Covid conundrum: The way forward

Dr.M.D. NairThursday, November 24, 2022, 08:00 Hrs  [IST]

The Oxford Dictionary defines ‘Conundrum’ as ‘Confusing problem or question that is very difficult to solve’. That is precisely the current situation with the Covid 19 pandemic, which is still ravaging the world.

The current Covid pandemic is in its third year. During this period the infection has led to mortality in unprecedented numbers, caused high levels of morbidity, resulted in grave economic and social disruptions and a confused public not knowing ‘what next’. In the pandemic over? If it has, what were the causative factors? What are the lessons we have learnt from the pandemic? What are the chances of new pandemics in coming years or periodically and if so, are there ways of predicting them?  Are the vaccines in use a major factor in reducing incidence? Are the several new variants reported likely to create new waves of infection? Like in the case of many epidemics are we prepared to face another pandemic, should it happen in future days? Has immunity played a part?

Did the infection   result from human errors due to negligence or was it an accident in the Wuhan Laboratories in China or was any animal vector responsible. The most important question for which there is no clear answer is whether we are prepared to face another pandemic in the future?

In December 2019 a new respiratory Corona virus later designated as Covid 19 appeared in Wuhan province of China. It spread across countries to Europe, Middle East and even North and South America. Because it was a novel respiratory virus, no one anywhere had immunity to the virus and by March 2020, the virus had infected half a million people in different parts of the world which resulted in over 300,000 deaths.

The WHO declared it as a global pandemic since it already had crossed the standards set for an epidemic. The infection did not limit itself to any geographical region and was universal in its spread. Its aetiology remained (and still remains) speculative. Even the research lab in Wuhan was implicated, so too transmission through infected vectors such as bats. Human to human transmission was not established but it was conjectured as possible or even most probable. There was no universal approach to management and control by WHO or any other international body.

However, considering that in all infectious diseases, public health measures play an important part it was strongly recommended to reduce human contacts, ensure safe hygienic measures such as washing hands, wearing masks, use of sanitizers etc. Some countries or some regions within countries resorted to lock down of all activities, public gatherings were banned, educational and religious institutions, tourist spots and resorts etc were closed and both domestic and international travel was subjected to several restrictions. Healthcare workers were provided with protection gears and hospitals set up special Covid wards.

Repurposing existing drugs
The first attempts of getting a therapeutic agent as a curative for the Covid infected population was to try out whether any of the existing drugs used for another disease condition can be effective against this novel virus. This approach at finding new drugs is known as repurposing or repositioning an existing drug.

Drug discovery process
It can take five to 10 years and an investment of around $ three billion to develop a single drug and Covid infections which had already become a pandemic could not afford such high costs and long gestation periods, in addition to working out logistics of distribution. It was an emergency situation and required timely action.

The repurposing route was attempted by many companies including the large research based MNCs, initially trying out antipyretics, anti virals, anti -parasitics, antibiotics, anti-inflammatory drugs, steroids etc.  Paracetamol, Hydroxy chloroquine, Acyclovir, Azithromycin, Remdesivir, Plaxovid, Ritinovir, Molnupiravir, Baricitinab, Ivermectin etc were some of the first molecules to be tried out.

None of these had formal new drug approval or an Investigational new drug approval from the regulators for Covid and they were allowed to be tried as an emergency medication, a system not part of any drug approval process in any country till now. The rationale for the selection of these drugs was perhaps because most of them were developed as anti-viral drugs based on earlier trials.

They were   developed as antI retrovirals or protease inhibitors for the treatment of HIV/AIDS and some other viral diseases. Use as a drug for which the drug has not been approved also would be violative of drug rules since this approach will fall under “Off Label Drug Use”, which is not permitted under drug regulations. While repurposing was being tried out for emergency use many other drugs are even now being clinically tested for their efficacy.

Vaccine development
The repurposing strategy did not yield any positive outcomes at least as judged by clinical follow up of symptoms and hence as a treatment modality it was more or less abandoned. In the absence of approved new drugs or repurposed drugs effective against Covid infection, a flurry of activities for the development of vaccines were initiated in many countries.

