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Bioengineered soluble ACE2 for brain protection against SARS-CoV-2 infection

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In a recent study posted to the bioRxiv* preprint server, researchers compared the efficiency of bioengineered soluble angiotensin converting enzyme-2 (ACE-2) concerning brain protection during coronavirus disease 2019 (COVID-19).

Study: Superiority of intranasal over systemic administration of bioengineered soluble ACE2 for survival and brain protection against SARS-CoV-2 infection. Image Credit: Kateryna Kon/Shutterstock

Background

Studies have noted the potential of ACE2 proteins in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralization using human organoids. The cellular model proposed in the present study expressed human ACE2, an important receptor of SARS-CoV-2 entry in human cells, and transmembrane serine protease 2 (TMPRSS2), which is a protease important for SARS-CoV-2-ACE2 complex internalization.

The k18-hACE2 model has proven deadly when infected with wild-type (WT) SARS-CoV-2 and mimics severe lung disease observed in humans. While there is sufficient evidence of significant brain injury reported by the model, the reason for the universal lethality is yet unknown.

About the study

In the present study, researchers examined the impact of an ACE2 618-DDC-ABD, a bioengineered soluble ACE2 protein with a sufficient duration of action and strong SARS-CoV-2 binding affinity.

In the k18-human ACE2 (hACE2) mouse, the team compared the impact of intraperitoneal (IP) versus intranasal (IN) delivery of the soluble ACE2 protein called ACE2 618-DDC-ABD. As per the study protocol, animals that exhibited a weight loss of over 20% of their body weight or displayed a clinical score of three or more were euthanized.

Four of the nine healthy mice from the IN-pre group were euthanized on day 5 to harvest organs for comparison with the IP-pre group, while the other five mice belonging to the IN-pre group lived until day 14, which was the final day of the study. In contrast, the surviving mice in the IP-pre-group had to be euthanized by the seventh day due to deteriorating clinical ratings and weight loss.

The team utilized k18-hACE2 mice, which expressed human ACE2 in its entirety and are sensitive to SARS-CoV-2 infection. Five to nine days after infection, animals with this viral load always succumb to the disease. The researchers examined the effects of pre-and post-treatment with the ACE2 618-DDC-ABD protein and compared intranasal (IN) and intraperitoneal (IP) delivery effects using distinct methodologies. In the pre-treatment cohorts, ACE2 618-DDC-ABD was delivered IV or IP to k18-hACE2 mice one hour before SARS-CoV-2 infection and then subsequently 24 and 48 hours for three doses. Control animals were administered bovine serum albumin (BSA) in phosphate-buffered saline (PBS), both IP and IN, at dosages and intervals similar to the ACE2 618-DDC-ABD post-treated mice.

Results

All infected untreated control mice had to be euthanized on the fifth day, had serious body weight loss, and received a high clinical score. In the subject mice administered ACE2 618-DDC-ABD before and after viral inoculation, the day 5 survival rate was 90% across the IN-pre group and 40% across the IP-pre group. The survival rate was 0% among untreated infected controls on day 5. In addition, the IN-pre-group had minimal weight loss and superior clinical scores. In contrast, the IP-pre-group reported weight loss and poor clinical ratings.

In mice administered ACE2 618-DDC-ABD after viral inoculation, the survival rate was 30% on day 5 and 20% on day 14 in the IN+IP-post group. Furthermore, in the IN-post cohort, the survival rate on day 5 was 20% and on day 14 was 10%. The IP-post group had a 20% survival rate on day 5 but a 0% survival rate on day 14.

On day five, 0% of untreated and infected mice survived. Most mice that were administered ACE2 618-DDC-ABD post-viral inoculation experienced significant weight loss and deteriorating clinical score, while a few recovered and survived up to day 14.

In the IN-pre group, there were no detectable brain antibodies. On the other hand, brain titers were elevated in five out of eight mice in the IP-pre cohort, which was considerably greater than that in the IN-pre group. The brain virus titers of post-treated mice were slightly and not significantly lower than those of infected untreated animals. Brain titers, however, were undetectable on the fourteenth day within the few survivors of the post-treatment groups. The lung SARS-CoV-2 titers of animals treated with ACE2 618-DDC-ABC.

Conclusion

Overall, the study findings showed that ACE2 618-DDC-ABD provided significantly superior survival and organ protection when administered IN than IP or after viral inoculation and that reducing brain titers is a crucial predictor of survival and organ protection.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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Canada to donate up to 200,000 vaccine doses to combat mpox outbreaks in Africa

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The Canadian government says it will donate up to 200,000 vaccine doses to fight the mpox outbreak in Congo and other African countries.

It says the donated doses of Imvamune will come from Canada’s existing supply and will not affect the country’s preparedness for mpox cases in this country.

Minister of Health Mark Holland says the donation “will help to protect those in the most affected regions of Africa and will help prevent further spread of the virus.”

Dr. Madhukar Pai, Canada research chair in epidemiology and global health, says although the donation is welcome, it is a very small portion of the estimated 10 million vaccine doses needed to control the outbreak.

Vaccine donations from wealthier countries have only recently started arriving in Africa, almost a month after the World Health Organization declared the mpox outbreak a public health emergency of international concern.

