Modelling the Dynamics of SARS-CoV-2 in All of Its Twists and Turns

Modelling the Dynamics of SARS-CoV-2 in All of Its Twists and Turns

Prof Melissa Penny, Dr Andrew Shattock (Swiss Tropical and Public Health Institute, University of Basel) and colleagues have contributed to the understanding of SARS-CoV-2 dynamics and public health interventions for the pandemic. Their research has been relevant for the Swiss government and policy makers in other countries.

With a background in applied mathematics and public health, Prof Melissa Penny has long experience in modelling infectious diseases. At the Swiss Tropical and Public Health Institute (Swiss TPH), where she’s head of the Disease Modelling unit, a group of 22 researchers, she has been focusing on malaria for many years – developing analyses and different mathematical models to support product development and to assess vaccines and drugs for malaria.

A pandemic pivot

When SARS-CoV-2 emerged at the beginning of 2020, like other modelling scientists Melissa Penny and part of her team shifted their attention to COVID-19. She formed an especially close alliance with her colleague Dr Andrew Shattock from her unit at Swiss TPH. Dr Shattock, who has worked with more than 20 national governments on the control of HIV/AIDS, spent the early months of the pandemic collaborating with the European Centre for Disease Prevention and Control (ECDC) in Sweden.

Melissa Penny, on her part, became involved in the early stages of the Swiss National COVID-19 Science Taskforce, as a member of the data & modelling group. "Our first modelling steps were aimed at understanding the biology of the virus", says Penny, "but soon we turned to the dynamics of the disease itself, with data from the lab and from epidemiological studies."

In late 2020 and early 2021, one key scientific question the Swiss government turned to was the impact that vaccination against COVID-19 would have on the disease and hospitalisation burden of the pandemic, and how vaccination would possibly alter decisions on other, non-pharmaceutical interventions (NPIs) such as social distancing or the wearing of protective masks. In early 2021 Prof Penny conducted a study on this question* in close collaboration with Dr Shattock. They developed an individual-based transmission model of SARS-CoV-2 dynamics, comparing the impact of various vaccination and NPI strategies on the epidemic in Switzerland. "It was a key period in Switzerland ", Shattock says, "there was pressure to relax NPIs as vaccinations were only beginning to be rolled out." "Our findings stressed the importance of rapid vaccination scale up alongside a gradual relaxation of NPIs" says Penny. Their conclusion also confirmed that emerging viral variants of SARS-CoV-2 would have to be closely watched and responded to if public health officials wanted to keep control of the Swiss epidemic. The modelling was hence included in Cantonal documents as well as Taskforce documents.

New variants and the next twist

As so often happens in research, where answering one question leads to a brand new one, Penny and Shattock modelled the risk of new variants in a following study.* "The Delta variant was already present at that point", Penny recalls, "with Omicron increasing at the end of 2021." Engaging with the scientific community, the Swiss TPH team estimated the range of risks posed by Omicron or possible new variants, "depending on any change to disease severity with Omicron or new variants, or due to the variant’s ability to escape a person’s immune system, or if new variants have increased ability to transmit compared to Delta."  In their paper* they concluded that "increasing vaccination is projected to have the biggest public health benefit for mitigating highly infectious, severe variants to which the immune system is able to respond." However, they also emphasized that variants not controlled by any previously gained immunity, even less severe ones, would require alternative measures for control.

This graphical summary of the research paper* Le Rutte et al. 2022 shows the interplay between the potential infectivity, immune evasion and severity of future SARS-CoV-2 variants of concern (VOC) on its chances of becoming the next dominant variant, its associated public health burden, and the potential impact of interventions. Credit: the Swiss TPH COVID-19 modelling team of the group of Prof Melissa Penny.

 

A turn yet again

Meanwhile, in September 2021, the dynamics of COVID-19 had changed yet again, and the question public health officials raised was: Which vaccination strategies should we recommend to people, with immunity waning and possibly more transmissible variants of concern emerging? Or, to put it more simply: "How often do we vaccinate? Is it once a year? Twice a year? Is it just the high-risk population – or everyone?" Those were the scenarios which Melissa Penny and her colleagues examined in fall 2022.* They found that the most optimal scenario to reduce hospitalisations was to have a "well-timed" booster once a year, meaning three to four months ahead of a winter peak, whether or not new variants of concern emerge. That conclusion applied not just to the high-risk population, but to everyone eligible for vaccination. "The rationale was to allow some additional population-level immunity with the booster", explains Melissa Penny, "which is what most of the governments have recommended." The results were also shared with the ECDC, with Dr Andrew Shattock collaborating and supporting the EU agency. "Our findings really highlighted the societal effect of low-risk individuals getting an annual booster. Boosting your own immunity helps to protect those most at risk" Dr Shattock says.

A final twist?

In 2023, SARS-CoV-2 may be loosening its grip on the world. Even so, COVID-19 doesn’t belong to the past for many people. Cue the next question for Melissa Penny’s BRCCH project to investigate: "Now we are looking at therapeutic interventions for COVID-19 ", she says, "modelling different scenarios. Which treatment is effective in addition to high vaccination coverage to support those at higher risk of severe disease and beneficial to save health system costs?"

The COVID-19 pandemic has been characterized by several twists and unexpected turns and as yet still unanswered questions remain. In a scenario where new variants of the virus might emerge in the future, it is certainly good to know which treatments and adapted vaccines could help, and it remains crucial to have the mathematical tools to support evidence on new questions.

 

Background

Professor Melissa Penny leads the Disease Modelling Research Unit in the Epidemiology and Public Health department at Swiss TPH and is currently an assistant professor at the University of Basel. She leads a BRCCH research project "Using Model-based Evidence to Optimise Medical Intervention Profiles and Disease Management Strategies for COVID-19 Control." Her work, and that of her colleague Dr Shattock, is part of the overarching progamme: BRCCH’s Fast Track Call for COVID-19 Research.

