Virus that causes COVID-19 is widespread in wildlife, scientists find

SARS-CoV-2, the virus responsible for COVID-19, is widespread among wildlife species, according to Virginia Tech research published Monday (July 29, 2024) in Nature Communications. The virus was detected in six common backyard species, and antibodies indicating prior exposure to the virus were found in five species, with rates of exposure ranging from 40 to 60 percent depending on the species.

Genetic tracking in wild animals confirmed both the presence of SARS-CoV-2 and the existence of unique viral mutations with lineages closely matching variants circulating in humans at the time, further supporting human-to-animal transmission, the study found.

The highest exposure to SARS CoV-2 was found in animals near hiking trails and high-traffic public areas, suggesting the virus passed from humans to wildlife, according to scientists at the Fralin Biomedical Research Institute at VTC, the Department of Biological Sciences in Virginia Tech's College of Science, and the Fralin Life Sciences Institute.

The findings highlight the identification of novel mutations in SARS-CoV-2 in wildlife and the need for broad surveillance, researchers say. These mutations could be more harmful and transmissible, creating challenges for vaccine development.

The scientists stressed, however, that they found no evidence of the virus being transmitted from animals to humans, and people should not fear typical interactions with wildlife.

Investigators tested animals from 23 common Virginia species for both active infections and antibodies indicating previous infections. They found signs of the virus in deer mice, Virginia opossums, raccoons, groundhogs, Eastern cottontail rabbits, and Eastern red bats. The virus isolated from one opossum showed viral mutations that were previously unreported and can potentially impact how the virus affects humans and their immune response.

"The virus can jump from humans to wildlife when we are in contact with them, like a hitchhiker switching rides to a new, more suitable host," said Carla Finkielstein, professor of biological sciences at the Fralin Biomedical Research Institute at VTC and one of the paper's corresponding authors. "The goal of the virus is to spread in order to survive. The virus aims to infect more humans, but vaccinations protect many humans. So, the virus turns to animals, adapting and mutating to thrive in the new hosts."

SARS CoV-2 infections were previously identified in wildlife, primarily in white-tailed deer and feral mink. The Virginia Tech study significantly expands the number of species examined and the understanding of virus transmission to and among wildlife. The data suggests exposure to the virus has been widespread in wildlife and that areas with high human activity may serve as points of contact for cross-species transmission.

"This study was really motivated by seeing a large, important gap in our knowledge about SARS-CoV-2 transmission in a broader wildlife community," said Joseph Hoyt, assistant professor of Biological Sciences in Virginia Tech's College of Science and corresponding author on the paper. "A lot of studies to date have focused on white-tailed deer, while what is happening in much of our common backyard wildlife remains unknown."

The research team collected 798 nasal and oral swabs across in Virginia from animals either live-trapped in the field and released, or being treated by wildlife rehabilitation centers. The team also obtained 126 blood samples from six species. The locations were chosen to compare the presence of the virus in animals in sites with varying levels of human activity, from urban areas to remote wilderness.

The study also identified two mice at the same site on the same day with the exact same variant, indicating they either both got it from the same human, or one infected the other.

Researchers are not certain about the means of transmission from humans to animals. One possibility is wastewater, but the Virginia Tech scientists believe trash receptacles and discarded food are more likely sources.

"I think the big take home message is the virus is pretty ubiquitous," said Amanda Goldberg, a former postdoctoral associate in Hoyt's lab, who is the study's first author. "We found positives in a large suite of common backyard animals."

While this study focused on the state of Virginia, many of the species that tested positive are common wildlife found throughout North America. It is likely they are being exposed in other areas as well, and surveillance across a broader region is urgently needed, Hoyt said.

"The virus is indifferent to whether its host walks on two legs or four. Its primary objective is survival. Mutations that do not confer a survival or replication advantage to the virus will not persist and will eventually disappear," said Finkielstein, who is also director of the Virginia Tech Molecular Diagnostics Lab. The Roanoke lab was established in April 2020 to expand COVID-19 testing.

"We understood the critical importance of sequencing the genome of the virus infecting those species," Finkielstein said. "It was a monumental task that could only be accomplished by a talented group of molecular biologists, bioinformaticians, and modelers in a state-of-the-art facility. I am proud of my team and my collaborators, their professionalism, and everything they contributed to ensure our success."

Surveillance for these mutations should continue and not be dismissed, the scientists said. More research is needed about how the virus is transmitted from humans to wildlife, how it might spread within a species, and perhaps from one species to another.

"This study highlights the potentially large host range SARS-CoV-2 can have in nature and really how widespread it might be," Hoyt said. "There is a lot of work to be done to understand which species of wildlife, if any, will be important in the long-term maintenance of SARS-CoV-2 in humans."

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Llama nanobodies: A breakthrough in building HIV immunity

A research team at Georgia State University has developed tiny, potent molecules that are capable of targeting hidden strains of HIV. The source? Antibody genes from llama DNA.

The research, led by Assistant Professor of Biology Jianliang Xu, uses llama-derived nanobodies to broadly neutralize numerous strains of HIV-1, the most common form of the virus. A new study from this team has been published in the journal Advanced Science.

"This virus has evolved a way to escape our immune system. Conventional antibodies are bulky, so it's difficult for them to find and attack the virus' surface," Xu explained. "These new antibodies can do this in an easier way."

Scientists in pursuit of effective HIV treatment and prevention have been working with animals in the camelid family -- like llamas -- for about 15 years. That's because the shape and features of their antibodies make them nimbler and more effective at identifying and neutralizing foreign objects, like the HIV virus.

This new research presents a widely applicable method to enhance the performance of nanobodies. Nanobodies are engineered antibody fragments that are about one-tenth the size of a conventional antibody. They are derived from flexible, Y-shaped heavy chain-only antibodies -- made up of two heavy chains -- which are more effective at fighting certain viruses than conventional antibodies with light chains.

The nanobodies are derived from flexible, Y-shaped antibodies made up of heavy-chain peptides which may be more effective at fighting certain viruses.

For the study, researchers immunized llamas with a specially designed protein which results in the production of neutralizing nanobodies. Xu and his team then identified nanobodies that can target vulnerable sites on the virus. When the team engineered the nanobodies into a triple tandem format -- by repeating short lengths of DNA -- the resulting nanobodies demonstrated remarkable effectiveness, neutralizing 96 percent of a diverse panel of HIV-1 strains.

Further analysis uncovered that these nanobodies mimic the recognition of the CD4 receptor -- a key player in HIV infection. To enhance their potency, the nanobodies were fused with a broadly neutralizing antibody (bNAb), resulting in a new antibody with unprecedented neutralizing abilities.

"Instead of developing a cocktail of antibodies, now we can make a single molecule that can neutralize HIV," Xu said. "We are working with a broadly neutralizing nanobody that can neutralize over 90 percent of the circulating HIV strains, and when we combine that with another bNAb which also neutralizes some 90 percent, together, they can neutralize close to 100 percent."

Xu began this research at the National Institutes of Health Vaccine Research Center in Bethesda, Md., where he collaborated with a team of more than 30 scientists. The team included Peter Kwong, professor of biochemistry and molecular biophysics at Columbia University and co-author of the study. Since coming to Georgia State in 2023, Xu has been mentoring Payton Chan, a Ph.D. candidate at Georgia State. Together, they are working to expand these potential remedies.

Chan said she is excited about the prospects of the innovative research.

"These nanobodies are the best and most potently neutralizing antibodies to date, which I think is very promising for the future of HIV therapeutics and antibody research," Chan said. "I hope one day there will be approval of these nanobodies for the treatment of HIV."

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Drug limits dangerous reactions to allergy-triggering foods, Stanford Medicine-led study of kids finds

A drug can make life safer for children with food allergies by preventing dangerous allergic responses to small quantities of allergy-triggering foods, according to a new study led by scientists at the Stanford School of Medicine.

The research will be published Feb. 25 in the New England Journal of Medicine. The findings suggest that regular use of the drug, omalizumab, could protect people from severe allergic responses, such as difficulty breathing, if they accidentally eat a small amount of a food they are allergic to.

