Category Archives: Immunology

The antibodies in blood samples from around the world could reveal where previously identified pathogens are popping up and where new ones are emerging.

By Robert BazellJun. 13, 2020 , 8:00 AM

Sciences COVID-19 reporting is supported by the Pulitzer Center.

Michael Mina is out for bloodmillions of samples, which a nascent effort dubbed the Global Immunological Observatory (GIO) would monitor for signs of pathogens spreading through the population. Instead of a telescope, it will rely on technology that can measure hundreds of thousands of distinct antibodies in a microliter of blood. If the GIO can overcome technical and logistical hurdles and find sustained funding, he says, it could provide a powerful tool for monitoring and responding to disease outbreaks.

For now, the idea is just a pilot project to track the spread of COVID-19. The stealthy spread of that disease through the population underscored the need for such a monitoring system, says Mina, an immunologist and epidemiologist at Brigham and Womens Hospital and the Harvard School of Public Health, who with colleagues outlines the GIO concept this week in eLife. (The co-authors include Jeremy Farrar, an infectious disease specialist and director of the Wellcome Trust, as well as vaccine and immunology specialists Adrian McDermott and Daniel Douek of the National Institutes of Health.)

Disease surveillance in the United States now relies on a patchwork of hospitals, clinics, and doctors to report unusual events to state health departments, which pass the information on to the Centers for Disease Control and Prevention (CDC). The need for faster, more comprehensive surveillance, Mina says, was starkly clear with the inability to identify and model local circulation of COVID-19 in a timely fashion.

Mina wants to watch for outbreaks by looking for antibodies to infectious agents in regularly collected, anonymized blood samples from every possible sourceblood banks, plasma collection centers, even the heel needle sticks of newborns, which are taken in most states from every baby in order to identify genetic diseases. The samples would be identified only by geographical area. Chip-based platforms that can identify hundreds of thousands of antibodies are already produced commercially by companies including VirScan and Luminex. Mina says these could easily be scaled up to look at huge numbers of samples, either individually or in batches

This is an extraordinary and exciting concept, says infectious disease specialist William Schaffner of the Vanderbilt University Medical Center. It is an example of the kind of fresh new thinking we need in public health. But, Schaffner adds, The logistical challenges for such an endeavor could be daunting.

Mina and his co-authors envision initially testing about 10,000 samples per day and later, if they secure funding to build up the project, some 100,000 per day for the United States alone. Even the smaller number would detectfar faster than the current reporting systeman outbreak of Zika virus in rural Louisiana, for example, or an eruption of West Nile virus in Colorado. The GIO could also accelerate the monitoring of seasonal influenza, allowing hospitals to prepare for possible surges and for public health officials to be sure vaccine is distributed as efficiently as possible.

When a new infectious disease such as COVID-19 appears, the GIO could track its spread. The antibody-detecting chips wouldnt necessarily have to be updated to spot a new pathogen, such as SARS-CoV-2, the cause of COVID-19. Researchers might see a rise in antibodies that nonspecifically target known pathogens--and might flag their unknown relatives. For example, a burst of antibodies that cross-react various coronaviruses would likely have been seen in people in Wuhan, China, who were infected with the novel coronavirus.

Antibodies, which typically appear 1 to 2 weeks after an infection starts, can signal not just people who are currently infected but also those who had the disease and recovered. The GIO would also identify the particular strains of a bacteria or virus infecting people because each produces a unique antibody signature.

The idea of regularly monitoring entire populations for antibodies arose in the lab of evolutionary biologist Bryan Grenfell at Princeton University, where Mina worked as a postdoctoral fellow. Now, Mina has joined Grenfell and Jessica Metcalf, also an evolutionary biologist at Princeton, in expanding the concept.

The GIO team is already building a pilot laboratory in Massachusetts, while it looks to secure financial support. Given the importance we believe this could have, we are beginning to look for funding from some of the major philanthropic donors of public health work, Mina says. We are currently exploring and open to all options.

Meanwhile, the team s pilot project, supported by the Open Philanthropy foundation, is gathering millions of anonymous blood samples from a plasma-collecting company Octapharma. By screening them for antibodies to SARS-CoV-2, Mina and his colleagues hope to learn how useful widespread antibody testing can be in tracing the spread of the new coronavirus and possibly predicting future hot spots or localized outbreaks.

People often do not develop antibodies until well after infections; for SARS-CoV-2 it takes 1 or 2 weeks. But Mina says the antibody testing still provides valuable information. A week into an outbreak isn't huge, he said. For example, if we were doing this with [blood from] just a small fraction of New York, we would have detected that [the SARS-CoV-2] was there in February and could have given [Governor Andrew] Cuomo plenty of ammunition to close down the city March 1 instead of March 19.

Originally posted here:
Could a global 'observatory' of blood help stop the next pandemic? - Science Magazine

Immunology

Ecoimmunology – Wikipedia

June 13, 2020 medical

Ecoimmunology or Wild Immunology is an interdisciplinary field combining aspects of immunology with ecology, biology, physiology, and evolution. The field of ecoimmunology, while young, seeks to give an ultimate perspective for proximate mechanisms of immunology.

Classical, or mainstream, immunology works hard to control variation (inbred/domestic model organisms, parasite-free environments, etc.) and asks questions about mechanisms and functionality of the immune system using a reductionist method. Comparative immunology investigates the major changes of the immune system among taxa. While ecoimmunology originated from these fields, it is distinguished by its focus to describe and explain natural variation in immune functions,[1] and, more specifically, why and how biotic and abiotic factors contribute to variation in immunity in animals. Study of the trade-offs between immunity and other physiological mechanisms are a central study topic within the field, but have been expanded to include roles in species and individual variation, sex, social aspects, and mating system differences, and progress is also being made to develop methods to explore this variation.[2] Many studies involve in vivo laboratory experiments, but there have been recent calls for immunologists to study immune variation more in wild animals in particular.[3] Multiple institutes engage in ecoimmunological research, such as the Center for Immunity, Infection and Evolution at the University of Edinburgh and the Max Planck Institute for Immunoecology and Migration. The US National Science Foundation has funded a Research Coordination Network) to bring methodological and conceptual unity to the field of ecoimmunology.

The immune systemcan be regarded as diary of exposition to viruses. Migration of animals lead to different exposure to animals as virus hosts. Combination of migration routes where individuals might be exposed to virus hosts can be used to cross-validate anti-gens and anti-bodies detected in the immune system of e.g. in migratory animals. For some viral infections you can detect in an early phase of the infection antibodies of the Immunglobulin class M (IgM) and later in the infection the detection of antibodies of the Immunglobulin class G (IgG) recommended. This basic example shows, how the integration of different approaches:

One of the fields seminal papers, by Folstad and Karter,[4] was a response to Hamilton and Zuks famous paper on the handicap hypothesis for sexually selected traits.[5] Folstad and Karter proposed the immunocompetence handicap hypothesis, whereby testosterone acts as a mediator of immunosuppression and thus keeps sexually-selected traits honest.[4] Although there is only moderate observational or experimental evidence supporting this claim up until now, the paper itself was one of the first links to be made suggesting a cost to immunity requiring trade-offs between it and other physiological processes. In 1996, a foundational paper for the field invoked trade-offs, the allocation of limited resources among competing, costly physiological functions, as a prime cause of variation in immunity.[1] Evidence for these putative trade-offs has often proven to be elusive [6]

More recently, ecoimmunology has been the theme of three special issues in peer-reviewed journals, in Philosophical Transactions of the Royal Society B, in Functional Ecology, and in Physiological and Biochemical Zoology (see External links).

Non-allergic asthma linked with increased risk of severe COVID-19 – HSPH News

June 13, 2020 medical

However, study finds allergic asthma did not significantly increase the risk of severe illness

June 11, 2020Adults with asthma who became infected with the coronavirus that causes COVID-19 were at higher risk of developing severe illness compared with adults who did not have asthma, according to a new study led by researchers at Harvard T.H. Chan School of Public Health and Massachusetts General Hospital.

The study, the first to specifically examine the longitudinal relationship between asthma and risk of developing COVID-19, also showed that the risk was largely driven by non-allergic asthma. Allergy-induced asthma, according to the findings, did not significantly increase the risk of severe illness.

A pre-proof of the study was published online in The Journal of Allergy and Clinical Immunology on June 6, 2020.

Despite reasonable speculation that asthma could be a risk factor for severe COVID-19, rigorous, population-based research is needed to know whether asthma and its major subtypes actually increase risk, said Liming Liang, corresponding author of the study and associate professor of statistical genetics at Harvard Chan School. Based on these new findings, clinicians can improve risk-stratification and target COVID-19 prevention in patients with asthma, particularly those with non-allergic asthma.

Since the start of the pandemic, clinicians have suspected that patients with asthma have increased susceptibility to COVID-19, but no longitudinal studies have analyzed the actual risk. For the new study, the research team analyzed data from 492,768 participants in the UK Biobank, which stores biologic samples from participants and is linked to their medical records. The researchers found 65,677 participants had asthma and 641 patients had severe COVID-19.

After adjusting for age, sex, body mass index, and other factors, the researchers found that having non-allergic asthma increased the risk of severe COVID-19 by as much as 48%. They also found that the risk of severe COVID-19 increased by as much as 82% among people with asthma and chronic obstructive pulmonary disease. Importantly, however, the study showed that people with allergic asthma had no statistically significant association with severe COVID-19.

