National Webinar on: ‘Challenges to combat Covid-19’
Intro: The coronavirus pandemic is a global health crisis of our time and the greatest challenge we have faced. The need of the hour is to combat Covid-19 by developing a vaccine. In this webinar session, Dr. Ruchi Jain Dey will enrich our knowledge on various treatment methods for coronavirus and challenges in drug development.
Speaker Intro: Dr. Ruchi Jain Dey, Assistant Professor at BPHC- PhD from Department of Biochemistry, University of Delhi. She is a seasoned researcher for 15 years in the area of infectious diseases particularly pertaining to TB. Her thesis during her PhD was primarily focused on the study of immunology of mycobacteria, development and evaluation of different prime boost vaccination strategies of TB. She pursued her Postdoctoral studies from Johns Hopkins University and MGH and Broad Institute of Harvard and MIT, USA. She has been recognised and conferred with many awards from institutes and organisations like DBT, DST, CSIR. She has two US and three Indian patents. She has 12 publications to her credit, she has also worked in the area of genetically engineered vaccines against TB and bladder cancer. She has authored 6 books on various scientific topics. She is continuing with her research projects, dedicated to the development of diagnostic therapeutics and vaccines against infectious diseases. She is actively working on the development of a vaccine for the Covid pandemic.
Q. 1. We are all bombarded with negative news, can we start this discussion with some positive trends in this ongoing pandemic.
A.1. "Something unique has happened in recent times, the whole definition of the word "warrior" has suddenly changed, doctors and nurses are now our new frontline warriors. We are appreciating life much more. There are definitely some positive trends I've seen in the last few months, which is definitely an eye opener. Unlike the past, increase in google search about COVID-19 suggests a sudden surge in public's interest in this disease. We have seen an increase in government funding and R& D in the field of Covid-19. There is an enhancement in realization of the importance of “personal hygiene and hand wash” across the age groups and economic strata. Not only the public is now aware about social distancing and mask usage, we are all following it also strictly. Lockdowns have forced us to adopt e-learning. It has forced publishers to make their resources open access to all, it has also prompted educational institutes to provide open access resources and e-learning to students. On the personal front, realizing the fragile nature of life, we are spending much more time with our loved ones and families and focussing on other important aspects of life than just work.
Of course, there are many challenging aspects- people who are working from home are stressed out, due to lack of support and burden of work people are experiencing panic and depressive thoughts. Those who are engaged in their own businesses are affected by the economic downturn and are worried about the future. But if looked at carefully, I think there are a lot more positive trends than negative trends and it is definitely pushing our society towards greater awareness about self and about their environment.
Q.2. What are the things we are going to focus on in this discussion?
A.2. We are mainly going to focus on the various aspects of Covid-19 disease, how important it is to know our enemy, I will also try to summarize the progress so far in testing, treating and preventing the disease. We will also talk about clinical presentation of Covid-19 and arsenal being used against the enemy- therapies, drugs and vaccines. We will also talk about the role of research and development- new and repurposed drugs, how India is innovating, challenges of dealing with other ongoing epidemics during the times of Covid. What are the challenges and opportunities for educators and students, what needs to be done to win this war.
Q.3. Can you briefly describe about Corona family?
A.3 Meet the Corona family:
- SARS-CoV, MERS-CoV, SARS-CoV-2(Covid-19), these viruses are considered to have animal origin.
- Studies in the past have shown that there is a high degree of similarity between SARS-CoV-2 and Covid-19. We have noticed that both follow a similar entry mechanism using the ACE2 Receptor, both have spike proteins which are acted upon by the host proteases, both of these infections cause production of antibodies in the body of the infected.
- Covid-19 is the most dangerous in its family. Unlike the seasonal flu, the number of people that can be affected by one person is far more, it's incubation time is much longer, there is more hospitalisation and more case fatality rate.
Q.4. What has been the progress so far in the field of Covid research?