"I'm excited that we have a promising new treatment for multifood allergic patients. This new approach showed really great responses for many of the foods that trigger their allergies," said the study's senior author, Sharon Chinthrajah, MD, associate professor of medicine and of pediatrics, and the acting director of the Sean N. Parker Center for Allergy and Asthma Research at Stanford Medicine.

"Patients impacted by food allergies face a daily threat of life-threatening reactions due to accidental exposures," said the study's lead author, Robert Wood, MD, professor of pediatrics at Johns Hopkins University School of Medicine. "The study showed that omalizumab can be a layer of protection against small, accidental exposures."

Omalizumab, which the Food and Drug Administration originally approved to treat diseases such as allergic asthma and chronic hives, binds to and inactivates the antibodies that cause many kinds of allergic disease. Based on the data collected in the new study, the FDA approved omalizumab for reducing risk of allergic reactions to foods on Feb. 16.

All study participants were severely allergic to peanuts and at least two other foods. After four months of monthly or bimonthly omalizumab injections, two-thirds of the 118 participants receiving the drug safely ate small amounts of their allergy-triggering foods. Notably, 38.4% of the study participants were younger than 6 years, an age group at high risk from accidental ingestions of allergy-triggering foods.

Allergies are common

Food allergies affect about 8% of children and 10% of adults in the United States. People with severe allergies are advised to fully avoid foods containing their allergy triggers, but common allergens such as peanuts, milk, eggs and wheat can be hidden in so many places that everyday activities such as attending parties and eating in restaurants can be challenging.

"Food allergies have significant social and psychological impacts, including the threat of allergic reactions upon accidental exposures, some of which can be life-threatening," Chinthrajah said. Families also face economic impacts from purchasing more expensive foods to avoid allergens, she added.

In the best available treatment for food allergies, called oral immunotherapy, patients ingest tiny, gradually increasing doses of allergy-triggering foods under a doctor's supervision to build tolerance. But oral immunotherapy itself can trigger allergic responses, desensitization to allergens can take months or years, and the process is especially lengthy for people with several food allergies, as they are usually treated for one allergy at a time. Once they are desensitized to an allergen, patients also must continue to eat the food regularly to maintain their tolerance to it -- but people often dislike foods they were long required to avoid.

"There is a real need for treatment that goes beyond vigilance and offers choices for our food allergic patients," Chinthrajah said.

Omalizumab is an injected antibody that binds and deactivates all types of immunoglobin E, or IgE, the allergy-causing molecule in the blood and on the body's immune cells. So far, omalizumab appears able to provide relief from multiple food allergens at once.

"We think it should have the same impact regardless of what food it is," Chinthrajah said.

Injections stave off severe reactions

The study included 177 children with at least three food allergies each, of whom 38% were 1 to 5 years old, 37% were 6 to 11 years old, and 24% were 12 or older. Participants' severe food allergies were verified by skin-prick testing and food challenges; they reacted to less than 100 milligrams of peanut protein and less than 300 milligrams of each other food.

Two-thirds of the participants were randomly assigned to receive omalizumab injections, and one-third received an injected placebo; the injections took place over 16 weeks. Medication doses were set based on each participant's body weight and IgE levels, with injections given once every two or four weeks, depending on the dose needed. The participants were re-tested between weeks 16 and 20 to see how much of each allergy-triggering food they could safely tolerate.

Upon re-testing, 79 patients (66.9%) who had taken omalizumab could tolerate at least 600 mg of peanut protein, the amount in two or three peanuts, compared with only four patients (6.8%) who had the placebo. Similar proportions of patients showed improvement in their reactions to the other foods in the study.

About 80% of patients taking omalizumab were able to consume small amounts of at least one allergy-triggering food without inducing an allergenic reaction, 69% of patients could consume small amounts of two allergenic foods and 47% could eat small amounts of all three allergenic foods.

Omalizumab was safe and did not cause side effects, other than some instances of minor reactions at the site of injection. This study marks the first time its safety has been assessed in children as young as 1.

More questions

More research is needed to further understand how omalizumab could help people with food allergies, the researchers said.

"We have a lot of unanswered questions: How long do patients need to take this drug? Have we permanently changed the immune system? What factors predict which people will have the strongest response?" Chinthrajah said. "We don't know yet."

The team is planning studies to answer these questions and others, such as finding what type of monitoring would be needed to determine when a patient gains meaningful tolerance to an allergy-triggering food.

Many patients who have food allergies also experience other allergic conditions treated by omalizumab, Chinthrajah noted, such as asthma, allergic rhinitis (hay fever and allergies to environmental triggers such as mold, dogs or cats, or dust mites) or eczema. "One drug that could improve all of their allergic conditions is exactly what we're hoping for," she said.

The drug could be especially helpful for young children with severe food allergies, she added, because they tend to put things in their mouths and may not understand the dangers their allergies pose, she added.

The drug could also make it safer for community physicians to treat food allergy patients, since it cannot trigger dangerous allergic reactions, as oral immunotherapy sometimes does. "This is something that our food allergy community has been waiting a long time for," Chinthrajah said. "It's an easy drug regimen to implement in a medical practice, and many allergists are already using this for other allergic conditions."

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SARS-CoV-2: Neutralization of BA.1 and BA.2 by therapeutic monoclonal antibodies

The SARS-CoV-2 Omicron BA.1 sublineage has been supplanted in many countries by the BA.2 sublineage. Although Omicron is responsible for less severe forms in the general population, immunocompromised people are still at higher risk of developing severe forms of COVID-19. Several monoclonal antibodies are currently available in clinical practice as a preventive treatment for these patients. Scientists from the Institut Pasteur, the CNRS, the Vaccine Research Institute (VRI), in collaboration with Orléans Regional Hospital, the Paris Public Hospital Network (AP-HP), KU Leuven (the Catholic University of Leuven) and Université Paris Cité, studied the sensitivity of Omicron BA.1 and BA.2 to nine monoclonal antibodies, some of which are used in pre-exposure prophylaxis in immunocompromised individuals. The scientists showed a loss of neutralizing activity against BA.1 and BA.2 in people treated with two antibody cocktails (Ronapreve® or Evusheld®). These findings were published in Nature Medicine on March 23, 2022.

The Omicron sublineage BA.2 has become increasingly common and is now dominant in several countries, including France. Scientists from the Institut Pasteur's Virus and Immunity Unit (a joint research unit with the CNRS) and the VRI began by studying the sensitivity of the Omicron BA.1 and BA.2 sublineages to therapeutic monoclonal antibodies in a cell culture system. This step involved isolating an infectious BA.2 strain in collaboration with the Rega Institute at KU Leuven. They then examined the efficacy of pre-exposure prophylaxis in immunocompromised individuals at risk of developing severe COVID-19. The scientists first described the in vitro sensitivity of BA.2 to nine therapeutic antibodies, as compared to the Delta variant and Omicron BA.1. They went on to examine the clinical implications of these observations by measuring the neutralizing activity of the antibodies in sera from 29 individuals who had been treated with Ronapreve® (a cocktail of two antibodies developed by Roche/Regeneron) and/or Evusheld® (a cocktail of two antibodies developed by AstraZeneca).

The scientists compared the ability of the patients' sera to tackle BA.1 and BA.2 between 3 and 30 days after treatment. The results of the study show that therapeutic sensitivity varies depending on the Omicron sublineage.

"We show that the antibodies and corresponding sera are inactive or only weakly active against BA.1, but more active against BA.2. As compared to the Delta variant, neutralizing titers were more markedly decreased against BA.1 (344-fold) than BA.2 (9-fold)," explained Timothée Bruel, lead author of the study and a scientist in the Virus and Immunity Unit at the Institut Pasteur (a joint research unit with the CNRS) with regard to Evusheld®.

Four Omicron infections were also reported among the 29 patients treated with antibodies (including one severe case). "This shows that, in this case, treatment does not fully protect against infection or against severe forms," explained Thierry Prazuck, co-last author of the study and Head of the Infectious Diseases Department at Orléans Regional Hospital.

"To our knowledge, this is the first study to directly describe the seroneutralization of individuals treated with monoclonal antibodies against Delta, BA.1 and BA.2, and to link the results with infections. BA.1, and to a lesser extent BA.2, is less sensitive to Evusheld® and Ronapreve® than Delta. This suggests that these treatments are probably less clinically effective against Omicron infection than against Delta," commented Olivier Schwartz, last author of the study and Head of the Virus and Immunity Unit at the Institut Pasteur (a joint research unit with the CNRS).