Zhaozhong Zhu, first author of the study and a research fellow at Harvard Chan School, noted that the new findings are consistent with recent studies that have shown low levels of receptors for novel coronavirus (SARS-CoV-2) on the airway cells of individuals with allergic diseases and asthma.

The findings are especially important amidst allergy season, said study co-author Kohei Hasegawa, a physician at Massachusetts General Hospitals Department of Emergency Medicine. This study should provide some reassurance during allergy season to the tens of millions of people with allergic asthma, Hasegawa said.

Funding for this study came from National Institutes of Health grant R01 AI-127507.

Association of asthma and its genetic predisposition with the risk of severe COVID-19, Zhaozhong Zhu, Kohei Hasegawa, Baoshan Ma, Michimasa Fujiogi, Carlos A. Camargo,and Liming Liang, The Journal of Allergy and Clinical Immunology, June 6, 2020, doi: https://doi.org/10.1016/j.jaci.2020.06.001

Chris Sweeney

Photo: iStock

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Non-allergic asthma linked with increased risk of severe COVID-19 - HSPH News

Immunology

Some Forms of Common Cold May Give COVID-19 Immunity Lasting up to 17 Years, New Research Suggests – Science Times

June 13, 2020 medical

Immunology experts recently released a paper suggesting that coronavirus immunity might be possible through a different genetic pattern of SARS, or the common cold. They claim that this possible immunity may last up to 17 years.

Coronavirus related symptoms that mimic the common cold, called betacoronavirus, may either have immunity or be infected by a milder form of the virus. Betacoronaviruses, specifically OC43 and HKU1, are the cause of common colds as well as severe chest infections, leaving the young and elderly in critical conditions.

The beta virus has similar genetic features with its SARS family, such as COVID-19 and Middle East Respiratory Syndrome (MERS). If an individual had been previously exposed to the common cold, the body develops memory T cells, which become a defense system when a similar infection enters the body, resulting in immunity.

T cells, a type of white blood cell, is a prominent part of the immune system, adjusting the body to respond to specific attacking pathogens. Because of their ability to create lasting shields against viruses, they are called 'memory cells.'

Professor Antonio Bertoletti, an immunologist from the Duke-NUS Medical School in Singapore, and his team have new findings on the function of T cells amidst the global pandemic. They discovered that patients who survived the SARS lung virus in 2003 had immune responses to COVID-19 antibodies.

'These findings demonstrate that virus-specific memory T cells induced by betacoronavirus infection are long-lasting, which supports the notion that COVID-19 patients would develop long-term T cell immunity,' said the team. 'Our findings also raise the intriguing possibility that infection with related viruses can also protect from or modify the pathology caused by SARS-Cov-2 [the strain of coronavirus that causes COVID-19].'

Four blood samples were taken from coronavirus patients who had recovered, 23 who has SARS, and 18 individuals who had exposed to neither deadly viruses.

What surprised Bertoletti's team was that 50% of unexposed patients had defensive T-cells which could defend their immune system against the betacoronaviruses SARS and COVID-19. Most likely, the scientists concluded, their immunity developed memory cells from obtaining common colds caused by betacoronavirus or other unknown pathogens.

In another study of T cell immunity, virologist Angela Rasmussen of Columbia University agrees with the Singaporean team. Alongside Shane Crotty and Alessandro Sette, immunologists at the La Jolla Institute for Immunology, bioinformatic tools were used to predict which viral protein fragments would trigger the strongest T cell responses.

Read Also: First American to Receive Placental Cell Treatment For COVID-19 is an Acclaimed Broadway Scenic Designer

Ten recovered patients were exposed to the immune cells where their 'helper T cells...recognized the SARS-CoV-2 spike protein.' 'The immune system sees this virus and mounts an effective immune response,' said Sette. Rasmussen said, 'these papers are really helpful because they start to define the T cell component of the immune response.'

New insight on adaptive immunity against coronavirus antibodies is the key to developing a 'vaccine design and evaluation of candidate vaccines,' notes Bertoletti's study. Moreover, understanding more about immunity today will be important for 'epidemiological model calibration of future' pandemics and social distancing measures.

Read Also:Italy Nears Herd Immunity As Over Half of Its Covid-19 Epicenter's Population Tested Positive for Antibodies

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Some Forms of Common Cold May Give COVID-19 Immunity Lasting up to 17 Years, New Research Suggests - Science Times

Immunology

State and Centre trying hard, but didnt spread awareness about community risk – Hindustan Times

June 13, 2020 medical

As the state hit the one lakh mark for Covid-19 cases on Friday, Dr Satyajit Rath, retired scientist from Delhi-based National Institute of Immunology, and currently adjunct professor at the Indian Institute of Science Education and Research, Pune, spoke on factors behind the rise in Covid-19 cases, states handling of the outbreak and public health care system. Excerpts:

What are the factors responsible for the large number of Covid-19 cases in Maharashtra and Mumbai?

Globally, much of Sars-CoV-2 transmission seems to be direct, meaning from being in close proximity to an infected person. Since the entry of the infection into India is from overseas, it is quite unsurprising that the high-volume international entry points, Mumbai and Delhi, have had most seeding of local outbreaks. When that is coupled with crowded urban conditions, especially in Mumbai, again, the number and size of local outbreaks are unsurprising, as also the outcome that infection has spread to surrounding areas (western Maharashtra, Gurgaon) from these initial seeding points. These are not really huge numbers, given the numbers some other countries with early high-volume outbreaks have had and continue to have. The pandemic is going to be with us in fits and starts for a long time.

Has the state done enough to contain the epidemic?

The state (the Centre and Maharashtra government) is trying hard, and with good intentions, and acknowledges and tries to act on evidence-based directions and approaches needed (unlike the government leaderships in the two countries ahead of India Brazil and the USA). It also acknowledges some of its own limitations and shortcomings.

And the inadequacies?

The state has failed to address the core issue, which is to build a community partnership in which there is clarity about the fact that the pandemic is not so much an individually lethal risk as a community risk. The result is stigmatisation, ostracisation, fear and concealment, disruption of non-Covid-related health services and their usage (childrens vaccinations, other non-pandemic illness handling, et cetera), and the like. The state has not built robust and generous public support structures for the underprivileged anywhere near the extent needed.

What is your assessment of the public health infrastructure?

The state (the Centre and Maharashtra government), most directly, have not yet acknowledged the sad state of public health care systems, especially at community level. It is a contributor to the quantitatively inadequate pandemic response. As a simple example, the general consensus globally is that for efficient community-based Covid-19 case identification and contact tracing, one skilled and trained health worker will be needed per three thousand people. This kind and level of manpower in neighbourhoods, backed up with infrastructure, data handling, and testing-technical capacity, was not available before the pandemic, has not been aimed at so far, and is not being built for the future.

Data shows that the state has been carrying out about 14,000 tests everyday as against the testing capacity of 38,000. Its a similar case with Mumbai too. Should we be testing more?

Given these numbers, it is quite likely that larger numbers of testing would help; more tests will still likely identify more cases. However, a major issue has come to be; how easy is it to get tested, and how clear, supportive and unthreatening are the practical decision streams for what is to be done if the test comes positive and how it is to be done?

What has been the consequence of constant changes in testing criteria by Indian Council for Medical Research (ICMR)?

The major consequence is that it becomes difficult if not impossible to compare data from testing under one set of criteria with data from testing under another set. This makes it hard to say anything much about the trajectory of the epidemic in the country. However, it is also true that ICMR has had to work in practical constraints of test and related resource (swabs, transport) availability, and of changing case numbers.

How do you gauge the potential impact following the easing of lockdown restrictions in Maharashtra/Mumbai?

It is quite likely that numbers will go up with a delay of a week or two, especially because there is no cultural assimilation in the community of the need for physical distancing (not social distancing; we need social solidarity). Case numbers are most likely to go up, not in some orderly and well-distributed fashion, but as increasing numbers of local, scattered outbreaks.

Suggestions to control further spread of the infection and revive the economy range from a ban on gathering of more than two or five people, enforcement of a stringent containment strategy and cyclical lockdown. Your comments.

A single strategy wont work everywhere, all the time. All of these and more are likely to be invoked and used, in reactive fashion, in different local situations at different times. It would be helpful if some systematic analytical thought has been given to identifying which local circumstances would warrant which of these containment approaches; I do not know if governments are doing this kind of planning.

What is the takeaway, three months into the pandemic?

Unless we persuade ourselves, culturally, as a community, that physical distancing and social solidarity need to become the new normal, and unless we re-commit ourselves, as a representative government, to the idea of major, long-term, durable investment in comprehensive public health systems as a core responsibility of governance, the outcomes of the pandemic are likely to be bleak for us.

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State and Centre trying hard, but didnt spread awareness about community risk - Hindustan Times

Immunology

Cancer CART therapy: What are the benefits and stakes? – Express Pharma

June 13, 2020 medical

The last decade has been termed the immunotherapy decade in the oncology-immunology sphere thanks to the rapid and successful research and development pipeline of cutting-edge cancer therapies that are indeed showing promise in curing relapsed and refractory cancer. From pre-clinical research and approved clinical trials to actual marketed launch of these super drugs the title is appropriately bestowed.