Interview article: Irène Dietschi

*Research articles

SHATTOCK AJ, LE RUTTE EA, DÜNNER RP, Sen S, KELLY SL, CHITNIS N,  PENNY MA. 2022. "Impact of Vaccination and Non-pharmaceutical Interventions on SARS-CoV-2 Dynamics in Switzerland." Epidemics. https://doi.org/10.1016/J.EPIDEM.2021.100535

 

LE RUTTE EA, SHATTOCK AJ, CHITNIS N, KELLY SL, PENNY MA. 2022. "Modelling the Impact of Omicron and Emerging Variants on SARS-CoV-2 Transmission and Public Health Burden." Communications Medicine. https://doi.org/10.1038/s43856-022-00154-z

 

KELLY SL, LE RUTTE EA, Richter M, PENNY MA, SHATTOCK A. 2022. "COVID-19 Vaccine Booster Strategies in Light of Emerging Viral Variants: Frequency, Timing, and Target Groups." Infectious Diseases and Therapy. https://doi.org/10.1007/s40121-022-00683-z

 

Names in all caps indicate inclusion in BRCCH consortium

 

 

A New Approach to Understand Patients’ Incomplete Recovery from COVID-19

A New Approach to Understand Patients’ Incomplete Recovery from COVID-19

In a study* published in the journal Nature Immunology, Prof Christoph Hess (University of Basel and University of Cambridge, UK), Dr Hélène Ruffieux (University of Cambridge, UK), Dr Glenn R Bantug (University of Basel) and international collaborators present a new approach to understand incomplete recovery from SARS-CoV-2, including long COVID, based on biological features such as cellular and metabolic changes.

Why do people react so differently to the SARS-CoV-2 virus, especially in the long term? How does the course of the immune response after infection relate to clinical sequelae i.e., the chronic effects following the disease’s initial acute phase? A team from the Cambridge Institute of Therapeutic Immunology and Infectious Diseases followed a group of 215 patients between late March 2020 and early August 2021 to study the dynamics of recovery from SARS-CoV-2 infection and the biology underlying patient-to-patient differences. The study cohort covered a spectrum of clinical severities: from hospitalized and ventilated patients, to patients with only mild or no symptoms. Uninfected healthy individuals also participated in the study, serving as controls.

A patient-centric study design

"We were primarily interested in collecting biological data, not at the level of the virus, but at the level of the host, i.e., the patients", says Prof Hess, senior author of the study. Specifically, the team wanted to investigate differences in cellular immunology, in inflammatory proteins and in metabolism over time at the patient level. “The goal of our work was to define the biological features characterizing patients with unfavourable outcomes, irrespective of demographic or clinical information”, explains Prof Hess.

To evaluate how biological parameters encompass information about the extent and dynamics of recovery from infection, the research team deployed a statistical framework tailored to the longitudinal analysis of multiple related parameters. This allowed them to reconstruct the disease trajectories of individual patients, and to characterize differences in their immune and metabolic profiles over weeks to several months post infection. Based on parameters measured soon after disease onset, they then built a predictive model and thus identified an early biological signature, predictive of poor prognosis.

New predictions based on the biological signature can be generated using their online tool (pictured above), designed to test the research findings prospectively. Not (yet) meant for clinical use! Image courtesy of Ruffieux et al. 2023

 

Explore the tool yourself at http://shiny.mrc-bsu.cam.ac.uk/apps/covid-19-systemic-recovery-prediction-app/

The biological markers of long COVID

So which biological parameters are we talking about? Prof Hess explains:

  • There is – unsurprisingly – the aspect of inflammation: High and persistent inflammation correlated with long-term sequelae. In particular, the levels and dynamics of the C-reactive protein, an indicator of inflammation in the body, during the acute and convalescence phases were associated with the overall recovery profile of patients, months after infection.
  • The researchers also found strong predictive value of a measurement of a type of innate immune cells, the natural killer (NK) cells. Specifically, low NK cell numbers were associated with poor outcomes. How exactly NK cells contribute to the pathophysiology of SARS-CoV-2 remains to be defined.
  • Interlinked with the immune response, tryptophan metabolism has been implicated in the pathophysiology of long COVID. Tryptophan (an amino acid) is a precursor of the neurotransmitter serotonin, which regulates mood and other key bodily functions. However, tryptophan can also be funnelled into the kynurenine pathway. During inflammation, such as triggered by SARS-CoV-2 infection, this breakdown pathway is induced, diverting tryptophan away from the one leading to the formation of serotonin.

Indeed, Prof Hess, Dr Ruffieux and their team did discover low serotonin levels in a subset of the patients they studied. At the same time, they found an accumulation of potentially neurotoxic metabolites, which are formed as degradation products of the tryptophan-degrading metabolic pathway.

All this, says Prof Hess, coincides with one important clinical aspect of long COVID: "Key clinical elements of long COVID can be that patients experience a lack of concentration, patients tire quickly, and they may show signs and symptoms of depression. This fits with the excessive activation of the kynurenine pathway."

Clinical relevance

Prof Hess and his newly founded start-up company, Hornet Therapeutics, identified a drugable metabolic target that may affect serotonin levels, and aim to perform a clinical trial in patients with long COVID. If preventing depletion of serotonin indeed is effective to ameliorate the above-described symptoms, this would constitute a major step in the treatment of long COVID.

Background

Prof Christoph Hess leads the Immunobiology lab at the University of Basel and is the Professor of Experimental Medicine at the University of Cambridge, UK. Prof Hess’ research focuses on the translational aspects of lymphocyte function and its metabolic basis. The goal of his work is to improve our understanding of patients suffering from disorders of immunometabolic regulation.

Read more about the BRCCH-supported research of Prof Hess and co-author Dr Glenn R Bantug- ISINC-19: Immune Senescence in COVID-19. This project is part of the BRCCH’s Fast Track Call for COVID-19 Research.