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Vaccine and antibody treatment effectiveness blunted by all three Omicron subvariants

Only one currently authorized antibody treatment retains its activity against all Omicron subvariants, according to new research by scientists at Columbia University and the University of Hong Kong. The study also shows that the effectiveness of mRNA vaccines is reduced against all three subvariants of Omicron.

The findings were published in Nature on March 2 by David D. Ho, MD, director of the Aaron Diamond AIDS Research Center and the Clyde'56 and Helen Wu Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons.

Omicron is a highly transmissible variant of SARS-CoV-2 that has caused the biggest surge in COVID cases so far in many countries. Researchers have identified three subvariants of Omicron that share 21 mutations in the spike protein, and named them BA.1, BA.1.1 and BA.2.

When Omicron was first identified in November 2021, the dominant variant was BA.1. Since December, BA.1 cases have declined, while BA1.1 cases have risen and now make up around 40% of all Omicron cases sequenced globally. The BA.2 subvariant currently represents only 10% of all Omicron cases globally but is increasing in prevalence.

In laboratory experiments, Ho and his team studied the ability of 19 monoclonal antibodies and the sera from individuals immunized with one of two available mRNA vaccines to neutralize the three known subvariants of Omicron.

Consistent with their previous study on the BA.1 variant, the researchers observed a similar loss of neutralization activity against BA.1.1 and BA.2 in blood samples from individuals who had received two mRNA shots. However, the decline in neutralization was less prominent in blood samples from individuals who had received three mRNA shots, reinforcing the importance of booster shots for sustaining immunity.

In neutralization experiments, all three variants exhibited a strong resistance to most of the monoclonal antibodies tested. Of 19 antibodies, 17 were ineffective against the BA.2 subvariant. The researchers found that bebtelovimab, the latest monoclonal antibody to receive FDA Emergency Use Authorization, is the only currently available antibody therapy that can adequately treat all three Omicron subvariants.

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COVID-19 can trigger self-attacking antibodies

Infection with the virus that causesCOVID-19 can trigger an immune response that lasts well beyond the initial infection and recovery -- even among people who had mild symptoms or no symptoms at all, according to Cedars-Sinai investigators. The findings are published in the Journal of Translational Medicine.

When people are infected with a virus or other pathogen, their bodies unleash proteins called antibodies that detect foreign substances and keep them from invading cells. In some cases, however, people produce autoantibodies that can attack the body's own organs and tissues over time.

The Cedars-Sinai investigators found that people with prior infection with SARS-CoV-2, the virus that causes COVID-19, have a wide variety of autoantibodies up to six months after they have fully recovered. Prior to this study, researchers knew that severe cases of COVID-19 can stress the immune system so much that autoantibodies are produced. This study is the first to report not only the presence of elevated autoantibodies after mild or asymptomatic infection, but their persistence over time.

"These findings help to explain what makes COVID-19 an especially unique disease," said Justyna Fert-Bober, PhD, research scientist in the Department of Cardiology at the Smidt Heart Institute and co-senior author of the study. "These patterns of immune dysregulation could be underlying the different types of persistent symptoms we see in people who go on to develop the condition now referred to as long COVID-19."

To conduct their study, the Cedars-Sinai research team recruited 177 people with confirmed evidence of a previous infection with SARS-CoV-2. They compared blood samples from these individuals with samples taken from healthy people prior to the pandemic. All those with confirmed SARS-CoV-2 infection had elevated levels of autoantibodies. Some of the autoantibodies also have been found in people with diseases in which the immune system attacks its own healthy cells, such as lupus and rheumatoid arthritis.

"We found signals of autoantibody activity that are usually linked to chronic inflammation and injury involving specific organ systems and tissues such as the joints, skin and nervous system," said Susan Cheng, MD, MPH, MMSc, director of the Institute for Research on Healthy Aging in the Department of Cardiology at the Smidt Heart Institute and co-senior author of the study.

Some of the autoantibodies have been linked to autoimmune diseases that typically affect women more often than men. In this study, however, men had a higher number of elevated autoantibodies than women.

"On the one hand, this finding is paradoxical given that autoimmune conditions are usually more common in females," Fert-Bober said. "On the other hand, it is also somewhat expected given all that we know about males being more vulnerable to the most severe forms of COVID-19."

The research team is interested in expanding the study to look for the types of autoantibodies that may be present and persist in people with long-haul COVID-19 symptoms. Because this study was in people infected before the advent of vaccines, the researchers will also examine whether autoantibodies are similarly generated in people with breakthrough infections.

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COVID-19 infection detected in deer in six Ohio locations

Scientists have detected infection by at least three variants of the virus that causes COVID-19 in free-ranging white-tailed deer in six northeast Ohio locations, the research team has reported.

Previous research led by the U.S. Department of Agriculture had shown evidence of antibodies in wild deer. This study, published today (Dec. 23, 2021) in Nature, details the first report of active COVID-19 infection in white-tailed deer supported by the growth of viral isolates in the lab, indicating researchers had recovered viable samples of the SARS-CoV-2 virus and not only its genetic traces.

Based on genomic sequencing of the samples collected between January and March 2021, researchers determined that variants infecting wild deer matched strains of the SARS-CoV-2 virus that had been prevalent in Ohio COVID-19 patients at the time. Sample collection occurred before the Delta variant was widespread, and that variant was not detected in these deer. The team is testing more samples to check for new variants as well as older variants, whose continued presence would suggest the virus can set up shop and survive in this species.

The fact that wild deer can become infected "leads toward the idea that we might actually have established a new maintenance host outside humans," said Andrew Bowman, associate professor of veterinary preventive medicine at The Ohio State University and senior author of the paper.

"Based on evidence from other studies, we knew they were being exposed in the wild and that in the lab we could infect them and the virus could transmit from deer to deer. Here, we're saying that in the wild, they are infected," Bowman said. "And if they can maintain it, we have a new potential source of SARS-CoV-2 coming in to humans. That would mean that beyond tracking what's in people, we'll need to know what's in the deer, too.

"It could complicate future mitigation and control plans for COVID-19."

A lot of unknowns remain: how the deer got infected, whether they can infect humans and other species, how the virus behaves in the animals' body, and whether it's a transient or long-term infection.

The research team took nasal swabs from 360 white-tailed deer in nine northeast Ohio locations. Using PCR testing methods, the scientists detected genetic material from at least three different strains of the virus in 129 (35.8%) of the deer sampled.

The analysis showed that B.1.2 viruses dominant in Ohio in the early months of 2021 spilled over multiple times into deer populations in different locations.

"The working theory based on our sequences is that humans are giving it to deer, and apparently we gave it to them several times," Bowman said. "We have evidence of six different viral introductions into those deer populations. It's not that a single population got it once and it spread."

Each site was sampled between one and three times, adding up to a total of 18 sample collection dates. Based on the findings, researchers estimated the prevalence of infection varied from 13.5% to 70% across the nine sites, with the highest prevalence observed in four sites that were surrounded by more densely populated neighborhoods.

White-tailed deer functioning as a viral reservoir of SARS-CoV-2 would likely result in one of two outcomes, Bowman said. The virus could mutate in deer, potentially facilitating transmission of new strains to other species, including humans, or the virus could survive in deer unmutated while it simultaneously continues to evolve in humans, and at some point when humans don't have immunity to the strains infecting deer, those variants could come spilling back to humans.

How transmission happened initially in these deer, and how it could happen across species, are among the pending questions related to these findings. The research team speculated that white-tailed deer were infected through an environmental pathway -- possibly by drinking contaminated water. Research has shown that the virus is shed in human stool and detectable in wastewater.

The white-tailed deer tested for this study were part of a population control initiative, so they are not a transmission threat.

Though there are an estimated 600,000 white-tailed deer in Ohio and 30 million in the United States, Bowman said this sampling focused on locations close to dense human populations and is not representative of all free-ranging deer.

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Natural infection and vaccination together provide maximum protection against COVID variants

A combination of vaccination and naturally acquired infection appears to boost the production of maximally potent antibodies against the COVID-19 virus, new UCLA research finds.

