COVID-19 vaccine-generated antibodies last at least 6 months

How long does COVID-19 vaccine-generated immunity last? New laboratory results provide a partial answer to that Read more

Killing viruses, pointy ears or not

After success finding flu virus-killing peptides in frog slime, immunologist Joshy Jacob and his colleagues at Emory Vaccine Center turned their attention from influenza to Zika. Their follow-up paper on an antiviral peptide that destroys Zika virus was published earlier this year in Scientific Reports. The findings illustrate how frogs’ skin secretions are a rich source of potential antiviral weapons, even though Zika itself is not thought to infect frogs. Jacob reports his team is Read more

New antibiotic tactic vs gonorrhea

A new antibiotic compound can clear infection of multi-drug resistant gonorrhea in mice with a single oral dose, according to a new study led by researchers at Penn State and Read more

COVID-19 vaccine-generated antibodies last at least 6 months

How long does COVID-19 vaccine-generated immunity last? New laboratory results provide a partial answer to that question.

Antibodies generated by a currently available COVID-19 vaccine declined over time, but remained at high levels in 33 study participants 6 months after vaccination, according to data published Tuesday in the New England Journal of Medicine.

The results could begin to inform public health decisions about COVID-19 booster vaccinations and how frequently people should receive them. In older study participants, antiviral antibody activity tended to decay more rapidly than in those aged 18-55.

From Doria-Rose et al (2021). Note that neutralizing antibody activity was (on average) higher at day 209 than on day 29, when the second vaccine dose was administered. It takes two weeks for the immune system to kick into high gear after the second shot.

Emory Vaccine Center’s Mehul Suthar, co-lead author of the brief report, said that the “correlates of protection” are not yet known from COVID-19 vaccine studies – that is, what levels of antiviral antibodies are needed to fend off infection. Other forms of immunity, such as T cells, could be contributing to antiviral protection as well.

He cautioned that the decay in antibody activity over time – not surprising in itself – may combine with increased prevalence of emerging SARS-CoV-2 variants that may allow viruses to escape the immune system’s pressure.

“Still, these are encouraging results,” Suthar says. “We are seeing good antibody activity, measured three different ways, six months after vaccination. There are differences between age groups, which are consistent with what we know from other studies.”

The findings come from analysis of samples from the Moderna mRNA-1273 phase I clinical trial, which began last year. Reports of clinical outcomes from Pfizer/BioNTech also indicate that their vaccine remains effective after six months.

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Killing viruses, pointy ears or not

After success finding flu virus-killing peptides in frog slime, immunologist Joshy Jacob and his colleagues at Emory Vaccine Center turned their attention from influenza to Zika. Their follow-up paper on an antiviral peptide that destroys Zika virus was published earlier this year in Scientific Reports.

The findings illustrate how frogs’ skin secretions are a rich source of potential antiviral weapons, even though Zika itself is not thought to infect frogs. Jacob reports his team is currently investigating peptides with activity against SARS-CoV-2. Lab Land is expecting to hear more about that soon.

But before SARS-CoV-2, you may recall Zika as a virus of public health concern. Carried by mosquitoes, its insidious infection can lead to neurological birth defects and disabilities in infants and Guillain-Barre syndrome in adults. Neither antiviral drugs or vaccines are available against Zika, leaving the field wide open for Jacob’s amphibian approach.

Jacob and his crew decided to call their antiviral Zika-destroying peptide Yodha, which means “warrior” in Sanskrit. Just in case you might have some other associations for that word, which sounds like the name of a few recent Bollywood movies, as well as a diminutive Jedi trainer from the Star Wars universe.

The Yodha peptide emerged from a screen of many frog peptides, and it was the only one of several Zika-killing peptides that was not toxic to human red blood cells. The peptide comes from the skin of Indosylvirana aurantiaca which lives in the western Ghats of India and is commonly known as the “golden frog.” (The website India Biodiversity, linked above, has photos of the frogs.)

