COVID-19 pandemic, caused by SARS CoV-2 has become devastating. With explosive spread affecting approximately over 5,50,000 people and a mortality of more than 25,000 persons the world over, it is now a global calamity. The Rajiv Gandhi Centre for Biotechnology (RGCB) located in Thiruvananthapuram, Kerala, is Government of India’s autonomous institution for research and development in disease biology that in addition also does extensive public health services.
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Kerala holds an entire conjoining geography with the Western Ghats forests considered as the source of emergence and persistence of several virus infections such as Kysanur Forest Disease, dengue, chikungunya and more recently Nipah in the country. The vulnerability of Kerala as an entry point of novel viruses into the country or emergence of new infections also come from the fact that it has one of the highest numbers of expatriates working in all parts of the world, especially in the Middle East; its direct global connectivity owing to the presence of four international airports; its global reputation as a preferred tourist destination; and a tropical climate with high rain, humidity and temperature with proximity to rain forests of the Western Ghats. With excellent state-of-the-art infrastructure, the RGCB has now set up a clear clinical and discovery research roadmap on COVID-19 to support outbreak management and maximise benefit to the public.
The current approach to diagnose SARS CoV-2 infection is by Nucleic Acid Testing (NAT) using real-time reverse transcription Polymerase chain reaction (RRT-PCR) screening of samples collected from patients. The RGCB is also such an approved testing facility. This test is costly, time-consuming and not adaptable to large-scale screening to avoid disease spread to other individuals. Antibody detection tests cannot be used in the early phase of the disease as these molecules are elicited at least 5-7 days after the onset of symptoms, by which time transmission to others will have already occurred. Also, there are no available alternative tests for early diagnosis or prediction of severity. The RGCB has one of the best proteomic facilities in the country that will be put to use for biomarker identification. The RGCB has designed analysis of early and late plasma samples from COVID-19 patients to identify protein markers for developing alternative tests for diagnosis and prediction of severity.
The SARS CoV-2 is an RNA virus that is capable of undergoing rapid genetic changes. In a pandemic situation, where large numbers of people are affected, chances of mutation are significantly increased. Once characterised, the RGCB will correlate observed mutations with disease severity and neutralisation antibody response. This is critical for efficient design of vaccines and predicting severity of future outbreaks in new geographical areas and their management.
Our worst fear at present is whether a community spread has already started, thereby taking India into the third stage of the COVID-19. Naturally, checking this is a priority. Rather than directly going into the community for verification at this stage, we strategically planned two hospital-based approaches. Since patients with severe COVID-19 develop viral pneumonia, to appraise the SARS-CoV-2 transmission situation in Kerala, a Statewide pneumonia-screening programme is being done. Initially, 10 sentinel hospitals from the government and private sector will be selected in each district. All patients with pneumonia will be tested for SARS-CoV-2. Severe cases will also be tested for Influenza A, Influenza B, H1N1, Respiratory Syncytial Virus, Human Metapneumo virus, and Adeno virus. The second hospital-based approach would look into SARS CoV-2 antibody responses in the hospital staff, including doctors and nursing staff. They form the target group since they are the people who would have contact with undiagnosed COVID-19 patients and would be ideal sentinels for the study.
New drug candidates
Another aspect that needs immediate attention being addressed by the RGCB is development of both new drug candidates and drug repurposing of approved drugs for treatment of COVID-19 patients. It is now known that ACE2 is the SARS CoV-2 receptor and peptidase that is important to cleave S protein for priming and entry into cells. RGCB will make tagged pseudovirions and track the entry of virus particles into the cells. This will be a model to screen for viral entry inhibitors using endocytosis tools developed in the institute. Also being done at the RGCB is repositioning of existing drugs active against RNA viruses using rapid assays in cell culture and then adapting them to the clinical environment
Monoclonal antibody therapy using humanised monoclonal antibody (HmAb) therapy is becoming an accepted therapy for infectious diseases. The feasibility of using antibodies from COVID-19-recovered patients in the form of plasma therapy has already been demonstrated in the trials conducted in China. Using immune cells from recovered patients, the RGCB has started protocols for engineered therapeutic humanised monoclonal antibodies against the pandemic. Once developed and scaled up, this will be a valuable biological for treating severe COVID-19 patients.
India has a rich tradition of Ayurveda and use of natural compounds in acute and chronic disorders. The RGCB recently discovered, characterised and transferred to the industry one such molecule from a plant source for liver cancer. Traditional knowledge and ancient Ayurveda texts describe methods thought to be useful in managing febrile conditions. Modern science assumes that these mostly work through immunomodulation and the RGCB has strong preliminary data for this. Hence, studies evaluating both standard Ayurveda formulations such as Rasayanas and Ghrutams and many natural products for their antiviral and more importantly immunomodulatory properties have started at the RGCB.
The RGCB has proven record in developing rapid antigen-based detection kits for swine fever and snake bite venom detection rapid kits. The RGCB is in the process of developing a highly cost-effective Corona-detection kit, reducing the detection time by nearly half of that of today’s kits. The highlight of this kit, on completion, will be that it can be used in limited resource laboratories that do not have real-time PCR machines, which are costly to procure and operate. A second methodology being developed by the RGCB is field-testing of samples using-RNA based detection completely bypassing the PCR machine, but with the similar sensitivity and specificity of conventional PCR. This capability has already been previously developed and demonstrated in dengue virus detection by the RGCB. In response to “Make In India” call of the Honourable Prime Minister, the RGCB and Kerala Start up Mission manage an excellent technology development incubator called BioNest that currently has 23 start-up companies. The RGCB works very closely with these companies to promote development of low cost new diagnostic kits that can be used as point-of-care tools for rapid diagnosis of Corona virus infection. This will allow widespread screening in the population not possible now with expensive time-consuming methodology.
(Professor M. Radhakrishna Pillai is Director of Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram.
The author acknowledges support from the RGCB Corona Response Team.
The opinions expressed are personal)