'To Control Omicron, Need Cohesive Data On Genomes, Clinical Signs, Geography'

To understand if India's testing capabilities are adequate, the quality of its genomic data, and what its public health response in testing should be, with the rise of Omicron, the new variant of the SARS-CoV-2 virus, we spoke to two experts.

The first, Manisha Bhinge, is the managing director for health at the Rockefeller Foundation and the managing director of the Global Networks and Partnerships with the Pandemic Prevention Institute, which was set up in 2021. She has earlier worked with Tata Trusts in India and with the Bangladesh nonprofit, BRAC. A graduate of Harvard University, she has specialisations in health economics and international development.

Taslimarif Saiyed is a neuroscientist with a doctorate from the Max Planck Institute for Brain Research in Germany, and has undertaken postdoctoral training at the University of California, San Francisco.

Edited excerpts from the interview:

Dr Bhinge, tell us about your effort to drive testing capacity, in the face of the new variant.

MB: Variants are not new. We have been through this, have had multiple variants come through over the past year. Repeated testing is a frontline defence for identifying new, emerging pathogens as well as variants of those pathogens. So I think the work that we have done over the past year--the Indian government, the private sector, research institutes, leading centres, like the one that Taslim is leading at C-CAMP and with which we partnered--has been critical for that underlying capacity around diagnostics and testing, to really be vigilant around these new and emerging variants and pathogens.

There are two points to consider. The first is the RT- PCR technology [reverse transcription polymerase chain reaction], which has been the gold standard across the world and on which we in India leaned heavily in the early part of last year to bring up capabilities manifold. I think Taslim will be better placed to give the numbers around that. Self-sufficiency around that was important for a country as big as India. We've seen the early response to South Africa [where the new Omicron variant was detected] was travel bans. And that is a standard containment issue--it's not surprising, we should have seen that coming. But what comes with it are other consequences, like import challenges, supply chain challenges.

The commercial airlines carry a lot of the reagents and the cargo that is essential for the scientific efforts and not being reliant on that is a key consideration for a country the size of India, given that we have the capability. What we found out last year through Taslim's work is that we had latent capacity to be a biotechnology hub for the world and can use this opportunity to really unlock that potential. And again, this is a critical first step to genomic sequence--if you don't have testing, you don't have a lot to sequence in order to gather genomic data. I think our genomic data has increased with the INSACOG alliance, by an order of magnitude. Could we do it better? Could we do it faster? Yes, and efforts are under way, but we have progressed by leaps and bounds. What is missing though is a clear aggregation or alignment around adjacent information.

It's not enough just to have sequencing information. You need to understand the host behaviours, you need to understand how diseases are presenting themselves within those hosts. And that is the missing element that we need to work on to have both clinical data and sequencing data, along with metadata in terms of what the geography is, what the testing technology is, to really get ahead of these variants of concern.

When you say there are gaps, do you mean in the world in general or more so in countries like India?

MB: The world in general is a good starting point. In India, because of its size, scale and inherent challenges and diversity, that issue tends to get amplified. But across the world, it's very difficult to find data in a cohesive manner -- we get piecemeal information, hence, we get a piecemeal view of the emergence and transmissibility of these pathogens.

Dr Saiyed, you are working with over 130 manufacturers now and trying to create domestic capacity. Tell us about what your effort has been? Where are we in terms of self sufficiency, and in retaining the gold standard of RT-PCR, and being ready for newer variants.

TS: Last year when the COVID-19 pandemic struck, once we realised that India is not necessarily immune to it, immediately, we realised that we didn't have enough resources to actually fight it. And one of the most important, or the most important, resources that we needed was testing, so that we could see who is infected so that they didn't infect others, and the spread cóuld be prevented. And we didn't have enough testing capability in India. We relied heavily on the inputs and the input kits from different parts of the world, but that was not enough. So we had two issues. At that time, one issue was that we didn't have access to kits, and hence limited testing, and hence, we couldn't fight the pandemic, in terms of preventing spread and taking care of people early on so that they wouldn't get into severity.