A.4. R& D has progressed a lot on multiple fronts:
- Research is being conducted at lightning speed, the genome of the virus has been sequenced. Within 7 hours, we have the capability to sequence the genetic material, we are looking at the protein structures of the spike proteins and other proteins of Covid-19, we are understanding if these proteins can be targeted by antibodies or drugs.
- Scientists are studying 'epitopes' of two types:
a) B-Cell: small part of the protein which is recognised by the antibodies
b) T-Cell: part of the protein which is recognised by T-cell of our body
- We also know how long after a person is affected can the virus be detected, the cycle of the virus and the nucleic acid test (start of symptoms) and antibody test (after 7-10 days) to diagnose these patients. However the gray area is that, between both these tests, there is approximately a week's time where the nucleic acid starts disappearing and the antibodies are very low in numbers.
- We also came to know about different types of antibodies produced in our body which help in clearing the infection. Our bodies can remember these and remake them to protect us in case of re-infection.
- There is an increase in the usage of Nucleic Acid Test(NAAT) for diagnosis. It mainly involves isolating the sample, followed by RNA extraction, conversion to cDNA followed by amplification and PCR to detect the presence of nucleic acids. Both antibody and NAAT are useful in diagnosing the disease, however, NAAT is better in the early stages of infection when antibodies are yet to be produced by the infected person. The antibody test is most likely useful in the later half of the infection or post-infection to determine your immune response.
- Challenges of combating Covid-19 with antibody diagnosis alone- If someone doesn't produce detectable amounts of the antibody, or if they have lost antibody response over time(may result in a false positive or negative), there is precedence that antibodies do not guarantee protection against future strains of the new virus(especially when mutations of viruses are occurring)
Q. 5. Can you talk about current approaches for Vaccines and how are they tested?
A.5. Currently many vaccines are being tested. Typically it involves designing and synthesizing certain antigens or proteins from Covid-19 followed by mixing with adjuvants and immunization of host which could then be tested in an animal model eg. Mouse or monkey. Introduction of Covid antigens in the body generates B-Cell response or T-Cell response and trains the immune system to respond in face of infection with Covid-19. These animals are then infected with the virus to determine the protection against disease and longevity and quality of immune response. Once a vaccine passes the preclinical stage, it can be approved for clinical trials in humans.
Q.6. What is Convalescent Serum therapy and is it effective?
A.6. People who have recovered from the infection are sources of readymade antibodies which their bodies have manufactured to neutralize the virus. So if sera from these individuals post-clearance of the live virus, can be isolated and given to those who are either not yet exposed and those who are infected and are in various stages of the disease, it can act as prevention and treatment respectively.
Q. 7. How antibodies neutralise viruses and is there a chance that a virus can evade antibodies?
A.7. Viruses need to attach to a cell surface receptor and then open up their protein coat to release RNA into the host cell. After the release of RNA, replication of viral genome and packaging of viruses initiates. However, if an antibody is present, it will aggregate the viruses, block the attachment of the virus due to steric hindrance or make a structural change in the virus so that it cannot enter the cell or open up to release RNA inside the cell.
However when mutations occur, the genetic material changes and as a consequence proteins change, thereby changing the regions of protein called “epitope” recognized by the immune system. If there are a lot of changes, it is essentially a new virus unknown to our immune system, so our existing antibodies fail to recognise the virus and allow it to enter, replicate and spread.
Q.8. Do all patients have similar symptoms?
A.8. No, there are diverse clinical presentations of Covid-19 such as:
- Asymptomatic infection- Patient carries the virus without showing any signs of disease
- Mild infection
- Moderate infection
- Severe infection
- Critical infection- Patient needs hospitalisation, the virus has spread all across the body to other organs like heart, kidney, so their system is failing altogether
Q9. Why do we experience these symptoms?