Interview article: Irène Dietschi

*Research Paper 

Hélène Ruffieux, Aimee L Hanson, Samantha Lodge, Nathan G Lawler, Luke Whiley, Nicola Gray, Tui H Nolan, Laura Bergamaschi, Federica Mescia, Lorinda Turner, Aloka de Sa, Victoria S Pelly, The Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) BioResource COVID-19 Collaboration, Prasanti Kotagiri, Nathalie Kingston, John R Bradley, Elaine Holmes, Julien Wist, Jeremy K Nicholson, Paul A Lyons, Kenneth GC Smith, Sylvia Richardson , Glenn R Bantug , Christoph Hess. 2023. A patient-centric modelling framework captures recovery from SARS-CoV-2 infection. Nature Immunology. https://www.nature.com/articles/s41590-022-01380-2

 

 

Insights into the University of Zimbabwe Birth Cohort study

Insights into the University of Zimbabwe Birth Cohort study

Prof Kerina Duri, associate professor in the Immunology Unit at the Faculty of Medicine and Health Science, University of Zimbabwe (UZ-FMHS), and her Master of Philosophy student Mr Arthur Mazhandu talk about their research studying mother-child health, focusing on HIV and its comorbidities in high-density residential areas in Harare, Zimbabwe. They are collaborating with the Department of Visceral Surgery and Medicine (University Hospital Bern) and Prof Randall Platt (ETH Zurich) on a BRCCH project entitled Living Microbial Diagnostics to Enable Individualised Child Health Interventions. This autumn, as part of this work, Prof Duri and Mr Mazhandu visited their Swiss collaborators, Prof Andrew Macpherson, Prof Benjamin Misselwitz and Prof Randall Platt, and the BRCCH took the opportunity to interview them.

 

Prof Kerina Duri, Mr Arthur Mazhandu, thank you for your time. Prof Duri, could you tell us about your research interests?

Kerina Duri (KD): My background is in biochemistry and biotechnology. I became interested and pursued my doctoral research in the field of viral immunology at the University of Norway, Oslo, and joined the University of Zimbabwe Faculty of Medicine and Health Sciences (UZ-FMHS) Parirenyatwa Teaching Hospital in 2010. At that time, we had some issues with high HIV prevalence. I worked hand-in-glove with paediatricians, who saw more and more HIV-uninfected babies born from HIV-infected mothers presenting with high mortality and morbidity, almost like HIV-infected babies.

Using funding from the Wellcome Trust for my postdoctoral work, we established the University of Zimbabwe Birth Cohort Study (UZBCS) aiming to understand why these HIV-exposed but uninfected babies were at higher risk of dying. The hypothesis was that their immune system was impaired during foetal development due to maternal exposure to HIV and the baby’s exposure in utero, and/or during the breastfeeding period to the mother’s lifelong antiretroviral therapy (ART).

We recruited 1200 pregnant women who were at least 20 weeks into gestation and followed up on three groups of babies: HIV-uninfected babies that were born to HIV-infected mothers, HIV-infected babies that were born to HIV-infected mothers, though this was a small number due to effective ART, and a healthy group of babies that were born to HIV-uninfected mothers. The main strengths of this study are the relatively large sample size and the simultaneous recruitment of HIV-infected pregnant women alongside HIV-uninfected pregnant women from the same community. Thus, all research participants reside in highly similar environmental conditions in high-density areas of Harare, resulting in an unusually homogenous study population.

Mr Mazhandu, how did you become interested in this research?

Arthur Mazhandu (AM): I am a biochemist currently working directly under Prof Duri in the Immunology Unit and working on my Master of Philosophy degree on Helicobacter pylori colonization in babies from birth until two years of age. I first met Prof Duri during an internship that was a requirement of my undergraduate studies in biochemistry. That is when I was introduced to her lab, her team and the work that she is doing. I caught the bug of being involved in clinical research.

Prof Duri, you have a long-standing collaboration with Prof Andrew Macpherson (University Hospital Bern) and now with Prof Randall Platt (ETHZ). How did that relationship develop, and how did you decide to also collaborate on this BRCCH project?

KD: We first met one of the researchers in Prof Andrew Macpherson’s lab, Prof Benjamin Misselwitz, when he visited UZ-FMHS in October 2018. At the time, they were and still are collaborating on inflammatory bowel disease (IBD) research in adults with Dr Leo Katsidzira in the Department of Medicine at UZ-FMHS, studying how diet and nutrition shape the microbiome profile in IBD patients. They thought to do a parallel study of the microbiome profiles in babies, since early life factors like low birth weight or the maternal microbiome impact infant microbiome colonization, and consequently their health and behaviour, even up to adulthood.

At the same time, we wanted to expand our research horizon in the UZBCS to why these HIV-exposed but uninfected babies were getting sick. That is where the microbiome collaboration came in. We know that microbiome colonization in babies affects the development of their immune system, so it is important to understand how maternal HIV infection and the baby’s exposure to ART in utero and during breastfeeding moderate or modulate the microbiome profile and immunity. The Bern group were also interested in studying the impact of malnutrition, as malnutrition in babies is a problem in Zimbabwe. So, we also want to see how malnutrition impacts early-life microbiome colonization and health trajectories in children.

There are a lot of synergies in this collaboration. We have an amazing biobank of samples from the cohorts of babies and their mothers including longitudinal paired mother-baby stool and breast milk samples, which is why we are here in Switzerland. We are adapting and applying Prof Platt’s technique, Record-seq, which was developed in mice exposed to gastrointestinal stresses. We want to gain a deeper understanding of Record-seq and to try to apply this technology to understand what happens in vivo in malnourished babies.

Could you tell us more about the importance of this research in the local context? Why is it important to study the microbiome in mother-baby pairs in Zimbabwe? 

KD: We want to apply this technology to understand the biological stress from HIV exposure that characterizes the HIV-exposed uninfected children. This is of public health importance because these babies are the future. This group is growing every year because with the advent of ART, more HIV-infected women are more willing to have babies since the risk of HIV transmission to their children has reduced (from 33% before the ART era to about 2.7% now1). In the future, these babies will probably constitute a large part of the population, but we don’t understand them; for example, how cognitive development and learning ability are impaired in school-aged children and how they fare when compared to healthy babies born to HIV-uninfected mothers remain elusive.

AM: It is also important in the local context because the clinical findings we learn from this study could have a tangible effect on society now. For example, based on some of the UZBCS data, we have just submitted a paper on the factors responsible for women becoming anaemic in pregnancy. We publish that sort of information for the community. That is the biggest achievement we hope for with this research and these cohorts.

What motivates the mothers to participate in your research?