The second issue was that the tests which were available were exorbitantly expensive, like almost Rs 4500 or something. Possibly some people you know can afford, but you can imagine people who are earning Rs 250-300 a day, how could they afford it. So, India has had a challenge to build homegrown capacity. The Rockefeller Foundation supported our effort for indigenisation of diagnostics, which is more or less like a platform effort where we build in collaborations with a few academic organisations, and a very large number of companies to help them use their earlier capabilities for high quality reagent and kit manufacturing. So what we have done over a year and a half has been to take each and every company, work on each and every region and get them to a level which is satisfactory to build a kit per se. Working with 130 or 150 companies, we are actually doing almost 900,000 to a million tests per day, all RT-PCR tests that we have the capacity to manufacture now, having started from nothing.

At the same time, we know that during this time, the cost for the RT-PCR, which was around Rs 4500, is now almost Rs 250 to Rs 300 in many places. And while it is, if I may just add, a short-term response, it has prepared the nation for anything that will happen in future because the capacity has been built.

In between the test and the reagent, what is the component that you're actually able to bring down the cost of? Also, what is the most complex aspect or ingredient of these two elements, which, if you import substitute or substitute, you're able to crash the cost?

TS: Through this, while building self sufficiency, we also, more or less, built sections of self sufficiency for each and every region be it oligos [DNA or RNA strands], enzymes like transcriptase, or even the other components of the kit, which once we called the Master Mix. The kit costs, on the ground, below Rs 10--at the delivery it may become Rs 250 or Rs 300. That is absolutely unimaginable, something that would be very useful not only for India, but also if we are to now support other countries and to provide them high quality, affordable testing capability. This is where we are ready. This is where we can actually do global partnerships.

Manisha, so we are looking at a new variant now. How confident are you about the work that you've been doing in identifying, spotting and responding to this new variant and, of course, future variants as well?

MB: Juxtapose this situation with what we had seen last April, when we had a new virus [SARS-CoV-2, the Covid-19 virus] coming into the country. This is an exported, or rather, imported, variant. The kind of testing technology and the speed of deployment of that testing technology at airports, at hotspots, contact tracing, these are muscles that we have built over the past year and this technology exists. It exists at scale, it exists at price points that allow for mass deployment in a very targeted manner. And the various authorities have guidance, protocols and algorithms needed to move from testing to contact tracing, to what is the guidance, what happens when you have a positive [case] and now the sequencing protocols are in place. So given the mechanisms that we have built over the past year, and those that are coming into play right now, I think there is high confidence that we will find the variants quickly, we have the processes in place to manage it, and contain it.

The challenges remain. We do still have a vast group of people that are unvaccinated, and variants emerge because of transmission across unvaccinated people. So until we get protection across the majority of the population, the threat remains and vulnerability remains. And with a country the size of India, the population and the density of India, it's always going to be much harder to manage after the fact than contain it at the onset. So the quick answer is, I have a high degree of confidence in our mechanisms, I think we still have challenges to manage, and also confidence in the innovation and creativity of our scientists.

I don't want to pin either of you down on this but could you tell me how many variations we've already looked at? What is our speed of identifying those variations? What's the library looking like? And what does the library tell us about what lies ahead?

MB: I think the global community has been tracking the variants across the board. The very fact that we are at Omicron, granted that we skipped Nu and Xi [the greek alphabets, on which the variants are named] for no other reasons, we have done a very good job of managing and assessing the origins [of the variants]. We have variants that are under monitoring. And there are a number of those which are visible on the WHO sites, as well as with the National Center for Disease Control in India, and across our centers. We have variants of interest, which we are monitoring, and variants of concern. Delta was a variant of concern, Omicron is a variant of concern. So given the nomenclature, given that we have categories that we are concurrently tracking, there are established libraries that are publicly available. What is something to celebrate is the global coordination across scientists and across countries to really keep an eye on this particular pathogen and its variants.

TS: I think Manisha has very rightly pointed out the effort, which is global in terms of detecting these variations early, and possibly work with other scientists and public health experts to assess those variants and how they are increasing either transmission, or possibly the severity of the disease, and then work around to bring down the spread of it, and so on. I think genomic sequencing, early genomic sequencing and prospective, early genomic sequencing allows that to happen. I think, many countries, including India, need to keep building this capability and do it in multiple cities, not only metros and so on, but we'll have to do it in multiple cities. So even if it is happening in other cities, we can pick them early and see if suddenly hotspots are emerging of variants and track them and then bring in the public health policy to address that.

