Tag: antibodies

Categories : Diseases, Syndromes and Conditions New Compounds and TreatmentsTags :

New Antibody Treatment for Crimean-Congo Haemorrhagic Fever

On By ModernMedia
Deer tick (Ixodes scapularis). Photo by Erik Karits on Unsplash

Working with international colleagues, US Army scientists have developed and tested an antibody-based therapy to treat Crimean-Congo haemorrhagic fever virus (CCHFV). 

The deadly virus is carried by ticks and has a high mortality rate, killing up to 60% of those infected. Their findings are published in the journal Cell.

The researchers characterised the human immune response to natural CCHFV infection by using blood samples donated by disease survivors. They were able to identify several potent neutralising antibodies that target the viral glycoprotein–a viral component which has a key role in disease development. A number of of these antibodies, administered individually or in combination, successfully protected mice from CCHFV when exposed to the virus after antibody administration.

In order to treat mice that had already been infected with the virus, the team created ‘bispecific’ antibodies that combined potency with the ability to bind to two different sites on the CCHFV glycoprotein. One of these bispecific antibodies, called DVD-121-801, overcame CCHFV infection in mice with just a single dose administered 24 hours after challenge with live virus.

DVD-121-801 as a potential therapeutic for human patients, according to co-first author Andrew H. Herbert, Ph.D., of the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID).

CCHFV is the most prevalent tick-borne virus that causes human disease, and is endemic in countries across Europe, Asia, and Africa. CCHF occurs most frequently among agricultural workers following the bite of an infected tick, and to a lesser extent among slaughterhouse workers exposed to the blood and tissues of infected livestock and medical personnel through contact with the body fluids of infected patients. In spite of its high lethality and widespread distribution, there are no vaccines or specific treatments for it. It has been designated a priority pathogen by the World Health Organization.

Study co-first author Andrew H Herbert, PhD, US Army Medical Research Institute of Infectious Diseases, said: “Rodent models of CCHFV infection are useful in testing and down-selecting neutralising antibodies. However, to advance a lead candidate for therapeutic use, it will be necessary to conduct studies in larger animal models that more faithfully recapitulate human disease.”

Source: Medical Xpress

Journal information: J. Maximilian Fels et al, Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever, Cell (2021). DOI: 10.1016/j.cell.2021.05.001

Categories : COVIDTags :

Little Traitors: Infection-Enhancing Antibodies in Severe COVID

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Osaka University researchers have discovered that infection with SARS-CoV-2 results in not only the production of neutralising antibodies that prevent infection, but also of infection-enhancing antibodies.

Both neutralising antibodies that protect against infection as well as infection-enhancing antibodies that increase infectivity are produced after infection with SARS-CoV-2 by analysing antibodies from COVID patients.

Virus-specific antibodies generally are considered antiviral, playing an important role in the control of virus infections. In some cases however, the presence of specific antibodies can benefit the virus. This activity is known as antibody-dependent enhancement of virus infection, a phenomenon in which virus-specific antibodies enhance the entry of virus, and in some cases the replication of virus, into monocytes/macrophages and granulocytic cells through interaction with Fc and/or complement receptors. 

In COVID infections, antibodies that target the receptor binding site (RBD) of the SARS-CoV-2 spike protein play an important function as neutralising antibodies that suppress SARS-CoV-2 infection by preventing it from binding to the human receptor, ACE2. However, the function of antibodies against other sites of the spike protein was not known.

“We found that when infection-enhancing antibodies bind to a specific site on the spike protein of SARS-CoV-2, the antibodies directly cause a conformational change in the spike protein, resulting in the increased infectivity of SARS-CoV-2. Neutralising antibodies recognise the RBD, whereas infection-enhancing antibodies recognise specific sites of the N-terminal domain (NTD),” explained lead researcher Professor Hisashi Arase. “Furthermore, the production of infection-enhancing antibodies attenuated the ability of neutralising antibodies to prevent infection.”

The study found that patients with severe COVID produced more infection-enhancing antibodies. Non-infected individuals were also found to possibly have small amounts of infection-enhancing antibodies.

Though infection-enhancing antibodies may be involved in the development of severe disease, further research is necessary to determine whether they are in fact involved in the worsening of infection in the body.

A possible benefit would be that by analysing the antibody titer of infection-enhancing antibodies, it would be possible to see who would be prone to severe COVID. The findings are also important for the development of vaccines that do not induce the production of infection-enhancing antibodies.

“It is important to analyse not only neutralising antibodies but also infection-enhancing antibodies. In the future, it may be necessary to develop vaccines that do not induce the production of infection-enhancing antibodies, because infection-enhancing antibodies may be more effective against mutant strains in which neutralising antibodies are not sufficiently effective,” says Professor Hisashi Arase.