KD: The mothers want to contribute and have a sense of responsibility, duty and altruism. We explain to them that they themselves, or their children, might not benefit from this research, but we also explain to them, “If you decide to participate in this project, future mothers will benefit from the results of your participation, just as you now benefit from research done in the past and the participation of past mothers.” In addition, sick mothers and their babies are attended to by the clinicians for free. That is another benefit, because doctor visits can be expensive and 21% of the mothers are living under a dollar a day.2

We have a lot of data that we initially obtained from index babies that we first enrolled at the inception of the project and followed for two years. As of 2022, we are including all subsequent pregnancies and babies from the same mothers who are interested in having their other children included. Thus, incredibly, we have a mother-siblings dataset that dampens down statistical noise and confounders associated with environmental differences and household variability.

We are planning to provide the participating mothers with basic medication – paracetamol, analgesics and antipyretics – since currently local primary healthcare services are no longer providing these medicines. As part of our social corporate responsibility, we should give back to the community that is providing priceless, invaluable information that can benefit humankind.

Has the team faced any challenges in this project? How are you overcoming them?

KD: It is a challenge to motivate mothers to participate long-term in the project, especially during the COVID-19 pandemic. In addition, the national economic situation in Zimbabwe is concerning, such that some of the mothers are moving from the city back to their villages where life is relatively cheaper and less stressful. Some mothers now live 10 hours away, and some have even crossed the borders to neighbouring countries, especially South Africa. Now, after about five years, we have 600 mothers and babies actively participating in the study, which I think is still a phenomenal achievement given the circumstances.

What do you hope to learn or advance from this work and collaboration?

KR: We are grateful to our collaborators here for the technology transfer in 16S gene sequencing techniques. We are now writing a lot of papers and publishing profusely. Even today, we are supposed to submit a paper.

The results from the UZBCS are impacting and will continue to impact policymakers and shape policy. Our main focus is HIV, but we also look at comorbidities: infections such viral hepatitis, cytomegalovirus, syphilis and latent tuberculosis and non-communicable diseases such as malnutrition and anaemia and their associated risk factors. For example, we also ask mothers how much they earn as a family or how much they spend on food to understand the factors influencing malnutrition. The data shows that spending less than $60 monthly per family (~3 people) on food predisposes mothers to anaemia. We can sit with the Ministry of Health and policymakers and engage with them about this information and with evidence to reduce inequalities and strengthen sustainable livelihood support for the vulnerable in order to reduce anaemia malnutrition and thereby, improve health outcomes for their children.

We hope to continue this research because of the paucity of data on a very important growing population of HIV-exposed but uninfected babies. In the literature, most studies have only followed babies for one or two years. Our babies are already five years old. It is important to follow these babies to adolescence and, if resources permit, to establish a parallel rural group of mothers and babies to better understand the effects of different environments, microbial exposure and diets on these children’s health.

AM: I am learning all aspects of the project, not just the biochemistry and lab. I am learning how to approach mothers about the study and answer their questions, to keep relationships with the mothers over time, process and analyse the samples and write papers.

I also want to have an impact on my immediate surroundings. If I can continue my studies, I will continue to have great outputs, such as papers, that can also influence policy for the betterment of the community.

KD: If I can comment: We do quite a lot with little resources, and the output is quite astronomical. That is because of these iconic students like Arthur and other members of my team currently at home, Mr Privilege Munjoma (pursuing a Doctorate of Philosophy) and Mr Panashe Chandiwana (pursuing a Master of Philosophy), who are also supported by the BRCCH. We depend on the motivated students who go above and beyond what is required of their studies to advance the UZBCS. I really commend them.

We are coming to the end of our talk. Thank you again for sharing your insights. Are there any last thoughts that you would like to share?

AM: Through this project, I have gained insights into the health system, especially from the perspective of children – how delicate they are and how much attention they need. For me, I can have a direct contribution to society. That has been really meaningful to me.

KD: It is a passion for me. I want this project to work and continue like the famous Framingham Heart Study in the USA. We are doing everything, all the aspects involved in running and maintaining the study. And we depend on the students. We can do it for a certain time, but it is not sustainable as is. We work so hard, and the output is there, but we also want to put bread on the table and pay bills. We want to survive. We have children.

It is about equity and survival and the unpredictable economic blips. That is our biggest challenge because we need a non-static adjustable living salary for these youngsters like Arthur in order for us to retain our students in Zimbabwe. If they can focus on their work,  we achieve much more and build capacity. I am getting old; I also want Arthur to take my lab to a higher level or to have his own, better lab in the future.

This collaboration is really great, and I can see the exponential increase in tangible results clearly coming out of it. I think we are one of the few groups in Zimbabwe to work on the microbiome. I want to thank all the mothers and babies participating in the study, the students and support staff, and our collaborators Prof Andrew Macpherson, Prof Benjamin Misselwitz and Prof Randall Platt. Last but not least, I wish to sincerely thank the BRCCH for our research funding over the years. 

Background:

Prof Kerina Duri (PhD, MSc, BSc Hons) is an associate professor at the University of Zimbabwe in the Faculty of Medicine and Health Science. Her research interest is in understanding how maternal comorbidities such as HIV, Helicobacter pylori and intestinal helminths infections, malnutrition and mental health affect pregnancy outcomes, infant growth and health, immune development and immune dysregulation through gut microbiota profiles and composition from birth to adolescence, with a special focus on HIV-exposed but uninfected infants and children. She established a birth cohort of 1200 mother-infant pairs in urban Zimbabwe, from which there has been an incredible accumulation of data. The cohort study can be found at www.clinicaltrials.gov, under registration number NCT04087239.

Within the context of the BRCCH, she is a Collaborator on the research project Living Microbial Diagnostics to Enable Individualised Child Health Interventions led by Prof Randall Platt (ETH Zurich). This project is part of the BRCCH’s Multi-Investigator Programme.

