For the first time, researchers have successfully measured antibodies against specific respiratory viruses in exhaled air. This is shown in a new study involving, amongst others, the Karolinska Institutet, published in eBioMedicine. The method may make it easier to study the immune system in the small airways of the lungs.
Antibodies in the mucosal lining of the respiratory tract play an important role in protecting against respiratory viruses such as influenza virus, SARS-CoV-2 and respiratory syncytial virus (RSV). While antibodies in the upper airways are relatively easy to measure, sampling from the lower airways has previously required invasive procedures such as bronchoscopy.
In the new study, researchers used a non-invasive method called PExA (Particles in Exhaled Air). By breathing into a specially designed instrument, participants generated tiny exhaled particles originating from the respiratory tract lining fluid of the small airways. These particles were collected and analysed for virus-specific antibodies.
“Antibodies in the nasal mucosa are important for protection against respiratory infections, but immune responses further down the lungs are also crucial, particularly for preventing severe disease such as pneumonia. This method opens up new possibilities for understanding how immunity differs between the upper and lower airways,” says Charlotte Thålin, adjunct professor at the Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, and co-last author of the study.
The study included 28 participants in the COMMUNITY cohort at Danderyd Hospital, 18 of whom had recently experienced a respiratory tract infection. The researchers analysed paired samples from blood, nasal secretions and exhaled breath.
In the exhaled breath samples, the researchers successfully detected IgA and IgG antibodies directed against SARS-CoV-2, influenza virus and RSV. Virus-specific IgG levels in the lower airway samples largely mirrored those observed in blood, whereas IgA showed a different pattern, consistent with a greater contribution from local mucosal antibody responses.
“Sampling is relatively simple, as participants simply need to breathe into a device. This enables us to collect samples from the small airways without invasive procedures, which is particularly valuable if we wish to take repeated samples and monitor the immune system over time,” says Katherina Aguilera, a PhD student at the same department, and the study’s first author.
In the future, the method could help researchers investigate how immune responses in the lower airways change following respiratory infections or vaccinations, and and support the evaluation of preventive treatments. The researchers emphasise that this was an initial methodological study involving a limited number of participants and that further validation in larger studies is needed.
The study was conducted in collaboration between Karolinska Institutet, Danderyd Hospital, Uppsala University, and SciLifeLab. Funding was provided by the European Research Council (ERC), the Knut and Alice Wallenberg Foundation and the Swedish Society for Medical Research (SSMF).
Two linked studies provide effective recommendations for publishers, funders, institutions, and manufacturers
Tubes of samples going into clinical waste. Image credit: Only Good Antibodies team at the University of Leicester (CC-BY 4.0)
A widespread failure to validate research antibodies before use is estimated to lead to the avoidable waste of millions of animal and human tissue samples worldwide, and an international expert panel has reached consensus on how to address the problem, according to two studies published October 6th in the open access journal PLOS Biology by Harvinder Virk of the University of Leicester, UK, and colleagues.
Antibodies are critical reagents that enable researchers to detect, quantify, and isolate specific proteins in biological samples. However, research antibodies do not always bind their intended targets, or may bind additional unintended targets. Studies have suggested that many antibodies do not bind as advertised. This lack of specificity can misdirect biomedical research across fields.
In the first study, Virk and first author Michael Biddle combined data from focus groups (12 researchers), a survey (107 researchers), and an analysis of 785 publications linked to antibodies that had failed rigorous, knockout-controlled testing. Among 760 publications where validation status could be determined, only 120 (15.8%) presented any validation evidence, despite 72.0% of surveyed researchers reporting having used at least one recommended validation method. The papers lacking antibody validation used a minimum of 8064 animal samples and 4424 human tissue samples. Extrapolating, the researchers estimate that millions of animal and human tissue samples have been consumed globally without adequate validation.
“This study provides, to our knowledge, the first systematic quantification of biological sample waste attributable to the use of poorly performing antibodies without context-specific validation,” the researchers say.