Using electron microscopy, Jacob’s lab could show that the Yodha peptide blasts Zika virus particles apart with a few minutes of exposure. It was active against Zika and all four varieties of the related dengue virus.

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New antibiotic tactic vs gonorrhea

A new antibiotic compound can clear infection of multi-drug resistant gonorrhea in mice with a single oral dose, according to a new study led by researchers at Penn State and Emory.

Like other antibiotics, this one targets the ribosome, the factories that generate proteins in bacterial (and human) cells. But it does so at a site that is different from other antibiotics. This one interferes with the process of trans-translation, which bacteria use to rescue their ribosomes out of rough spots.

The results were published in Nature Communications. This was a collaboration involving several groups: biochemist Christine Dunham’s at Emory and Ken Keiler’s at Penn State, along with others at Florida State, the Uniformed Services University and the Massachusetts-based pharmaceutical company Microbiotix.

Zachary Aron, director of chemistry at Microbiotix, is the first author of the paper, and the compound is called MBX-4132. It is also active against other Gram-positive bacteria, including tuberculosis and Staph aureus, and the company says it will continue to optimize it.

At Emory, Dunham’s lab used cryo-electron microscopy to produce high-resolution images of the compound as it binds to the bacterial ribosome — see below.

Christine Dunham’s lab specializes in ribosomal structural studies

“A derivative of MBX-4132 binds to a location on the ribosome that is different from all known antibiotic binding sites,” Dunham says. “The new drug also displaces a region of a ribosomal protein that we think could be important during the normal process of trans-translation. Because trans-translation only occurs in bacteria and not in humans, we hope that the likelihood of the compound affecting protein synthesis in humans is greatly reduced, a hypothesis strongly supported by the safety and selectivity studies performed by Microbiotix.”

Multi-drug resistant gonorrhea is listed by the CDC as one of the five most urgent threats, among antibiotic resistant bacteria. Half of all gonorrhea infections are resistant to at least one antibiotic.

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Regrowing adult heart muscle

In adulthood, our hearts generally can’t grow again in response to injury. Emory cardiology researchers Ahsan Husain and Nawazish Naqvi and their colleagues have been chipping away at this biological edifice in animal models, demonstrating that it is possible to remove constraints that prevent the heart from growing new muscle cells.

Husain and Naqvi’s teams accomplished this by combining the thyroid hormone T3 — already FDA approved — with siRNA-based inhibition of an enzyme called DUSP5. Their latest paper, published in the journal Theranostics, applies the combination in an animal model of drug-induced heart failure.

The anticancer drug doxorubicin is sometimes known as the “red devil”

The anticancer drug doxorubicin is notorious for its cardiotoxicity, yet it is a mainstay of treatment for breast cancer in adults and several types of cancer in children. Cardiotoxicity affects a fraction of breast cancer patients treated with doxorubicin (20 percent in some studies) and severely impacts mortality and quality of life.

In the mouse model, doxorubicin generates severe heart failure, with a 40 percent drop in left ventricular ejection fraction (LVEF), a measure of the heart’s pumping capacity. In response to the combination of T3 and DUSP5 siRNA, a large increase in LVEF is seen. The researchers also report that the treatment has a marked effect on the health of the animals, restoring their activity levels, grooming and posture. See the video for an example of a mouse heart treated with the T3/DUSP5 siRNA combination.

The results are potentially applicable to other situations when doctors would want to regrow or repair cardiac muscle. Husain reports plans for a clinical study in patients with drug-induced or other forms of heart failure, supported by a generous gift from the Atlanta-based ten Broeke Family Foundation.

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Steer microglia toward the angels – with a drug based on sea anemone venom

Researchers interested in Alzheimer’s and other neurodegenerative diseases are focusing their attention on microglia, cells that are part of the immune system in the brain.