Amongst immunotherapies, the latest and most innovative is CARTT-cell based immunotherapy. 2017-2018 saw two big pharma companies launch two such drugs that were successful in treating refractory haematological malignancies Novartis Kymriah (for paediatric and young adults B-cell ALL) and Gilead Yescarta (refractory non-Hodgkin lymphoma). Soon after, there have been a plethora of activities R&D, regulatory and commercial that has globally bolstered the technological promise of this new therapy. Developing nations such as India have also been considering the efficacy and superiority of this technology however high cost remains a challenge in the adoption of this technology (more on that later).

Technology

A chimeric antigen receptor is a synthetic protein that is developed by the fusion of extracellular antigen-recognising domains and intracellular signalling domains. These T-cells can additionally be modified by genetic engineering to augment desired immunological outcomes. Recently, gene-editing technologies such as CRISPR are also being incorporated into the design of such cells.

Steps of the therapy Patients T-cells are harvested and genetically engineered to insert the tissue-specific marker (in this case cancer-specific marker) as well as co-stimulatory inserts (as required). Next, the cells are expanded and infused back into the patient. This whole activity takes two weeks.After infusion, the T-cells target the specific tumour, proliferate and activate killing mechanism by various effector mechanisms.

Core advantages Precise targeting, patients own T-cells harvested (effective auto-immunity tolerance), relatively fast time for the entire activity, robust effector mechanisms, one-time infusion as cells multiply and augment responses

Side effects Cytokine release syndrome and neurological symptoms are the primary clinical side-effects encountered during the therapy.

Pitfalls Selection of markers have to be very specific (a lot of research is underway to select specific markers for various cancers), high cost as several steps involved (off-the-shelf T -cells are being tested to minimise the manufacturing and transport resources).

Cancer indications

Both KYmriah and Yescarta is CD19-based CART therapy treating B-cell ALL and non-Hodgkin lymphoma with successful clinical outcomes.

The therapy has shown challenges in combating solid tumours this has been mainly due to the immunological micro-environment of such tumours and the relatively imprecise targeting markers of such tumour. Several studies in the pre-clinical phase are underway that are selecting specific markers for several indications such as colorectal, breast, gliomas and ovarian cancer. A few of them are being tested in Phase 1,2 clinical trials.

Regulatory approvals and current clinical trials

USA clinical trials database has 135 clinical trials (ongoing and just completed) in different phases (Phase 1,2 and 3) testing either newer cancer indications or modifications to haematological cancers (lymphomas, leukaemias and myelomas) as well as treatment monitoring over a long-term period. Many of these trials are centred on combination effects of chemotherapy and CART therapy and whether this has a better outcome than either alone. In Europe, there are 37 CART-related ongoing trials in different stages of clinical trials (Phase1, 2 and 3) testing the safety, efficacy or even long-terms effects of such infusion (clinical trials registry/EU). Most solid tumour indications are in the pre-clinical stage however and have a long way before being marketed.

Patient success stories (and failures)

Pivotal post-marketing analysis with Yescarta has shown robust and significant remission rates (and years gained) in older B-cell lymphoma patients who have failed two initial lines of cancer treatment. Another dataset pointed out to an astonishing three-year survival rate of 50 per cent.

Its close competitor the only other CART therapy already running successfully in the market Novartis Kymriah has shown increased efficacy with fewer side-effects in both paediatric and adult patients. The post-marketing follow-up trial has shown enhanced promise of CART adoption by clinicians and oncologists.

The most frequent side-effect that persists in the infused patients is cytokine release syndrome and intense inflammatory conditions that are mitigated by proper steroidal treatment. The other notable side-effect is neurotoxicity that has resulted in fatalities as well.

The long-standing effect of such infusions is currently being tested in several clinical trials.

Commercial scenario

Global CART therapy market can be divided into geography, type of antigen and cancer indication. The US dominates the market followed by Europe. Big pharma companies operating in this domain are listed below with different operations ranging from product development to expanding clinical pipeline to licensing deals and acquisitions.

Antigens (markers specific for specific cancer) are still in the nascent stage and are being tested in various pre-clinical phase especially for solid tumours. Some of the notable ones that have already made their way into clinical trials are CD19, CD22, BCMA, muc16, L1CAM.

Different cancer indications being tested are lymphoma, leukaemia, myeloma and solid cancers such as gliomas, breast, colorectal cancers (a lot of solid cancer therapy is being under pre-clinical and safety/efficacy phases).

Big players and their pipeline

Novartis the first CART product Kymriah was approved in two cancer indications both paediatric and adult ALL and B-cell lymphoma and is successfully been adopted by clinicians. Other trials in phase 1 and 2 are being conducted targeting mainly haematological indications.

Gilead Kite pharma innovated Yescarta was marketed by Gilead after its buy-out. Yescarta is targeted for older patients who have relapsed lymphoma after 2 initial lines of treatment and is currently being evaluated promisingly at the post-marketing stage. Other trials at phase1/2 targeting ALL and solid tumours are also in the pipeline.

Juno Therapeutics 11 clinical trials (Phase1/2) addressing different cancer indications including solid tumours like lung, breast, neuroblastoma and ovarianhttps://www.junotherapeutics.com/our-pipeline/

Celyad currently in developing allogeneic off-the-shelf and modified CART T cells for wider distribution and cost redressal solutions. Solid tumour indications and B-cell malignancies are in the pre-clinical stage while colorectal cancer and AML are in phase 1https://www.celyad.com/en/our-pipeline

Cellectis Off-the-shelf CART therapy for alleviating the cost of manufacturing. Mostly phase 1 studies targeting haematological cancers.

Allogene off-the-shelf and edited CART therapy for non-Hodgkins and myelomas mainly in clinical phase 1 stage and rest of pipeline in the pre-clinical stage. (They acquired the cell-based oncology asset from Pfizer).

Celgene (Bristol-Myers Squibb) Several clinical trials including phase 3 for lymphomas and multiple myelomas are in the pipeline.

Bluebird Pre-clinical and clinical-stage trials underway the main focus is that of haematological cancer but with a specialised type of antigen marker (B cell maturation antigen).

Novartis dominates the market, followed by Kite Pharma, Inc., Juno Therapeutics, Pfizer Inc, Celgene Corporation, Cellectis, Sorrento Therapeutics, Bluebird Bio, and Immune Therapeutics. Collectively the key players ensure technology development through partnerships and licensing deals with smaller biotech firms as well as academic research centres. They also sponsor clinical trials to validate the technology across several countries. Mergers and acquisitions abound in the immunotherapy domain Kites CART (Yescarta) has been acquired by Gilead. Similarly, Juno Therapeutics has now been acquired by Celgene. Celgene, Gilead and Autolus are at the forefront of the industry-sponsored CART clinical trials.

Belgium-based Celyad and France-based Cellectis are two companies who are innovating on cost-effectiveness by off-the-shelf development of CART cells. This if successfully leveraged- would benefit enormously on mitigating cost and thus effectively introduce the technology to a wider population globally.

How is it shaping up in India?

India has shown a substantial promise in immunotherapy and has many cancer hospitals and clinicians adopting immunotherapy either alone or in combination with chemotherapy. However, the field of CAR-T therapy is in pre-absorption stage and will take time and effort to reach the equilibration stage. One of the main caveats is the high price of manufacturing such cells and additionally the lack of a health insurance reimbursement system in India.

To adopt and equilibrate this technology, the following measures need to be implemented:

This is the right stage for CART research in institutes and hospital labs whereby eminent scientists are developing the optimal platform and the best approach for CAR-T therapy. Recently, a specialised cell therapy (including CAR-T therapy)-based Immmuneel Therapeutics have been set up with the purpose of scalability and commercialisation of CAR-T therapy into Indian cancer market it is currently testing the expansion and accessibility measures of CAR-T adoption in India. Concomitantly, research departments in IIT-Bombay and clinicians at TATA Memorial Hospital are investigating and addressing scientific advancements to the CAR-T technology to make it more suitable and accessible for Indian patients.

Prof Dr SV Chiplunkar, Director ACTREC, Tata Memorial Centre and Current President of Immuno-Oncology Society of India feel that it is still a dream due to the following three main hurdles:

1) Infrastructure requirement Although bone marrow transplants are routinely done here, the cell-based therapies require different infrastructural setup and expertise. There are not enough cGMP labs, although there is serious effort to establish them at few institutes and multinationals.

2) Regulatory bodies to certify these cGMP facilities for cell therapies and clinical trials for cell therapies are not in place ICMR is in the process of developing guidelines for immune cell therapies.

3) Affordability and concomitant health insurance coverage would remain a challenging hurdle.

Dr Arun Anand, Chief Operating Officer and Dr Shashwati Basak, Senior Director, Quality from Immuneel Therapeutics also note the above challenges but at the same time feel it can be combated by adopting strategic and sustainable efforts across all three domains: technological, regulatory and commercial. There is a huge unmet need however acceptance would primarily be fostered through augmenting both efficacy and convenience. Pricing remains a detriment but even if there is a 10-fold reduction (from $450,000 to $55,000) in India, it would benefit a subset of patients: terminally ill and relapsed/recurrent and refractory to first/second line of treatment. Strategic initiatives with the Government to adopt policies and guidelines for cell-based therapy and to establish an ecosystem for CAR-T development and adoption is the main goal. To achieve this goal, Immuneel is collaborating globally across academic-industry platforms spanned across technology, manufacturing, clinical trials, and affordability.

