Search This Blog

Tuesday, July 27, 2021

First published data backs CanSino’s inhaled COVID vaccine

 Early-stage clinical data with CanSino Biologics’ inhaled COVID-19 vaccine show that it was able to stimulate neutralising antibodies against SARS-CoV-2 at a dose well below that required with intramuscular administration.

Published in The Lancet, a phase 1 study conducted in China showed that a two-dose regimen of aerosolised Ad5-nCoV was similar to that achieved with a single, intramuscular dose of the same vaccine.

Administration of the new version was painless and the regimen well tolerated in the phase 1 trial, write the authors of the study. It was also found to stimulate both neutralising antibodies and T cell responses – the latter is thought to play a role in recognising and killing infected cells and stimulating antiviral cytokines – after a single dose.

The study also hints that aerosol vaccination could trigger a higher ratio of neutralising antibodies to total antibodies than intramuscular vaccinations, and that a combination of an intramuscular first dose followed by an aerosol second may provide the best results overall.

The researchers acknowledge however that the study is small, so those hypotheses will have to be tested in ongoing phase 2 and 3 trials.

Ad5.nCoV is already approved in China and other countries around the world as a one-dose jab called Convidecia, and was shown to be around 66% protective in a clinical trial reported in February. CanSino moved the inhaled formulation into clinical testing in April.

While the current injected COVID-19 vaccines are effective, the majority of people around the world remain unvaccinated, and there remains a need for new options that are easy to administer.

In the case of Ad5-nCoV, the dose needed was 20% or 40% of that needed with the injected version, which could make supplies of the vaccine stretch further, and it needs standard refrigeration temperatures so is easy to store and ship.

The hope is that inhaled vaccines may also be more effective at stimulating mucosal immunity in the lungs, which provides a first line of defense against respiratory pathogens, and the researchers suggest their early data on antibody and cellular responses back up this hypothesis.

CanSino is working with the Beijing Institute of Biotechnology on the inhaled vaccine, which is delivered using a nebuliser.

Other groups are also working on alternative means of COVID-19 vaccine delivery, including UK’s Imperial College London, which is running a small trial of its mRNA-based candidate and the AstraZeneca/Oxford University vaccine to see if they can be delivered to the lungs rather than by injection into the muscle.

Intranasal delivery is also being explore, although one front runner in this category – Altimmune – abandoned its candidate after finding weaker-than-expected immune responses in a phase 1 trial.

https://pharmaphorum.com/news/first-published-data-backs-cansinos-inhaled-covid-vaccine/

Association of Sleep, β-Amyloid Pathology in Older Cognitively Unimpaired Adults

 Philip S. Insel, PhD1,2Brian S. Mohlenhoff, MD1,3Thomas C. Neylan, MD1,3et al

doi:10.1001/jamanetworkopen.2021.17573


Key Points

Question  What is the magnitude and time of onset of the association between daytime and nighttime sleep with β-amyloid (Aβ) pathology in cognitively unimpaired older adults?

Findings  In this cross-sectional study of 4425 cognitively unimpaired participants, each additional hour of nighttime sleep was associated with a statistically significant reduction of Aβ positron emission tomographic standardized uptake value ratio, whereas daytime sleep was associated with increased regional accumulation of Aβ. The association occurs early, before significant Aβ accumulation or cognitive impairment, and in specific regions of the brain.

Meaning  If longer sleep duration leads to reduced amyloid levels, treatments increasing sleep duration may reduce Aβ accumulation and aid in delaying the onset of cognitive dysfunction associated with Aβ deposition.

Abstract

Importance  Disrupted sleep commonly occurs with progressing neurodegenerative disease. Large, well-characterized neuroimaging studies of cognitively unimpaired adults are warranted to clarify the magnitude and onset of the association between sleep and emerging β-amyloid (Aβ) pathology.

Objective  To evaluate the associations between daytime and nighttime sleep duration with regional Aβ pathology in older cognitively unimpaired adults.

Design, Setting, and Participants  In this cross-sectional study, screening data were collected between April 1, 2014, and December 31, 2017, from healthy, cognitively unimpaired adults 65 to 85 years of age who underwent florbetapir F 18 positron emission tomography (PET), had APOE genotype information, scored between 25 and 30 on the Mini-Mental State Examination, and had a Clinical Dementia Rating of 0 for the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study. Data analysis was performed from December 1, 2019, to May 10, 2021.

Exposures  Self-reported daytime and nighttime sleep duration.

Main Outcomes and Measures  Regional Aβ pathology, measured by florbetapir PET standardized uptake value ratio.

Results  Amyloid PET and sleep duration information was acquired on 4425 cognitively unimpaired participants (mean [SD] age, 71.3 [4.7] years; 2628 [59.4%] female; 1509 [34.1%] tested Aβ positive). Each additional hour of nighttime sleep was associated with a 0.005 reduction of global Aβ standardized uptake value ratio (F1, 4419 = 5.0; P = .03), a 0.009 reduction of medial orbitofrontal Aβ (F1, 4419 = 17.4; P < .001), and a 0.011 reduction of anterior cingulate Aβ (F1, 4419 = 15.9; P < .001). When restricting analyses to participants who tested Aβ negative, nighttime sleep was associated with a 0.006 reduction of medial orbitofrontal Aβ (F1,2910 = 16.9; P < .001) and a 0.005 reduction of anterior cingulate Aβ (F1,2910 = 7.6; P = .03). Daytime sleep was associated with a 0.013 increase of precuneus Aβ (F1,2910 = 7.3; P = .03) and a 0.024 increase of posterior cingulate Aβ (F1,2910 = 14.2; P = .001) in participants who tested Aβ negative.

