Plasma use likely behind coronavirus mutation


Informist, Wednesday, Apr 28, 2021

By Rajat Mishra and Pragya Srivastava

NEW DELHI - The deadly second wave of the COVID-19 pandemic has wreaked havoc in India and brought the healthcare system to its knees, forcing people to fend for themselves in getting hospital beds, oxygen, life-saving drugs, and blood plasma.

While social media platforms are flooded with requests for blood plasma, with the government also urging COVID-19 recovered patients to donate, Raman R. Gangakhedkar, a renowned epidemiologist, is of the opinion that the indiscriminate use of plasma therapy could be one of the reasons behind the mutation of the coronavirus.

He Says The Use Of Convalescent Plasma Exposes The Virus To Multiple Antibodies And Challenges It With Multiple Targets. "And The Virus Will Make An Attempt To Overcome In Each Cycle Of Replication."

"The ability of COVID-19 virus to mutate is low but at the same time there are no antiviral drugs, and yet the virus is mutating," Gangakhedkar, former deputy director of the Indian Council for Medical Research, tells Informist in an interview.

"Part of the reason why this is happening is because of the indiscriminate use of convalescent plasma."

Gangakhedkar, an expert in epidemiology and communicable diseases and a Padma Shri awardee, was the face of the Indian Council for Medical Research at government briefings during the first wave of the pandemic before he retired in June.

He says the use of convalescent plasma exposes the virus to multiple antibodies and challenges it with multiple targets. "And the virus will make an attempt to overcome in each cycle of replication."

Placid and Platina trials have provided evidence for limited use of plasma therapy but guidelines to this effect are not being rationally used, he says.

To curb the spread of the pandemic, Gangakhedkar suggests rapid vaccination in areas where the wave is less severe.

"Because then you would also protect them if the outbreak turns severe in that area, maybe after one-and-a-half months," he says.

Gangakhedkar blames re-opening of schools, elections, religious gatherings, and lowering of guard by people for the current surge.

Following are edited excerpts of the interview with Gangakhedkar:

Q. Do you think we have squandered away the gains we had made in containing the spread of the virus?

A. Typically, when you have a second wave, it will have more impact on healthcare infrastructure than the earlier one. Until we eliminate this infection or protect the entire population, the vulnerability will always be there. You cannot say whether we have squandered, which means we did it ourselves. When you handle a pandemic that tends to come, let's say once in 100 years, of a new organism, we are constantly learning. If you look at Israel, far-east countries like South Korea, Japan and China for that matter, how did they manage to pull off a better show? In order to eliminate any disease one cannot lower the guard. When there was a decline (in cases), a stronger policy to detect, trace contacts and isolate would have had made a huge difference as the cases were low. For China, it was occurring in restricted area, and they put in rigorous restrictions across the country. They tested entire city or town, even if they detected a single case. It is easier to blame without understanding the complexities.

Now would I say we could have been better prepared in the hindsight? Everybody can criticise in hindsight. But the rate of rise in second wave has been far higher than what one could have anticipated. It poses different kinds of challenges. Though we ramped up industrial capacity to provide various critical medical supplies, it was also a complex issue of production and inventory control. There was low demand in the intervening time of 2-3 months and the outbreak was occurring elsewhere--the US had access to Remdesivir. Our market had shrunk due to the decline in cases. For the government, the challenge was more on whether they should continue to sustain the COVID Care Centres, a temporary hospital set up, when there were no patients to admit. I feel that currently we are fighting a major war against this virus. Instead of focusing on what went wrong, we should focus on how one can mitigate the impact and make efforts to win this war. We need to accept that we are in a challenging situation, and need to make comprehensive and coordinated efforts to control this infection.

Q. Do you think that the government prematurely declared that India had won the fight against COVID? And when we are dealing with a near collapse of the healthcare infrastructure, what do you think can be done?

A. When the infection started getting established in India, the entire world was worried, given the fact that we have large population, high population density in urban areas including slums, a heterogeneous healthcare infrastructure, and low science literacy. They thought that our magnitude of infection would be very high. We used lockdown effectively when we ramped up our capacity of healthcare infrastructure adequately and then used this time to educate people on prevention. The lockdown enabled us to not only delay the onset of first wave but achieve a faster decline with a manageable case load. The world started praising our effective implementation of strategies. The narrative affected all of us alike, and led to complacency.

