̽��ֱ�� of Cambridge - Department of Biotechnology (DBT)

Delhi outbreak highlights challenge of herd immunity in the face of Delta variant

cjb250 — Thu, 14 Oct 2021 18:00:35 +0000

SARS-CoV-2 had spread widely throughout India in the first wave, with initial results from the Indian Council of Medical Research finding one in five (21%) adults and one in four (25%) 10 to 17 year old adolescents had been infected. ̽��ֱ��figures were much higher in Indian megacities: by February 2021, over a half (56%) of individuals in Delhi were thought to have been infected.

Since the first case of COVID-19 was detected in Delhi in March 2020, the city had experienced multiple outbreaks, in June, September and November 2020. After reaching a high of almost 9,000 cases daily in November 2020, new cases steadily declined, with very few new infections between December 2020 and March 2021.

̽��ֱ��situation reversed dramatically in April 2021, going from approximately 2,000 daily cases to 20,000 between 31 March and 16 April. This was accompanied by a rapid rise in hospitalisations and ICU admissions, severely stressing the healthcare system, with daily deaths spiking to levels three-fold higher than previous waves.

In research published today, an international team of scientists used genomic and epidemiological data, together with mathematical modelling, to study the outbreak. ̽��ֱ��work was led by the National Centre of Disease Control and the CSIR Institute of Genomics and Integrative Biology, India, with collaborators from the ̽��ֱ�� of Cambridge and Imperial College London, UK, and the ̽��ֱ�� of Copenhagen, Denmark.

To determine whether SARS-CoV-2 variants were responsible for the April 2021 outbreak in Delhi, the team sequenced and analysed viral samples from Delhi from the previous outbreak in November 2020 until June 2021. They found that the 2020 outbreaks in Delhi were unrelated to any variant of concern. ̽��ֱ��Alpha variant (B.1.1.7) was identified only occasionally, primarily in foreign travellers, until January 2021. ̽��ֱ��Alpha variant increased in Delhi to about 40% of cases in March 2021, before it was displaced by a rapid increase in the Delta variant (B.1.617.2) in April.

Applying mathematical modelling to the epidemiological and genomic data, the researchers found that the Delta variant was between 30-70% more transmissible than previous SARS-CoV-2 lineages in Delhi, including the Alpha variant. Importantly, the model also suggested that the Delta variant was able to infect people who had previously been infected by SARS-CoV-2 – prior infection provided only 50-90% of the protection against infection with Delta variant that it provides against previous lineages.

To look for actual evidence of reinfection to support their modelling work, the researchers examined a cohort of individuals recruited by the Council of Scientific and Industrial Research (CSIR), India. In February, 42.1% of unvaccinated subjects participating in the study had tested positive for antibodies against SARS-CoV-2. In June, the corresponding number was 88.5%, suggesting very high infection rates during the second wave. Among 91 subjects with prior infection before Delta, about one-quarter (27.5%) showed increased levels of antibodies, providing evidence of reinfection.

When the team sequenced all the samples of vaccination-breakthrough cases at a single centre over the period of the study, they found that among 24 reported cases, Delta was seven-fold more likely to lead to vaccination breakthroughs than non-Delta lineages.

Dr Anurag Agrawal from the National Centre of Disease Control and the CSIR Institute of Genomics and Integrative Biology, India, senior author and co-lead investigator, said: “This work helps understand the global outbreaks of Delta, including in highly vaccinated populations, because the Delta variant can transmit through vaccinated or previously infected people to find those who are susceptible.”

Co-author Professor Ravi Gupta from the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the ̽��ֱ�� of Cambridge, UK, said: “ ̽��ֱ��concept of herd immunity is critical in ending outbreaks, but the situation in Delhi shows that infection with previous coronavirus variants will be insufficient for reaching herd immunity against Delta. ̽��ֱ��only way of ending or preventing outbreaks of Delta is either by infection with this variant or by using vaccine boosters that raise antibody levels high enough to overcome Delta’s ability to evade neutralisation.”

Previous research led by Professor Gupta showed that the Delta variant has most likely spread through its ability to evade neutralising antibodies and its increased infectivity.