A.9. Suppose a cell gets infected, it starts releasing chemicals inside the body called “alarmone” which is a signal to the entire immune system that there is an infection going on in the body at a particular site. This helps us in three ways, the cell which is experiencing the infection signals it’s neighbors so that they can apriori develop mechanisms to destroy the incoming viruses. Secon, they may also give signals to the nearby cells to die so that virus do not enter inside them. Third, these chemicals or alarmons called cytokines alarm the whole immune system and attract the cells of the immune system to reach the site of infection. The incoming cells, relase more cytokines which are release into the bloodstream and thereby transported to the entire body. The immune system uses the cytokines to sound the COVID alarm. This process is called “inflammation” and if it continues in an unregulated fashion, we experience a process called “Cytokine Storm” where lots of cytokines are produced causing collateral damage to the bystander uninfected cells across various organ systems.
Q.10. Why is cytokines a danger sign?
A.10. Cytokines when recognised by the cells of the immune system in our body for example in lungs, they start producing a large amount of mucus which starts accumulating in the airway leading to symptoms like coughing and lung congestion. The airways get totally inflamed, full of mucus and at the same time the immune cells are attracted towards lung the primary site of infection. Though the infiltration of these immune cells towards the lungs is to help the cells which are infected, lungs become highly inflamed compromising the breathing capacity of lungs. Also, these cytokines activate multiple cell death mechanisms causing collateral damage (the cells which are not even infected).
Q.11. Can we learn about how survivors and non- survivors of the infection differ from each other?
- For the survivors, the immune system is very regulated. They do not respond in an inflammatory manner and they are able to control the infection. They may experience mild symptoms.
- For non- survivors, those people who progress to the critical stage of the disease, their body is unable to regulate and control these symptoms and as a result, there are a lot of inflammatory responses like cell death, blood clotting, vasoconstriction. As a result, the heart, kidney, liver, brain and a lot of other organs are affected because of the Cytokine Storm and the direct infection in the cells.
Q.12. What are the reasons for the extreme symptoms?
- Infection causes blood clots to form in small blood vessels throughout the body.
- The clots can block the flow of oxygen rich blood to the body’s organs such as the brain, kidneys and heart.
- Direct infection, cytokine storm, low oxygen, accumulation of blood clots damage organs.
Q.13. What is the role of R&D in this pandemic?
A.13. R&D is critical and indispensable for development of new drugs, vaccines and diagnostics. As no specific drugs were available to treat the infection so doctors needed new tests which are more rapid, instant, more reliable and they can be used at the point of care diagnostics. Doctors need drugs that can help in specifically targeting this virus which is safe in humans which can be manufactured in our own country, in a low source setting. Focus of R& D for prevention is on two kinds of strategies:
- Identify potential vaccines
- Identify monoclonal Antibodies
Both are critical for community protection and are expected to be safe in humans, active against COVID-19, quickly manufactured and deliverable in low resource settings.
Q. 14. When can we expect a vaccine or can you talk about the timeline for treatment and prevention?
There are more than 66 programs working on 3 different approaches, so we can expect something soon:
- 7 purposed drugs/solidarity drugs that are used for HIV, Malaria and Ebola
- 16 antibodies which are produced in the laboratory from the animals and even the bio engineering is done to make antibodies that can be used for treating the patients
- 43 vaccines that are right now in clinical trial
Q. 15. Can you describe the rationale behind the designing of the drugs?
A.15. Drugs are designed based on our understanding of
- How the infection happens.
- How the virus enters inside our cells.
- How the virus releases its genetic material into the cell.
- How the proteins get activated.
- How the viral replication starts in the body and how it spreads to various organs.
There are drugs which are able to block entry and membrane fusion, block Lysosomal acidification and activation of spike protein needed for uncoating of virus, block protease which activate viral proteins, block transcription and replication, stopping the cytokine storm, stimulates antiviral defence.
Q. 16. How the viral infection is affecting the spleen?
Spleen is a site which is a lymphoid organ where all the T-cells, B-cells and RBCs are stored. People are experiencing symptoms because even the virus spreads to the spleen as well. People are also experiencing symptoms such as splenomegaly where the spleen becomes very large in size because it's totally inflamed and also it is now actively replicating all these T-cells and B-cells and trying to churn out more number of cells into the blood so that the cells can reach the site of infection. So the lymphoid organs are affected by the spread of this virus.