In the second study, Virk and first author Katherine Blades convened 32 international experts – including researchers, publishers, funders, antibody manufacturers and institutional leaders – for a two-round Delphi consensus exercise to rate proposed reforms for antibody validation. The panel agreed that 15 actions, including institutional training, dedicated validation budgets in grant applications, and publisher reporting requirements, were both effective and feasible for implementation by 2030; a further 15 actions were judged effective but of uncertain feasibility. Participants pointed to diffuse ownership of the problem, and market incentives that fail to reward antibody quality as key barriers.
“The findings lend themselves to a programme of targeted stakeholder consultation,” the authors say. “To support this, we have prepared separate documents for each stakeholder group – publishers, funders, institutions, and manufacturers – presenting consensus recommendations alongside implementation options derived from the panel’s qualitative feedback. These present options rather than prescriptions, recognising that the optimal approach will vary across organisations, countries, and contexts.”
Harvinder Virk (corresponding author on both papers) says, “Around ten years ago I discovered that data I had submitted in a grant application relied on an antibody that did not detect its intended target. The data included staining of bronchial biopsies from patients who had given informed consent. They would not have expected their donation to be wasted. That has driven this work ever since.”
Michael Biddle (first author, “Inadequate antibody validation places substantial numbers of animal and human tissue samples at risk of waste”) adds, “Researchers told us they validate their antibodies: 72% reported using at least one recommended method. But only 120 of the 760 papers we could assess showed any validation evidence. The other 640 studies reported at least 8,064 animal and 4424 human tissue samples used with antibodies that had failed independent testing; we describe these samples as at risk of waste. In the clearest cases – where the antibody has since been withdrawn from sale, so the work cannot be reproduced at all – scaling to the commercial antibody market gives a lower-bound global estimate of 4 to 7 million animal samples and 6 to 11 million human tissue samples.”
Katherine Blades (first author, “Actionable solutions to address antibody validation failures”) states, “What struck us was the level of agreement once researchers, funders, publishers, institutions and manufacturers were brought into the same process. The panel reached consensus on 15 actions that are both effective and achievable by 2030. Progress is held back not by disagreement about what to do, but because no single group owns the problem – so everyone waits for someone else to move first.”
Harvinder Virk notes, “Together these papers show the problem has significant impact with ethical dimensions, and is solvable. Since completing this work, we have embedded champions for better practice in 14 UK research institutions, and the University of Leicester has made antibody validation training mandatory for its bioscience postgraduate researchers. We are working with two national funders – the NC3Rs and Cancer Research UK – on implementation solutions, and have built free tools publishers can use to protect the integrity of what they publish.”
Vaccine approach yields high numbers of HIV-neutralising antibodies in non-human primates
Colourised scanning electron micrograph of HIV (yellow) infecting a human T9 cell (blue). Credit: NIH
A new HIV vaccine developed by La Jolla Institute for Immunology (LJI), Scripps Research scientists, and IAVI has the potential to protect humans from developing HIV infection and AIDS. This HIV vaccine is the first to generate a high number of ‘broadly neutralising’, virus-fighting antibodies in primates.
“This feels like a huge success,” says LJI Professor and Chief Scientific Officer Shane Crotty, PhD, who co-led the research with Scripps Research Professor William Schief, PhD. “We constructed a successful vaccine from the ground up, which required a deep understanding of the immune system.”
This groundbreaking research, published inNature, is the result of 14 years of collaboration between La Jolla Institute for Immunology and Scripps Research, as part of the Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD). “This has been one of those Apollo moon mission-type projects, where there is an exceptional goal and the team has to accomplish a myriad of discoveries and inventions along the way,” says Crotty.
Outsmarting HIV
The new vaccine works by intervening in a process called B cell maturation. B cells make antibodies. Like many immune cells, B cells have an early ‘naïve’ stage before they are ready to make antibodies. B cells start to mature once they get the signal that a pathogen, such as a virus, is trying to attack. B cells see pieces of that pathogen’s molecular structure and start producing antibodies that can bind to that structure and halt infection.
It can take a little while for B cells to find the right “bullseye” on a pathogen. But B cells keep trying. As they mature, B cells tweak their antibody production, refining antibody structures to bind to a pathogen in just the right, vulnerable spots.
Scientists describe B cell development as a training process or bootcamp. In most cases, the body is left with a well-honed B cell army.
