plus point of the memo because it will uplift COVID-19 research collaborations in India, Agarwal said.
Such widespread data-sharing could lead to many insights. For example, when multiple labs are allowed to sequence viral genomes and publish them, the resulting data could highlight whether any genetic changes, which are frequent in RNA viruses like SARS-CoV-2, are associated with more severe versions of the disease in some patients.
But without such a large collection of genetic sequences, drawing such correlations would be impossible. “You need at least a hundred patients corresponding to each distinct genetic sequence to give you the statistical power to differentiate [patient] outcomes,” he said.
Thus far, the NIV has been the only Indian lab sequencing SARS-CoV-2 – and it had been slow to publish its results on the global open-access database GISAID. In fact, it would seem only two samples from India are visible on GISAID.
“The power of the official memo lies in the fact that it creates multiple stakeholders, empowers them, and asks them to share their information,” Agarwal said. “This is very different from when only a few people generate data. It’s like a transition from the Microsoft world to the Linux world.”
Priyanka Pulla is a science writer.
The reporting for this story was funded by a public health journalism grant to Priyanka Pulla from The Thakur Family Foundation.