Author Donna Jackson Nakazawa titled her recent book on microglia “The Angel and the Assassin,” based on the cells’ dual nature; they can be benign or malevolent, either supporting neuronal health or driving harmful inflammation. Microglia resemble macrophages in their dual nature, but microglia are renewed within the brain, unlike macrophages, which are white blood cells that infiltrate into the brain from outside.

At Emory, neurologist Srikant Rangaraju’s lab recently published a paper in PNAS on a promising drug target on microglia: Kv1.3 potassium channels. Overall, the results strengthen the case for targeting Kv1.3 potassium channels as a therapeutic approach for Alzheimer’s.

Kv1.3 potassium channels have also been investigated as potential therapeutic targets in autoimmune disorders, since they are expressed on T cells as well as microglia. The peptide dalazatide, based on a toxin from the venom of the Caribbean sea anemone Stichodactyla helianthus, is being developed by the Ohio-based startup TEKv Therapeutics. The original venom peptide needed to be modified to make it more selective toward the right potassium channels  – more about that here.

Kv1.3 potassium channels are potential therapeutic targets in autoimmune disorders and Alzheimer’s — blockable with peptides based on venom of the sea anemone Stichodactyla helianthus

It appears that Kv1.3 levels on microglia increase in response to exposure to amyloid-beta, the toxic protein fragment that accumulates in the brain in Alzheimer’s, and Kv1.3 may be an indicator that microglia are turning to the malevolent side.

In the Emory paper, researchers showed that Kv1.3 potassium channels are present on a subset of microglia isolated from Alzheimer’s patients’ brains. They also used bone marrow transplant experiments to show that the immune cells in mouse brain that express Kv1.3 channels are microglia (internal brain origin), not macrophages (transplantable w/ bone marrow).

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Simpler, more portable ECGs: Emory experts hosting computing challenge

An electrocardiogram or ECG is a basic non-invasive diagnostic tool for cardiologists, which conventionally uses 12 electrodes to gather information about electrical signals in the heart and its rhythms. Emory biomedical informatics specialists are hosting an international computing contest aimed at reducing that number as low as possible, so that future portable or wearable ECG devices can be smaller, more convenient and lower in cost.

“We are challenging the research community and industry to design algorithms that classify a large range of cardiac abnormalities using ECGs with varying numbers of channels,” says co-organizer Gari Clifford, PhD, chair of biomedical informatics at Emory University School of Medicine. “The aim is to determine how low we can go — that is, how many channels of data do we need to make an accurate diagnosis?”

The devices could aid in diagnosing common conditions such as atrial fibrillation or supraventricular tachycardia.

“Reduced-lead ECGs are more accessible than standard twelve-lead ECGs in many parts of the world, and the development of effective open-source algorithms for reading reduced-lead ECGs is key for tackling the growing problem of cardiac events internationally,” says co-organizer Matthew Reyna, PhD, assistant professor of biomedical informatics and pharmacology and chemical biology.

The 2021 PhysioNet/Computing in Cardiology Challenge is titled “Will Two Do? Varying Dimensions in Electrocardiography” and calls for designers to build an algorithm that can classify cardiac abnormalities based on 12, 6, 3 and 2-lead ECGs.

So that participants can try out their algorithms, contest organizers are sharing the world’s largest and most diverse set of publicly available ECG data: over 45,000 recordings from China, Europe, Russia and the USA. A similar amount of data has been hidden for the organizers to test the competitors’ algorithms, and a separate evaluation metric will reflects errors of misdiagnosis.

This year’s contest builds upon previous years; in 2017, the challenge was to classify atrial fibrillation based on a single lead, and last year’s was a challenge to diagnose a variety of cardiac problems using standard 12 leads. Contest participants are invited to submit an abstract describing their algorithm, open-source code for their algorithm and a paper on their work.