HIV is hard to beat because it doesn’t give B cells a chance to develop effective antibodies. The first problem is that HIV disguises itself from the immune system. The virus is wrapped in an ever-shifting cloak of sugar molecules, called glycans. This lets HIV sneak undetected past human cells, which are also covered in glycans.
The second big problem is that HIV mutates very quickly. “The worldwide diversity of HIV mutations is extraordinary. Even the diversity within one individual person living with HIV is dramatic,” says LJI Instructor Patrick Madden, Ph.D., who served as study co-first author with Jon Steichen, Ph.D., an institute investigator at Scripps Research.
The third problem is that HIV changes its shape when it infects human cells. Even if B cells get a glimpse of its viral structure – snap! – the structure changes.
Taken together, these problems rarely give B cells a chance to hone their antibody responses against HIV. Even if a B cell manages to make neutralising antibodies, the virus can mutate or change its shape, rendering those antibodies useless.
The LJI and Scripps Research teams spent years hunting for ‘broadly neutralising’ antibodies that can actually bind to HIV and recognise key viral structures, even if the rest of the virus mutates. These antibodies are very, very rare, but they can be found in blood samples from a small number of people living with HIV.
An effective HIV vaccine would need to prompt the immune system to make these same broadly neutralising antibodies. “How could we flip the whole immune response on its head so the rare responses become the common responses? That was a critical challenge we faced,” says Crotty.
Testing the new vaccine
It was time to go back to B cell bootcamp. The scientists studied what made the HIV-fighting B cells special. Then they reversed the process to see exactly how those B cells matured. By looking back at the maturation process, the researchers could track how the B cells changed when they saw specific pieces of the HIV structure.
The team discovered that B cells matured to make broadly neutralising antibodies after they got an early look at parts of HIV’s outer “envelope” protein. Because these viral sites sparked an immune response, scientists would call them “antigens.”
An effective HIV vaccine would likely need to include models of these antigens. The antigens would work like mugshots of America’s most wanted. If B cells saw those antigens early and often, they would get really good at recognising and even neutralising HIV. “We were trying to mimic the progression of those neutralising antibodies,” says Madden.
In a feat of molecular engineering, the Schief Lab developed vaccine molecules that resembled the real HIV antigens. The scientists then worked with Emory National Primate Research Center, to test this potential HIV vaccine in a non-human primate species called rhesus macaques.
The researchers first administered a “priming” vaccine meant to activate each animal’s naïve B cells. The animals then received a series of “shepherding” booster shots to help their B cells develop along the right path.
“This series of vaccinations will guide, or ‘walk’, a B cell from its naïve state to its broadly neutralising state,” says Madden.
This new type of vaccine approach is called “germline targeting” because it targets naïve B cells in their ‘germline’ or naïve form, before they begin their training process.
The scientists found that around 44 percent of the animals went on to produce broadly neutralising antibodies against HIV in their blood. These antibodies were impressively abundant.
“We succeeded in taking ultra-rare antibody responses and turning them into common responses by the end of the vaccination process,” adds Crotty. In other research recently published, they reported a new strategy to accelerate related vaccine antibody responses [See Nature Immunology paper].
The team didn’t test whether these antibodies could prevent infection, but it’s significant that these antibodies could be found in the blood, where they could encounter and potentially block HIV.
Bringing the HIV vaccine to humans
The Crotty Lab plans to investigate how they might change the booster shot regimen to make the HIV vaccine even more effective. “It was incredible to get those results, but of course we’d like to see a response in 100 percent of the animals,” says Madden.
Importantly, the antibodies found in the animal subjects resembled the exact kinds of broadly neutralising antibodies seen in those rare humans who made their own neutralising antibodies. It’s clear that our immune systems can make these powerful antibodies, given the right training.
“We believe this vaccine approach is even more likely to succeed in humans, because of the immunogenetics,” Crotty says.
The priming immunogen used in this study was evaluated in humans in the HVTN 144 trial and is currently being tested in the Phase 1 trial IAVI G004. IAVI, Scripps Research, the HIV Vaccine Trials Network, and partners are now advancing plans to further evaluate the full immunisation regimen in a future human clinical study.