Early diagnosis of COVID is critical to prevent secondary transmissions among family members and close contacts. About four-fifths of the infections are transmitted in two days before and two days later after development of symptoms. It is prudent to test even if one may be having any COVID related symptoms at the earliest during this wave, rather postponing the test. Until the time the test results come, they should isolate themselves. We need to decongest the load on hospital infrastructure. People should not panic. Not every person actually requires hospital admission. But the scare is so high that everybody is trying to occupy an oxygen bed, ventilator bed, and those who go for home isolation, buy oxygen cylinders. It is also important that we ramp up capacity for COVID care centres in population dense areas where people cannot follow safe distancing due to small houses. In home isolation, people may be staying in very small houses where they cannot maintain distance and perhaps will run a risk of transmitting it to their own family members. One must remember houses are the places where ventilation tends to be poor and that the risk of transmission increases immensely. So, one thing that we may have to do is keep them isolated in institutionalised facilities and manage the infection a little more systematically based on protocol-driven approaches. 

One other issue that is emerging is that I have heard in many cases, people are receiving oxygen at home, which is very difficult to understand. Also, there is a perception that all patients should be given Remdesivir, which is absolutely ridiculous. It is only in a very small proportion of patients for which Remdesivir tends to work. This drug has been approved under emergency-use authorisation. Unfortunately it is being used irrationally. The doctors prescribe it and patients demand it for all patients as if it is a magical remedy. So we have to strictly adhere to national guidelines and educate the community.

We also will have to reduce the pressure on the healthcare system. If there are 10,000 new cases every day, let's say in Mumbai or Pune, the healthcare staff, which is already meagre and low, is also expected to trace contacts. Basically they are expected to do contact tracing for 20 to 30 persons for each index case. This becomes a huge number for any city to actually trace out. You can do this just by involving the community when it comes to contact tracing. Involving community, community-based organisations, and civil society is critical to reduces the workload of healthcare workers.

I believe by following rational approaches in treatment, for admissions, and even the medical supplies, you would still meet the demand. You may have to open up the temporary hospitals, the way we are doing this in Delhi.

Another thing is wherever the outbreak is less severe, you have to use this as an opportunity to vaccinate people above the age of 45 years rapidly. Most often people continue to be complacent until the time COVID starts affecting their own cities or states. Because then you would also protect them if the outbreak turns severe in that area, maybe after one-and-half months. You then have reduced mortality per se. This does not mean that we should not provide vaccines where outbreak is severe. We will need innovative approaches in vaccination drive against this.

Q. One of the biggest criticisms the government is facing is it went on to export vaccines to other countries, under vaccine diplomacy. Do you think it could have been avoided and should be avoided in future?

A. These are the first generation vaccines and what it essentially means is that if one receives the vaccine, the person may not develop severe COVID disease or die. Its protection against death is almost 100%. The first two vaccines produced by Pfizer and Moderna had published their Phase III trial results before they were accorded Emergency Use Authorisation by the US Food and Drug Administration. However, our vaccines that we used had launched Phase III trial in December 2020. The lack of information about their efficacy and side effects led to vaccine hesitancy. It was so high that it delayed the opening of vaccines for other groups that required it the most. Despite the fact that we are the largest manufacturers, we could not provide the dosages that we intended to provide in first two phases of vaccine rollout. Another issue was the shelf life of vaccines. If you recall, in the beginning, when the government thought of purchasing the vaccines, they were to expire by the month of April. So if they were going to expire, would you let them expire in India? Or instead fulfil whatever commitments you had with the rest of the world, whether it was towards the World Health Organization’s COVAX programme or with other countries. It was an attempt, to my mind, for rationalised utilisation of vaccines. However, I don't see that happening now.

With higher vaccine hesitancy, you will always have a problem of inventory control. Lower-than-expected vaccine turnout will lead to vaccine mismatch, which makes it far more difficult for the government to maintain inventories.

Q. Amid a marked rise in COVID-19 cases in India, many states have imposed partial lockdowns, do you think this would be a useful strategy in containing the spread of the virus?

A. We went for a national lockdown very quickly in response to the threat of an imported infection. Now when we are in the second wave, we know the seeds of infections are there in almost every state; in fact, in every district. So a nationwide lockdown is not going to serve any purpose; it will have far more severe collateral damage. Now if I want to stop infections when I know hospitals are challenged in the worst possible way, the only way you can try to contain this is by balancing health and economic outcomes. You should go for micro containment strategies where the virus is active. Establish micro-containment zones as a measure of calibrated lockdown, in a particular area, a residential complex, or a particular flat. We can have lockdown in residential areas but keep the industrial areas open.

