Tag: 13/7/21

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Nose Drops of ‘Friendly’ Bacteria Protects Against Meningitis

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Photo by Mathilde Langevin on Unsplash
Photo by Mathilde Langevin on Unsplash

Researchers have shown that nose drops of genetically modified ‘friendly’ bacteria protect against a form of meningitis.

The study, published in the journal Science Translational Medicine, was led by Professor Robert Read and Dr Jay Laver from the NIHR Southampton Biomedical Research Centre and the University of Southampton, and is the first of its kind.

The researchers spliced a gene into a harmless bacteria type, which enabled it to remain in the nose for longer than normal, triggering an immune response. Then, via nose drops, they administered these altered bacteria into the noses of healthy volunteers. The results showed a strong immune response against bacteria that cause meningitis and long-lasting protection.

Meningitis protection

Meningitis occurs in people of all age groups but affects mainly infants, young children and the elderly. Meningococcal meningitis, a bacterial form of the disease, can lead to death in as little as four hours after symptom onset.

Around 10% of adults carry Neisseria meningitidis in the back of their nose and throat without any signs or symptoms. In certain people however, it can invade the bloodstream, potentially leading to life-threatening conditions including meningitis and septicaemia.

The ‘friendly’ bacteria Neisseria lactamica also lives in some people’s noses naturally. By occupying the nose, it denies a foothold to its close relative N. meningitidis.

Boosted immune response

The study is an extension of the team’s previous work aiming to exploit this natural phenomenon. Nose drops of N. lactamica in that previous study prevented N. meningitidis from settling in 60% of participants. The team sought to improve on this.

They gave N. lactamica one of N. meningitidis’ key weapons; by giving it the gene for a ‘sticky’ surface protein that grips the cells lining the nose.
Those modified bacteria managed to remain longer and produced a stronger immune response. From at least 28 days, most participants (86%) still carried it at 90 days, it caused no adverse symptoms.

This is a promising find for this new way of preventing life-threatening infections, without drugs, especially in the face of growing antimicrobial resistance.

Dr Jay Laver, Senior Research Fellow in Molecular Microbiology at the University of Southampton, commented: “Although this study has identified the potential of our recombinant N. lactamica technology for protecting people against meningococcal disease, the underlying platform technology has broader applications.

“It is theoretically possible to express any antigen in our bacteria, which means we can potentially adapt them to combat a multitude of infections that enter the body through the upper respiratory tract. In addition to the delivery of vaccine antigens, advances in synthetic biology mean we might also use genetically modified bacteria to manufacture and deliver therapeutics molecules in the near future.”

Prof Read, Director of the NIHR Southampton Biomedical Research Centre said: “This work has shown that it is possible to protect people from severe diseases by using nose drops containing genetically modified friendly bacteria. We think this is likely to be a very successful and popular way of protecting people against a range of diseases in the future.”

Source: University of Southampton

Journal reference: Laver, J.R., et al. (2021) A recombinant commensal bacteria elicits heterologous antigen-specific immune responses during pharyngeal carriage. Science Translational Medicine. doi.org/10.1126/scitranslmed.abe8573.

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MRI and Ultrasound Combo Opens Blood-brain Barrier

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In a mouse model study of MRI-guided focused ultrasound-induced blood-brain barrier (BBB) opening at MRI field strengths ranging from ­approximately 0 T (outside the magnetic field) to 4.7 T, the static magnetic field dampened the detected microbubble cavitation signal and decreased the BBB opening volume. Credit: Washington University School of Medicine in St. Louis

Using a combination of ultrasound, MRI field strength and microbubbles can open the blood-brain barrier (BBB) and allow therapeutic drugs to reach the diseased brain location with MRI guidance. 

Using the physical phenomenon of cavitation, it is a promising technique that has been shown safe in patients with various brain diseases, such as Alzheimer’s diseases, Parkinson’s disease, ALS, and glioblastoma.
While MRI has been commonly used for treatment guidance and assessment in preclinical research and clinical studies, until now, researchers did not know the impact that MRI scanner’s magnetic field had on the BBB opening size and drug delivery efficiency.