An international research group directed by UMC Utrecht have developed and characterised two first-in-class antibodies that specifically block the high-affinity IgG receptor FcγRI. Their findings open new perspectives for therapeutic modulation of FcγRI-driven inflammation in autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and immune thrombocytopenia (ITP).
FcγRI, also known as CD64, is a high-affinity receptor on myeloid cells that binds to the Fc region of immunoglobulin G (IgG) antibodies. It plays a key role in immune defence by triggering cellular functions such as phagocytosis and cytokine production. In a normal immune response, FcγRI is activated by immune complexes – clusters of antibodies bound to pathogens, which mark them for clearance. In autoimmune diseases, however, the immune system mistakenly targets the body’s own tissues (such as joint proteins in RA, nuclear antigens in SLE, or platelets in ITP), which results in the production of autoantibodies that form immune complexes. These misdirected complexes activate FcγRI unnecessarily, driving chronic inflammation and subsequent tissue damage.
The study, led by Prof Jeanette Leusen, PhD from the Antibody Therapy research group at the Center for Translational Immunology (UMC Utrecht) and carried out by PhD candidate Tosca Holtrop MSc, was a true team effort, in collaboration with experts from Kiel University (Germany), Leiden University Medical Center, Utrecht University, and Friedrich-Alexander University Erlangen-Nürnberg (Germany).
Discovery of first-in-class antibodies
For over 30 years, scientists have tried to generate antibodies against the IgG-binding domain of CD64, but the receptor’s extremely high affinity for IgG made this impossible with earlier technologies. Combining the UMAB unique immunisation method with novel phage display antibody libraries, the team bypassed this challenge by excluding the Fc region of the antibodies. This allowed them to discover two unique Fc-silent antibodies, C01 and C04, that bind purely via their Fab domains to FcγRI. Crystal structural analysis confirmed that C01 binds precisely within the IgG-binding site on EC2, making binding mutually exclusive.
High affinity for FcγRI
Quantitative binding studies revealed that both antibodies have higher affinity for FcγRI than human IgG, allowing them to efficiently displace IgG or pathogenic immune complexes up to 60 percent and block binding up to 90 percent. Importantly, neither antibody triggered FcγRI activation, a critical distinction from earlier anti-FcγRI antibodies, which could inadvertently trigger receptor clustering and cytokine release.
Subsequently. an in vitro model for immune thrombocytopenia was set-up, where C01 and C04 effectively inhibited opsonized platelets from binding to immune cells from ITP patients. In a preclinical in vivo ITP model, the antibodies significantly reduced IgG-dependent platelet depletion. The antibodies were also tested in an in vitro rheumatoid arthritis models, where they effectively inhibited patient-derived autoantibody–immune complex binding to monocytes, macrophages, and neutrophils from healthy donors.
Promising therapeutic candidate drugs
The study demonstrates that direct Fab-mediated inhibition of FcγRI is feasible and effective, opening a new avenue for treating autoimmune diseases characterised by IgG-autoantibody complexes. By preventing immune complex–driven activation without triggering the receptor, C01 and C04 represent a promising next step toward targeted, inflammation-sparing immunotherapy. “I think we found the needle in the haystack, after searching over a decade and thanks to a true team effort,” says Jeanette Leusen, principal investigator of the study. “Each research partner contributed a critical piece, from antibody discovery and structure determination to patient sample testing and preclinical models. Only together could we bring this to fruition. These antibodies not only provide a unique tool for studying FcγRI biology, but also hold promise as therapeutic candidates in autoimmune and infectious diseases.”
In Sub-Saharan Africa, more than 300 000 people are bitten by venomous snakes annually, 3000 of whom die – but with the underreporting that goes hand in hand with the lack of healthcare infrastructure, the real number could be as much as five times higher. Many more face amputations. Even if patients manage to make it to a clinic or hospital in time, there is no guarantee that there will be any anti-venom available to treat them. As a South African case study shows, just having antivenom in the right place is a problem even in Western Cape’s relatively well-developed healthcare system, with antivenom’s three-year shelf life and cold chain failures posing a major problem for rural healthcare centres.