The findings, published in the peer-reviewed journal mBio, raise the possibility that vaccine boosters may be equally effective in improving antibodies' ability to target multiple variants of the virus, including the delta variant, which is now the predominant strain, and the recently detected omicron variant. (The study was conducted prior to the emergence of delta and omicron, but Dr. Otto Yang, the study's senior author, said the results could potentially apply to those and other new variants.)

"The main message from our research is that someone who has had COVID and then gets vaccinated develops not only a boost in antibody amount, but also improved antibody quality -- enhancing the ability of antibodies to act against variants," said Yang, a professor of medicine in the division of infectious diseases and of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA. "This suggests that having repeated exposures to the spike protein allows the immune system to continue improving the antibodies if someone had COVID then been vaccinated."

(The spike protein is the part of the virus that binds to cells, resulting in infection.)

Yang said it is not yet known whether the same benefits would be realized for people who have repeated vaccinations but who have not contracted COVID-19.

The researchers compared blood antibodies in 15 vaccinated people who had not been previously infected with SARS-CoV-2, the virus that causes COVID-19, with infection-induced antibodies in 10 people who were recently infected with SARS-CoV-2 but not yet vaccinated. Several months later, the 10 participants in the latter group were vaccinated, and the researchers then reanalyzed their antibodies. Most people in both of the groups had received the Pfizer-BioNTech or Moderna two-dose vaccines.

The scientists evaluated how antibodies acted against a panel of spike proteins with various common mutations in the receptor-binding domain, which is the target for antibodies that help neutralize the virus by blocking it from binding to cells.

They found that the receptor-binding domain mutations reduced the potency of antibodies acquired both by either natural infection or vaccination alone, to about the same degree in both groups of people. When previously infected people were vaccinated about a year after natural infection, however, their antibodies' potency was maximized to a point that they recognized all of the COVID-19 variants the scientists tested.

"Overall, our findings raise the possibility that resistance of SARS-CoV-2 variants to antibodies can be overcome by driving further maturation through continued antigenic exposure by vaccination, even if the vaccine does not deliver variant sequences," the researchers write. They suggest that repeated vaccinations may have the capacity to accomplish the same thing as getting vaccinated after having had COVID-19, although further research will be required to address that possibility.

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Discovering new drugs with help from Darwinian principles

Our body must constantly defend itself against bacteria and viruses. It generates millions of different antibodies, which are selected to recognise the enemy and trigger the best possible immune response. Scientists use these antibodies to for therapeutic purposes to target proteins and disrupt their harmful. However, identifying the small molecules that will form the basis of the drug is a long and tedious process. Chemists at the University of Geneva (UNIGE), Switzerland, have developed a technique inspired by the theory of Darwinian evolution: amplifying the best combinations and generating diversity allows biology to find solutions to new problems. They have created a new methodology that rapidly generates millions of combinations of small molecules through programmed assembly using DNA-pairing processes, finding the best possible combination to counter a target protein within two weeks. These results, published in the journal Nature Chemistry, will open up a new and untapped space for drug development.

The way drugs work is based on the molecular recognition of a target protein involved in the disease, in order to disarm it. To do this, scientists use high-throughput screening to identify which molecule could become a drug, specifically targeting the protein of interest. Over the last ten years, the technique has been improved by encoding small molecules with DNA tags that simplify their identification, as DNA is easy to decode.

Drawing inspiration from Darwinian evolutionary forces to find efficient assemblies

Today, chemists at the UNIGE have gone one step further, drawing inspiration from Darwin's theories: "Biology always finds a solution to a problem, explains Nicolas Winssinger, professor in the Department of Organic Chemistry at the Faculty of Science, UNIGE, and the corresponding author of the study. This is the principle of natural evolution, which consists of amplifying the best individuals, while generating diversity to adapt and survive changing conditions. That's what we've set up for small molecules." Indeed, the scientists have developed a technology that generates diversity by creating more than 100 million assemblies of molecules via their DNA, which they then select to best match a particular protein.

"We were inspired by the characteristics of antibodies that recognise target proteins and sought to mimic them in the form of simpler molecules to allow them to be assembled in different combinations, directed by DNA sequences," explains Nicolas Winssinger. These combinations are then selected and amplified several times to find the best possible match with the protein to be targeted, all in one to two weeks, compared with months or even a year for traditional high-throughput screening.

A proven, easily reproducible and inexpensive technique

To validate the effectiveness of this methodology, the Geneva team focused on the PD-L1 protein, which protects cancer cells by diverting the immune system. "Thanks to our methodology, we quickly identified an assembly that specifically targets PD-L1, confirming that it works effectively," says Nicolas Winssinger.

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Immune system-stimulating nanoparticle could lead to more powerful vaccines

A common strategy to make vaccines more powerful is to deliver them along with an adjuvant -- a compound that stimulates the immune system to produce a stronger response.

Researchers from MIT, the La Jolla Institute for Immunology, and other institutions have now designed a new nanoparticle adjuvant that may be more potent than others now in use. Studies in mice showed that it significantly improved antibody production following vaccination against HIV, diphtheria, and influenza.

"We started looking at this particular formulation and found that it was incredibly potent, better than almost anything else we had tried," says Darrell Irvine, the Underwood-Prescott Professor with appointments in MIT's departments of Biological Engineering and Materials Science and Engineering; an associate director of MIT's Koch Institute for Integrative Cancer Research; and a member of the Ragon Institute of MGH, MIT, and Harvard.

The researchers now hope to incorporate the adjuvant into an HIV vaccine that is currently being tested in clinical trials, in hopes of improving its performance.

Irvine and Shane Crotty, a professor at the Center for Infectious Disease and Vaccine Research at the La Jolla Institute for Immunology, are the senior authors of the study, which appears today in Science Immunology. The lead authors of the paper are Murillo Silva, a former MIT postdoc, and Yu Kato, a staff scientist at the La Jolla Institute.

More powerful vaccines

Although the idea of using adjuvants to boost vaccine effectiveness has been around for decades, there are only a handful of FDA-approved vaccine adjuvants. One is aluminum hydroxide, an aluminum salt that induces inflammation, and another is an oil and water emulsion that is used in flu vaccines. A few years ago, the FDA approved an adjuvant based on saponin, a compound derived from the bark of the Chilean soapbark tree.

Saponin formulated in liposomes is now used as an adjuvant in the shingles vaccine, and saponins are also being used in a cage-like nanoparticle called an immunostimulatory complex (ISCOM) in a Covid-19 vaccine that is currently in clinical trials.

Researchers have shown that saponins promote inflammatory immune responses and stimulate antibody production, but how they do that is unclear. In the new study, the MIT and La Jolla team wanted to figure out how the adjuvant exerts its effects, and to see if they could make it more potent.

They designed a new type of adjuvant that is similar to the ISCOM adjuvant but also incorporates a molecule called MPLA, which is a toll-like receptor agonist. When these molecules bind to toll-like receptors on immune cells, they promote inflammation. The researchers call their new adjuvant SMNP (saponin/MPLA nanoparticles).

"We expected that this could be interesting because saponin and toll-like receptor agonists are both adjuvants that have been studied separately and shown to be very effective," Irvine says.

The researchers tested the adjuvant by injecting it into mice along with a few different antigens, or fragments of viral proteins. These included two HIV antigens, as well as diphtheria and influenza antigens. They compared the adjuvant to several other approved adjuvants and found that the new saponin-based nanoparticle elicited a stronger antibody response than any of the others.

One of the HIV antigens that they used is an HIV envelope protein nanoparticle, which presents many copies of the gp120 antigen that is present on the HIV viral surface. This antigen recently completed initial testing in phase 1 clinical trials. Irvine and Crotty are part of the Consortium for HIV/AIDS Vaccine Development at the Scripps Research Institute, which ran that trial. The researchers now hope to develop a way to manufacture the new adjuvant at large scale so it can be tested along with an HIV envelope trimer in another clinical trial beginning next year. Clinical trials that combine envelope trimers with the traditional vaccine adjuvant aluminum hydroxide are also underway.

"Aluminum hydroxide is safe but not particularly potent, so we hope that (the new adjuvant) would be an interesting alternative to elicit neutralizing antibody responses in people," Irvine says.