Q. 17. What is hydroxychloroquine and why is working against COVID-19?
A. 17. Hydroxychloroquine is an antiprotozoal drug. It is used to treat Malaria. It is a weak base which increases the pH of the Endosome and Lysosome. This drug is used to block the acidification because the formation of the acid in this Lysosomal compartment is important for activation of the spike proteins and the opening up of the virus release of the genetic material. Due to this action it has been used in some cases. But it's not specific and is not very efficacious and fraught with dangers of side effects.
Q. 18. What are the goals of vaccine development?
A.18. There are multiple goals and expectations from a new vaccine, some of them are:
- Generate specific and efficient neutralising antibodies
- Generate Long lived immunity
- Should not cause any collateral damage or unwanted immune enhancement effects causing side effects.
- It should creat herd immunity and protect the population from infection and transmission and should reduce the morbidity and mortality associated with the disease.
Q. 19. Is the plasma therapy good enough or there are risk involved.
A.19. There are clinical trials going on right now and there are certain signs from India and other nations that the convalescent therapy was able to help certain patients, but the extent of protection depends on the stage of the disease when the patient is given the therapy.
If the patient has approached critical stage of disease where massive damage has already occured, treating such patients with plasma may confer much protection because by the time the therapy starts, the organs have already started getting damage and it may not be possible to reverse the organ damage and thus, the patient may not survive despite the therapy.
Risk is involved in any therapy. Other than effect of positive effect of antibodies on neutralization of the viruses, there is another hypothesis suggesting that virus captured by antibodies might help the virus in entry by allowing them to be engulfed by the cells and if the virus is smarter than our immune system then it might have better intake into the cell and also can replicate faster. Second, all the antibodies are not protective. Many antibodies may recognize virus and bind it, but may not neutralize it or block its entry.
Q. 20. What are the new vaccines which can see the light of the day in near future?
A.20. We have so many vaccines which are currently in different stages some are in the exploratory stages in which researchers are designing, some vaccines have shown promising evidence of protection and immunogenicity in the animal models like in mice or in monkeys, and some have already crossed the stage of preclinical testing and have reached the clinical trial stage in humans.
The vaccine belong to the following different categories:
- Live Attenuated vaccine
- Viral Vector based vaccine - that is a lookalike virus which is not infectious. It does not cause disease but it serves as a vehicle to kill the proteins of interest or the antigens of interest and load into these viral vectors and give it as a vaccine.
- Recombinant Protein based vaccine (eg: spike protein)
- DNA vaccine
- mRNA vaccine - People are loading these to the Lysosomes and these mRNA are going to go and express the antigen and release a sustained amount of proteins.
Q. 21. Why do you think, BCG vaccine can be used to protect against Coronavirus?
A.21. BCG is a 100 old year vaccine for Tuberculosis. It is currently used as a repurposed vaccine against Covid-19. Mainly, it is due to a nonspecific immunostimulatory effect of this vaccine. When BCG is given, it trains the innate and adaptive arm of the immune system and it enhances the ability of the cells of the innate immune system, such as macrophages and the monocytes to be more effective in engulfing and killing these viruses. Prior immunization with vaccines such as BCG also functions to enhance the antigen presenting ability of the cells.
Q. 22. What is the basis of using Sepsivac- a vaccine for Leprosy and sepsis against Covid-19?
A.22. Sepsivac marketed by Cadila belongs to the category of a repurposed vaccine. It was initially discovered as a vaccine for Leprosy and TB in India by Prof. G.P. Talwar. It was then called the Mycobacterium w (Mw). Later on, it also found its utility against cancer and sepsis. Since, wide spread viremia or spread of viruses in large number across body, leads to symptoms similar to bacterial sepsis, it is anticipated that Sepsivac may also protect against Covid-19 lik BCG through it immuno-regulatory mechanism controlling the excessive inflammation caused by viremia.