Within 10 months of starting operations, they have developed a strong global and national network and infrastructure to achieve its mission of CAR-T therapy development, delivery, adoption and accessibility in India.

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Cancer CART therapy: What are the benefits and stakes? - Express Pharma

Immunology

It has become clear in the past few months that for at least somepeople with COVID-19, halting ‘cytokine storm’ is key to survival – Wilkes-Barre…

June 13, 2020 medical

Many coronavirus patients seem to get better at first, then rapidly decline and are overtaken by an overwhelming immune response that causes the body to turn on itself.

This cytokine storm was once an arcane phenomenon familiar mainly to rheumatologists who study when and how the immune systems safeguards fail.

But it has become increasingly clear in the past few months that, at least in a subset of people who have the virus, calming the storm is the key to survival.

At least a dozen candidate drugs to treat the coronavirus rely on this premise. A few devices that purify the blood, as dialysis machines do, are also being tested. One promising drug made by Roche is in several clinical trials, including a late-stage trial in combination with the antiviral drug remdesivir. And a recent paper in the journal Science Immunology described preliminary data on a drug that stems the flood of cytokines at its source, and seems to lead to rapid recovery.

Immunity run rampant

When immune cells first encounter a pathogen, they release molecules called cytokines to recruit even more cells to the fight. Once the danger recedes, the immune system usually turns itself off. But occasionally it doesnt shut up, said Dr. Jose Scher, a rheumatologist at New York University Langone Health. The immune system goes on and on and on and on.

This unrelenting response can exhaust the immune system; shut down lungs, kidneys and liver; and prove fatal. It can do so even in young people and children who have no underlying conditions. In a milder form, this same mechanism is at play in autoimmune diseases like lupus and rheumatoid arthritis. Most of the drugs that doctors have tried for the coronavirus, including steroids and hydroxychloroquine, are treatments for those diseases, disrupting their supplies.

Our medicines have been co-opted from us, said Scher, adding that they are often being deployed with little insight into their proper use or pitfalls.

First signals

Early in the pandemic, doctors in China and Italy recognized the telltale signs of a body in cytokine shock fever, a racing heart and plummeting blood pressure and treated patients with the drug tocilizumab. That drug is marketed by Roche as Actemra, which blocks a cytokine called interleukin-6.

Anecdotal evidence and preliminary trials soon confirmed their hunch. Since then, several studies have shown that high levels of IL-6 portend respiratory failure and death, and that Actemra lowers these risks.

Other drugs that quell IL-6 activity have shown promising results, as has Kineret, a drug that quiets a different cytokine called IL-1.

A more efficient solution than blocking any single cytokine would be to break the cycle of inflammation at its origin, experts said. For example, blood pressure drugs that mute the chemical signals that precede cytokines have shown some benefit in mouse studies and are being tested in people.

In the paper published in Science Immunology, scientists identified that the cancer drug Calquence, made by AstraZeneca and also called acalabrutinib, can cut off the cytokine supply at its source.

Treating patients with drugs like tocilizumab is like cutting the branches off a tree, said Dr. Louis Staudt, a scientist at the National Cancer Institute who was one of the lead investigators of the study. Acalabrutinib is going for the trunk of the tree.

The team identified macrophages scavenger cells that chew up bacteria and viruses as the key source of the cytokine surge in COVID-19, the disease caused by the coronavirus.

These patients get in trouble because their house is on fire in their lungs, Dr. Staudt said. This drug can put out this inflammatory fire by disabling macrophages.

The involvement of macrophages might also explain why some people suddenly deteriorate weeks into infection. Large number of the cells would become involved only after the virus had substantially damaged the lungs. Theres a time delay there, he said.

People who have diabetes, obesity and hypertension have a higher baseline of inflammation, so its also possible, he said, that this may explain why they are particularly vulnerable to becoming seriously ill. AstraZeneca plans to test Calquence in larger trials.

The insights gained from studying COVID-19, especially because of the large numbers of people affected, might allow researchers to understand inflammatory syndromes that have long remained mysterious, Staudt said.

Purifying blood

The pandemic has also popularized an approach that is commonplace for treating some diseases, but has not been proved in clinical trials to work for coronavirus patients. For example, the Food and Drug Administration has authorized the use of a cartridge that continually filters excess cytokines from the blood, similar to the way a dialysis machine removes toxins. The purified blood is then pumped back into the body.

The device, called CytoSorb, is about the size of a drinking glass and is filled with coarse polymers, each roughly the size of a grain of salt. Every grain, or bead, has millions of pores and channels that add up to a surface area of roughly seven football fields and filter out molecules roughly the size of cytokines. One cartridge can purify an entire bodys blood volume roughly 70 times in a 24-hour period.

Bigger objects like cells go around the beads and are unaffected, and smaller things like electrolytes go straight through, said Dr. Phillip Chan, the chief executive of CytoSorbents Corp., which makes the device. CytoSorb may also remove some proteins that the body needs.

But in a life-threatening illness when you have a cytokine storm, Chan said, its more or less a race to remove what will kill you versus the temporary inconvenience of removing things that your body manufactures all the time anyway.

In Europe, CytoSorb has been commercially available since 2013 and has been used more liberally. Dr. Stephan Ziegeler, who leads a specialized pulmonary intensive care unit at a hospital in Ibbenburen, Germany, has so far treated eight people with CytoSorb. Of these people, three have been discharged, three are being weaned off ventilation and two have died.

Patients with bacterial sepsis typically need a maximum of three cartridges one per day at $1,200 but coronavirus patients have such astronomical levels of cytokines, Ziegeler said, that some have needed dozens of cycles, with two fresh cartridges per day.

It seems that COVID-19 has a prolonged cytokine storm a prolonged, really effective inflammatory state compared to other sepsis states, he said.

CytoSorb is not the only mechanical approach being used; the FDA has also authorized the use of another device, called Oxiris, for coronavirus patients. And there are plans to try CytoSorb in combination with tocilizumab.

All of these approaches are worth pursuing, Scher said, but they all must be tested in rigorous clinical trials with the right control groups: That will be the only way to learn for sure.

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It has become clear in the past few months that for at least somepeople with COVID-19, halting 'cytokine storm' is key to survival - Wilkes-Barre...

Immunology

Immunology Drugs Market: What Effect is COVID 19 Bringing That Will Change Key Players Position: Thermo Fisher Scientific Inc., ERS Genomics, CRISPR…

June 13, 2020 medical

(Jan 2020) WMR has released a report on Immunology Drugs Market 2027. It provides key insights through details and gives customers a competitive advantage. Immunology Drugs Industry Size, Market Share Value, Competitor Surveys, Industry Outlook and Analytics cover a variety of factors such as geographic analysis, Immunology Drugs types, applications, and more.

Worldwide Market Reports Immunology Drugs Industry information includes surveys based on Current Scenarios, Historical Records and Future Forecasts. Organize accurate data from various aspects. It provides a 360 overview of the industrys competitive environment. This helps companies understand threats and challenges in front of their business.

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Following Key Players are Analysed in this Report: Thermo Fisher Scientific Inc., ERS Genomics, CRISPR THERAPEUTICS, Merck KGaA, Editas Medicine, GE Healthcare Dharmacon Inc., Takara Bio USA

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Immunology Drugs Market: What Effect is COVID 19 Bringing That Will Change Key Players Position: Thermo Fisher Scientific Inc., ERS Genomics, CRISPR...

Immunology

The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients – Science

June 12, 2020 medical

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that first emerged in late 2019 is responsible for a pandemic of severe respiratory illness. People infected with this highly contagious virus can present with clinically inapparent, mild, or severe disease. Currently, the virus infection in individuals and at the population level is being monitored by PCR testing of symptomatic patients for the presence of viral RNA. There is an urgent need for SARS-CoV-2 serologic tests to identify all infected individuals, irrespective of clinical symptoms, to conduct surveillance and implement strategies to contain spread. As the receptor binding domain (RBD) of the spike protein is poorly conserved between SARS-CoVs and other pathogenic human coronaviruses, the RBD represents a promising antigen for detecting CoV-specific antibodies in people. Here we use a large panel of human sera (63 SARS-CoV-2 patients and 71 control subjects) and hyperimmune sera from animals exposed to zoonotic CoVs to evaluate RBD's performance as an antigen for reliable detection of SARS-CoV-2-specific antibodies. By day 9 after the onset of symptoms, the recombinant SARS-CoV-2 RBD antigen was highly sensitive (98%) and specific (100%) for antibodies induced by SARS-CoVs. We observed a strong correlation between levels of RBD binding antibodies and SARS-CoV-2 neutralizing antibodies in patients. Our results, which reveal the early kinetics of SARS-CoV-2 antibody responses, support using the RBD antigen in serological diagnostic assays and RBD-specific antibody levels as a correlate of SARS-CoV-2 neutralizing antibodies in people.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for an ongoing pandemic that has already killed over 320,000 people and paralyzed the global economy (1). Currently, the main method for laboratory diagnosis of SARS-CoV-2 is PCR testing of nasopharyngeal swabs. There is an urgent need for highly specific and sensitive antibody detection assays to answer fundamental questions about the epidemiology and pathogenesis of SARS-CoV-2 and to implement and evaluate population-level control programs (2). Efforts to understand the pathogenesis and define risk factors for severe SARS-CoV-2 disease have been hampered by our inability to identify all infected individuals, irrespective of clinical symptoms. To contain the pandemic, many countries resorted to the widespread quarantine of cities and regions. By deploying reliable antibody assays for population-level testing, it will be possible to obtain the high-resolution spatial data needed to implement policies for containing the epidemic and informing strategies for re-opening communities and cities.