Rapid flow

When vaccines are injected into the arm, they travel through lymph vessels to the lymph nodes, where they encounter and activate B cells. The research team found that the new adjuvant speeds up the flow of lymph to the nodes, helping the antigen to get there before it starts to break down. It does this in part by stimulating immune cells called mast cells, which previously were not known to be involved in vaccine responses.

"Getting to the lymph nodes quickly is useful because once you inject the antigen, it starts slowly breaking down. The sooner a B cell can see that antigen, the more likely it's fully intact, so that B cells are targeting the structure as it will be present on the native virus," Irvine says.

Additionally, once the vaccine reaches the lymph nodes, the adjuvant causes a layer of cells called macrophages, which act as a barrier, to die off quickly, making it easier for the antigen to get into the nodes.

Another way that the adjuvant helps boost immune responses is by activating inflammatory cytokines that drive a stronger response. The TLR agonist that the researchers included in the adjuvant is believed to amplify that cytokine response, but the exact mechanism for that is not known yet.

This kind of adjuvant could also be useful for any other kind of subunit vaccine, which consists of fragments of viral proteins or other molecules. In addition to their work on HIV vaccines, the researchers are also working on a potential Covid-19 vaccine, along with J. Christopher Love's lab at the Koch Institute. The new adjuvant also appears to help stimulate T cell activity, which could make it useful as a component of cancer vaccines, which aim to stimulate the body's own T cells to attack tumors.

Read more at Science Daily

COVID-19: The older you are, the more antibodies you have, study finds

With the emergence of SARS-CoV-2 variants worldwide, the pandemic's spread is accelerating. A research team led by Joelle Pelletier and Jean-François Masson, both professors in Université de Montréal's Department of Chemistry, wanted to find out whether natural infection or vaccination led to more protective antibodies being generated.

In their study published today in Scientific Reports, they observe that those who received the Pfizer BioNTech or AstraZeneca vaccine had antibody levels that were significantly higher than infected individuals. These antibodies were also effective against the Delta variant, which wasn't present in Quebec when the samples were collected in 2020.

Masson, a biomedical instruments specialist, and Pelletier, a protein chemistry expert, were interested in an understudied group: people who have been infected by SARS-CoV-2 but were not hospitalized as a result of the infection.

32 non-hospitalized COVID-19 positive Canadian adults

Consequently, 32 non-hospitalized COVID-19 positive Canadian adults were recruited by the Centre hospitalier de l'Université Laval 14 to 21 days after being diagnosed through PCR testing. This was in 2020, before the Beta, Delta and Gamma variants emerged.

"Everyone who had been infected produced antibodies, but older people produced more than adults under 50 years of age," said Masson. "In addition, antibodies were still present in their bloodstream 16 weeks after their diagnosis."

Antibodies produced after an infection by the original, "native" strain of the virus also reacted to SARS-CoV-2 variants that emerged in subsequent waves, namely Beta (South Africa), Delta (India) and Gamma (Brazil), but to a lesser extent: a reduction of 30 to 50 per cent.

A surprising reaction to the Delta variant

"But the result that surprised us the most was that antibodies produced by naturally infected individuals 50 and older provided a greater degree of protection than adults below 50, " said Pelletier.

"This was determined by measuring the antibodies' capacity to inhibit the interaction of the Delta variant's spike protein with the ACE-2 receptor in human cells, which is how we become infected," he added. "We didn't observe the same phenomenon with the other variants."

When someone who has had a mild case of COVID is vaccinated, the antibody level in their blood doubles compared to an unvaccinated person who has been infected by the virus. Their antibodies are also better able to prevent spike-ACE-2 interaction.

"But what's even more interesting," said Masson, "is that we have samples from an individual younger than 49 whose infection didn't produce antibodies inhibiting spike-ACE-2 interaction, unlike vaccination. This suggests that vaccination increases protection against the Delta variant among people previously infected by the native strain."

Both scientists believe more research should be conducted to determine the best combination for maintaining the most effective level of antibodies reactive to all variants of the virus.

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Scientists identify new antibody for COVID-19 and variants

A research collaboration between scientists at Duke University and the University of North Carolina at Chapel Hill has identified and tested an antibody that limits the severity of infections from a variety of coronaviruses, including those that cause COVID-19 as well as the original SARS illness.

The antibody was identified by a team at the Duke Human Vaccine Institute (DHVI) and tested in animal models at UNC-Chapel Hill. Researchers published their findings Nov. 2 in the journal Science Translational Medicine.

"This antibody has the potential to be a therapeutic for the current epidemic," said co-senior author Barton Haynes, M.D., director of DHVI. "It could also be available for future outbreaks, if or when other coronaviruses jump from their natural animal hosts to humans."

Haynes and colleagues at DHVI isolated the antibody by analyzing the blood from a patient who had been infected with the original SARS-CoV-1 virus, which caused the SARS outbreak in the early 2000s, and from a current COVID-19 patient.

They identified more than 1,700 antibodies, which the immune system produces to bind at specific sites on specific viruses to block the pathogen from infecting cells. When viruses mutate, many binding cites are altered or eliminated, leaving antibodies ineffectual. But there are often sites on the virus that remain unchanged despite mutations. The researchers focused on antibodies that target these sites because of their potential to be highly effective across different lineages of a virus.

Of the 1,700 antibodies from the two individuals, the Duke researchers found 50 antibodies that had the ability to bind to both the SARS-CoV-1 virus as well as SARS-CoV-2, which causes COVID-19.

Further analysis found that one of those cross-binding antibodies was especially potent -- able to bind to a multitude of animal coronaviruses in addition to the two human-infecting pathogens.

"This antibody binds to the coronavirus at a location that is conserved across numerous mutations and variations," Haynes said. "As a result, it can neutralize a wide range of coronaviruses."

With the antibody isolated, the DHVI team turned to researchers at UNC who have expertise in animal coronaviruses. The UNC team, led by co-senior author Ralph S. Baric, Ph.D., epidemiology professor at UNC Gillings School of Global Public Health, tested it in mice to determine whether it could effectively block infections, or minimize the infections that occurred.

They found that it did both. When given before the animals were infected, the antibody protected mice against developing SARS, COVID-19 and its variants such as Delta, and many animal coronaviruses that have the potential to cause human pandemics.

"The findings provide a template for the rational design of universal vaccine strategies that are variant-proof and provide broad protection from known and emerging coronaviruses," Baric said.

When given after infections, the antibody reduced severe lung symptoms compared to animals that were not treated with the antibody.

"The therapeutic activity even after mice were infected suggests that this could be a treatment deployed in the current pandemic, but also stockpiled to prevent the spread of a future outbreak or epidemic with a SARS-related virus," said David Martinez, Ph.D., a post-doctoral researcher in the Department of Epidemiology at UNC's Gillings School.

"This antibody could be harnessed to prevent maybe SARS-CoV-3 or SARS-CoV-4," Martinez said.

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Scientists discover a highly potent antibody against SARS-CoV-2

Scientists at Lausanne University Hospital (CHUV) and EPFL have discovered a highly potent monoclonal antibody that targets the SARS-CoV-2 spike protein and is effective at neutralizing all variants of concern identified to date, including the delta variant. Their findings are published in the journal Cell Reports.

The newly identified antibody was isolated using lymphocytes from COVID-19 patients enrolled in the ImmunoCoV study being carried out by CHUV's Service of Immunology and Allergy. This antibody is one of the most powerful identified so far against SARS-CoV-2. Structural characterization of the antibody indicates that it binds to an area that is not subjected to mutations of the spike protein. Through this tight interaction, the antibody blocks the spike protein from binding to cells expressing the ACE2 receptor, which is the receptor the virus uses to enter and infect lung cells. That means the antibody halts the viral replication process, enabling a patient's immune system to eliminate SARS-CoV-2 from the body. This protective mechanism was proven through in vivo tests on hamsters; specimens that were administered the antibody were protected against infection even after receiving a highly infectious dose.

In addition to its antiviral properties, the new antibody is designed to have a lasting effect in humans. A typical unaltered antibody provides protection for up to 3-4 weeks. But this new one can protect patients for 4-6 months. That makes it an interesting preventive-treatment option for unvaccinated at-risk individuals or for vaccinated individuals who are unable to produce an immune response. Immunocompromised patients, organ transplant recipients and those suffering from certain kinds of cancer could be protected against SARS-CoV-2 by receiving antibody injections two or three times a year.