But now, scientists have developed a new kind of antivenom that is effective for 17 different snake species, including mambas, cobras and a rinkhals. The study, published in Nature, makes use of a nanobody-based cocktail that targets common mechanisms across venoms – and which is also more effective at preventing the tissue damage that leads to amputations.
A huge obstacle to creating broad-spectrum antivenoms is the enormous diversity of venomous snakes and the complexity of their venoms – a single species’ venom may contain 100 toxins from multiple different protein families. Listen to our podcast to hear a deep dive into Africa’s snakebite burden and how the international team of researchers accomplished their feat:
SARS-COV-2 has been very good at mutating to keep infecting people – so good that most antibody treatments developed during the pandemic are no longer effective. Now a team led by Stanford University researchers may have found a way to pin down the constantly evolving virus and develop longer-lasting treatments.
The researchers discovered a method to use two antibodies, one to serve as a type of anchor by attaching to an area of the virus that does not change very much and another to inhibit the virus’s ability to infect cells. This pairing of antibodies was shown to be effective against the initial SARS-CoV-2 virus that caused the pandemic and all its variants through omicron in laboratory testing. The findings are detailed in the journal Science Translational Medicine.
“In the face of an ever-changing virus, we engineered a new generation of therapeutics that have the ability to be resistant to viral evolution, which could be useful many years down the road for the treatment of people infected with SARS-CoV-2,” said Christopher O. Barnes, the study’s senior author, an assistant professor of biology.
An overlooked option
The team led by Barnes and first author Adonis Rubio, a doctoral candidate in the Stanford School of Medicine, conducted this investigation using donated antibodies from patients who had recovered from COVID-19. Analysing how these antibodies interacted with the virus, they found one that attaches to a region of the virus that does not mutate often.
This area, within the Spike N-terminal domain, or NTD, had been overlooked because it was not directly useful for treatment. However, when a specific antibody attaches to this area, it remains stuck to the virus. This is useful when designing new therapies that enable another type of antibody to get a foothold and attach to the receptor-binding domain, or RBD, of the virus, essentially blocking the virus from binding to receptors in human cells.
An illustration of the bispecific antibodies the Stanford-led research team developed to neutralise the virus that causes COVID-19. Named “CoV2-biRN,” these two antibodies work together by attaching to different areas of the virus.The bispecific antibodies target two areas of the virus: One attaches to the “NTD,” or Spike N-terminal domain, an area on the virus that does not change very much. This allows the second antibody to attach to the “RBD,” or receptor-binding domain, essentially preventing the virus from infecting human cells. | Christopher O. Barnes and Adonis Rubio using Biorender stock images
The researchers designed a series of these dual or “bispecific” antibodies, called CoV2-biRN, and in laboratory tests they showed high neutralisation of all the variants of SARS-CoV-2 known to cause illness in humans. The antibodies also significantly reduced the viral load in the lungs of mice exposed to one version of the omicron variant.
More research, including clinical trials, would have to be done before this discovery could be used as a treatment in human patients, but the approach is promising – and not just for the virus that causes COVID-19.
Next, the researchers will work to design bispecific antibodies that would be effective against all coronaviruses, the virus family including the ones that cause the common cold, MERS, and COVID-19. This approach could potentially also be effective against influenza and HIV, the authors said.
“Viruses constantly evolve to maintain the ability to infect the population,” Barnes said. “To counter this, the antibodies we develop must continuously evolve as well to remain effective.”
Photo by Wendy Wei: https://www.pexels.com/photo/mother-breastfeeding-her-child-3074935/
A study led by researchers at the found that breast milk provides protection against rotavirus, a common gastrointestinal disease in infants. Babies whose mothers had high levels of specific antibodies in their breast milk were able to fend off the infection for a longer period than infants whose mothers had lower levels. The researchers also uncovered an unexpected relationship between BMI and antibody levels.
Published in the Journal of Clinical Investigation, the University of Rochester Medical Center-led study also found significant differences in antibody profiles in breast milk between mothers in high-income countries (HICs) and low- and middle-income countries (LMICs). Researchers analysed human milk samples from 695 women in Finland, the US, Pakistan, Peru, and Bangladesh, and measured specific IgA and IgG antibodies, which are common antibodies produced in breast milk, against 1607 proteins from 30 pathogens.