Q. 23. How effective are alternative treatments?
A.23. There are many promising alternative treatments and natural compounds which were found in vitro to be active against COVID-19, but efficacy of these treatments is currently being tested in clinical trials in India, such as
Q. 24. How is India doing?
A.24. So far, India is doing fantastically well, the mortality rate is low and treatment success rate is very high. We were also able to stop the spread initially at the very early stage through early lockdowns. The media has played an important role in this scenario spreading awareness on this . In fact the media, the government, the state and the central government all have united together on this front. Not only the research aspect, not just the biologist, but many engineers came into the forefront because they thought that their expertise could be utilised to create some novel ways which can still help in managing the disease. The sample collection kiosk, in-house created PPE gowns and facemasks using nanomaterial, biodegradable face shields, ‘jivan lite’ ventilators, infrared thermometers, sanitization tools,feluda paper-strip test and biosensors for detection of virus and ongoing clinical trials of vaccines in India, reflect that we are working successfully on multiple fronts. It also reflects that early and rapid decisions from the end of government and public contributions both financially, technically and emotionally are playing a critical role in containment and management of the pandemic.
Q. 25. What challenges do you think exist in pandemic control in a tropical country like India?
A. 25. Our country is not only just affected by covid pandemic, we are simultaneously impacted by so many ongoing epidemics. We are suffering deaths because of TB, diarrhea, Rota virus, malaria etc. you name an infectious disease, it finds its presence in india in significant numbers. In this situation, sudden surge in the covid-19 pandemic, has impacted the management of other pandemics critically due to diversion of resources both human and others. So there are additional challenges and burden on public health care due to those preexisting infectious diseases which are rampant in our country alongside Covid-19.
Q. 26. Would you like to tell how TB and covid-19 differ and how they are similar?
A.26. There are a lot of similar symptoms between a TB patient and covid-19 patient. There are some differences but the initial symptoms can be very similar and can be very challenging to test either for covid-19 or TB. The difference is that TB is a chronic disease that means it happens slowly and increases slowly but covid is a very sudden onset and within 15-20 days it will be decided whether you are going to survive or not. But people suffering with TB do survive for several years. And if we compare the TB situation and covid situation together you will be surprised to know that India alone has 2.6 million new cases in 2018 which is a huge number and 4.4 lakhs deaths occured due to TB in 2018 that is close to 1200 deaths per day. So unlike Covid-19, TB which is also a respiratory infection which is contagious, did not catch the attention of the public much. We were continuing with our lives with an existing threat, but emergence of covid has got the hotspot attention of the public in general and researchers in particular from various fields. Not only that, it has attracted funding resources as solutions are anticipated at the earliest possible to contain this disease. In case of TB we do have DOTS drug therapy, we have vaccines, we have treatments but in case of covid we don’t have any specific treatment and that’s the reason there is lot of panic due to this parallel pandemic.
Q. 27. Can you highlight some challenges and opportunities for Students and Educators?
A.27. Everyone has now resorted to E-learning and work from home. We are referring to a lot of E-resources. Many top-notch institutes like Harvard, MIT etc have made their resources open to everyone. Therefore rather than considering Covid-19 as a challenge we should make use of these resources and get ourselves enrolled in such valuable programmes in order to sharpen and learn new skills. As teachers, we are also adapting to these changes and learning new tools to engage students in online classes. Colleges are also figuring out how to expand their facilities and train the next generation of scientists and technicians to participate in research in Covid-19, as we have to prepare ourselves against ongoing and future pandemics.
But yes, teachers and students in remote villages do not necessarily have the optimum resources and internet connections to fully enjoy the benefits of online learning. Many primary schools are unable to engage in teaching due to this, hence this situation does pose a challenge for e-learning in the population residing in villages.
Q. 28. What do we need to win this war?
A. 28. Definitely, after doctors and nurses we need Research Warriors, who may not represent the forefront in fighting this disease but will provide extensive research support to everyone.