My biggest worry is that if this second wave strikes badly, then we may not be able to avoid the impact on consumption and industries. In response industries may shift towards semi-automatic or automated operation to minimise the need of manpower. This may impact employment prospects.

We also need to develop guidelines on how to apply lockdown or lift it in a calibrated manner for the second wave.

Q. Double mutant variant of the coronavirus has been found in India. In this cases, when do you see the current rise in cases peaking out?

A. There are multiple factors that can impact the duration. Opening of schools, issues related to elections, festivals, religious gatherings and weddings, coupled with complacency, lifting the lockdown, all came together to fuel this surge. If a larger portion of population adopts COVID appropriate behaviour, restricts their mobility and get vaccinated, that would make a huge difference. It is a reflection of both, the policies that the state adopts to fight this infection in terms of non-pharmacological intervention and at the same time COVID appropriate behaviour by the community. Hence, it is very difficult to comment when this would end. Generally second wave subsides--if you see the global pattern--in three to four months of its onset, as a worse case scenario. We can still bend it, if we fight together.

Q. Some experts have argued that India has lagged behind in genome sequencing of the novel coronavirus which increases the risk of development of new strains of the virus. Do you think this is the case?

A.  I would not easily believe what we are talking about unless there is evidence to that effect. Nobody has given any well documented evidence that the current RT-PCR test comes negative among people infected by a variant. Neither do we have any robust evidences to suggest that we can attribute the rapid spread of infection to variants. If my treatment seeking behaviour is poor, if I don’t test in time, stay in the household and spread it to my own family members in 2-3 days, we can’t say it happened because of a variant. Looking at what has been reported in the West about three variant which tend to spread faster, the UK variant has 30% more mortality rate. We need to have robust evidence to support both increase in transmission efficiency of the virus and virulence among Indian variants. When we say a variant, then this is normal among RNA viruses. Viruses or any microbes and human beings have been in constant battle for centuries. The viruses also know if they have to survive they have to bypass your immune system, any drug or immune pressure that it faces. Virus also knows that if it kills an individual, it also means a death sentence for the virus. So it would like to transmit quickly and ensure that the host does not succumb to that particular infection.

Mutations are very common, but would I say that these mutations have some element of surprise? Yes. The reason is that this virus tends to mutate less commonly or less often compared to other viruses like human immunodeficiency virus and influenza. The ability of COVID-19 virus to mutate is low but at the same time there are no antiviral drugs, and yet the virus is mutating. Part of the reason why this is happening is because of the indiscriminate use of convalescent plasma. This virus survives only for 15 days in our body. And there are some people in whom it will survive longer as they are immunodeficient people. But when I use convalescent plasma, I will expose that virus to multiple neutralising antibodies and add to their spectrum other than what the host has produced. You challenge the virus with multiple targets. And the virus will make an attempt to overcome in each cycle of replication. The more the number of people infected the more is the accumulation of mutations. Hence, it is critical we follow COVID appropriate behaviour to control the infection.

Q. Would you then suggest against the use of plasma therapy?

A. Yes, it should be avoided as much as possible. Placid and Platina trial conducted in India have provided a robust evidence. One may provide plasma only in the first 2-3 days of infection. This is something we have been saying even in the guidelines. But the guidelines are not being rationally used.

Due to non-availability of an effective therapeutic option, plasma is offered in desperation. If we are able to develop a drug which is really effective, together with the vaccine and the COVID-19 appropriate behaviour, we will be able to eliminate this infection rapidly. Let us hope those days are not far.

Q. What is the ideal level of population that India should vaccinate to ensure that we don’t witness a third wave?

A. I will address two issues here. First, these vaccines may not guard us from acquisition of infection and only reduce the risk of harm a virus can do. If I am vaccinated, and I go around without a mask and meet someone COVID-19 infected, I will still get infected. So vaccines will have an indirect impact rather than giving 100% protection against acquiring infection. Neither natural COVID infection protects us as the antibody titres wane over 4-6 months.

Second issue is the level of herd immunity. The level of herd immunity that we estimate is through standard formulas based on one function of protection due to the disease-specific antibody through natural infection—which wanes--and due to vaccines. There are different estimations done by different countries based on the varying assumptions. They range between 58% to 78%. But now since variants have been generated, the vaccine efficacy would get reduced. So achieving a protective level of herd immunity is likely to be a constantly moving target. Now that there are variants that reduce the protective efficacy of vaccines, we require higher levels of vaccine-induced protection and at a rapid pace. This will reduce the risk emergence of a third wave. End

Edited by Maheswaran Parameswaran

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