The research, led by Dr Kirsi Jarvinen-Seppo, MD, PhD, professor at UR Medicine Golisano Children’s Hospital (GCH), tracked antibody levels and kinetics over time to analyse antibody responses to a wide range of respiratory, diarrhoeal and sepsis pathogens in human milk. The primary aim of the study, funded by the Bill and Melinda Gates Foundation, was to understand the protective properties of these antibodies and how they vary across different geographic and economic regions.
“We would expect to find differences in antibody levels in different countries, due to different diseases circulating among areas of the world, but this is one of the first times that there’s been a head-to-head comparison for dozens of pathogens across several continents,” said Jarvinen-Seppo. “It was encouraging to see such a clear link between higher antibody levels and a delay to rotavirus infection, and this was consistently observed among an independent validation cohort.”
Other notable findings from the study:
Milk from women in LMICs had higher levels of IgA and IgG antibodies against various intestinal and respiratory pathogens compared to milk from HICs. This difference was particularly notable for pathogens such as Shigella and pneumococcus, which are major contributors to morbidity and mortality in young children.
Higher body mass index (BMI) was associated with lower antibody levels, which went against expectations.
“The variation in antibody profiles between regions highlights the impact of economic and environmental factors on maternal immunity,” said Jarvinen-Seppo.
In addition to Rotavirus findings, the discovery that a higher BMI was associated with lower antibody counts in breast milk was also unexpected.
“We had anticipated that underweight mothers might have lower antibody levels due to poorer nutritional status,” said Jarvinen-Seppo. “Due to rising obesity rates worldwide, this could be a significant finding, but this is preliminary and additional research is needed since this is the first time this has been measured.”
“While the data on rotavirus protection is compelling, the geographical and BMI-related variations highlight areas where further research is essential. The study sets the stage for additional investigations that could lead to better understanding and interventions for improving infant health globally,” said Jarvinen-Seppo.
A long-term analysis conducted by leading microbiologists at the Icahn School of Medicine at Mount Sinai reveals that antibody responses induced by COVID vaccines are long-lasting. The study results, published online in the journal Immunity, challenge the idea that mRNA-based vaccine immunity wanes quickly.
The emergence of SARS-CoV-2 in late 2019 sparked the global pandemic that is now in its fifth year. Vaccines that were developed at record speed have saved millions of lives. However, the emergence of SARS-CoV-2 variants and waning immunity have decreased the effectiveness of the vaccines against symptomatic disease. The common perception now is that mRNA-based vaccine-induced immunity wanes quickly. However, this assumption is largely based on data from short-term studies that include a very limited number of data points following peak responses.
The Mount Sinai research team’s analysis of more than 8000 samples collected over a three-year period in New York City examined how antibody responses to the virus’s spike protein changed after infections, during the primary immunisation series, during monovalent and bivalent booster vaccination, and during breakthrough infections.
They found that upon primary immunisation, participants with pre-existing immunity (those who had previously been infected with the virus) mounted higher antibody responses faster and achieved higher steady-state antibody titres than individuals who had not been previously infected. The waning of antibody response was characterised by two phases: an initial rapid decay from the strong peak after vaccination, followed by a stabilisation phase with very slow decay, suggesting that antibody levels were very long-lasting. Booster vaccination equalised the differences in antibody concentration between participants with and without pre-existing immunity. Breakthrough infections increased antibodies to similar levels as an additional vaccine dose in individuals who had not previously been infected.
This investigation represents one of the most extensive and in-depth assessments of the longevity of SARS-CoV-2 immune responses to date. Its major conclusion is that changes in the virus that allow it to evade immunity, rather than waning immunity, are the major reason for breakthrough infections.