 

References

  1. Duri K, Mataramvura H, Chandiwana P, Mazhandu AJ, Banhwa S, Munjoma PT, Mazengera LR and Gumbo FZ (2022). Mother-to-Child Transmission of HIV within 24 Months after Delivery in Women Initiating Lifelong Antiretroviral Therapy Pre/PostConception or Postnatally; Effects of Adolescent Girl and Young Woman Status and Plasma Viremia Late in Pregnancy. Frontiers in Virology. doi: 10.3389/fviro.2022.906271.
  2. Duri K, Munjoma PT, Mataramvura H, Mazhandu AJ, Marere T, Tabvuma T, Chandiwana P, Gumbo FZ and Mazengera LR (under review). Burden of Anaemia in Pregnancy: Associated Risk Factors and Adverse Birth Outcomes in a Resource-Limited Setting.

 

 

Getting Ahead of Viral Evolution Using Artificial Intelligence

Getting Ahead of Viral Evolution Using Artificial Intelligence

It has been nearly three years since the emergence of SARS-CoV-2, and it is plainly apparent the world faces a future reality of an ever-changing virus that is here to stay. We now have diagnostics, vaccinations and therapies to fight COVID-19, but the continued emergence of new viral variants means that we too must continually assess, adapt and respond to these threats. Prof Sai Reddy (ETH Zurich and BRCCH) and his colleagues are doing just that by using artificial intelligence to prepare for future variants.

Within the scope of the BRCCH’s Fast Track Call for COVID-19 research funding programme, Prof Reddy and his consortium have developed an artificial intelligence method, deep mutational learning, that predicts the ability of SARS-CoV-2 variants to bind to human cells and escape antibodies. This prediction for current and prospective variants may guide the future development of therapeutic antibody treatments and next-generation COVID-19 vaccines. The information can also be generated in real-time to aid faster public health decision-making. And from a global health perspective, the development of vaccines that protect against future variants improves their efficaciousness and may even help to address vaccine inequity.

In this conversation, Prof Reddy joins BRCCH to discuss this exciting new method. He explains how this research came to be, “This work was enabled by the generous support of the Fondation Botnar to promote, in the very early stages of the pandemic, innovation to overcome the challenges that were known at the time of the peak of the pandemic. But at that time, new challenges, like variants, breakthrough infections and the evolution of SARS-Cov-2, were not necessarily anticipated.

The Fondation’s early commitment to supporting the FTC programme enabled us to respond quickly to this changing pandemic landscape and actually to come up with a new strategy focused on SARS-CoV-2 specifically, instead of applying a band-aid approach using existing, and perhaps inadequate or outdated, methods.”

In the journal Cell, Prof Reddy and his team published this new method called deep mutational learning, a machine learning-guided protein engineering technology that can help us understand how a new variant will affect vaccinated or previously infected people, potentially in real-time as the variant emerges in a population.

Graphical abstract: "Selection and emergence of SARS-CoV-2 variants are driven in part by mutations within the viral spike protein and in particular the ACE2 receptor-binding domain (RBD), a primary target site for neutralizing antibodies. The researchers develop deep mutational learning (DML), a machine learning-guided protein engineering technology, which is used to interrogate a massive sequence space of combinatorial mutations, representing billions of RBD variants, by accurately predicting their impact on ACE2 binding and antibody escape. A highly diverse landscape of possible SARS-CoV-2 variants is identified that could emerge from a multitude of evolutionary trajectories. DML may be used for predictive profiling on current and prospective variants, including highly mutated variants such as Omicron, thus guiding the development of therapeutic antibody treatments and vaccines for COVID-19." -Taft et al. 2022

 

The ability to make these predictions have big implications for how we may face the future of the pandemic. For example, researchers could use this method to identify therapeutic antibodies or develop next-generation vaccines that have the broadest coverage and the potential to be most effective against current and emergent variants. From a public health perspective, the method could be used to perform surveillance and a real-time assessment, so that governing bodies could leverage that wealth of information to guide public health decisions sooner and more effectively.

“This method allows us to prospectively gather lots and lots of information about the potential evolutionary trajectories of any virus and that makes us a little bit more proactive, rather than always waiting and being a step behind the virus. This may even allow, someday, for us to get ahead of viral evolution.” - Prof Reddy

Additionally, this technology has the potential for societal impact and improving vaccine inequity. In the current global health situation, countries differ greatly in access to vaccines. The inequity is exacerbated by time. The more time that passes between getting a vaccine and when it was designed, the higher the probability of it being less efficacious against variants that have since emerged. In other words, people who receive vaccinations later run the risk of not being protected against the newest variants and only being protected from older variants that are no longer circulating in the population.

“Part of the importance of this method could be that we eventually can make vaccines that have broader coverage and have a longer shelf life of being useful. So even if populations do not get immediate access, they are still at least getting an effective vaccine. This is where there's an opportunity for us to make a difference in global and public health. Our research team cannot solve the problems with manufacturing, distribution and the economics of vaccinations, but we can at least contribute to the science behind the design of vaccines, which represents a highly important part of the science value chain on the path to global translation.” -Prof Reddy

The science behind the technology is indeed innovative, as ETH News explains:

Since viruses mutate randomly, no one can know exactly how SARS-CoV-2 will evolve in the coming months and years and which variants will dominate in the future. In theory, there is virtually no limit to the ways in which a virus could mutate. And this is the case even when considering a small region of the virus: the SARS-CoV-2 spike protein, which is important for infection and detection by the immune system. In this region alone there are tens of billions of theoretical possible mutations.

That’s why the new method takes a comprehensive approach: for each variant in this multitude of potential viral variants, it predicts whether or not it is capable of infecting human cells and if it will be neutralized by antibodies produced by the immune system found in vaccinated and recovered persons. It is highly likely that hidden among all these potential variants is the one that will dominate the next stage of the COVID-19 pandemic.

To establish their method, Reddy and his team used laboratory experiments to generate a large collection of mutated variants of the SARS-CoV-2 spike protein. The scientists did not produce or work with live virus, rather they produced only a part of the spike protein, and therefore there was no danger of a laboratory leak.

The spike protein interacts with the ACE2 protein on human cells for infection, and antibodies from vaccination, infection or antibody therapy work by blocking this mechanism. Many of the mutations in SARS-CoV-2 variants occur in this region, which allows the virus to evade the immune system and continue to spread.