Hong Chen, associate professor of biomedical engineering at Washington University in St. Louis, and her lab have found for the first time that the magnetic field of the MRI scanner decreased the BBB opening volume by 3.3-fold to 11.7-fold, depending on the strength of the magnetic field, in a mouse model. The findings were in Radiology.

Prof Chen conducted the study on four groups of mice. After they were injected microbubbles, three groups received focused-ultrasound sonication at different strengths of the magnetic field: 1.5 T (teslas), 3 T and 4.7 T, and one group was never exposed to the field. 

The researchers found that the microbubble cavitation activity, or the growing, shrinking and collapse of the microbubbles, decreased by 2.1 decibels at 1.5 T; 2.9 decibels at 3 T; and 3 decibels at 4.7 T, compared with those that had received the dose outside of the magnetic field. Additionally, the magnetic field decreased the BBB opening volume by 3.3-fold at 1.5 T; 4.4-fold at 3 T; and 11.7-fold at 4.7 T. No tissue damage from the procedure was seen.

Following focused-ultrasound sonication, the team injected a model drug, Evans blue dye, to investigate whether the magnetic field affected drug delivery across the BBB. The images showed that the fluorescence intensity of the Evans blue was lower in mice that received the treatment in one of the three strengths of magnetic fields compared with mice treated outside the magnetic field. The Evans blue trans-BBB delivery was decreased by 1.4-fold at1.5 T, 1.6-fold at 3.0 T and 1.9-fold at 4.7 T when compared with those treated outside of the magnetic field.

“The dampening effect of the magnetic field on the microbubble is likely caused by the loss of bubble kinetic energy due to the Lorentz force acting on the moving charged lipid molecules on the microbubble shell and dipolar water molecules surrounding the microbubbles,” said Yaoheng (Mack) Yang, a doctoral student in Prof Chen’s lab and the lead author of the study.

“Findings from this study suggest that the impact of the magnetic field needs to be considered in the clinical applications of focused ultrasound in brain drug delivery,” Prof Chen said.

In addition to brain drug delivery, cavitation is also used in several other therapeutic techniques, such as histotripsy, the use of cavitation to mechanically destroy regions of tissue, and sonothrombolysis, a therapy used after acute ischaemic stroke. The magnetic field’s damping effect on cavitation is expected to affect the treatment outcomes of other cavitation-mediated techniques when MRI-guided focused-ultrasound systems are used.

Source: Washington University in St. Louis

Journal information: Yang, Y., et al. (2021) Static Magnetic Fields Dampen Focused Ultrasound–mediated Blood-Brain Barrier Opening. Radiology. doi.org/10.1148/radiol.2021204441. 

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Immunotoxin Treatment Stops Liver Fibrosis

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A microscopic image of liver tissue affected by non-alcoholic fatty liver disease (NAFLD). The large and small white spots are excess fat droplets filling liver cells (hepatocytes). Credit: Dr. David Kleiner, National Cancer Institute/NIH
A microscopic image of liver tissue affected by non-alcoholic fatty liver disease (NAFLD). The large and small white spots are excess fat droplets filling liver cells (hepatocytes). Credit: Dr David Kleiner, National Cancer Institute/NIH

A new study successfully used immunotoxins to prevent the progression of liver fibrosis by targeting a protein specific to that disease.

Fibrosis, the buildup of collagen and scar tissue, can be caused by alcohol abuse and disease. University of California San Diego School of Medicine researchers and their collaborators are looking for ways to treat fibrosis by preventing liver cells from producing collagen. 

“So we thought…what if we take immunotoxins and try to get them to kill collagen-producing cells in the liver,” explained team lead Tatiana Kisseleva, MD, PhD, associate professor of surgery at UC San Diego School of Medicine. “If these antibodies carrying toxic molecules can find and bind the cells, the cells will eat up the ‘gift’ and die.”

The study focussed on immunotoxins designed to bind a protein called mesothelin, which is rarely found in the healthy human body. The protein is only produced by cancer cells and collagen-producing liver cells, known as portal fibroblasts.