“Ours is one of the longest-running COVID-19 studies out there,” said Viviana Simon, MD, PhD, Professor of Microbiology, Medicine and Pathology, Molecular and Cell-Based Medicine, at Icahn Mount Sinai and lead author of the paper. “Following the same group of people monthly over time is rare and powerful because you can compare immune responses on an individual level. SARS-CoV-2 continues to evolve, so this research is important to provide an understanding about the impact of new variants and new vaccine doses on a healthy immune system, and to guide all of us to make the best choices to maintain protection against the virus that continues to circulate in our communities.”
This in-depth analysis was made possible through the Protection Associated with Rapid Immunity to SARS-CoV-2 (PARIS) study, an observational, longitudinal cohort of health care workers of the Mount Sinai Health System that was initiated in April 2020. At that time, the densely populated New York metropolitan area was hit with an exponential increase in severe SARS-CoV-2 infections, and essential workers in the health care system were at high risk for infection. In response to the crisis, a team of leading virologists, physician-scientists, and pathologists at Mount Sinai established a specific and sensitive SARS-CoV-2 binding enzyme-linked immunosorbent assay to accurately measure the SARS-CoV-2 antibody titres. This test was used to measure immune responses in the PARIS cohort in order to determine how quickly the antibody defences were mounted and much these changed over the months and years of follow up.
In addition to showing the impact on a person’s individual antibody response to vaccines based on the type of vaccine received and whether or not they were infected before receiving the first dose, the PARIS study made possible the development of a mathematical model that can be used to predict and characterize antibody responses of both individual people and populations.
“People have pandemic fatigue and vaccine uptake has slowed, especially after the vaccines started to be charged to insurance,” said Komal Srivastava, MS, Director of Strategy and Operation of the Mount Sinai Center for Vaccine Research and Pandemic Preparedness and co-first author of the paper. “We were pleasantly surprised to see that the booster doses promoted a large antibody response regardless of a person’s personal infection history, so we are hopeful that our study findings will encourage people to get their vaccine boosters when eligible and to stay engaged in research. Our work also showcases the impact of viral evolution over time and why it’s critical to keep studies like this going, despite the pandemic fatigue.”
According to the research team, the PARIS model has broad applications for studying the kinetics of antibodies produced to different COVID vaccines in diverse populations. They stress much more work remains to analyse side effects, applications of the antibody model and continued research about new vaccines and viral variants.
“This study adds an essential piece of data to understand the intricate immune response elicited by SARS-CoV-2 infection and COVID-19 vaccination,” says Juan Manuel Carreno Quiroz, PhD, Assistant Professor in the Department of Microbiology and co-first author of the paper. “In light of the emerging viral variants, which predominantly induce a cross-reactive antibody response against the spike protein, it will be exciting to characterise in depth the role of these antibodies – in particular the non-neutralising ones – in protection against the most recent circulating viral variants. Likewise, monitoring the induction of variant-specific antibodies after multiple exposures by breakthrough infections and by administration of updated COVID-19 vaccines, such as the XBB.1.5 monovalent booster, will be key to understand the evolution of the antibody response over time.”
Researchers at Karolinska Institutet have found further links between Epstein–Barr virus and multiple sclerosis. A study published in Science Advances shows that some individuals have antibodies against the virus that mistakenly attack a protein in the brain and spinal cord.
Many years ago, the Epstein–Barr virus (EBV), which infects most people early in life and then usually lies dormant was linked to multiple sclerosis (MS) but the reason remained a mystery. Increasing evidence, including two papers published in Science and Nature last year, suggests that EBV infection precedes MS and that antibodies against the virus may be involved. However, the molecular mechanisms seem to vary between patients and remain largely unknown.
“MS is an incredibly complex disease, but our study provides an important piece in the puzzle and could explain why some people develop the disease,” says Olivia Thomas, postdoctoral researcher at the Department of Clinical Neuroscience, Karolinska Institutet and shared first author of the paper. “We have discovered that certain antibodies against the Epstein-Barr virus, which would normally fight the infection, can mistakenly target the brain and spinal cord and cause damage.”
The researchers analysed blood samples from more than 700 patients with MS and 700 healthy controls. They found that antibodies that bind to a certain protein in the Epstein-Barr virus, EBNA1, can also bind to a similar protein in the brain and spinal cord called CRYAB, whose role is to prevent protein aggregation during conditions of cellular stress such as inflammation. These misdirected, cross-reactive antibodies may damage the nervous system and cause severe symptoms in MS patients, including problems with balance, mobility and fatigue. The antibodies were present in about 23 percent of MS patients and 7% of control individuals.