Studies with SARS-CoV-2 and other human CoVs demonstrate that people rarely develop specific antibodies within the first 7 days after onset of symptoms (37). By 10-11 days after onset of symptoms, greater than 90% of SARS-CoV-2 patients develop specific IgG and IgM (36). For SARS-CoV-1 and the more distantly related MERS-CoV, IgG antibodies have been observed to persist for at least one year after infection (8, 9). These observations strongly support the feasibility of using antibody assays for identifying recent and remote SARS-CoV-2 infections and for conducting population-level surveillance.

SARS-CoV-2 is a -coronavirus, a subgroup that includes the closely related SARS-CoV-1 and the more distantly related MERS-CoV and the common-cold human CoVs (HCoV-OC43 and HCoV-HKU1) (10). Many companies have quickly developed tests for SARS-CoV-2 antibody detection. These assays utilize the inactivated whole virion, viral nucleocapsid protein or viral spike protein as antigens in ELISA, lateral flow or other testing platforms. While the performance of these assays has not been fully evaluated, some assays appear quite sensitive when used 10 days or more after the onset of symptoms (6, 11). The specificity of SARS-CoV-2 antibody assays has not been adequately addressed. Humans are frequently infected with HCoV-OC43 and HCoV-HKU1 and most adults have antibodies to these viruses (10). Any antibody cross-reactivity between common HCoVs and SARS-CoV-2 would result in false-positive results interfering with antibody-based testing and surveillance for SARS-CoV-2.

SARS-CoV-1 and HCoV OC43 elicit antibodies that cross-react against related CoVs (12, 13). Following the SARS-CoV-1 outbreak in 2003, the overall specificity of serological assays utilizing the nucleocapsid protein of SARS-CoV-1 was poor, whereas assays based on the spike protein were more specific (1416). In recent studies, the receptor binding domain (RBD) of the spike protein of SARS-CoV-2 has shown promise as an antigen for specific antibody detection (4, 17, 18). Here we report the production of properly folded recombinant receptor binding domains (RBDs) from the spike proteins of SARS and common-cold HCoVs in mammalian cells. We use these recombinant antigens and a large diverse panel of human and animal sera to evaluate the RBD as an antigen for SARS-CoV-2 serology. We demonstrate that the recombinant SARS-CoV-2 RBD antigen is highly sensitive and specific for detection of antibodies induced by SARS-CoVs. We also observed a strong correlation between the levels of RBD-binding antibodies and levels of SARS-CoV-2 neutralizing antibodies in patients. Our results support the use of RBD-based antibody assays for serology and as a correlate of neutralizing antibody levels in symptomatic people who have recovered from SARS-CoV-2 infections.

The S1 and S2 subunits of the spike (S) protein of Coronaviruses are required for viral entry. The surface accessible receptor binding domain (RBD) on the S1 subunit binds to receptors on target cells, whereas the exposure of the fusion loop in the S2 subunit induces fusion of the viral envelope to the host cellular membranes (19). The RBDs of SARS-CoVs, which bind to angiotensin-converting enzyme 2 (ACE2) receptor on the host cells, are also a major target of human antibodies (Fig. 1A and B). As the RBD is a common target of human antibodies and poorly conserved between SARS-CoVs and other pathogenic human coronaviruses (Fig. 1C), this domain is a promising candidate for use in antibody-based diagnostic assays. We expressed the RBD of 2003 and 2019 SARS-Co-Vs and four common human coronaviruses (HCoV-HKU-1, -OC43, -NL63 and -229E) as fusion proteins that were secreted from human cells. The recombinant RBDs were purified from the cell culture medium by affinity chromatography and purity was confirmed by SDS-PAGE (Fig. 1D). We used sera and monoclonal antibodies from animals immunized with SARS-CoV-1 or -2 spike proteins to assess the structural integrity of the purified recombinant RBD antigens. Pooled serum from mice immunized with SARS-CoV-2 spike protein had antibodies that bound well to the RBD of SARS-CoV-2 and poorly to the RBDs of SARS-CoV-1 and other common HCoVs (Fig. 1E). Sera from mice or rabbits immunized with SARS-CoV-1 or cross-reactive monoclonal antibody 240C reacted with the RBDs of SARS CoV-1 and -2 but not common human CoVs (Fig. 1E). Human serum collected before SARS-CoV-2 emerged contained antibodies to common - and -HCoVs (NL63 and HKU-1) but not to SARS-CoV RBD antigens (Fig. 1E). These results suggest that the purified recombinant RBD antigens retain native structures required for specific antibody binding.

Production and characterization of the RBD of the coronavirus spike antigens. (A) The spike protein on the virion surface engages its cognate receptor via the RBD. (B) RBD of the spike protein is the main human antibody target in SARS-CoV-1. (C) The amino acid sequence corresponding to RBD of the spike protein is poorly conserved between SARS-CoV-2 and common human coronaviruses. (D) Coomassie-stained SDS-PAGE of purified spike RBD antigens from different CoVs. (E) Binding characterization of the spike RBD antigens with immune sera and a monoclonal antibody. SARS-CoV-1 monoclonal antibody (240C), serum from a mouse immunized with VRP expressing SARS-CoV-2 or SARS-CoV-1 spike protein, serum from a rabbit immunized with SARS-CoV-1 spike protein and an archived human sample collected before SARS-COV-2 were tested for binding against RBD spike antigens from SARS-CoV-2, SARS-Co-V-1, HCoV (NL63) and HCoV (HKU-1).

To evaluate the specificity of the recombinant SARS-CoV-2 RBD in serology, we used human sera collected from different populations before the current pandemic. The sera were tested at a high concentration (1:20 dilution) for binding to the recombinant RBDs from SARS-CoV-1, SARS-CoV-2 and common - and -HCoVs (Fig. 2). Sera collected from healthy American adults (N = 20) before the SARS-CoV-2 pandemic frequently had high levels of antibodies to the recombinant RBDs of NL63 and HKU-1 CoVs but not to SARS-CoVs (Fig. 2A). We also tested archived pre-SARS-CoV-2 pandemic sera collected from individuals in South Asia, the Caribbean and Central America who had recently recovered from arbovirus infections. As in the case of healthy adults from the USA, most of the subjects from different parts of the world had high levels of antibodies to the RBD of common HCoVs but no antibodies to the RBD of SARS-CoVs (Fig. 2B). To assess if other human respiratory viruses stimulated antibodies that cross-reacted with the recombinant SARS-CoV RBD, we tested early convalescent sera from people with laboratory confirmed influenza A and respiratory syncytial virus infections and sera from guinea pigs immunized with a panel of different human respiratory viruses (Fig. 2 C and D). Except guinea pigs immunized with SARS-CoV-1, none of the sera had detectable levels of antibodies to the recombinant RBD of SARS-CoVs.

Spike RBD antigen binding was assessed by in-house ELISA assay against a panel of de-identified archived serum specimens obtained from (A) American healthy adults; (B) Convalescent sera from dengue/Zika patients in South Asia, Caribbean, and Central America; (C) People who had recently recovered from viral respiratory illnesses; and (D) Guinea pigs immunized with respiratory viruses or SARS-CoV-1 spike protein. The cutoff values determined by the receiver operating (ROC) curve analysis (Fig S3) for the ELISA assay are indicated by the broken line.

The known pathogenic human CoVs are members of the -coronavirus and -coronavirus genera (Fig. 3A). HCoV-NL63 and 229E are two -coronaviruses that frequently infect and cause a mild common-cold-like illness in most people. HCoV-OC43 and HKU-1 are two group 2A -coronaviruses that also commonly infect people and cause mild disease. Most adults (>90%) have antibodies to these common-cold HCoVs. SARS-CoV-1 and -2 and MERS-CoV are group 2B and 2C zoonotic -coronaviruses that have recently crossed into humans and caused severe illness. The - and -coronavirus genera also contain a large number of zoonotic viruses that infect different animal hosts, which have not been implicated in human disease to date. To further assess the specificity of SARS-CoV-2 RBD for serology, we obtained and tested sera from people who had recently recovered from a laboratory-confirmed common-cold HCoV infection and sera from guinea pigs immunized with different animal CoVs (Fig. 3 B and C). None of the immune sera from people exposed to recent HCoV infections cross-reacted with the recombinant RBD of SARS-CoVs. None of the guinea pigs vaccinated with different zoonotic CoVs had antibodies that cross-reacted with the recombinant SARS-CoV RBDs (Fig. 3B and C). These results establish that most individuals, including people who have been recently exposed to acute common HCoV infections, do not have detectable levels of cross-reactive antibodies to the recombinant RBD of SARS-CoVs.