̽��ֱ��research was supported by the Indian Ministry of Health and Family Welfare, Council of Scientific and Industrial Research, and Department of Biotechnology.

Reference
Mahesh Dhar, Robin Marwal, Radhakrishnan VS, Kalaiarasan Ponnusamy, Bani Jolly, Rahul Bhoyar, et al. Genomic characterization and Epidemiology of an emerging SARS-CoV-2 variant in Delhi, India. Science; 14 Oct 2021; DOI: 10.1126/science.abj9932

̽��ֱ��severe outbreak of COVID-19 in Delhi, India, in 2021 showed not only that the Delta variant of SARS-CoV2 is extremely transmissible but that it can infect individuals previously infected by a different variant of the coronavirus, say a team of international scientists writing in Science.

̽��ֱ��concept of herd immunity is critical in ending outbreaks, but the situation in Delhi shows that infection with previous coronavirus variants will be insufficient for reaching herd immunity against Delta

Ravi Gupta

Government of India

Health care workers administering COVID-19 vaccination in New Delhi

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Cambridge and Indian partners launch collaboration to transform India’s "Green Revolution”

ag236 — Thu, 22 Feb 2018 09:58:15 +0000

̽��ֱ��adoption of modern methods and new technologies in agriculture that propelled India to self-sufficiency in grain production in the second half of the 20th century is known as the country’s “Green Revolution”. It allowed India to overcome poor agricultural productivity, especially in regions like the Punjab and Uttar Pradesh, although it relied on overuse of water, fertilisers and pesticides.

Today, climate change, continuing population growth and the rapid process of urbanisation have put added pressure on India’s ability to feed its population. TIGR2ESS – an acronym for “Transforming India’s Green Revolution by Research and Empowerment for Sustainable food Supplies” – is a £7.8 million programme funded by the UK Global Challenges Research Fund (GCRF) to develop more resilient, equal and diverse food systems in India. It aims to define the requirements for a second more sustainable Green Revolution, and to deliver this through a suite of research programmes, training workshops and educational activities

̽��ֱ��TIGR2ESS launch event took place in the context of a three-day workshop that brought together all the UK and India partners to discuss and finalise a plan for the programme’s effective implementation.

TIGR²ESS will support 14 postdoctoral researchers employed at partner research institutions and universities across India, as well as eight post-doctoral research associates from collaborating institutions in the UK

̽��ֱ��programme will create 3-year research opportunities for a total of 22 early-career researchers in the UK and India, and also promote academic exchanges at all levels in laboratories across India and the UK.

One of TIGR²ESS’ objectives is to foster mutually beneficial knowledge exchange and collaborative research through workshops in Cambridge and India. In addition, it will deliver a programme of outreach, education and entrepreneurship. In doing so, TIGR²ESS will help strengthen Indian research capacity in key areas of the food system, and will contribute to the development of smart agriculture in India.

At the heart of the TIGR2ESS proposal are a series of Flagship Projects tackling fundamental research questions, and addressing the associated social issues facing farmers in the context of increasing urbanisation and climate change.

Professor Stephen Toope, Vice-Chancellor of the ̽��ֱ�� of Cambridge, said: “TIGR²ESS will inform best practice in crop development and growth. It will allow greater genetic understanding of crop resilience to drought and disease. It will contribute to more effective use of scarce water supplies. It will build capacity and foster education.”

“It will empower women and entrepreneurs, and encourage innovation along the food supply chain. It will create opportunities for early-career researchers, and in doing so will contribute to India’s efforts to ensure it is able to meet the needs of its growing population. I am delighted that Cambridge is a part of this extraordinary initiative.”

Professor Ashutosh Sharma, Secretary of India’s Department of Science and Technology and Department of Biotechnology, added: “"India is a diverse country, and negotiating this diversity is the key to developing any interventions. ̽��ֱ��TIGR²ESS programme takes into account this diversity, and that will define its success. We need to take a holistic view at the nexus between agriculture, environment, water, climate, energy and health. Assessing the impact of technology applications or interventions in a larger setting is very important."