“This shows that, whilst these antibody responses are not required for disease development, they may be involved in disease in up to a quarter of MS patients,” says Olivia Thomas. “This also demonstrates the high variation between patients, highlighting the need for personalised therapies. Current therapies are effective at reducing relapses in MS but unfortunately, none can prevent disease progression.”
“We are now expanding our research to investigate how T cells fight EBV infection and how these immune cells may damage the nervous system in multiple sclerosis and contribute to disease progression,” says joint first author of the paper Mattias Bronge, affiliated researcher at the Department of Clinical Neuroscience, Karolinska Institutet.
According to new research from the Universities of Cambridge and Edinburgh, COVID vaccination protection in people with severe obesity wanes faster than in people of normal weight. The study suggests that people with obesity are likely to need more frequent booster doses to maintain their immunity.
Previous studies on COVID vaccines have suggested that antibody levels may be lower in vaccinated people who have obesity and that they may remain at higher risk of severe disease than vaccinated people with normal weight. The reasons for this have, however, remained unclear.
This study, published in the journal Nature Medicine, shows that the ability of antibodies to neutralise the virus (their ‘neutralisation capacity’) declines faster in vaccinated people who have obesity. The findings have important implications for vaccine prioritisation policies around the world.
During the pandemic, people with obesity were more likely to be hospitalised, require ventilators and to die from COVID. In this study, supported by the NIHR Bioresource and funded by UKRI, the researchers set out to investigate how far two of the most extensively used vaccines protect people with obesity compared to those with a normal weight, over time.
A team from the University of Edinburgh looked at real-time data tracking the health of 3.5 million people in the Scottish population as part of the EAVE II study. They looked at hospitalisation and mortality from COVID in adults who received two doses of COVID vaccine (either Pfizer-BioNTech or AstraZeneca).
They found that people with severe obesity (a BMI > 40kg/m2) had a 76% higher risk of severe COVID outcomes, compared to those with a normal BMI. A modest increase in risk was also seen in people with obesity (30-39.9kg/m2), which affects a quarter of the UK population, and those who were underweight. ‘Break-through infections’ after the second vaccine dose also led to hospitalisation and death sooner (from 10 weeks) among people with severe obesity, and among people with obesity (after 15 weeks), than among individuals with normal weight (after 20 weeks).
University of Edinburg leader Prof Sir Aziz Sheikh said: “Our findings demonstrate that protection gained through COVID vaccination drops off faster for people with severe obesity than those with a normal body mass index. Using large-scale data assets such as the EAVE II Platform in Scotland have enabled us to generate important and timely insights that enable improvements to the delivery of COVID vaccine schedules in a post-pandemic UK.”
The University of Cambridge team studied people with severe obesity attending the Obesity clinic at Addenbrooke’s Hospital in Cambridge, and compared the number and function of immune cells in their blood to those of people of normal weight.
They studied people six months after their second vaccine dose and then looked at the response to a third ‘booster’ vaccine dose over time. The Cambridge researchers found that six months after a second vaccine dose, people with severe obesity had similar levels of antibodies to the COVID virus as those with a normal weight – but those antibodies were less effecctive.
The antibodies’ neutralisation capacity was reduced in 55% of individuals with severe obesity were found to have unquantifiable or undetectable ‘neutralising capacity’ compared to 12% of people with normal BMI.
“This study further emphasises that obesity alters the vaccine response and also impacts on the risk of infection,” said first author Dr Agatha van der Klaauw. “We urgently need to understand how to restore immune function and minimise these health risks.”
The researchers found that antibodies produced by people with severe obesity were less effective at neutralising the SARS-CoV-2 virus, potentially because the antibodies were not able to bind to the virus with the same strength.
When given a third (booster) dose of a COVID vaccine, neutralisation capacity was restored in both the normal weight and severely obese groups. But the researchers found that immunity again declined more rapidly in people with severe obesity, putting them at greater risk of infection with time.