Evaluation of SARS-CoV-2 spike RBD antigen specificity against common human CoVs and animal CoVs sera. (A) Phylogenic tree of the spike protein from representative coronaviruses. Coronavirus genera are grouped by classic subgroup designations (, a-d, , and ). SADS-CoV is a distinctive member of the subgroup (indicated by *). Numbers following the underscores in each sequence correspond to the GenBank accession number. Spike RBD antigen binding was assessed by in-house ELISA assay using (B) human convalescent samples obtained from PCR-confirmed HCoV (NL63, black) and HCoV (OC43 (red), HKU-1 (blue)) infections and (C) sera from guinea pigs or pigs immunized with spike antigen from SARS-CoV-1 or indicated animal CoV. The cutoff values for the ELISA assay are indicated by the broken line. Feline Infectious Peritonitis Virus, 79-1146 (Feline CoV, Pink); respiratory coronavirus strain ISU-1(Porcine CoV, green); Porcine Transmissible Gastroenteritis Virus (TGEV, orange); Bovine Coronavirus strain mebus (Bovine CoV, cyan); Avian Infectious Bronchitis Virus, Massachusetts (Avian CoV, violet); Turkey Coronavirus, Indiana (Turkey CoV, yellow); Canine Coronavirus strain UCD1 (Canine CoV, hot pink); SARS-CoV-2 (SARS, brown).

To evaluate the sensitivity of the RBD of SARS-CoV-2 for identifying infected individuals, we obtained a total of 77 serum samples from 63 patients with laboratory-confirmed (i.e., PCR positive) SARS-CoV-2 infections collected at different times after the onset of symptoms. All the samples were tested for binding of total immunoglobulin (Ig) and IgM antibodies to recombinant RBD antigens from SARS-CoVs and common-cold HCoVs. The sensitivity of the assay was high (98% and 81% respectively for Ig and IgM) for specimens collected 9 days or more after onset of symptoms (Fig. 4A). As expected, overall sensitivity was lower (57% and 43% respectively for Ig and IgM) for specimens collected between 7 and 8 days after onset of symptoms (Fig. 4A). With samples collected 9 days or more after onset of symptoms, we observed some Ig and IgM antibody cross reactivity with the RBD of SARS-CoV-1 (67% and 30% respectively for Ig and IgM), which was anticipated as these viruses are closely related group 2B -coronaviruses (20, 21). When the specimens were further analyzed to estimate the timing of seroconversion, we observed a marked transition from seronegative to seropositive for both Ig and IgM about 9 days after the onset of symptoms (Fig. 4A and B). By day 9 after onset of symptoms, most patients had high end-point titers in the RBD Ig ELISA (Fig. S1). To analyze the kinetics of all three of the major isotypes of serum antibodies within the first 6 weeks after the onset of symptoms, we separately measured IgG, IgA, and IgM in 49 serum samples obtained from SARS-CoV-2 infected patients at >9 days after onset of symptoms. Most individuals (46/49) developed IgG responses (Fig. 4C). IgA and IgM responses were observed less frequently (IgA = 38/49, IgM =34/49) than IgG (Fig. 4C). For 14 individuals with laboratory-confirmed SARS-CoV-2 infection, we had two specimens collected at different times early in the infection (Fig. 4D). Two subjects (P70 and P50) were seronegative within the first 4 days and seropositive for both Ig and IgM 9 or more days after onset (Fig. 4D). For three subjects (P58, P56, P52) the acute samples were collected after 9 days and the convalescent samples were collected 21 days or more after onset. In these individuals both acute and convalescent samples were positive, and we observed an increase in Ig and IgM levels in the second specimen. For the remaining 9 subjects, the acute specimen was collected on day 7 after onset and the convalescent specimen was collected >9 days after onset. Six out of the 9 subjects already had specific Ig, IgM or both in the acute specimen collected on day 7. All the subjects except one (P54) seroconverted or had elevated levels of antibody in the convalescent sample collected >9 days after onset of symptoms. These results indicate that most people seroconvert between days 7 and 9 after onset of symptoms. Subject P54 was an outlier and did not develop specific Ig or IgM antibodies. All the individuals with documented SARS-CoV-2 had Ig but not IgM antibodies that bound to the RBD of common HCoVs, which is consistent with their high prevalence in humans (Fig. 4A). These results demonstrate that the RBD of SARS-CoV-2 is a highly sensitive antigen for antibody detection in patients 9 days or more after onset of symptoms.

Evaluation of SARS-CoV-2 spike RBD antigen sensitivity. (A) Overall SARS-CoV-2 spike RBD antigen sensitivity as assessed by the in-house Ig and IgM ELISA assays using clinical specimens obtained from PCR-confirmed SARS-CoV-2 subjects. For comparison, binding results of the RBD spike antigens from a representative HCoV (HKU-1) with the same specimens are also presented. The changes of the levels of (B) total Ig and (C) IgG, IgA and IgM antibodies binding to RBD of the SARS-CoV-2 spike antigen. The binding of the spike RBD antigen from SARS-CoV-2 to 49 de-identified serum samples obtained from SARS-CoV-2 positive subjects at different time points since onset of symptoms are presented. The cutoff values for the ELISA assay are indicated by the broken line. The dashed blue box in (B) indicates a single PCR positive and seronegative subject. Seroconversion of (D) total Ig and (E) IgM antibodies against RBD of the SARS-CoV-2 spike antigen among 14 representative SARS-CoV-2 patients during the acute phase since onset of symptoms. The first sample (green) and follow-up sample (red) are connected by black arrow. The time interval between the first and follow-up sample are provided on the x-axis. The binding signals below the broken line are denoted as seronegative.

The administration of convalescent plasma containing antibodies to SARS-CoV-2 is being evaluated for patients with severe disease. While the FDA has not approved convalescent plasma therapy, on May 1, 2020, the FDA recommended that SARS-CoV-2 neutralizing titers of at least 1:160 should be used for human passive immunization studies. Further, the FDA also recommended that a titer of 1:80 may be acceptable if an alternative matched unit is not available. As the RBD domain of S protein is critical for viral entry, antibodies targeting this domain of SARS-CoV-2 are likely to be neutralizing and potentially protective, as is seen in cell culture and animal models for other pathogenic CoVs (19, 22). To assess the relationship between the RBD-binding activity and the neutralizing antibody response, we tested 50 PCR-confirmed SARS-COV-2 patient immune sera in a SARS-CoV-2 luciferase neutralization assay (Fig. 5). As judged by the Spearman test ( = 0.86, P < 0.0001), we observed that the magnitude of the total RBD-binding Ig antibody strongly correlated with the levels of neutralizing antibodies in SARS-CoV-2 patients (Fig. 5A). Moreover, the patient samples with high levels of IgM antibodies were strongly associated with the highest neutralizing antibody titers in early convalescence (Spearman = 0.83, P < 0.0001; Fig. 5B, <6 weeks after onset of symptoms). The neutralizing antibody kinetics in patients mirrored the kinetics of RBD antibody development (Fig. 5C and Fig. S2). None of the patients with confirmed SARS-CoV-2 infection (0/8) had any detectable levels of neutralizing antibodies within the first eight days after the onset of symptoms. While low levels of neutralizing antibody titers were detectable in 91% of patients (20/22) 21 days after the onset of symptoms, only 73% of patients (16/22) had a neutralization titer of at least 1:80.

Correlations between (A) total Ig and (B) IgM RBD binding and the SARS-CoV-2 neutralizing antibody titers. Scatter plots were generated using individual serum binding to RBD antigen (y-axis) versus SARS-CoV-2 neutralizing antibody titers (x-axis). The nonparametric Spearman correlation coefficient (rs) and the associated two-tailed p-value were calculated (GraphPad Prism, version 5.0). (C) Relationship between SARS-CoV-2 neutralizing antibody titer and days after onset of symptoms. (D) Total Ig antibody binding to RBD as a surrogate for identifying people with high SARS-CoV-2 neutralizing antibodies. A total of 50 serum samples collected between 1 and 39 days after onset of symptoms from PCR-confirmed SARS-CoV-2 subjects were measured for Ig and IgM binding to spike RBD antigen and SARS-CoV-2 neutralization assay. The FDA-recommended neutralizing antibody titer for plasma therapy (1:160) is indicated by the broken green line.

Currently, patients who have had a documented SARS-CoV-2 infection identified by RT-PCR or a serologic test, and who are clear of symptoms for at least 14 days, are recruited for convalescent plasma donation. We evaluated the neutralizing potency in patient samples collected between 1 and 40 days with a titer of at least 1:160 (Fig. 5D). We observed that 32% of patients (7/22) developed weak to no neutralizing antibodies even 21 days after onset of symptoms, suggesting that days after the start of symptoms is a poor determinant of the levels of SARS-CoV-2 neutralizing antibodies in the patients included in our study, particularly within the early convalescent phase (<6 weeks). To evaluate whether a simple RBD ELISA can be used as a surrogate for neutralizing potency in SARS-COV-2 patients, we analyzed the relationship between the level of total Ig antibody to RBD and a neutralizing antibody titer of at least 1:160. We observed that 22/24 people who had a substantial total Ig binding antibody to RBD (>1.5 OD) also developed a robust neutralizing antibody titer (Fig. 5E). Notably, only 3/26 people who developed a relatively weak RBD-binding antibody had a neutralizing antibody titer higher than 1:160. One subject (P54) neither seroconverted for RBD antigen nor developed neutralizing antibodies to SARS-CoV-2 (Fig. 4D and E, and Fig. S2).