The contest culminates in the Computing in Cardiology conference, scheduled for September 12-15 in Brno, Czech Republic. More information about the contest is available at PhysioNet.org and requirements for entry and the schedule are detailed at the PhysioNet/Computing in Cardiology Challenge 2021 site. The initial deadline for applying to enter the contest is April 9, 2021.

The contest is part of PhysioNet, an archive of biomedical computing resources supported by the National Institute of Biomedical Imaging and Bioengineering (R01EB030362). It is being co-sponsored by the Gordon and Betty Moore Foundation, Google and MathWorks. Complementary MATLAB licenses and Google Cloud Platform credits are being made available for this year’s challenge. The sponsors are also making it possible to offer several prizes worth several thousand dollars.

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First (and massive) whole-genome study of IBD in African Americans

In African Americans, the genetic risk landscape for inflammatory bowel disease (IBD) is very different from that of people with European ancestry, according to results of the first whole-genome study of IBD in African Americans. The authors say that future clinical research on IBD needs to take ancestry into account.

Findings of the multi-center study, which analyzed the whole genomes of more than 1,700 affected individuals with Crohn’s disease and ulcerative colitis and more than 1,600 controls, were published on February 17 in the American Journal of Human Genetics.

As part of their analysis, the researchers developed an algorithm that corrects for ancestry when calculating an IBD polygenic risk score. Polygenic risk scores are tools for calculating gene-based risk for a disease, which are used for IBD as well as other complex conditions such as coronary artery disease.

“Even though the disease destination looks the same, the populations look very different, in terms of what specific genes contribute to risk for IBD,” says lead author Subra Kugathasan, MD. “It shows that you can’t develop a polygenic risk score based on one population and apply it to another.”

Kugathasan is scientific director of the pediatric IBD program and director of the Children’s Center for Transplantation and Immune-mediated Disorders at Children’s Healthcare of Atlanta, as well as Marcus professor of pediatrics and human genetics at Emory University School of Medicine.

The first author of the paper is geneticist Hari Somineni, PhD, who earned his doctorate working with Kugathasan at Emory, and is now working at Goldfinch Bio in Massachusetts.

The primary sites to recruit study participants were Emory, Cedars-Sinai and Rutgers, along with Johns Hopkins and Washington University at Saint Louis. Along with Kugathasan, the co-senior authors and co-organizers of the study were Steven Brant, MD from Rutgers and Dermot McGovern, MD, PhD from Cedars-Sinai.

“One of our goals in treating IBD is to move toward a more personalized approach,” says McGovern, the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics at Cedars-Sinai. “Deciphering the genetic architecture is an important part of this effort. Studies such as this one are vital to ensure that diverse populations, including African-Americans, benefit from the tremendous advances promised by genomic medicine.”

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Emory researchers SNARE new Alzheimer’s targets

Diving deep into Alzheimer’s data sets, a recent Emory Brain Health Center paper in Nature Genetics spots several new potential therapeutic targets, only one of which had been previous linked to Alzheimer’s. The Emory analysis was highlighted by the Alzheimer’s site Alzforum, gathering several positive comments from other researchers.

Thomas Wingo, MD

Lead author Thomas Wingo and his team — wife Aliza Wingo is first author – identified the targets by taking a new approach: tracing connections between proteins that are altered in abundance in patients’ brains and risk genes identified through genome-wide association studies.

The list of 11 genes/proteins named as “consistent with being causal” may be contributing to AD pathogenesis through various mechanisms: vesicular trafficking, inflammation, lipid metabolism and hypertension. We asked Wingo which ones he wanted to highlight, and he provided this comment:

“The most interesting genes, to me, are the ones involved in the SNARE complex (in the paper, STX4 and STX6) and the others involved in vesicular trafficking. There is already a deep body of literature that describe a role for some of these components in AD, and I’m hopeful providing specific targets might be useful to those studies.”