Over a hundred vaccine candidates are in trial for emergency use. The types of vaccines developed belonged to the usual types including live attenuated, inactivated mRNA, and viral vector vaccines. Only two vaccines are fully approved for manufacture and use in India. Another 11 vaccines are allowed use as emergency vaccines and a few more are under trial. The first nasally delivered vaccine has been approved by the Indian regulatory body.  Licenced in vaccines from Russia, China and Europe are among those approved under the new emergency use provision under the Drugs and Cosmetic Act (India).

Facing future pandemics
Global pandemics such as the Spanish Flu, Cholera Epidemics, Bubonic plague, several Asian Flus all resulted in high mortality and had multiple waves of infections lasting   for two to three years.  In the absence of any drugs or vaccines, in those cases, none of the infected were treated. The diseases   disappeared on their own; the possible explanation being that   the wide transmission across large populations developed herd immunity and weakened the virility of the viruses concerned.

India has so far been subjected to only one major pandemic, the Covid virus infections, even though a number of other viral infections including human and animal flu, HIV/AIDS, respiratory viral diseases such as SARS, Ebola, MERS, Dengue, Leptospirosis etc had epidemic status in different regions in the country.

So far, all pandemics have been of viral origin; however, even emergence of bacterial pandemics cannot be ruled out. For example, antibiotic resistant micro-organisms such as those resistant to anti TB drugs, Vancomycin, Methicillin etc can reach pandemic levels. Neither vaccines nor drugs are available for these resistant organisms.

The need is to discover and develop new antiviral and antibacterial drugs through conventional methods of drug discovery based on structure activity relationships, rational drug design as well as newer methods such as Crispr technology, gene editing, gene therapy, immune therapy, tools of synthetic and systems biology etc.

In other words, R&D based pharmaceutical companies need to add to their research portfolio anti-viral and anti-bacterial development programmes just like their involvement in many non-communicable, chronic ailments such as cardiovascular diseases, central nervous system disorders, diabetes, cancer, metabolic diseases etc.

As of now, immunology research and development of anti-viral drugs are not priority areas for research in large multi -national corporations primarily for commercial reasons. The pandemic has shown us that Covid made no distinction between the rich and the poor or the developing or developed countries.  

TB is a good example for not undertaking research in neglected diseases. The last antibiotic marketed was the anti-TB drug, Rifampicin in early 40s and since then there have been very little research for discovery of drugs for communicable diseases. Drug resistant TB poses major problem and fatality is on the rise.

Whatever drugs were introduced were all derivatives of already marketed anti-infectives. In view of the fact that therapeutic approach has largely failed in the case of Covid infections, the other options are to follow the successful models adopted by some countries for the control of Covid infection during the current pandemic.

One of the important contributions that WHO made after it set up a science department with Dr. Sowmya Swaminathan as the Chief Scientist was to prepare   standard guidelines for clinical management, post covid infection which can be used universally.

According to the WHO guidelines, every time a clinical trial reported results, the results will be updated so that the public would know which drugs would be effective. Methods of facing future infections include strict adherence to public health measures like physical man to man contacts, use of masks as a barrier to transmission, and treatment of symptoms with known drugs.

Even though many new variants have been appearing including delta variants, omicron etc, partly due to vaccinations, they present relatively mild symptoms which can be handled through palliative treatment and the prognosis has so far been good. Nevertheless, one cannot rule out newer infections which are more virile causing serious damage to the various organs and tissues of the body in the short or long term.

The events of the last three years of the pandemic have taught us lessons regarding the possible transmission routes of the virus, vaccine development technologies, control and management of disease symptoms and reduction in morbidity and mortality.

Minimising physical and social contacts, hand washing, maintaining proper hygiene and isolation from infected individuals have to be built in as life style practices. Hopefully in the future, complete lockdown of all activities may not become necessary and even if a fresh wave of infection surfaces in any part of the world, it can be managed using known and established   precautions. In the meanwhile, creation of adequate awareness among the population should be of highest priority.

(The author is a senior research scientist and industry expert)