Serology is critical to understanding the transmission, pathogenesis, mortality rate and epidemiology of emerging viruses. In the few months after the discovery of SARS-CoV-2 as a human pathogen, scientists have developed a large number of antibody assays and many commercial tests are now available. Although none of the assays have been fully validated yet, the FDA has granted emergency use authorization (EUA) for multiple tests, while stressing the need for further validation. Investigators have already encountered problems with the specificity and sensitivity of commercial assays rushed to market (4, 22). Widespread use of inaccurate antibody assays could lead to policies that exacerbate the current SARS-CoV-2 pandemic instead of containing it.

To address the need for reliable antibody-based diagnostic assays, we focused on the RBD domain of the spike protein because this region is poorly conserved between different CoVs and is also known to be a major target of human antibodies (19). A major concern with using a protein domain instead of a full-length protein or whole virion for antibody detection is possible reduction in assay sensitivity. However, we observed that over 95% of SARS-CoV-2 patients developed antibodies to the RBD 9 days after onset of symptoms. Although our study included only a few recent convalescent sera and relatively large numbers of presumably positive samples from past common human CoV infections, the high specificity of the RBD antigen was also evident with the serum specimens from animals that were hyperimmunized with other zoonotic CoVs. Some patients infected with SARS-CoV-2 had antibodies that cross-reacted with the RBD of SARS-CoV-1. We have not tested the more distantly related RBD Ag from MERS CoV or the serum samples from individuals with confirmed MERS infection. Since SARS-CoV-1 and MERS CoV seroprevalence are very low in humans, the SARS-CoV-2 antibody cross-reactivity with SARS-CoV-1 is unlikely to pose diagnostic challenges. Other recent studies that have been published or under peer review also support the high specificity and sensitivity of the SARS-CoV-2 RBD for antibody detection (4, 17, 18). Amanat and colleagues tested samples from SARS-CoV-2 patients collected at the beginning of the epidemic in the USA and reported that the full length S protein and the RBD performed well for specific antibody detection (17). Okba and colleagues compared the performance of different SARS-CoV-2 antigens for antibody detection using samples from 10 SARS-CoV-2 patients in Europe (4). For the SARS-CoV-2 spike RBD, they observed levels of specificity and sensitivity that were comparable to our results reported here. The S2 subunit, which comprises conserved regions between CoVs, was less specific than the RBD (4). Perera and colleagues evaluated the performance of the RBD for antibody detection using samples from 24 SARS-CoV-2 patients in Hong Kong (18). They also observed high specificity and sensitivity when patients were tested 10 days or more after onset of illness. Our study with 77 specimens from 63 documented SARS-CoV-2 patients, which includes patients presenting to hospitals in North Carolina and Georgia with varying levels of severity, together with these recent studies conducted in New York, Europe and Hong Kong, strongly support the use of SARS-CoV-2 RBD as an antigen for antibody detection.

We designed the assay for separate detection of RBD-specific total Ig and IgM. As the pandemic is ongoing and most infections are likely to have occurred within the past few months, infected individuals have variable levels of antigen-specific IgG, IgM and IgA (Fig. 4C). To maximize assay sensitivity and to prevent different antibody isotypes competing for binding sites and reducing assay signal, we measured total Ig. We did not observe any decrease in assay specificity by designing the assay to monitor levels of total Ig instead of IgG binding to the RBD even at high serum concentration or with hyperimmune sera. Our study showed that IgM and IgA antibodies can also be detected using RBD-based serological assays. Both IgA and IgM antibodies are relatively short lived and indicative of a recent exposure. When conducting large scale population level surveillance for SARS-CoV-2 antibodies, it will be possible to distinguish recent from remote infections by measuring both total Ig and IgM (or IgA) binding to the RBD.

Antibody assays that correlate with protective immune responses in individuals who have recovered from SARS-CoV-2 infection and also reflect herd immunity at a population level are urgently needed to define each individuals risk of disease and to identify communities at high risk for new waves of infection. In animal studies with SARS-CoV-1, virus-neutralizing antibodies were strongly correlated with protective immune responses (19). We observed a striking correlation between the levels of RBD antibodies in patients and the ability of patient sera to neutralize SARS-CoV-2 virus. Other groups have recently reported finding a strong correlation between spike/RBD antibodies and SARS-CoV-2 neutralization in patients infected with SARS-CoV-2 (4, 17, 18). Our results point out that roughly one-third of patients develop very low or no neutralizing antibodies to SARS-CoV-2 and that Ig and IgM antibodies are useful predictors of neutralizing antibody levels in patients in the early convalescent phase (<6 weeks). As people developing a high level of RBD-binding antibodies (>1.5 OD) also have a robust neutralizing response, a simple RBD-based ELISA can be a useful tool to identify blood plasma donors. While further studies are needed to fully evaluate RBD antibodies as correlate of protective immunity, the results to date indicate that RBD antibodies are a promising correlate of protection in the early convalescent phase. A simple antibody detection assay that also predicts individual-level risk of disease will be a major advance for vaccine development and immunogenicity of vaccines because SARS-CoV-2 neutralization assays are time-consuming and require BSL-3 containment.

One SARS-CoV-2 patient (P54) who tested positive for viral RNA and required hospitalization did not develop RBD-specific Ig, IgM or neutralizing antibodies, even at 16 days after the onset of symptoms. This was the only person among the 68 PCR positive subjects who did not seroconvert by 9 days after onset of symptoms in the RBD-based assay. While we cannot rule out the possibility of a false positive PCR test result, others have also reported rare instances where people infected with SARS-CoVs have atypical, dampened immune responses (23). Further studies are needed to establish the frequency and significance of atypical antibody responses in SARS-CoV-2 patients and characterize the serological repertoire and epitopes targeted by the antibodies in convalescent sera.

As SARS-CoV-2 infections in the southeastern U.S. have started to increase relatively recently, all convalescent samples used in this study were collected within 90 days following onset of symptoms. In most patients, the convalescent sera had high end-point titers (>1:1000) in the RBD Ig ELISA supporting the utility of this assay even as antibody levels start to wane over time. We need to prioritize studies to prospectively monitor SARS-CoV-2 patients to determine the long-term kinetics of antibody levels and the performance of antibody detection assays over time.

All the SARS-CoV-2 human immune sera used for this study were collected from symptomatic patients that included many with serious illness requiring hospitalization. The research community currently does not know if individuals experiencing mild/inapparent symptoms after SARS-CoV-2 infection have similar kinetics and levels of RBD-binding antibodies as those experiencing symptomatic infections. Studies must be done with individuals experiencing mild/inapparent SARS-CoV-2 infections to define the kinetics and levels of RBD antibodies before implementing large population-level antibody testing.

The goal of the study was to evaluate the performance of RBD-based spike antigen for reliable detection of SARS-CoV-2-specific antibodies. We produced properly folded RBD from the spike proteins of SARS and common-cold HCoVs in mammalian cells and used this antigen to evaluate a large panel of human sera from documented SARS-CoV-2 patients and control subjects, and hyperimmune sera from animals exposed to zoonotic CoVs. We also used a SARS-CoV-2 luciferase neutralization assay to assess the dynamics of the neutralizing antibody response and its association with the RBD-binding activity.

The structure coordinate sets of the spike proteins, spike protein complexes with their cognate receptor ACE2 and monoclonal antibodies were obtained from the Protein Data Bank (PDB). The structures were aligned to the reference spike protein using the PyMOL Molecular Graphics System (Version 1.2r3pre, Schrdinger, LLC). Molecular figures were drawn using PyMol. The PDB coordinates used for the structural alignments and analysis were as follows: SARS-CoV-2 spike (6VSB), SARS-CoV-1 spike (6CRV), SARS-CoV-1 spike/S230 (6NB6), SARS-Co-V1 spike RBD/80R (2GHW), SARS-CoV-1 spike RBD/ m396 (2DD8), SARS-CoV-1 spike RBD/F26G19 (3BGF), SARS-CoV-2 spike RBD/CR3022 (6W41).

We used the following structure coordinates of the coronavirus spike proteins from the PDB to define the boundaries for the design of RBD expression constructs: SARS-CoV-2 (6VSB), SARS-CoV-1 (6CRV), HKU-1 (5I08), OC43 (6NZK), 229E (6U7H) NL63 (6SZS). Accordingly, a codon-optimized gene encoding for S1-RBD [SARS-CoV-1 (318 514 aa, P59594), SARS-CoV-2 (331 528 aa, QIS60558.1), OC43 (329 613 aa, P36334.1), HKU-1 (310 611 aa, Q0ZME7.1), 229E (295 433 aa, P15423.1) and NL63 (480 617 aa, Q6Q1S2.1)] containing human serum albumin secretion signal sequence, three purification tags (6xHistidine tag, Halo tag, and TwinStrep tag) and two TEV protease cleavage sites was cloned into the mammalian expression vector pH. S1 RBDs were expressed in Expi293 cells (ThermoFisher) and purified from the culture supernatant by nickel-nitrilotriacetic acid agarose (Qiagen).

To generate virus replicon particles (VRPs), the SARS-CoV-2 S gene was inserted into pVR21 3526 as previously described (24). In summary, the SARS-CoV-2 S gene was ligated into pVR21 following digestion by restriction endonuclease sites, PacI and ApaI. T7 RNA transcripts were generated using the SARS-CoV-2-S-pVR21 construct in conjunction with plasmids containing the Venezuelan equine encephalitis virus envelope glycoproteins and capsid protein. The RNA transcripts were then electroporated into baby hamster kidney fibroblasts and monitored for cytopathic effect. VRP were harvested 48 hours after electroporation and purified via high-speed ultra-centrifugation. To generate serum samples against SARS-CoV-2, 10-week-old BALB/c mice (Jackson Labs) were inoculated via footpad injection with the VRP and boosted with the same dose one time three weeks later. Serum samples were then collected from individual animals at 2 weeks post-boost and pooled for use in assays.