A simplistic way to look at the mechanism of Alzheimer’s disease is: proteins build up in the brain, in the form of amyloid plaques and neurofibrillary tangles. The functions of neurons and other brain cells are thought to be impaired by bits of beta-amyloid floating around.

Inside neurons, the SNARE complex is the core of the machinery that pushes vesicles to fuse with the cell membrane. Neurons communicate with each other by having vesicles inside the cell – bags full of neurotransmitters – release their contents. They’re like tiny packets of pepper or other spices that make the neuron next door sneeze. In Alzheimer’s, amyloid oligomers have been reported to block SNARE complex assembly, which may explain aspects of impaired cognition.

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Strengthening SARS-CoV-2 genomic surveillance: support from CDC, private foundations

As part of an effort to strengthen genomic surveillance for emerging strains of SARS-CoV-2, the Centers for Disease Control and Prevention (CDC) has awarded a contract to Emory University researchers to characterize viral variants circulating in Georgia.

The two-year contract is part of the SPHERES (SARS-CoV-2 Sequencing for Public Health Emergency Response, Epidemiology and Surveillance) initiative, with roughly $620,000 in total costs. The principal investigator is Anne Piantadosi, MD, PhD, assistant professor of pathology and laboratory medicine, with co-investigator Mehul Suthar, PhD, assistant professor of pediatrics (infectious diseases).

Both Piantadosi and Suthar are affiliated with Emory University School of Medicine and Emory Vaccine Center. Additional Emory partners include assistant professor of medicine Ahmed Babiker, MBBS, assistant professor of medicine Jesse Waggoner, MD and assistant professor of biology Katia Koelle, PhD.

“We are analyzing SARS-CoV-2 genomes from patients in Georgia to understand the timing and source of virus introduction into our community,” Piantadosi says. “We want to know whether there have been population-level changes in the rates of viral spread, and whether there are associations between viral genotype, viral phenotype in vitro, and clinical phenotype or clinical outcome.”

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Emory MVA COVID-19 Vaccine Safe and Effective in Animal Models

Researchers at Yerkes National Primate Research Center, Emory University, have developed a COVID-19 vaccine that has proven safe and effective in mice and monkeys. Results from this National Institute of Allergy and Infectious Diseases (NIAID)-funded study were published online Thursday, Feb. 4 in Immunity.

The Emory MVA COVID-19 vaccine induces protective immunity with the platform of modified vaccinia Ankara (MVA), a harmless version of a poxvirus that is well-known for its use in HIV/AIDS vaccines. Like the Moderna and Pfizer COVID-19 vaccines, the Emory MVA COVID-19 vaccine induces strong neutralizing antibodies, which support the immune system’s ability to fight infections. The Emory MVA COVID-19 vaccine also induces killer CD8 T cells, providing a multi-pronged approach to halting SARS-CoV-2.

In addition, the Emory researchers say the vaccine is easily adaptable to address disease variants and can be used in combination with existing vaccines to improve their ability to combat variants and has the potential to be equally effective with a single dose.

Lead researcher Rama Amara, PhD, built the Emory MVA COVID-19 vaccine based on his more than 20 years of experience working with MVA and animal models to develop an HIV/AIDS vaccine. He and his Yerkes-based research team tested two MVA SARS-CoV-2 vaccines in mice. One of them, MVA/S, used the complete spike protein of coronavirus to induce strong neutralizing antibodies and a strong killer CD8 T cell response against SARS-CoV-2.

“Generating neutralizing antibodies is an important component of a successful COVID-19 vaccine because the antibodies can block the virus from entering the body’s cells,” says Amara, Charles Howard Candler professor of microbiology and immunology at Emory University School of Medicine and a researcher in Yerkes’ Division of Microbiology and Immunology and Emory Vaccine Center. “It’s as important to activate CD8 T cells that can clear infected cells, so this allows us to approach halting the virus two ways simultaneously. The CD8 T cells also provide ongoing value because they are key to working against other variants of the virus, especially if antibodies fail.”

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