CHUV and EPFL now plan to build on these promising results in association with a start-up company which will perform clinical development and production of the antibody-containing drug, through cooperation and intellectual property agreements. Clinical trials of the drug should begin in late 2022.

Treatment or prophylaxy

This research was conducted jointly by CHUV's Service of Immunology and Allergy, headed by Prof. Giuseppe Pantaleo and Dr. Craig Fenwick, and by EPFL's Laboratory of Virology and Genetics, headed by Prof. Didier Trono and Dr. Priscilla Turelli. The research team was able to respond to the pandemic and discover this neutralizing antibody so quickly thanks to the multi-year support of the Swiss Vaccine Research Institute. Prof. Pantaleo's department at CHUV also received support from the Corona Accelerated R&D in Europe (CARE) program, which is part of the Innovative Medicine Initiative (IMI) -- a public-private partnership that seeks to address bottlenecks in the drug discovery and development process in Europe.

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Study with healthcare workers supports that immunity to SARS-CoV-2 is long-lasting

One year after infection by SARS-CoV-2, most people maintain anti-Spike antibodies regardless of the severity of their symptoms, according to a study with healthcare workers co-led by the Barcelona Institute for Global Health (ISGlobal), the Catalan Health Institute (ICS) and the Jordi Gol Institute (IDIAP JG), with the collaboration of the Daniel Bravo Andreu Private Foundation. The results suggest that vaccine-generated immunity will also be long-lasting.

One of the key questions to better predict the pandemic's evolution is the duration of natural immunity. A growing number of studies suggest that most people generate a humoral (antibody) and cellular (T cells) response that is maintained during several months, maybe years.

During the first wave of the pandemic, the team at ICS/IDIAP JG in collaboration with Carlota Dobaño's team at ISGlobal started a follow-up study of a cohort of healthcare workers with COVID-19 -- a total of 173 people working in healthcare centers of central Catalonia. Most infections were mild to moderate, although some cases required hospitalization.

The research team took regular blood samples from September 2020 onwards to measure the level and type of SARS-CoV-2-specific antibodies in these patients. This work was possible thanks to the support of the Daniel Bravo Foundation, which equipped ISGlobal with the latest technology and necessary resources to perform the study and rapidly reach conclusions during the subsequent waves.

"The results obtained until now lead us to believe that immunity to SARS-CoV-2 will last longer than we originally thought. Being a new virus, it is very important to understand how it behaves and affects different people," says Anna Ruiz Comellas, researcher at the Catalan Institute of Health and co-author of the study.

No significant decay in antibody levels was observed over the first five months, and at 9 months, 92.4% of peoples remained seropositive -- 90% of them had IgG, 76% had IgA and 61% had IgM recognising the Spike protein or the receptor binding domain (RBD). The results were similar among healthcare workers who had not been vaccinated in April (95% had IgG, 83% IgA and 25% IgM).

"These data confirm that IgG have a longer duration, but IgM levels, which are supposed to last less, were unexpectedly quite sustained over time," says Gemma Moncunill, ISGlobal researcher and senior co-author of the study, together with Ruíz-Comellas. Hospitalization, fever, and loss of smell and taste were associated with higher antibody levels at five or nine months.

Four reinfections were observed among the participants. Two of them were symptomatic and occurred in seronegative individuals. Another asymptomatic reinfection occurred in a subject with very low antibody levels. These results indicate that anti-Spike antibodies protect against symptomatic infections. "They also indicate that people who have not been previously infected should be prioritised for vaccination, since those who have already been infected may be protected for at least one year," says Anna Ramírez-Morros, first co-author of the study.

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New evidence of early SARS-CoV-2 infections in the United States

A new antibody testing study examining samples originally collected through the National Institutes of Health's All of Us Research Program found evidence of SARS-CoV-2 infections in five states earlier than had initially been reported. These findings were published in the journal Clinical Infectious Diseases. The results expand on findings from a Centers for Disease Control and Prevention study that suggested SARS-CoV-2, the virus that causes COVID-19, was present in the U.S. as far back as December 2019.

In the All of Us study, researchers analyzed more than 24,000 stored blood samples contributed by program participants across all 50 states between Jan. 2 and March 18, 2020. Researchers detected antibodies against SARS-CoV-2 using two different serology tests in nine participants' samples. These participants were from outside the major urban hotspots of Seattle and New York City, believed to be key points of entry of the virus in the U.S. The positive samples came as early as Jan. 7 from participants in Illinois, Massachusetts, Mississippi, Pennsylvania and Wisconsin. Most positive samples were collected prior to the first reported cases in those states, demonstrating the importance of expanding testing as quickly as possible in an epidemic setting.

"This study allows us to uncover more information about the beginning of the U.S. epidemic and highlights the real-world value of longitudinal research in understanding dynamics of emerging diseases like COVID-19," said Josh Denny, M.D., M.S., chief executive officer of All of Us and an author of the study. "Our participants come from diverse communities across the U.S. and give generously of themselves to drive a wide range of biomedical discoveries, which are vital for informing public health strategies and preparedness."

In studies like these, false positives are a concern, particularly when the prevalence of viral infections is low, as was the case in the early days of the U.S. epidemic. Researchers in this study followed CDC guidance to use sequential testing on two separate platforms to minimize false positive results.

All of Us worked with Quest Diagnostics to test samples on the Abbott Architect SARS-CoV-2 IgG ELISA and the EUROIMMUN SARS-CoV-2 ELISA (IgG) platforms. For a sample to be considered "positive" by the research team, it had to have positive results on both platforms, which target antibodies that bind to different parts of the virus. Both tests have emergency use authorization from the FDA.

"Antibody testing of blood samples helps us better understand the spread of SARS-CoV-2 in the U.S. in the early days of the U.S. epidemic, when testing was restricted and public health officials could not see that the virus had already spread outside of recognized initial points of entry," said Keri N. Althoff, Ph.D., lead author and associate professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health, Baltimore. "This study also demonstrates the importance of using multiple serology platforms, as recommended by the CDC."

Antibodies are proteins produced in the blood in response to an infection, such as a virus. They play a critical role in fighting infections and are helpful signs that a person may have been exposed to an infection in the past, even if they didn't show symptoms. In the All of Us study, researchers looked in participant samples for a type of antibodies called IgG. These antibodies do not appear until about two weeks after a person has been infected, indicating that participants with these antibodies were exposed to the virus at least several weeks before their sample was taken. In this study, the first positive samples came from participants in Illinois and Massachusetts on Jan. 7 and 8, 2020, respectively, suggesting that the virus was present in those states in late December.

The study authors noted several limitations to their study. While the study included samples from across the U.S., the number of samples from many states was low. In addition, the authors do not know whether the participants with positive samples became infected during travel or while in their own communities. Ideally, this study could be replicated in other populations with samples collected in the initial months of the U.S. epidemic and with multiple testing platforms to compare results.

All of Us expects to release more information following further analysis, and will offer participants whose samples were included in the study an opportunity to receive their individual results. The presence of antibodies in one's blood sample does not guarantee that a person is protected from the infection (has immunity), or that any such protection will last.

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Novel antibody drug wakes up the body's defense system in advanced-stage cancer

Researchers at the University of Turku, Finland, showed that the antibody treatment reactivates the immune defense in patients with advanced-stage cancer. The treatment alters the function of the body's phagocytes and facilitates extensive activation of the immune system.

The immune defense is the body's own defense system equipped to combat cancer. However, cancer learns to hide from immune attacks and harnesses this system to promote its own growth. Therefore, it would be beneficial to be able to return the immune defense back to restricting the advancement of cancer.

Macrophages, a type of white blood cell, are central in the fight against cancer. Cancer educates macrophages to subdue the defense system and renders many treatments targeting the immune system ineffective.

Academy Research Fellow Maija Hollmén's research group has searched for means of altering the activity of macrophages in order to direct the immune defense to attack cancer. The antibody bexmarilimab, developed based on this research and in collaboration with Faron Pharmaceuticals, is currently undergoing clinical trials in patients. Hollmén's group has studied the changes occurring in the defense systems of patients with cancer following antibody treatment.