Presenting TIGR²ESS, the ̽��ֱ�� of Cambridge’s Professor Howard Griffiths, the programme’s principal investigator, said: “This unprecedented programme of joint activities will enable capacity building both in the UK and India, and shape the policy needed to define a second Green Revolution for India.”

“TIGR²ESS will address the challenges identified by our colleagues in India, and translate research outcomes to build agriculture systems that support sustainable livelihoods, enhancing the well-being and health of rural communities with a particular focus on improving the opportunities for equality, female empowerment and youth employment, and market-led entrepreneurial opportunities.”

Daniel Shah, Director, Research Councils UK (RCUK) India, said “TIGR²ESS is a great example of the UK and the Indian research teams partnering to address issues around food security and agriculture systems. This initiative also aligns with Indian Prime Minister Narendra Modi’s vision to double farmers’ income by 2020."

Researchers met in New Delhi today to formalise the launch of a programme that aims to jointly address some of India’s most pressing food security challenges.

This unprecedented programme of joint activities will enable capacity building both in the UK and India, and shape the policy needed to define a second Green Revolution for India.

Prof Howard Griffiths

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A whole host of options

cjb250 — Fri, 09 Oct 2015 08:30:04 +0000

Professor Lalita Ramakrishnan is, it’s fair to say, a world authority on the biology of TB. She studies the disease – one which most people will know of as a disease of the lungs – using what at first sight seems an unusual model: the zebrafish.

“What most people don’t realise is that about 40% of human TB occurs outside the lungs,” explains Ramakrishnan. “It can infect the brain, bone, heart, reproductive organs, skin, even the ear. In fact, TB infection is a basic biology question, and this is the same in zebrafish as it is in humans.”

TB is caused by Mycobacterium tuberculosis, which is generally transmitted from person to person through the air. It has been around since at least the Neolithic period, but its prevalence in 19th-century literature led it to be considered something of a ‘romantic’ disease. ̽��ֱ��truth is a long way from this portrayal. ̽��ֱ��disease can cause breathlessness, wasting and eventual death. And while treatments do exist, the drug regimen is one of the longest for any curable disease: a patient will typically need to take medication for six months.

Ramakrishnan is involved in a new trial due to start soon that might allow doctors to reduce the length of this treatment. She is cautiously optimistic that it can be reduced to four months; if successful, however, it may eventually lead to treatments more on a par with standard antibiotic treatments of a couple of weeks.

̽��ֱ��trial builds on work in zebrafish carried out by Ramakrishnan and colleagues at the ̽��ֱ�� of Washington, Seattle, before she moved to the Department of Medicine in Cambridge in September 2014. These small fish, which grow to the length of a little finger, helped her and collaborator Professor Paul Edelstein from the ̽��ֱ�� of Pennsylvania (currently on sabbatical in Cambridge) to make an important discovery that could explain why it takes a six-month course of antibiotics to rid the body of the disease (rather than seven to ten days that most infections take) and yet in the lab can easily be killed.

Within our bodies, we have a host of specialist immune cells that fight infection. One of these is the macrophage (Greek for ‘big eater’). This cell engulfs the TB bacterium and tries to break it down. This, together with powerful antibiotics, should make eliminating TB from the body a cinch. Ramakrishnan’s breakthrough was to show why this wasn’t the case: once inside the macrophages, TB switches on pumps, known as ‘efflux pumps’. Anything that we throw at it, it just pumps back out again.

“Once we’d identified the pumps, we started to look for drugs that are out there in the market and tested a few of them,” she explains. “We found that verapamil, an old drug, made the bacteria susceptible to two of the antibiotics we use to fight TB.”

̽��ֱ��trial of verapamil, which is commonly used to treat high blood pressure, is due to start soon at the National Institute for Research in Tuberculosis (NIRT) in Chennai, India.

Ramakrishnan is one of a number of brilliant minds working as part of a collaboration between the NIRT and the ̽��ֱ�� of Cambridge to apply the very latest in scientific thinking and technology to the problem of TB.