Source: Osaka University

Journal information: Yafei Liu et al, An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies, Cell (2021). DOI: 10.1016/j.cell.2021.05.032

Categories : New Compounds and TreatmentsTags :

Antibodies May Hold The Key to Tooth Regeneration

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It may be possible to regenerate missing teeth using monoclonal antibodies, according to a new study by scientists at Kyoto University and the University of Fukui. 

The team reported that an antibody for one gene—uterine sensitisation associated gene-1 or USAG-1—can stimulate tooth growth in mice suffering from tooth agenesis, a congenital condition. The paper was published in Science Advances. Monoclonal antibodies are often used to treat cancers, arthritis, and vaccine development.

Although the normal adult mouth has 32 teeth, about 1% of the population has more or fewer due to congenital conditions; adults with too many teeth are of interest because they could hold genetic clues to tooth regeneration.

Katsu Takahashi, one of the lead authors of the study and a senior lecturer at the Kyoto University Graduate School of Medicine, said that the fundamental molecules responsible for tooth development have already been identified.

“The morphogenesis of individual teeth depends on the interactions of several molecules including BMP, or bone morphogenetic protein, and Wnt signaling,” said Takahashi.

BMP and Wnt are also involved in the development of organs when humans are mere embryos. This means that drugs directly affecting their activity are usually avoided, as side effects could impact the entire body. The team considered the gene USAG-1, as they guessed that it could be safer to target the factors that antagonise BMP and Wnt specifically in tooth development .

“We knew that suppressing USAG-1 benefits tooth growth. What we did not know was whether it would be enough,” added Takahashi.

The scientists therefore investigated the effects of several monoclonal antibodies for USAG-1. Since USAG-1 interacts with both BMP and Wnt, many of the antibodies resulted in poor birth and survival rates of mice, showing that BMP and Wnt are important for whole body growth. However one antibody managed to disrupt the interaction of USAG-1 with BMP only.

Experimentation showed that BMP signalling is necessary for the number of teeth in mice, and a single administration was enough to generate an entire tooth. The same effects were seen in ferrets.

“Ferrets are diphyodont animals with similar dental patterns to humans. Our next plan is to test the antibodies on other animals such as pigs and dogs,” explains Takahashi.

This is the first study to show the benefits of monoclonal antibodies on tooth regeneration, and offers new alternatives to implants.

“Conventional tissue engineering is not suitable for tooth regeneration. Our study shows that cell-free molecular therapy is effective for a wide range of congenital tooth agenesis,” concluded Manabu Sugai of the University of Fukui, another author of the study.

Source: Medical Xpress

Journal information: A. Murashima-Suginami et al, Anti–USAG-1 therapy for tooth regeneration through enhanced BMP signaling, Science Advances (2021). DOI: 10.1126/sciadv.abf1798

Categories : COVID TransplantsTags :

COVID Vaccination in Immunosuppressed Patients Produces Weak Response

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An article by Dorry Segev, MD, PhD for MedPage Today reveals poor results for COVID vaccination in immunosuppressed patients, with concerning implications. 

Dr Segev professor of surgery and epidemiology and associate vice chair of surgery at Johns Hopkins University School of Medicine and Bloomberg School of Public Health.

Dr Segev and colleagues launched a national study of vaccine immune responses in immunosuppressed solid organ transplant recipients. Among 436 COVID-naïve participants who received their first mRNA vaccine dose, only 17% of them mounted detectable antibodies to SARS-CoV-2.  The researchers also found that those taking anti-metabolites (eg, mycophenolate or azathioprine) were less likely to develop antibody responses, with 8.75% with detectable antibody found in those taking anti-metabolites versus 41.4% in those not taking them.

“Naturally, we were disappointed to see these findings, as we were hoping to be able to tell our immunosuppressed patients that the vaccines seemed to work well for them. Given this observation, the CDC should update their new guidelines for vaccinated individuals to warn immunosuppressed people that they still may be susceptible to COVID-19 after vaccination,
Dr Segev wrote. 

The current CDC guidelines are worded in a way that suggests vaccination translates into immunity, Dr Segev pointed out, but the study demonstrates that for most transplant recipients, as well as other immunosuppressed patients that the vaccine does not automatically confer immunity. This could also be a concern for the some 37.9 million people around the world living with HIV, although the effects of achieving viral suppression with antiretroviral therapy have so far not been well investigated in relation to COVID. Vaccine trials so far have not had sufficient numbers of participants living with HIV to draw any conclusions.

Notably, their previous research did show that rates of COVID infection and mortality were not greater for immunosuppressed transplant patients. 
Dr Segev noted that there are some implications for immunosuppressed patients; firstly, that they should at the very least receive the second dose of their vaccination (the current research is only on the effects of the first dose), and secondly, immunosuppressed patients should be aware that they may not necessarily be immunised after receiving a vaccination. They should speak to their provider about an antibody test to determine if the immunisation has been achieved.