A few days after the declaration in August, Global Affairs Canada announced a contribution of $1 million for mpox surveillance, diagnostic tools, research and community awareness in Africa.

On Thursday, the Africa Centres for Disease Control and Prevention said mpox is still on the rise and that testing rates are “insufficient” across the continent.

Jason Kindrachuk, Canada research chair in emerging viruses at the University of Manitoba, said donating vaccines, in addition to supporting surveillance and diagnostic tests, is “massively important.”

But Kindrachuk, who has worked on the ground in Congo during the epidemic, also said that the international response to the mpox outbreak is “better late than never (but) better never late.”

“It would have been fantastic for us globally to not be in this position by having provided doses a much, much longer time prior than when we are,” he said, noting that the outbreak of clade I mpox in Congo started in early 2023.

Clade II mpox, endemic in regions of West Africa, came to the world’s attention even earlier — in 2022 — as that strain of virus spread to other countries, including Canada.

Two doses are recommended for mpox vaccination, so the donation may only benefit 100,000 people, Pai said.

Pai questioned whether Canada is contributing enough, as the federal government hasn’t said what percentage of its mpox vaccine stockpile it is donating.

“Small donations are simply not going to help end this crisis. We need to show greater solidarity and support,” he said in an email.

“That is the biggest lesson from the COVID-19 pandemic — our collective safety is tied with that of other nations.”

This report by The Canadian Press was first published Sept. 13, 2024.

Canadian Press health coverage receives support through a partnership with the Canadian Medical Association. CP is solely responsible for this content.

The Canadian Press. All rights reserved.

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How many Nova Scotians are on the doctor wait-list? Number hit 160,000 in June

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HALIFAX – The Nova Scotia government says it could be months before it reveals how many people are on the wait-list for a family doctor.

The head of the province’s health authority told reporters Wednesday that the government won’t release updated data until the 160,000 people who were on the wait-list in June are contacted to verify whether they still need primary care.

Karen Oldfield said Nova Scotia Health is working on validating the primary care wait-list data before posting new numbers, and that work may take a matter of months. The most recent public wait-list figures are from June 1, when 160,234 people, or about 16 per cent of the population, were on it.

“It’s going to take time to make 160,000 calls,” Oldfield said. “We are not talking weeks, we are talking months.”

The interim CEO and president of Nova Scotia Health said people on the list are being asked where they live, whether they still need a family doctor, and to give an update on their health.

A spokesperson with the province’s Health Department says the government and its health authority are “working hard” to turn the wait-list registry into a useful tool, adding that the data will be shared once it is validated.

Nova Scotia’s NDP are calling on Premier Tim Houston to immediately release statistics on how many people are looking for a family doctor. On Tuesday, the NDP introduced a bill that would require the health minister to make the number public every month.

“It is unacceptable for the list to be more than three months out of date,” NDP Leader Claudia Chender said Tuesday.

Chender said releasing this data regularly is vital so Nova Scotians can track the government’s progress on its main 2021 campaign promise: fixing health care.

The number of people in need of a family doctor has more than doubled between the 2021 summer election campaign and June 2024. Since September 2021 about 300 doctors have been added to the provincial health system, the Health Department said.

“We’ll know if Tim Houston is keeping his 2021 election promise to fix health care when Nova Scotians are attached to primary care,” Chender said.

This report by The Canadian Press was first published Sept. 11, 2024.

The Canadian Press. All rights reserved.

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Newfoundland and Labrador monitoring rise in whooping cough cases: medical officer

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ST. JOHN’S, N.L. – Newfoundland and Labrador‘s chief medical officer is monitoring the rise of whooping cough infections across the province as cases of the highly contagious disease continue to grow across Canada.

Dr. Janice Fitzgerald says that so far this year, the province has recorded 230 confirmed cases of the vaccine-preventable respiratory tract infection, also known as pertussis.

Late last month, Quebec reported more than 11,000 cases during the same time period, while Ontario counted 470 cases, well above the five-year average of 98. In Quebec, the majority of patients are between the ages of 10 and 14.

Meanwhile, New Brunswick has declared a whooping cough outbreak across the province. A total of 141 cases were reported by last month, exceeding the five-year average of 34.

The disease can lead to severe complications among vulnerable populations including infants, who are at the highest risk of suffering from complications like pneumonia and seizures. Symptoms may start with a runny nose, mild fever and cough, then progress to severe coughing accompanied by a distinctive “whooping” sound during inhalation.

“The public, especially pregnant people and those in close contact with infants, are encouraged to be aware of symptoms related to pertussis and to ensure vaccinations are up to date,” Newfoundland and Labrador’s Health Department said in a statement.

Whooping cough can be treated with antibiotics, but vaccination is the most effective way to control the spread of the disease. As a result, the province has expanded immunization efforts this school year. While booster doses are already offered in Grade 9, the vaccine is now being offered to Grade 8 students as well.

Public health officials say whooping cough is a cyclical disease that increases every two to five or six years.

Meanwhile, New Brunswick’s acting chief medical officer of health expects the current case count to get worse before tapering off.

A rise in whooping cough cases has also been reported in the United States and elsewhere. The Pan American Health Organization issued an alert in July encouraging countries to ramp up their surveillance and vaccination coverage.

This report by The Canadian Press was first published Sept. 10, 2024.

The Canadian Press. All rights reserved.

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