An expansion of this collaboration has now become possible through the recent award of a £2 million joint grant from the UK Medical Research Council (MRC) and the Department of Biotechnology (DBT) in India, which will enable the exchange of British and Indian researchers. For Professor Sharon Peacock, the UK lead on the proposal, this means an opportunity to train a new cohort of early-career researchers in an environment where they will have access to outstanding scientific facilities and training, at the same time as becoming familiar with the clinical face and consequences of TB for people in India.

“India is home to a large pool of talented young people with the potential to help fight back against this deadly disease,” says Peacock. “Developing a close collaboration between Cambridge and Chennai involving two-way traffic of scientists and ideas is an exciting opportunity to start to tap into this.”

There are few places more suitable for the proposed work than India. According to the World Health Organization, India is home to almost one in four of all worldwide cases of TB, with over two million newly diagnosed cases in 2014.

Not only that, but it is one of the countries that has seen an increase in the number of cases of drug resistance to TB – including ‘multi-drug’-resistant, and even more worrying, ‘extremely’ drug-resistant strains of TB against which none of our first- and second-line drug treatments work. In part, this increase reflects improved access to diagnostic services, but the situation highlights why new approaches to tackling the disease are urgently needed, says Professor Soumya Swaminathan, Director of NIRT and the India lead in the collaboration.

“So far, the treatment of TB has focused almost exclusively on using drugs to try to kill the bacteria directly, but there’s increasing evidence that there may be benefits to targeting the host. TB is very clever and it manipulates the host immune system to its own advantage, so if we could use drugs to help the immune system, then we may be able to make it more effective.”

This is the approach that Professors Ken Smith and Andres Floto from the Department of Medicine at Cambridge, also part of the collaboration, are taking. Smith is looking at the role that specialist immune cells known as T cells play in the persistence of multi-drug-resistant strains of TB. His group has evidence that around two thirds of the population have T cells which have a tendency to become ‘exhausted’ when activated.

“It might be that exhausted T cells can’t fight multi-drug-resistant TB effectively, in which case we need to find a way to overcome this exhaustion and spur the T cells on to rid the body of the disease,” says Smith.

For Floto, the key may lie in the role played by the macrophages and their otherwise voracious appetites. As their Greek name suggests, macrophages ‘eat’ unwanted material (surprisingly similar in action to Pac-Man), effectively chewing it up, breaking it down and spitting it out again.

This process, known as autophagy (‘self-eating’), is a repair mechanism for clearing damaged bits of cells and recycling them for future use, but also works as a defence mechanism against some invading bacteria. So why, when it engulfs TB, does the bacterium manage to avoid being digested?

“Autophagy is partially inhibited by TB itself, but we found that if you overstimulate this mechanism – like flooring the accelerator of a car – you can overcome the bacteria,” explains Floto. “Clearly this will be applicable to normal TB, but we already have drugs that are effective against this. We want to know if this would work against multi-drug-resistant strains.”

Floto and colleagues already have a list of potential drugs that can stimulate autophagy, drugs that have already been licensed and are in use to treat other conditions, such as carbamazepine, which is used to treat epileptic seizures. These drugs are safe to use: the question is, will they work against TB?

“We’ve already shown that carbamazepine stimulates autophagy in cells to kill TB – even multi-drug-resistant TB. We now want to refine it and test it in mice and in fish, alongside a shortlist of around 30 other potential drugs,” he adds.

TB evolves through ‘polymorphisms’ – spontaneous changes in the letters of its DNA to create variants. Because the drug regimen to fight the disease lasts so long, many patients do not take the full course of their medicines. If the TB is allowed to relapse, it can evolve drug resistance.

These patterns of resistance can be detected using genome sequencing – reading the DNA of the bacteria. Peacock believes this technique may be able to help doctors more easily diagnose drug resistance in patients.

“TB is very slow to grow in the laboratory, which means that testing an organism to confirm which antibiotics it is susceptible or resistant to can take several weeks, especially in the case of more resistant strains,” she says. “There is increasing evidence that antibiotic resistance can be predicted from the genome sequence of the organism, and we want to establish and evaluate this technology in India, where it is needed.”