Although the collection of mutated variants the researchers have analysed comprises only a small fraction of the several billion theoretically possible variants – which would be impossible to test in a laboratory setting – it does contain a million such variants. These carry different mutations or combinations of mutations.

By performing high-throughput experiments and sequencing the DNA from these million variants, the researchers determined how successfully these variants interact with the ACE2 protein and with existing antibody therapies. This indicates how well the individual potential variants could infect human cells and how well they could escape from antibodies.

The researchers used the collected data to train machine learning models, which are able to identify complex patterns and when given only the DNA sequence of a new variant could accurately predict whether it can bind to ACE2 for infection and escape from neutralizing antibodies. The final machine learning models can now be used to make these predictions for tens of billions of theoretically possible variants with single and combinatorial mutations and going far beyond the million that were tested in the laboratory. (Read full article)

Background

This research was developed by a BRCCH-supported multi-disciplinary consortium working together and as part of a larger BRCCH research programme, the Fast Track Call for COVID-19 research (FTC). The programme aims to enable research that will help mitigate medical and public health challenges and contribute tangible solutions to reduce global disease burden due to COVID-19. Lead investigator Sai Reddy is Vice Director of BRCCH and a professor in the Department of Biosystems Science and Engineering, ETH Zurich

“This specific project was inspired and commenced as an extension of the original FTC project, which was initially based on developing a testing method for SARS-CoV-2 using a high throughput DNA sequencing method. As new variants emerged, such as Omicron this last winter, and the ensuing wave of breakthrough infections, we realised we could extend our work to develop technology and an approach where you could prospectively identify what combinations of mutations might escape from antibodies.” -Prof Reddy

 

Research article:

Taft JM, Weber CR, Gao B, Ehling RA, Han J, Frei L, Metcalfe SW, Overath M, Yermanos A, Kelton W, Reddy ST. 2022. "Deep Mutational Learning Predicts ACE2 Binding and Antibody Escape to Combinatorial Mutations in the SARS-CoV-2 Receptor Binding Domain." Cell. journal pre-proof. https://doi.org/10.1016/j.cell.2022.08.024

Related articles:

ETH News article "Preparing for Future Coronavirus Variants Using Artificial Intelligence"

MORE about Prof Reddy’s FTC research DeepSARS

MORE about the BRCCH-supported COVID-19 research

 

 

 

 

Conversation with Prof Sai Reddy

DeepSARS: Sequencing and testing at the same time

A new scientific platform called DeepSARS, developed by Prof Sai Reddy, BRCCH Vice Director and Professor of Systems and Synthetic Immunology at ETH Zurich, could support viral testing and tracking for future pandemics: While current diagnostic testing and genomic surveillance methods are being done separately, DeepSARS is able to perform both tasks simultaneously. This allows for earlier detection of emerging variants and profiling mutations at the population level. In this conversation, Prof Reddy joins journalist Irène Dietschi to discuss the consortium’s exciting new findings.

Graphical abstract: DeepSARS uses molecular barcodes (BCs) and multiplexed targeted deep sequencing (NGS) to enable simultaneous diagnostic detection and genomic surveillance of SARS-CoV-2. Image courtesy of Yermanos et al. 2022

 

The ongoing COVID-19 pandemic remains a major global health concern with novel variants of SARS-CoV-2, such as alpha, beta, gamma, delta and omicron, that are continuously emerging and resulting in new waves of infection. Potentially exacerbating the situation, many of the masking and social distancing rules are relaxed around the world.

The latest variant of SARS-CoV-2, omicron, with over 50 mutations is able to infect at a greater capacity than previous strains and often possesses substantial immune evasion, leading to many breakthrough infections in vaccinated or previously infected individuals. 

Genomic surveillance of SARS-CoV-2 has been a vital component in the monitoring of the pandemic, providing valuable information for guiding public health decisions. However, despite the fact that the SARS-CoV-2 genomes from infected patients have been sequenced at unprecedented levels, they still represent a small fraction of the total number of global infections. And countries vary widely in how they prioritize viral genome sequencing. What makes it even more problematic is that in the countries with low sequencing rates, they also tend to have high infection rates and are therefore at an especially high risk for new mutations to evolve. They are hotspots for new variants.

Key region: the receptor binding domain

That is where DeepSARS comes into play. "A number of researchers have previously embraced the idea that sequencing could be used not just for genomic surveillance, but also for diagnostic testing", says immunology professor Sai Reddy, Vice Director of the BRCCH. Prof Reddy, who is the principal investigator of the Laboratory for Systems and Synthetic Immunology at ETH Zurich, has actually pursued this idea to a practical level. In a paper published recently in BMC Genomics, he, his team and collaborators have established a scientific concept which has proven that sequencing and testing can be done simultaneously. Their system is called DeepSARS.

"One of the main challenges of the project was to determine which sites in the viral genome would yield maximum diagnostic and genomic information while maintaining sufficient coverage for each site", explains Prof Reddy. One region which is most associated with new variants is the spike protein of SARS-CoV-2, and within the spike protein it is particularly the so-called receptor binding domain – the site where the virus attaches itself to the host receptor ACE2 – where mutations most likely occur.

This receptor binding domain also happens to be the target site of neutralizing antibodies, generated from either vaccination or previous infection. Mutations which emerge from this region can influence variants’ attachment to host cells, potentially making them more transmissible and are allowing them to escape from neutralizing antibodies. "Therefore, when we are developing sequencing tests, it is very important to get information about the receptor binding domain", says Prof Reddy. "It was a central part for the design of DeepSARS."

Experimental protocol and ‘targeted deep sequencing’

Once this was established, Sai Reddy and colleagues proceeded in a stepwise manner to develop the DeepSARS system. "First we elaborated an experimental protocol, which is in fact very similar to the protocol in which all PCR tests are performed", says Prof Reddy. "The main difference is that we added little personalized markers to each sample of the PCR, so that when you perform a genomic sequencing experiment you know which patient it came from." This procedure is called molecular barcoding.