- We need a trained battalion of Scientists:Not just microbiologists and virologists, we need animal scientists,immunologists, epidemiologists, mathematicians,artificial intelligence, data scientists and many more. Everyone needs to join hands and utilize their resources to overcome this pandemic.
- We need to have a cross talk between doctors, engineers, biologists and teachers. We need to form consortiums to think and plan interdisciplinary areas of research where we have to start new programmes.
- We need to teach our students to be prepared against a pandemic not just as a victim but as a person who can proactively find solutions to fight it, so this might require new educational programs on Epidemic Management.
- It may require us to Re-learn and Re-train ourselves in challenging research areas and develop training programs.
- We have to re-purpose our expertise. For example, a virologist might have to learn microbiology and vice-versa. We have to upgrade our knowledge and technologies to prevent these pandemic within time.
- Re-source: We have to create new resources, diagnostic and vaccines and be very prompt in sharing these resources with the people.
- Re-define: People are depressed about losing their jobs and their future goals. This is the time where we redefine our goals and re align ourselves promptly to the newly arising situations
- Colleges can play a big role because they are the point of contact with the students, who can be motivated by the college to participate in research. Students with the help of their instructors can simplify the information for the people through animation, movie documentaries, printed media in local languages and make the general public aware about tackling this and other rampant disease, and helping poor to manage their skills and resources, identify and create new job opportunities and thus improve economic and social health of the country.
Q. 29.Is there a chance of re-infection with covid-19 after being previously infected with it?
A.29. Yes, there are instances of re-infection. Our immune system however has memory, it remembers the past exposure and kicks in the immune response rapidly on second exposure. If the same strain of virus enters, there's a better chance of capturing and neutralizing it and hence the person will remain asymptomatic. However, if the virus mutates then there's a problem in capturing by the antibodies which can only recognize the old antigens, and this new strain of virus can be more virulent or aggressive causing re- infection, in this scenario a person may show symptoms of disease.
Q.30. Do we know any mutations that have any effect on the structure of the protein and hence affect the vaccine development?
A.30. Yes, there are instances where viruses have not been the same across the country. It has a tendency to mutate. So many countries including India, USA and China have done a lot of DNA sequencing and found out that there are different strains of this virus that are prevalent in different regions of the country. However, during the process of vaccine design, care is taken that the portions of antigens chosen for vaccine design are conserved epitopes which have mutated the least across various strains, hence, chances of failure of such vaccines would be less. But yes, effectiveness of a vaccine depends upon the rate of mutation of the virus and which strain of virus is prevalent in a population.
Q.31. Do you think that herd immunity will help in eradication of covid-19?
A.31. Herd Immunity by getting exposed to the virus in the absence of vaccines may not be effective. The effect of such immunity will be variable across the population and may also lead to a large number of people who are sensitive to infection or do not have a very strong immunity to fully curb the virus resulting in morbidity and mortality. Also going by the past record, till date no infectious disease on Earth has ever been eradicated without a vaccine. Viruses can mutate, drug targets and protein structure will change and the drugs might fail at the end of it. But It's only the vaccines that will provide more uniform, long term effective protection against the disease. We have to develop herd immunity through vaccination and not by getting infected!
Q.32. We are approaching winters, can you comment on how are the symptoms of Covid-19 different from seasonal flu and common cold??
A.32. Covid-19 is the most dangerous in the family of Corona viruses. Unlike the seasonal flu, the number of people that can be affected by one person is far more, it's incubation time is much longer, there is more hospitalisation and more case fatality rate. Symptoms of coronavirus include flu,fever, breathlessness with wide spread symptoms in other body parts unlike flu which generally subsides within a few days of infection causing only mild cold symptoms in the majority of the people.
Q.33. What message would you like to convey to students?
A.33. Stay motivated, become a warrior and contribute in your own little ways to win against this pandemic and become part of the solution. Innovate, achieve and lead.