"In the majority of patients, the antibody treatment activated killer T cells, which are the body's strike force against cancer. Additionally, the antibody treatment successfully lowered the suppressive potential of macrophage precursors travelling in the blood circulation. The patients also showed increases in certain mediators of inflammation and types of white blood cell in the blood," describes Hollmén.

"The activation of the killer T cells is a very promising demonstration of the antibody's capability to boost the defense system against cancer. The treated patients had very advanced and poorly treatable cancers, which highlights the significance of the results," says Doctoral Candidate Jenna Rannikko.

Bexmarilimab May Benefit Patients for Whom Current Treatment Options Are Ineffective

The research also yielded new information on the mode of action of bexmarilimab. The antibody binds the molecule Clever-1 present on macrophages and alters its function.

Clever-1 transports material needless to the body inside macrophages to be degraded. Objects disposed in this manner are swept under the rug, in a manner of speaking. This kind of concealment is beneficial for the body's natural balance and helps to avoid stirring the immune defense unnecessarily.

"However, cells originating from cancer should be detected. When the antibody is used to block Clever-1 from performing its cleaning job, it facilitates the activation of cells of the immune defense. This in part leads to the waking up of the T cells in patients," describes Doctoral Candidate Miro Viitala.

There is demand for treatments that boost the activity of the immune defense since the current options on the market only help some patients.

"Bexmarilimab's mode of action is different from the drug treatments against cancer currently on the market. Therefore, it can be beneficial for patients for whom current treatment options are ineffective," concludes Postdoctoral Researcher Reetta Virtakoivu.

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New ebolavirus vaccine design seeks to drive stronger antibody defense

Scientists at Scripps Research have unveiled a new Ebola virus vaccine design, which they say has several advantages over standard vaccine approaches for Ebola and related viruses that continue to threaten global health.

In the new design, described in a paper in Nature Communications, copies of the Ebola virus outer spike protein, known as the glycoprotein, are tethered to the surface of a spherical carrier particle. The resulting structure resembles the spherical appearance of common RNA viruses that infect humans -- and is starkly different from the snake-like shape of the Ebola virus.

The scientists say the design is intended to stimulate a better protective immune response than standard vaccine approaches, which often expose the immune system to individual glycoproteins rather than realistic-looking virus particles.

In designing the vaccine, the researchers also modified the outer spike protein to be more stable than the normal, "wild-type" version found in actual Ebola virus. In tests in mice and rabbits, they showed that this stabilized version elicited virus-neutralizing antibodies more strongly than the wild-type glycoprotein used in prior Ebola vaccine approaches.

"Here, we did a step-by-step investigation of glycoprotein stability and how that affects the vaccine's ability to elicit antibodies," says Jiang Zhu, PhD, associate professor in the Department of Integrative Structural and Computational Biology at Scripps Research and inventor of the vaccine. "In the end, we were able to develop a really promising vaccine design."

Continued viral threat

Ebola virus is endemic in various African bat species and can jump to humans, causing outbreaks of hemorrhagic fever with high mortality rates. The largest known outbreak of occurred in West Africa during 2013-2016, killing more than 11,000 people.

About two decades ago, Canadian researchers developed a vaccine against Zaire ebolavirus, more commonly known as Ebola virus. The vaccine, which was later licensed to a major pharma company and is called rVSV-ZEBOV, uses a live virus -- vesicular stomatitis virus -- which has been modified to include the gene for the Ebola virus glycoprotein.

When injected, the rVSV-ZEBOV vaccine infects cells and produces copies of the glycoprotein, eliciting an immune response to protect against future exposure to Ebola virus. Tests in Africa amid the aforementioned outbreak suggested it worked well and it was approved by the Food and Drug Administration in late 2019. However, those tests lacked placebo groups and other standard features of typical large-scale phase-III trials. Thus, questions remain on true efficacy.

In developing their new ebolavirus vaccine design, Zhu and his team focused on the relative instability of the glycoprotein structure as a potential factor in vaccine effectiveness. They investigated the molecular sources of this instability in detail, and eventually came up with a set of modifications that greatly stabilize the glycoprotein. In mice and rabbits, their modified glycoprotein elicited a more potent neutralizing antibody response against two different ebolaviruses -- the Makona strain of Ebola virus and the Uganda strain of Bundibugyo ebolavirus -- and compared those with the wild-type glycoprotein.

The team's design also included special protein segments that self-assemble tightly into a ball-shaped "nanoparticle" that support multiple glycoproteins on their surface. This nanoparticle-based structure presents the glycoproteins to the immune system similar to common human viruses, and thus the body has learned to recognize the spherical particles.

"Think of our nanoparticle as your sport vehicle, with a roof rack that carries a mountain bike and a trunk where you stow your clothes, gears and food," Zhu explains. "The only difference here is that the Ebola virus spike is your mountain bike, and the locking domains and T-cell epitopes are your stuff in the trunk. We call that a multilayered design."

A new approach

This nanoparticle design is distinctively different from other nanoparticle platforms. Zhu explains that in his team's design, the genetic codes of the optimized glycoprotein, the nanoparticle-forming unit, the locking domain and the T-cell epitope are all contained in a single piece of DNA. In cells, this DNA generates a single protein chain that can self-assemble, forming the right structure and associating with other identical chains to create a virus-like protein ball with multiple layers.

"The idea is that the all-in-one design simplifies the manufacturing process and drives the vaccine cost lower," Zhu says.

His team already has used the nanoparticle platform to create a COVID-19 vaccine candidate, which has shown in animal models that it can induce a powerful antibody response to both SARS-CoV-1 and SARS-CoV-2. It also has shown to be effective against variants.

For Ebola virus, the nanoparticle-based vaccines showed far better results in mouse and rabbit virus-neutralization tests that tests that used only glycoproteins to stimulate immune response. Inoculating animals with the Ebola wild-type glycoprotein, which tends to fall apart, led to signs suggesting a vaccine phenomenon known as antibody-dependent enhancement -- in which a vaccine elicits not only virus-neutralizing antibodies, but also antibodies that paradoxically increase the virus's ability to infect cells. The researchers found that their best nanoparticle-based designs only minimally elicit these bad antibodies.

"There are a lot of things in the Ebola virus vaccine field that still need to be examined carefully, but in this study, we ended up with two nanoparticle-based designs that seem very suitable for further optimization and testing," Zhu says.

He says the vaccine approach can be extended to other members of the same virus family, such as Marburg virus, which is also a major threat. Ebolaviruses and marburgvirus both belong to a group of viruses, known as filoviruses, that have a bizarre thread-like shape when seen under a microscope.

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Our immune systems blanket the SARS-CoV-2 spike protein with antibodies

 The most complete picture yet is coming into focus of how antibodies produced in people who effectively fight off SARS-CoV-2 work to neutralize the part of the virus responsible for causing infection. In the journal Science, researchers at The University of Texas at Austin describe the finding, which represents good news for designing the next generation of vaccines to protect against variants of the virus or future emerging coronaviruses.

Previous research focused on one group of antibodies that target the most obvious part of the coronavirus's spike protein, called the receptor-binding domain (RBD). Because the RBD is the part of the spike that attaches directly to human cells and enables the virus to infect them, it was rightly assumed to be a primary target of the immune system. But, testing blood plasma samples from four people who recovered from SARS-CoV-2 infections, the researchers found that most of the antibodies circulating in the blood -- on average, about 84% -- target areas of the viral spike protein outside the RBD -- and, apparently, for good reason.

"We found these antibodies are painting the entire spike, both the arc and the stalk of the spike protein, which looks a bit like an umbrella," said co-corresponding author Greg Ippolito, who is a research associate professor in UT Austin's Department of Molecular Biosciences and an assistant professor of oncology at the university's Dell Medical School. "The immune system sees the entire spike and tries to neutralize it."

Many of these non-RBD-directed antibodies the team identified act as a potent weapon against the virus by targeting a region in a part of the spike protein located in what would be the umbrella's canopy called the N-terminal domain (NTD). These antibodies neutralize the virus in cell cultures and were shown to prevent a lethal mouse-adapted version of the virus from infecting mice.