This sequencing data could also then help inform the search for new drugs, explains Professor Sir Tom Blundell from the Department of Biochemistry. He is no stranger to TB: his grandfather died from the disease shortly after the war – though, as Blundell points out, this strain of TB is far less common now, as the organism has evolved in different communities throughout the world.

“We can take the polymorphisms and ask questions such as ‘What does this mean for the use of current drugs?’” says Blundell. “ ̽��ֱ��nature of the polymorphisms in the TB genome sequence of an infected individual can give us information on where that person was infected and what are the drugs that might be most effective. We can then begin to look at new targets for particular polymorphisms.”

Blundell plans to take the information gathered through the Chennai partnership and feed it into his drug discovery work. He takes a structural approach to solving the problem: look at the shape of the polymorphism and its protein products and try to find small molecules that can attach to and manipulate them. In essence, it’s akin to picking a lock by analysing the shape of its mechanism and trying to identify a key that could turn it, thus opening the door.

Yet even if the Chennai venture is successful, and research from the partnership leads to a revolution in how we understand and treat TB, the team recognise that this is unlikely to be enough to eradicate the disease for good.

“TB is as much a public health issue as one of infectious diseases,” says Ramakrishnan, pointing to Europe, where even before the introduction of antibiotics, the disease was already on the decline. “We need better nutrition, better air, less smoking, reductions in diabetes.”

Swaminathan agrees. “TB is very much associated with poverty and all the risk factors that go with it,” she says. “When people are living in very crowded conditions, when they’re malnourished, TB is going to continue to spread. This is happening in the slums of Mumbai, for example, where we’re seeing a mini-epidemic of multi-drug-resistant TB. Unless we see a rapid improvement in the living standards of people we’re not going to see a very major effect. There’s only so much we can do biomedically.”

Inset image: Macrophage engulfing Tuberculosis pathogen (ZEISS Microscopy).

Almost one in four of the world’s cases of tuberculosis (TB) are in India and the disease is constantly adapting itself to outwit our medicines. Could the answer lie in targeting not the bacteria but its host, the patient?

What most people don’t realise is that about 40% of human TB occurs outside the lungs ... It can infect the brain, bone, heart, reproductive organs, skin, even the ear

Lalita Ramakrishnan

Calcutta Rescue

Picture to educate people in villages that have no medical service about the spread of TB

̽��ֱ��Next Generation

If there’s one thing on the side of science v. TB, it’s the wealth of talent available in India.

Professor Sir Tom Blundell is quick to praise the Indian postdocs that come to work in his lab. “They tend to be naturally very inquisitive and interactive, with very enquiring minds,” he says.

This is something with which Professor Ashok Venkitaraman, Director of the Medical Research Council (MRC) Cancer Unit at Cambridge, wholeheartedly agrees. He has helped establish the Center for Chemical Biology and Therapeutics (CCBT) in Bangalore in part, he says, because “the number of really bright, well-trained young scientists in India is huge. ̽��ֱ��level of enthusiasm and commitment is something I find quite exceptional.”

̽��ֱ��CCBT is an inter-institutional centre that links the Institute for Stem Cell Biology and Regenerative Medicine and the National Center for Biological Sciences, both of which are world-class Indian research institutes studying fundamental biology. However, argues Venkitaraman, India needs the capacity to translate fundamental research to clinical application.

It is to help bridge this gap that the CCBT was established, with funding from the Department of Biotechnology (DBT) in India, recently supplemented by a £2 million joint award from the UK MRC and the DBT. ̽��ֱ��idea is to find innovative ways to discover ‘next-generation’ medicines against human diseases, by coupling biological research that reveals novel drug targets with approaches in chemistry and structural biology that create potential drug candidates.

Although Venkitaraman’s interest is in cancer, he predicts the work of the CCBT will be “disease agnostic”, because similar types of novel drug targets have been implicated in infectious diseases, cancer and even developmental defects.

“We desperately need to develop new medicines not just for currently problematic diseases like cancer and TB, but also for the new challenges that are being thrown at us all the time – antibiotic resistance, new infections, metabolic syndromes and diseases of ageing, for example. Nowhere is this need more critical than in emerging nations like India where the spectrum of disease is distinct from countries like the UK.”

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