All human specimens used in these studies were obtained after informed consent under good clinical research practices (GCP) and compliant with oversight by the relevant institutional review boards (IRBs). A list of the SARS-CoV-2 patient samples included in the study with basic demographic and clinical information can be found in Table S1.

UNC Hospital Specimens: Sera for this study were remnants from samples submitted to the UNC Hospital McLendon Clinical Laboratories or Blood Bank. SARS-CoV-2 patient samples were obtained from patients with positive RT-PCR test result (in-house assay developed and validated by UNC Hospital McLendon Clinical Laboratory) for SARS-CoV-2. SARS-CoV-2 negative samples were obtained from patients with other diagnoses or from samples collected prior to December 2019 and cryopreserved at -80C.

Emory University School of Medicine Specimens: Specimens were obtained from patients with symptomatic illness and clinical testing confirming SARS-CoV-2 by PCR (CDC SARS-CoV-2 test). De-identified specimens were shared with researchers at UNC consistent with local IRB protocols (Emory IRB# 00110683 and 00022371).

Blood plasma donor study: Convalescent sera was obtained from donors who volunteered for plasma collections at the UNC Donation Center. Fresh sera collected as part of the standard plasmapheresis procedure were saved for research from donors who signed informed consent. UNC IRB 20-1141 is conducted under good clinical research practices (GCP) and is compliant with institutional IRB oversight. All donors had confirmed SARS-CoV-2 infection by nasopharyngeal swab indicating the presence of SARS-CoV-2 RNA as performed by EUA approved qRT-PCR in a US laboratory with a Clinical Laboratory Improvement Amendments (CLIA) certification. All donors had recovered from their SARS-CoV-2 illness and were at least 14 days post last symptoms. Donors who presented for plasma collection prior to 28 days from their last symptoms had a confirmed negative nasopharyngeal RT-PCR test done within 72 hours prior to donation.

Healthy Unexposed Donors: Samples from healthy U.S. adult donors were obtained by the La Jolla Institute for Immunology (LJI) Clinical Core or provided by a commercial vendor (Carter Blood Care) for prior, unrelated studies between early 2015 and early 2018, at least one year before the emergence of SARS-CoV-2. The LJI Institutional Review Board approved the collection of these samples (LJI; VD-112). Samples from the Caribbean, Central America and South Asia were obtained from archived samples at UNC collected before December 2019 for other studies.

Human and Animal Specimens from BEI Resources: The following reagents were obtained through BEI Resources, NIAID, NIH as part of the Human Microbiome Project: Pooled sera obtained from rabbits dosed with a recombinant SARS-CoV spike protein (NRC-772), monoclonal anti-SARS-CoV S protein (Similar to 240C) (NR-616), anti-porcine respiratory coronavirus (PRCoV; ISU-1) serum obtained from Pig (NR-460), anti-porcine Transmissible Gastroenteritis Virus obtained from pig (NR-458), anti-porcine respiratory coronavirus (PRCoV; ISU-1) serum obtained from guinea pig (NR-459), Anti-SARS Coronavirus obtained from guinea pig (NR-10361), Anti-Bovine Coronavirus (mebus) obtained from guinea pig (NR-455), Anti-Feline Infectious Peritonitis Virus, 79-1146 obtained from guinea pig (NR-2518), Anti-Avian Infectious Bronchitis Virus, Massachusetts obtained from guinea pig (NR-2515), Anti-Turkey Coronavirus, Indiana obtained from guinea pig (NR-9465), Anti-Canine Coronavirus, UCD1 obtained from guinea pig (NR-2727), Anti-Human Parainfluenza Virus 2 obtained from guinea pig (NR-3231), Anti-Simian Virus 5 obtained from guinea pig (NR-3232), Anti-Human Parainfluenza Virus 3 obtained from guinea pig (NR-3235), Anti-Bovine Parainfluenza Virus 3 obtained from guinea pig (NR-3236), Anti-Human Parainfluenza Virus 4A obtained from guinea pig (NR-3239), Anti-Human Parainfluenza Virus 4B obtained from guinea pig (NR-3240), Human Convalescent Serum 001 to 2009 H1N1 Influenza A Virus (NR-18964), Human Convalescent Serum 002 to 2009 H1N1 Influenza A Virus (NR-18965), and Human Reference Antiserum to Respiratory Syncytial Virus (NR-4020). For some animal CoV anti-serum samples, the certificate of analysis provided by the BEI Resources confirmed the presence of neutralizing and binding antibodies (see Table S1).

All serum specimens tested by ELISA assay were heat-inactivated at 56C for 30 min to reduce risk from any possible residual virus in serum. Briefly, 50 l of spike RBD antigen at 4 g/ml in Tris Buffered Saline (TBS) pH 7.4 was coated in the 96-well high-binding microtiter plate (Greiner Bio-One cat # 655061) for 1 hour at 37C. Then the plate was washed three times with 200 l of wash buffer (TBS containing 0.2% Tween 20) and blocked with 100 l of blocking solution (3% milk in TBS containing 0.05% Tween 20) for 1 hour at 37C. The blocking solution was removed, and 50 l of serum sample at 1:20 or indicated dilutions in blocking buffer was added for 1 hour at 37C. The plate was washed in the wash buffer, 50 l of alkaline phosphatase-conjugated secondary goat anti-human secondary antibody at 1:2500 dilution was added for 1 hour at 37C. For measuring total Ig, a mixture of anti-IgG (Sigma Cat # A9544), anti-IgA (Abcam Cat # AB97212), and anti-IgM (Sigma Cat # A3437] were added together. For measuring specific antibody isotype, only secondary goat anti-human IgG or IgA or IgM was used. The plate was washed, and 50 l p-Nitrophenyl phosphate substrate (SIGMA FAST, Cat No N2770) was added to the plate and absorbance measured at 405nm using a plate reader (Biotek Epoh, Model # 3296573). For testing animal sera, the secondary antibody was matched to the species as follows: goat anti-mouse IgG (Sigma, A3688), goat anti-rabbit IgG (Abcam, ab6722), goat anti-pig IgG (Abcam, ab6916), and goat anti-guinea pig IgG (Abcam, ab7140).

Full-length viruses expressing luciferase were designed and recovered via reverse genetics and described previously (25, 26). Viruses were tittered in Vero E6 USAMRID cells to obtain a relative light units (RLU) signal of at least 20X the cell only control background. Vero E6 USAMRID cells were plated at 20,000 cells per well the day prior in clear bottom black-walled 96-well plates (Corning 3904). Neutralizing antibody serum samples were tested at a starting dilution of 1:20, and were serially diluted 4-fold up to eight dilution spots. Antibody-virus complexes were incubated at 37C with 5% CO2 for 1 hour. Following incubation, growth media was removed and virus-antibody dilution complexes were added to the cells in duplicate. Virus-only controls and cell-only controls were included in each neutralization assay plate. Following infection, plates were incubated at 37C with 5% CO2 for 48 hours. After the 48 hour incubation, cells were lysed and luciferase activity was measured via Nano-Glo Luciferase Assay System (Promega) according to the manufacturers specifications. SARS-CoV-2 neutralization titers were defined as the sample dilution at which a 50% reduction in RLU was observed relative to the average of the virus control wells.

Each data points in Fig. 1E, Fig. 2, Fig. 3B and 3C, Fig. 4 and 5 are presented as means of technical duplicates. The correlation of RBD binding and neutralization titers shown in Fig. 5A and Fig. 5B was evaluated using a Spearman correlation coefficient (rs) and the associated two-tailed p-value (GraphPad Prism, version 8). Receiver operating characteristic (ROC) analyses were performed to establish cutoff values for SARS-CoV-2 seropositivity using SPSS software. Statistical analyses were performed using SPSS software ver. 26.0 (IBM, Armonk, NY, USA).

immunology.sciencemag.org/cgi/content/full/5/48/eabc8413/DC1

Fig. S1. Titration curves of sera from SARS-CoV-2 positive patients.

Fig. S2. Seroconversion of SARS-CoV-2 neutralizing antibodies.

Fig. S3. Estimation of RBD ELISA assay cutoff.

Table S1. Summary of samples tested and associated characteristics (Excel spreadsheet).

Table S2. Raw data file (Excel spreadsheet).

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients - Science

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Health Matters: Covid-19 Update – Fact from Fiction – Red River Radio

June 12, 2020 medical

Health Matters: Covid-19 Update - Fact from Fiction - 061120

Airs Thursday, June 11, 2020, at 6 p.m. Information about COVID-19 in the news and on social media can be confusing. Tune in for Health Matters, Thursday at 6 p.m. Dr. Randall Brewer will be joined by Dr. Andrew Yurochko, PhD, Professor of Microbiology and Immunology, and Dr. Jeremy Kamil, Associate Professor of Microbiology and Immunology, both with LSU Health Shreveport, to help us separate fact from fiction and also tell us if the virus is showing mutations. Questions will be taken at 1-800-552-8502.

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Health Matters: Covid-19 Update - Fact from Fiction - Red River Radio