The NTD is also a part of the viral spike protein that mutates frequently, especially in several variants of concern. This suggests that one reason these variants are so effective at evading our immune systems is that they can mutate around one of the most common and potent types of antibody in our arsenals.

"There's an evolutionary arms race going on between the virus and our immune systems," said Jason Lavinder, research associate in the McKetta Department of Chemical Engineering and co-corresponding author of the new study. "We're all developing a standard immune response to this virus that includes targeting this one spot and that's exerting selective pressure on the virus. But then the virus is also exerting its evolutionary strength by trying to change around our selective immune pressures."

Despite these maneuvers by SARS-CoV-2, the researchers said about 40% of the circulating antibodies target the stalk of the spike protein, called the S2 subunit, which is also a part that the virus does not seem able to change easily.

"That's reassuring," Ippolito said. "That's an advantage our immune system has. It also means our current vaccines are eliciting antibodies targeting that S2 subunit, which are likely providing another layer of protection against the virus."

That's also good news for designing vaccine boosters or next-generation vaccines against variants of concern, and even for developing a vaccine that can protect against future pandemics from other strains of the coronavirus.

"It means we have a strong rationale for developing next-generation SARS-CoV-2 vaccines or even a pan-coronavirus vaccine that targets every strain," Ippolito said.

UT Austin researchers are among several in the world now aiming to develop a single coronavirus vaccine to fight infection from all coronaviruses, not just SARS-CoV-2.

The first author of the study is William Voss, a graduate student at UT Austin. In addition to Lavinder and Ippolito, senior authors from UT Austin are Jimmy Gollihar, Ilya Finkelstein, Brent Iverson, Jason McLellan and George Georgiou. Georgiou and Ippolito are also affiliated with UT Austin's Dell Medical School. Gollihar is also affiliated with the Army Research Laboratory South.

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Natural immunity to malaria provides clues to potential therapies

WEHI researchers have identified how natural human antibodies can block malaria parasites from entering red blood cells, potentially indicating how new protective therapies could be developed against this globally significant disease.

The research provides greater insight into how antibodies block the entry of Plasmodium vivax malaria parasites into young red blood cells called reticulocytes. It builds on an earlier discovery that the P. vivax latches onto the transferrin receptor 1 (TfR1) to enter cells.

The research, led by Associate Professor Wai-Hong Tham and PhD student Li-Jin Chan from WEHI, alongside Professor Christopher King from Case Western University, US, was published in Nature Communications.

At a glance
 

• By examining antibodies from people with a history of malaria infection, researchers observed that naturally occurring antibodies can block Plasmodium vivax from latching onto transferrin receptor 1 on reticulocytes.
• One way the antibodies work is by preventing parasite proteins from getting close enough to the cell to allow parasite entry.
• The discovery opens up new avenues for developing antibody-based therapies for malaria.
   
• Shedding light on pathogen-blocking antibodies
   
• Plasmodium vivax is the most widespread malaria parasite in the world, and the predominant cause of malaria in the vast majority of countries outside Africa. It is also the main parasite responsible for recurrent malaria infections.

The malaria parasite is a complex single-celled organism, with diverse proteins that help it to invade red blood cells, reproduce and spread. Adhesins on the surface of the parasite are key-like proteins that 'unlock' cells, allowing the parasite to enter.

Previous research studies in Papua New Guinea, Thailand and Brazil showed antibodies against P. vivax adhesins were correlated with protection against infection and disease, Associate Professor Tham said.

"We wanted to understand how these human antibodies in natural infection block the parasite from getting in. By extracting and examining antibodies from people who have had P. vivax infections, we identified the different ways human antibodies against P. vivax work. One of these ways, is by stopping the parasite adhesins from getting too close to the reticulocyte membrane, denying the parasite entry," she said.

This discovery opens the door to potentially preventing not only P. vivax malaria, but also P. falciparum malaria, another significant cause of deaths globally.

"Although this was a vivax study, we believe the implications are that a broadly neutralising antibody could be created to target both P. vivax and P. falciparum malaria infections," Associate Professor Tham said.

Improving detection of relapsing malaria

WEHI Professor Ivo Mueller said beyond understanding how antibodies can block infection, there was also a crucial need to understand the development of immunity and how this could be used to detect P. vivax infections in endemic populations.

"We are currently using this information to develop diagnostic tests that will be used in the field to identify and treat people with hidden vivax infection in their livers and spleens. This is a key step towards eliminating malaria, by preventing silently infected people reinfecting their communities," he said.

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Study reveals how some antibodies can broadly neutralize ebolaviruses

Some survivors of ebolavirus outbreaks make antibodies that can broadly neutralize these viruses -- and now, scientists at Scripps Research have illuminated how these antibodies can disable the viruses so effectively. The insights may be helpful for developing effective therapies.

Ebolavirus is a family of often-deadly viruses that includes Ebola virus and many lesser-known viruses such as Bundibugyo virus, Sudan virus and Reston virus.

Structural biologists at Scripps Research used electron microscopy techniques to visualize a set of antibodies that target a key site on these viruses called the "glycan cap." Their research showed that the antibodies work against ebolaviruses using the same three mechanisms to prevent the virus from infecting host cells.

The research, published in Cell Reports, is a step toward the creation of an antibody-based treatment that will be useful against a broad range of ebolaviruses.

"We now understand the molecular basis for these antibodies' abilities to neutralize ebolviruses with broad reactivity against different viral species," says the study's first author Daniel Murin, PhD, a staff scientist in the laboratory of Andrew Ward, PhD.

Ward, a professor in the Department of Integrative Structural and Computational Biology at Scripps Research, says he hopes the work will contribute the development of a "cocktail" of therapeutic antibodies that can save lives by treating many forms of the Ebola virus.

"The goal is to provide doctors in Ebola-prone regions their best weapon yet against these deadly outbreaks," Ward says. "The insights we have gained through our structural studies of the virus show how this may be possible."

Ever-emergent Ebola

The first known ebolavirus, now called Zaire ebolavirus or simply Ebola virus, was identified in 1976, named for the site of an outbreak that year near the Ebola river in what was then Zaire and is now the Democratic Republic of Congo.

Other species have since been added to this family of viruses, including Sudan ebolavirus and Bundibugyo ebolavirus. Ebola viruses colonize African fruit bats, often cause disease in chimpanzees and other non-human primates, and trigger outbreaks in humans every few years, on average. Infected people develop a hemorrhagic syndrome that is fatal in roughly half of untreated cases.

Vaccines against Ebola have been developed recently but have not yet been widely used. And although antibody-based treatments also have been developed, none has been shown effective against a broad range of ebolavirus species.

Nevertheless, studies in recent years have shown that some survivors of Ebola infections carry antibodies that, in lab-dish tests, can neutralize multiple ebolavirus species. A surprisingly high proportion of these broadly neutralizing antibodies target the glycan cap, a sugar-slathered site on a stalk-like protein -- called the glycoprotein -- that enables Ebola viruses to enter host cells.

In the new study, Murin and Ward, along with their colleagues in the James Crowe Lab at Vanderbilt University where the antibodies were isolated, used electron microscopy to analyze a set of glycan cap-targeting antibodies from survivors of various ebolaviruses. Their aim was to understand better how these antibodies target the virus so effectively.

Three ways to defeat the virus

Their analysis suggested that the most broadly effective of these glycan cap-targeting antibodies hit the same vulnerable site on the glycan cap, allowing them to thwart viral infectivity in three ways.

First, the antibody displaces a long viral structure near the glycan cap in a way that destabilizes the entire viral glycoprotein structure, sometimes causing it to fall apart.

Second, the glycan cap antibody -- when it binds to its target site -- can block a key event in the infection process, in which an enzyme called a cathepsin cleaves off the glycan cap. Blocking this cleavage event blocks the glycoprotein's ability to enter host cells.

Finally, the glycan cap antibody, by displacing the loose structure near the glycan cap, enables another type of neutralizing antibody to bind to a separate vulnerable site on the virus. Thus, a glycan cap antibody can "synergize" with another antibody to hit the virus significantly harder than either antibody does alone.

The scientists also determined the key genetic elements that allow glycan-cap antibodies to thwart ebolaviruses in these three ways.

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