The second step the researchers undertook was to identify regions for what they call "targeted deep sequencing". Prof Reddy: "Targeted deep sequencing means reducing the viral genome from 30’000 RNA bases to about 20 percent of that number - 6000 bases. And it means identifying those 20 percent of sites which give us information that will likely track the evolution of the virus, as well as identify emerging variants." To achieve that, Reddy and colleagues performed an extensive computational analysis (i.e., computational phylogenetics). In this way they identified target candidates of the viral genome and then implemented them in the experimental protocol.

Proof of concept on patients’ sample

Next, they validated their data on synthetic RNA templates of SARS-CoV-2, based on genomic sequences recovered early in the pandemic. "That allowed us to do very precise experiments to detect the amount of viral material, which was as low as 10 copies of the virus per sample", Prof Reddy explains.

The final step was testing DeepSARS on samples from patients. "We had samples from 30 patients, and we were able to show, based on nasal swabs or saliva, that the DeepSARS testing assay was very close to performing at the same level of diagnostic detection as a traditional PCR test", says Prof Reddy. And: "It was able to provide enough information about genomic surveillance to classify viral evolution, and whether there were any variants or not." In short: DeepSARS works. With the proof of concept, its science and technology may be regarded as well established.

A solid foundation for future pandemics

The exciting question is, could DeepSARS be applied at a larger scale? Could it even be deployed in the current COVID-19 pandemic? "DeepSARS certainly has a lot of potential", says Prof Reddy. "But right now, while we’re still in the COVID-19 pandemic, it wouldn’t make much sense to replace the current infrastructure for diagnostics and genomic surveillance with a new system." As Prof Reddy explains, that would implicate numerous changes in the logistics and regulations of the on-going pandemic, which, among other aspects, would be far too costly and require extensive regulatory approval.

Yet Sai Reddy is collaborating with public health experts in Switzerland as well as with clinicians at University Hospital Basel and other partners, discussing future applications, including clinical testing of DeepSARS. The goal is to examine the system at a larger scale. "We have shown that DeepSARS can be rapidly adapted for identification of emerging variants and for profiling mutational changes at a small scale but for a pandemic, this requires population level implementation", says Prof Reddy. "Practically speaking, DeepSARS could be of immense benefit in for future pandemics or possibly as SARS-CoV-2 transitions to an endemic stage."

Background

DeepSARS was developed by a BRCCH-supported consortium where bioengineers, immunologists, computational biologists and clinical scientists work together and as part of a larger BRCCH research programme, the Fast Track Call for COVID-19 research (FTC). The programme aims to enable research that will help mitigate medical and public health challenges and contribute tangible solutions to reduce global disease burden due to COVID-19.

This specific project aims for rapid transfer of these state-of-the art diagnostic methods across Switzerland and many other countries around the world, leading the way for innovative population level surveillance approaches of future variants and other disease outbreaks.

 

Interview: Irène Dietschi

Research article:

https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-022-08403-0

Yermanos A, Hong KL, Agrafiotis A, Han J, Nadeau S, Valenzuela C, Azizoglu A, Ehling R, Gao B, Spahr M, Neumeier D, Chang CH, Dounas A, Petrillo E, Nissen I, Burcklen E, Feldkamp M, Beisel C, Oxenius A, Savic M, Stadler T, Rudolf F & Reddy ST. 2022. "DeepSARS: simultaneous diagnostic detection and genomic surveillance of SARS-CoV-2." BMC Genomics. DOI:v10.1186/s12864-022-08403-0

MORE about the BRCCH-supported COVID-19 research by Prof Sai Reddy and consortium.

 

 

 

A New Frontier in Diagnosing Gut Health

A New Frontier in Diagnosing Gut Health

Every year, more than 200 million children worldwide do not reach their developmental potential. This is primarily due to infectious diseases as well as malnutrition and related disorders. Normal gut development and function are critical for determining a child’s development and health throughout life. Despite this, diagnostics that can measure the health status of the gut are severely lacking.  As part of the BRCCH’s Multi-Investigator funding programme, Prof Randall Platt (ETH Zürich), Prof Andrew Macpherson (University Hospital Bern) and fellow consortium members seek to develop a non-invasive, microbe-based diagnostic that is capable of sensing and recording the status of the gut.

In a new groundbreaking study published in Science*, Prof Platt, Prof Macpherson and co-authors have achieved the first critical steps towards making this ambitious idea a reality.

Behind this work is the innovative Record-seq technology pioneered by Prof Platt in 20181. The technology is based on CRISPR-engineered bacteria that can sense and create a molecular record of changes in their surrounding environment over time. These bacteria, or ''transcriptional recorders'' can then be analysed via sequencing approaches to reveal the history of events that they encountered. This technology holds enormous potential to provide real-time information on the status of the gut environment, which could then be harnessed to guide personalised therapeutic interventions.

In this new study, the researchers first set out to understand how the transcriptional recorders behave in a real-life gut environment and what they are able to report on whilst travelling through the intestine. The team demonstrated that these bacteria survive and traverse through the gut of mice, and that they can be successfully collected from faecal samples for further analysis. Importantly, the study revealed that the transcriptional recorders are able to capture important biological information throughout all regions of the gut. This represents a major advance over current omics-based technologies that are used to study the gut, as they are unable to provide insights into intestinal regions that are more difficult to access, such as the proximal colon.

The CRISPR-engineered bacteria (or transcriptional recorders) create molecular records of information about their surrounding environment as they transit through the gut. These bacteria can then be retrieved via faecal samples and their molecular records analysed through sequencing and computational methods. Image courtesy of Prof Randall Platt

 

Following these exciting results, the team then embarked on testing if the transcriptional recorders can reliably report on two elements which are critical for determining gut health: nutrition and inflammation.

To do this, mice were fed with different diets and the transcriptional recorders were collected from faecal samples over time. A Record-seq analysis revealed that these bacteria record unique molecular signatures that are diet-specific and are retained by the bacteria, even following a dietary switch. Therefore, not only are these transcriptional recorders capable of reporting on the real-time dietary status in vivo, these findings also suggest that they can provide a window into the nutritional history of the gut.