Scientists say they are trying to find out what really this virus can do, or what damage it can cause. As we look ahead to the next few weeks, tell us about the challenges and tasks you are seeing ahead?

MB: There is a lot of information that we still need about this variant--we have basic sequencing information. And I'll come back to an earlier point I made around having the infrastructure and the ability to get associated information about a sample. What is the clinical data? What is the host representation? What is the epidemiological data? How does one get this information in a coherent, consistent fashion across cities, across facilities so that we're not chasing the information, we have it, we can do the analysis, and have a measured and informed assessment of either the transmissibility, the immune escape, as well as the virulence of emerging variants. We have the pieces, I think the challenge and the opportunity is putting it all together in a cohesive manner across the country. So we know not only where the variants are, but how it is behaving across and moving across populations in a timely and informed manner.

TS: Absolutely, as we go further, we do know that there will be mutations that will emerge. That's how the game is played. And slowly and steadily as the mutations would happen, possibly the transmission and all will go down. But as we can't possibly lower our guard, what we need is a national and a global effort, a central effort to identify and control the variants of concerns early on. I think it will require a collective, concentrated effort for early identification and controlling of VOCs [variants of concern], which is very, very crucial. Many times, there has been a delay, and I think a collective effort, and something that has been happening would be the right way to go forward.

Let me ask you about another factor, that is speed. The United States is likely to ask for a 24 hour window for submitting your sample and getting a response. Earlier, it used to be 72 hours. Second, when you now land in many airports in India, you have to get an RT-PCR test at the airport and wait for the result, and only then can you leave. Cities like Mumbai or cities within Maharashtra are saying that you have to also go in for institutional quarantine and get tested many times. The on-site testing for international arrivals stands, as do the long waits for results. How do you see that playing out, Dr Saiyed?

TS: I think it's very, very dynamic. We all know the time taken by the virus to show symptoms, or even enough [viral] concentration that could be tested. And that's why people talk about 72 hours, because upon infection, there has to be enough load in an individual that it will be picked up. And that's what the larger game is. Now, as the RT-PCR becomes not 48 hours, not 24 hours, but with three hour or two hour turnaround times, the situation allows people to say that why don't you test it, let the results come out? In some countries, at the same time, people have been actually requested to (even in the UK) check themselves after six or seven days and upload results. Clearly shows that the system there believes that there might still be a mistake, even three hours or four hours or four days after, that you're not being picked up [even if you have the virus]. And that you may develop it later on, once you arrive. So it's all a combination of different things, but currently people are looking at best five days, you know, after the exposure, you will have enough viral load that could be picked up. And if you actually, at that point of time, are asymptomatic, or have possibly so low a viral load that it is below the threshold, that it would not affect you and your body will take care on its own. So it's a combination of technology, the viral dynamics and the human host response that matters here together.

Right. But if I submit a sample now, how long will it take for me to get a response, given the fact that I could be held up at various places, which will not allow me to either leave or enter till I have a result, which obviously should be negative before proceeding?

TS: The turnaround time has come down drastically. We used to have 48 hours--as you remember that you would come home and wait for an SMS to arrive and so on. Right now, in many technologies, normal path labs are giving [the test results] in a few hours, and specialised machines, such as Abbott and all, have been able to do it in half an hour. So that is absolutely lightning speed and that allows for immediate outcomes. Possibly institutional quarantines that could be avoided because if they're negative they will be allowed to move forward.

MB: I think this is where innovation and automation is going to be game changing, because the speed and the turnaround times have been largely because of transportation costs, labour intensive processes, discretionary processes. So as Taslim said, antigen oddities CRISPR-based technologies, decentralised sequencing, the use of SNP assays with PCR technologies, all take the analysis down to the to the frontlines, and I think the more we invest and build out that decentralised technology, the faster we are going to be in terms of getting our results. And I think that's where the world is headed.

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