Kisseleva teamed up with co-author Ira Pastan, MD, at the National Cancer Institute, part of the National Institutes of Health (NIH). Dr Pastan is co-discoverer of mesothelin and an expert on using immunotoxins to target the protein on cancer cells, and he leads several clinical trials using it in treating patients with ovarian cancer, mesothelioma and pancreatic cancer.

Since the immunotoxins specifically recognise human mesothelin, the researchers couldn’t use a traditional mouse model of liver fibrosis. So, they transplanted human liver cells isolated from patients to mice and treated them with the anti-mesothelin immunotoxin. Compared to untreated mice, 60 to 100 percent of human mesothelin-producing cells were killed by the immunotoxins, which also reduced the deposition of collagen.

Liver fibrosis treatment is very limited at present, with weight loss being currently the only known method for reducing liver fibrosis associated with non-alcoholic fatty liver disease. Alcoholic liver disease is most commonly treated with corticosteroids, but they are not highly effective. Early liver transplantation is the only proven cure, but it is rarely available.

“What we want to know now is, can this same strategy be applied to other organs?” Dr Kisseleva said. “Surprisingly enough, the same cells are responsible for fibrosis in the lung and kidneys. This is especially exciting because we already know from Dr Pasten’s cancer clinical trials that anti-mesothelin immunotoxins are safe in humans, potentially speeding up their application in other areas.”

The findings were published in Proceedings of the National Academy of Sciences

Source: University of California San Diego

Journal information:Nishio, T., et al. (2021) Immunotherapy-based targeting of MSLN+ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis. PNAS. doi.org/10.1073/pnas.2101270118. 

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Asymptomatic and Presymptomatic COVID Transmission is Significant

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A study of COVID transmission in a US university indicates that at least a fifth of asymptomatic COVID cases passed the infection on, suggesting that containing the SARS-CoV-2 virus is more difficult than previously thought. 

Even as multiple resurgences of the COVID pandemic occur in many countries, the risk posed by various degrees of infection, from asymptomatic through presymptomatic to symptomatic SARS-CoV-2 infection is still undefined.

Researchers in a new study found that at least a third of infected individuals were asymptomatic, and a fifth of them successfully passed on the virus to others. In comparison, about a quarter of symptomatic cases did so, especially when the symptoms included fever, cough and shortness of breath. In these instances, up to 30% of them transmitted the virus. The findings of the study are available on the medRxiv preprint server, and are not yet peer reviewed.

Asymptomatic carriage has been suspected and reported since the pandemic’s outset, though the exact proportion has been described to be anywhere between 40% and 77%. Such differences in ascertainment could be from varying demographic, testing, and interaction patterns.

Most systematic reviews have quoted figures of 30-45% as asymptomatic, which are considered to be much less transmissible. Secondary attack rates (SAR) of as low as 0.7% are reported in these cases, compared to 21% for symptomatic cases. Most of these studies had a lack of follow-up, meaningthat asymptomatic and presymptomatic cases could have been combined or misclassified.

The study was based on a campus population at a Midwestern university in the USA, during the northern hemisphere autumn of 2020. The study included about 13 000 students and 1600 confirmed cases.

The researchers found not only that SAR differed when patients were classified by symptom presence or absence, but the nature of the symptoms also determined the SAR. This could hamper containment efforts, especially as economic activity is burgeoning after a long hiatus.

Moreover, daily checks on individuals such as employees and students which are meant to help define transmission risk, may not yield the desired results when the wide difference in symptom types and timing in relation to infection, as well as the SAR, are taken into account.

The college campus in this study had a set of measures in place to reduce the risk of viral spread. In particular, this included a daily requirement to assess one’s own health and report on any issues; testing for the virus; contact tracing; case isolation and contact quarantine; and surveillance testing to monitor the spread of the virus.

In August, students began to come back to campus, and this was associated with 151 positive tests for the virus by reverse transcriptase polymerase chain reaction (RT PCR). This led to the suspension of in-person classes, with all teaching being online until August 24.

At this point, graduate and professional students again had in-person classes, while the others continued with online classes until September 2. The number of cases detected by a positive PCR test went down, from just over 600 in August to approximately 150 by September.