The researchers are continuing to investigate other aspects of immune response besides antibodies, such as T and B cells, and are also looking at other vulnerable populations.

Source: MedPage Today

Categories : COVID Immune SystemTags :

COVID Tracking in Space Company Employees Yields Antibody Clues

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SpaceX, an aerospace manufacturing company currently providing satellite launch services as well as transport of crew  to the International Space Station, collaborated with researchers from MIT to monitor the spread of COVID amongst its employees. 

Unusually, the paper included SpaceX CEO Elon Musk as a byline author. The technology entrepreneur is known to be quite hands-on in his company’s projects. However, he has also courted controversy by openly questioning COVID tests and saying he and his family would not take COVID vaccines, saying that achieving herd immunity naturally was a better strategy.

SpaceX was seeking data-driven methods to safeguard its essential workforce. The collaboration allowed the researchers to track the emergence of mild and asymptomatic cases in a cohort of adults as early as April, when data for such cases were rare.

“Essentially, this study indicates that it’s not simply the presence or absence of antibodies that matter; rather, the amount and type of antibodies may play a defining role in the development of a protective immune response,” said Professor Galit Alter, Harvard Medical School and Immunologist, Division of Infectious Diseases, Massachusetts General Hospital. 

The study was originally aimed at measuring antibody levels over time, but when reinfections began to be reported, the team realised their samples had some valuable information.

“In early spring, we weren’t sure if asymptomatic infection could drive long-lived antibodies,” said Prof Alter, “nor whether they possessed the capability to neutralise or kill the virus.”

The researchers knew that 120 participants had mild or asymptomatic COVID infections, resulting in their bodies producing antibodies. Using sophisticated techniques to analyse those antibodies, they found that individuals with stronger symptoms in mild COVID, had a larger number of antibodies and developed immune functions associated with natural immune protection. 

The study found that although the presence of antibodies was sufficient to determine whether an individual had experienced a COVID infection, they did not automatically mean that individual is protected against the virus in the long term.

Antibody effector functions (on the ‘long arm’ of the antibody) linked to long-term protection, such as T cell activation and virus neutralisation were only seen in certain immune responses. These involved high levels of antibodies targetting a part of the virus known as the receptor binding domain.

“Once you hit a certain threshold of these antibodies, it’s like a switch turns on and we can observe antibody effector functions,” said first author Yannic Bartsch, PhD. “These functions were not observed in individuals with lower antibody binding titers, and the level of protection from reinfections is uncertain in these individuals.”

Source: News-Medical.Net

Journal information: Bartsch, Y. C., et al. (2021) Discrete SARS-CoV-2 antibody titers track with functional humoral stability. Nature Communications. doi.org/10.1038/s41467-021-21336-8.

Categories : COVID Immune SystemTags :

New “Double Antibodies” can Treat COVID Variants

On By ModernMedia

A new generation of “double antibodies” has been developed which can protect against all SARS-CoV-2 variants, as well as inhibiting mutations against the antibodies.

These “bispecific”  antibodies were created by the Institute for Research in Biomedicine (IRB; Bellinzona, Switzerland), which is affiliated to the Università della Svizzera italiana (USI).

While traditional antibody-based immunisation is able to offer protection against SARS-CoV-2, there is still a need to protect against variants which may achieve “vaccine escape”, as well as inhibiting mutations which give rise to resistance, as with antibiotic resistance in bacteria.

The researchers overcame these difficulties by splicing together a pair of antibodies to make a “bispecific” antibody that simultaneously targets two viral sites. The bispecific antibody treatment has proved effective in mouse models, which maintained body weight when infected with SARS-CoV-2, compared to infected controls, which lost 20-30% body weight before humane euthanisation. The paper is available on the bioRxiv preprint server.

Study author Luca Varani of USI explained: “We exploited our knowledge of the molecular structure and biochemical traits of the virus to fuse together two human antibodies, obtaining a single bispecific molecule simultaneously attacking the virus in two independent sites critical for infectivity. Supercomputing simulations allowed us to refine and validate the bispecific antibody design, which was later produced and tested in the laboratory. Although the virus can mutate and escape from the attack of a single first-generation antibody, we have shown that it cannot do so against the double action of the bispecific.

“A single injection of the bispecific antibody provides instantaneous protection against the disease in pre-clinical trials. The antibody effectively reduces viral burden in the lungs and mitigates inflammation typical of COVID-19”, said Daniel Ruzek from the Czech Academy of Sciences who led the antibody pre-clinical testing.

The effectiveness of the bispecific antibodies holds promise for human clinical trials, with the prospect of being both an effective prevention and treatment of COVID.

Source: News-Medical.Net

Journal information: Gasparo, R D., et al. (2020) Bispecific antibody prevents SARS-CoV-2 escape and protects mice from disease. bioRxiv.doi.org/10.1101/2021.01.22.427567.