The researchers then took one step further by studying the transcriptional recorders in a mouse model of gut inflammation, to mimic the local environment in the presence of gastrointestinal disease.  Remarkably, the team discovered that the molecular signatures recorded by the bacteria could be used to distinguish healthy mice from those with gastrointestinal inflammation. Moreover, they could also provide a read-out for measuring the severity and biological indicators of inflammation within the gut.

Following this landmark work, we asked Prof Randall Platt about where the consortium plans to take Record-Seq from here:

''This highly collaborative and interdisciplinary project lays the groundwork towards realising the technology’s true potential for improving human health. The consortium is now focusing on translation, which primarily includes further rigorous testing in animal models of human conditions as well as ensuring robust safety and environmental containment of the genetically engineered bacteria''.

 

*Read the paper: https://www.science.org/doi/10.1126/science.abm6038

Schmidt F, Zimmermann J, Tanna T, Farouni R, Conway T, Macpherson AJ, Platt RJ: Noninvasive assessment of gut function using transcriptional recording sentinel cells. Science, 12 May 2022, doi: 10.1126/science.abm6038

About the researchers 

Professor Randall Platt is an Associate Professor at the Department of Biosystems Science and Engineering (D-BSSE) at ETH Zürich and the Department of Chemistry at the University of Basel.

Professor Andrew Macpherson is Professor and Director of Gastroenterology at University Hospital Bern.

Professors Platt and Macpherson, together with fellow consortium members, lead the BRCCH Multi-Investigator Project: Living Microbial Diagnostics to Enable Individualised Child Health Interventions.

1 Related articles

Recording device for cell history (ETH News 03.10.2018)

Bacteria with recording function capture gut health status (ETH News 12.05.2022)

 

 

Conversation with Prof Alexandar Tzankov

A Cell Fitness Marker for Predicting COVID-19 Outcomes

COVID-19 is unpredictable. Identifying which COVID-19 patients are likely to develop severe disease versus those at lower risk of complications remains a major clinical challenge. In a recent collaborative study*, BRCCH-funded investigator Professor Alexandar Tzankov (University Hospital Basel) and co-authors discovered a novel biomarker that could be used to predict the prognosis of COVID-19 patients more accurately. In this conversation, Prof Tzankov joins journalist Irène Dietschi to discuss          the consortium’s exciting new findings.

 

Assessing a patient’s risk of developing severe disease is difficult. Usually, individuals who test positive for SARS-CoV-2 are referred to their physician and sent home to isolate. Which patients will develop severe symptoms and require hospitalisation is largely unknown at this point. In a study published in EMBO Molecular Medicine, Prof Alexandar Tzankov and co-authors have now uncovered a means to predict the prognosis of COVID-19 patients more precisely: by using a genetic marker called hFwe-Lose, or simply Flower lose.

Behind this discovery is a relatively recent finding: cells constantly compare their fitness with each other in the body. Collaborators of Prof Tzankov, Prof Eduardo Moreno (Champalimaud Centre for the Unknown, Portugal) and Prof Rajan Gogna (University of Copenhagen), previously identified that the human flower gene (hFwe) can be expressed in different forms, which mark cells as either winners or losers. Fit or 'winning' cells express a form of the flower gene called hFwe-Win, whereas unfit or 'losing' cells express hFwe-Lose. This allows the body to identify unhealthy cells that need to be eliminated.

''The balance of expression of these flower genes is very important physiologically'' says Alexandar Tzankov. ''Their correct expression is critical in embryo and organ development, as well as in diseases such as cancer. hFwe-Lose is a kind of lifetime document for the whole body.'' It can provide insights into how fit a person’s body is at a given moment: What a person’s biological age is, how much cumulative toxicity they have been exposed to during life, if they have pathological obesity, how well does their body handle high blood sugar and hypertension.

In May 2020, Prof Tzankov had just published an autopsy study of 21 deceased COVID-19 patients, the first major observational cohort of its kind. Professors Morena and Gogna suspected that flower genes might play a role in the progression of COVID-19 and decided to reach out to Prof Tzankov. ''They suggested examining the tissues of deceased patients for hFwe-Lose, and that's what we did'' says Alexandar Tzankov. The team also examined hFwe-Lose in patients with co-morbidities such as hypertension, diabetes, obesity and chronic obstructive pulmonary disease (COPD). The results confirmed the researchers' original idea: ''In healthy lungs, the expression of hFwe-Lose is very low. In the lungs of patients with co-morbidities, its expression increases. In patients who died of COVID-19, it is very high'', Alexandar Tzankov explains.

hFwe-Lose is a genetic marker than can be used to predict outcomes in COVID-19 patients. Source: EMBO Molecular Medicine (2021) 13:e13714; https://doi.org/10.15252/emmm.202013714

 

The researchers then decided to go one step further: They analysed hFwe-Lose levels in nasopharyngeal swab samples collected from 283 COVID-19 -at that time unvaccinated - patients in Wisconsin, USA during the early waves of infection. The team discovered that the higher the hFwe-Lose level was in the nasal sample, the more likely the patient went on to develop severe disease and to undergo hospitalisation and/or die of COVID-19. Remarkably, using computational modelling, the team uncovered that hFwe-Lose levels could be used to predict the risk of hospitalisation and death with a high degree of accuracy. ''For about 85% of people for whom the level of hFwe-Lose predicted hospitalisation, they actually had to go to the hospital. For virtually no one who died, mathematical modelling predicted that they would not have died'' explains Alexandar Tzankov.

hFwe-Lose is relatively straightforward to analyse via the same nasal swab used to test for SARS-CoV-2 infection. ''This makes hFwe-Lose a very useful biomarker for COVID-19 patients'' says Alexandar Tzankov. So what could this mean for clinicians? ''You could potentially identify at-risk COVID-19 patients early, instruct these patients to pay very close attention to symptoms and keep the threshold for hospitalisation lower. That way, emergency situations could possibly be avoided.''

''I admit that this is an optimistic scenario for the use of this marker - but it has the potential.''

 

Interview: Irène Dietschi

Research article: https://www.embopress.org/doi/10.15252/emmm.202013714

MORE about the BRCCH-supported COVID-19 research by Prof Alexandar Tzankov and consortium.

MORE about COVID-19 research by the pathology team at University Hospital Basel.