A second rise was seen in the middle of October, and by the end of the semester, on November 20, over 1500 students were positive. Of these, daily health data was present for at least half the days for about 1200 students.

Testing was administered by a rapid antigen test if a student had symptoms suggestive of SARS-CoV-2 infection or had a history of exposure to someone with COVID. Negative results were validated by a PCR, with the result coming within 1-2 days during which time they were quarantined.

Positive rapid antigen tests led to 14 days isolation, along with contact tracing and quarantine. The quarantined students were also advised to do an antigen test, which, if positive, necessitated a PCR test. They were also expected to quarantine until tests on days four and seven were also negative, at which point they were released. The university also conducted surveillance monitoring to hopefully catch asymptomatic or presymptomatic cases.

The scientists found that nasal congestion, headache and dry cough was higher among those who tested positive within five days, with fever and sensory disturbances (anosmia/dysgeusia/ageusia) were higher among positives only three and two days previous to testing positive. Loss of taste and smell occurred in the greatest proportion of cases by day four after testing positive.

The SAR was 19% vs 25% for asymptomatic vs symptomatic index cases on day 14 after virus exposure. In the four days immediately following exposure, symptomatic cases showed a higher SAR, with presymptomatic cases showing lower SAR and asymptomatic cases the lowest.

Perhaps this was because symptomatic cases have delayed testing, indicating that they had more time to transmit the virus before testing positive.

After this period, presymptomatic COVID had the highest SAR, but symptomatic case SAR began to rise, becoming almost identical thereafter. At seven days post-exposure, the SAR in all categories flattened, therefore making it the quarantine limit for contacts.

Symptoms varied in their predictive capacity, but fever, shortness of breath and a dry cough at the onset of infection were found to be associated with an SAR of 30%, provided body aches and/or chills were also reported. The investigators suggest this could be owing to higher viral loads, and therefore greater ability to shed and spread the virus.  

The authors concluded that daily virus surveillance does not by itself help in containing transmission. The only way out may be rigorous face mask use until sufficient vaccine coverage is reached, along with social distancing, testing and quarantine. Both asymptomatic and presymptomatic viral transmission are significant contributors to viral spread, impeding efforts to stop the virus, especially with novel emerging SARS-CoV-2 strains.

Source: News-Medical.Net

Journal information: Krieg, S. J. et al. (2021). Symptomatic, Presymptomatic, and Asymptomatic Transmission of SARS-CoV-2. medRxiv preprint. doi: https://doi.org/10.1101/2021.07.08.21259871. https://www.medrxiv.org/content/10.1101/2021.07.08.21259871v1.

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A New Antibody-based Contraceptive for Women

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Photo by nine koepfer on Unsplash
Photo by nine koepfer on Unsplash

Researchers have developed a topical antibody-based contraceptive for use by women, which works like a glue, clumping and trapping sperm. 

Over 40 percent of pregnancies worldwide are unintended, even though multiple forms of contraception are available. As well as fuelling population growth, unintended pregnancies can negatively impact the physical, mental and economic wellbeing of mothers.

To address these problems, researchers from Boston University School of Medicine and ZabBio have developed an anti-sperm monoclonal antibody, the Human Contraception Antibody (HCA), which laboratory tests showed was safe and had potent sperm agglutination (clumping) and immobilisation activity.

“HCA appears to be suitable for contraceptive use and could be administered vaginally in a dissolvable film for a woman-controlled, on-demand birth control method,” explained senior author Deborah Anderson, PhD, professor of Medicine.

In order to assess its applicability as a topical contraceptive, the team tested HCA over a wide range of concentrations and under different physiologically relevant conditions in vitro. HCA was mixed with sperm from normal, healthy volunteers and then tested. Sperm became immobilised within 15 seconds, becoming stuck together. The researchers also found that HCA did not seem to cause vaginal inflammation in lab tissue culture tests.

Thanks to its safety and efficacy, HCA could fill current gaps in the contraception field. “HCA could be used by women who do not use currently available contraception methods and may have a significant impact on global health,” said Prof Anderson.  HCA is currently being tested in a Phase I Clinical Trial.

The researchers also believe that a combination of HCA with other antibodies such as anti-HIV and anti-HSV antibodies could make a multipurpose prevention technology, a product that would both serve as a contraceptive and prevent sexually transmitted infections.

These findings appear online in the journal EBioMedicine.

Source: Boston University School of Medicine

Journal information: Gabriela Baldeon-Vaca et al, Production and characterization of a human antisperm monoclonal antibody against CD52g for topical contraception in women, EBioMedicine (2021). DOI: 10.1016/j.ebiom.2021.103478

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Flu Shots May Offer Some COVID Protection

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Photo by Raghavendra V. Konkathi on Unsplash
Photo by Raghavendra V. Konkathi on Unsplash

The flu vaccine may provide a level of protection against COVID, a new study concludes.

An analysis of patient data from around the world strongly suggests that the annual flu shot reduces the risk of stroke, sepsis and DVT in patients with COVID. Flu-vaccinated COVID patients were also less likely to visit the emergency department and be admitted to the intensive care unit (ICU). The research was presented online at research being presented at the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID).

Global COVID vaccination is a daunting challenge and, although production and distribution of vaccines increases daily, some countries are not expected to vaccinate large numbers of their population until the start of 2023.

Recently, several modestly-sized studies suggested that the flu vaccine may provide some measure of protection against COVID.

Ms Susan Taghioff, of the University of Miami Miller School of Medicine, and colleagues carried out a retrospective analysis of data on tens of thousands of patients from around the world to find out more.

In the largest study of its kind, the team screened de-identified electronic health records held on the TriNetX research database of more than 70 million patients to identify two groups of 37 377 patients, from countries including the US, UK, Germany, Italy, Israel and Singapore.

The two groups were matched for factors that could affect their risk of severe COVID-19, including age, gender, ethnicity, smoking and health problems such as diabetes, obesity and chronic obstructive pulmonary disease.

The first group had received the flu vaccine between two weeks and six months before COVID diagnoses. The second group also had COVID but were not vaccinated against flu. 

The incidence of 15 adverse outcomes, including sepsis and death, within 120 days of testing positive for COVID was then compared between the two groups. Analysis showed that those not vaccinated for flu were significantly more likely (up to 20%) to have been admitted to ICU.

They were also significantly more likely to visit the Emergency Department (up to 58%), to develop sepsis (up to 45%), to have a stroke (up to 58%) and a deep vein thrombosis (up to 40%). However, the risk of death was not reduced.

It isn’t known exactly how the flu jab provides protection against COVID but most theories centre around it boosting the innate immune system.

The results strongly suggest that the flu vaccine protects against several severe effects of COVID, according to the study authors. Further research is needed to prove this possible link but, in the future, the flu shot could be used to help bolster protection in countries short of COVID vaccine doses.

Senior author Dr Devinder Singh, professor of plastic surgery at the University of Miami Miller School of Medicine, said: “Only a small fraction of the world has been fully vaccinated against COVID to date and, with all the devastation that has occurred due to the pandemic, the global community still needs to find solutions to reduce morbidity and mortality.

“Having access to real-time data of millions of patients is a powerful research tool. Together with asking important questions it has allowed my team to observe an association between the flu vaccine and lower morbidity in COVID patients.

“This finding is particularly significant because the pandemic is straining resources in many parts of the world. Therefore, our research – if validated by prospective randomised clinical trials – has the potential to reduce the worldwide burden of disease.”

Ms Taghioff added: “Influenza vaccination may even benefit individuals hesitant to receive a COVID vaccine due to the newness of the technology.

“Despite this, the influenza vaccine is by no means a replacement for the COVID vaccine and we advocate for everyone to receive their COVID vaccine if able to.

“Continued promotion of the influenza vaccine also has the potential to help the global population avoid a possible ‘twindemic’ – a simultaneous outbreak of both influenza and coronavirus.

“Regardless of the degree of protection afforded by the influenza vaccine against adverse outcomes associated with COVID, simply being able to conserve global healthcare resources by keeping the number of influenza cases under control is reason enough to champion continued efforts to promote influenza vaccination.”

Source: EurekAlert!