Conclusions and Relevance  In this cross-sectional study, the increased risk of Aβ deposition with reduced nighttime sleep duration occurred early, before cognitive impairment or significant Aβ deposition. Daytime sleep may be associated with an increase in risk for early Aβ accumulation and did not appear to be corrective for loss of nighttime sleep, demonstrating a circadian rhythm dependence of sleep in preventing Aβ accumulation. Treatments that improve sleep may reduce early Aβ accumulation and aid in delaying the onset of cognitive dysfunction associated with early Alzheimer disease.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2782215

Mental Health Disorders Tied to Higher COVID-19 Mortality

 Mental health disorders were associated with an increased risk of COVID-19-related mortality, according to a systematic review and meta-analysis of 16 studies from seven countries.

Results from these population-based cohort studies -- from the U.S., South Korea, Israel, and four European countries -- found that patients with mental health disorders were at an elevated risk of COVID-19 mortality as compared with those without mental health disorders, reported Guillaume Fond, MD, PhD, of Aix-Marseille University in France, and colleagues.

As they showed in their study in JAMA Psychiatry, this was the case when looking at both crude and adjusted odds ratios (ORs, P<0.05 for both):

  • Crude: OR 1.75 (95% CI 1.40-2.20)
  • Adjusted: OR 1.38 (95% CI 1.15-1.65)

Patients who had the most severe mental health disorders -- schizophrenia spectrum disorders and/or bipolar disorder -- had the highest likelihood for COVID-19-related mortality (crude OR 2.26, 95% CI 1.18-4.31; adjusted OR 1.67, 95% CI 1.02-2.73), Fond and co-authors found.

They noted that although they were able to determine the associations between severe mental health disorders and risk of COVID-19 mortality, it wasn't possible to identify significant differences between specific mental health disorders.

This was because all the studies (except one) that included patients with non-severe mental health disorders -- defined by the research team as mood disorders, anxiety disorders, personality disorders, eating disorders, and alcohol and substance misuses -- combined those patients with others who had severe mental health problems. It was only possible to distinguish between severe mental health disorders for six of the 16 studies included in the meta-analysis; some studies involved just patients with schizophrenia, while others combined those with bipolar disorders. In all, there were seven studies from the U.S.; three from South Korea; two from France; and one study from Denmark, Israel, Spain, and the U.K. each.

The definitions of the patient groups with mental health disorders also varied across countries; for example, the South Korean studies, two of the U.S.-based studies, and the U.K. study blended mental health disorders with substance-use disorders, without distinguishing between them. Two other U.S. studies included only patients with substance use disorders, and the Danish study examined substance use disorders separately from mental health disorders.

The meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines, and systematic bibliographic searches were carried out using Cochrane Methodology. The studies -- which covered December 2019 to July 2020 and included data from 19,086 patients -- were accessed through Medline, Web of Science, and Google Scholar, and the literature was assessed for biases using the Newcastle-Ottawa Quality Assessment Scale.

Fond and colleagues explained that they had aimed to determine whether patients with mental health disorders were at increased risk of admission to intensive care units (ICUs) as a result of COVID-19, in comparison with patients without mental health disorders. However, only four of the studies in the meta-analysis included data about ICU admissions, so the sample was deemed insufficient for meta-analysis. And among the four studies available, the results were heterogeneous and contradictory from country to country.

Other limitations, the team said, included that most of the studies in the analysis were conducted throughout the pandemic's first peak of COVID-19 cases, during which testing was limited in some countries, likely leading to discrepancies in mortality rates by country.

The team wrote that although there is still much to be learned about ICU admissions and COVID-19 mortality for patients with certain mental health problems, "patients with mental health disorders should have been targeted as a high-risk population for severe forms of COVID-19, requiring enhanced preventive and disease management strategies."

"Social factors (e.g., socioeconomic status, family or household composition, and environmental factors) were also reported to be associated with increased COVID-19 mortality and are known to be highly influential in patients with mental health disorders," Fond and team wrote. "These factors need to be explored in depth in future works on mental health disorders and COVID-19, and they need to be considered for health policies."


Disclosures

Britain Reports Highest Deaths From COVID-19 Since March as Johnson Urges Caution

 Britain reported its highest number of deaths and people in hospital with coronavirus since March on Tuesday, with Prime Minister Boris Johnson urging caution despite a week of lower reported numbers of infection.

Britain reported 131 new deaths from COVID-19, the highest daily total since March 17, though it came after just 14 deaths were reported on Monday, suggesting the weekend might have impacted when deaths were reported.

The number of COVID-19 patients in British hospitals has also steadily risen to 5,918, also the highest since March, following a spike in cases earlier this month.

The number of new infections has fallen each day for the last seven days, though Johnson stressed the pandemic was not over.

"It is very, very important that we don't allow ourselves to run away with premature conclusions about (lower case numbers)," Johnson told broadcasters, noting it would take a while for the lifting of restrictions in England to feed through to the data.

"People have got to remain very cautious and that remains the approach of the government."

Johnson has lifted restrictions in England and is betting he can get one of Europe's largest economies firing again because so many people are now vaccinated, a decision which marks a new chapter in the response to the novel coronavirus.

Imperial College epidemiologist Neil Ferguson said the effective end of Britain's pandemic could be just months away as vaccines have so dramatically reduced the risk of hospitalisation and death.

"We're not completely out of the woods but the equation has fundamentally changed," Ferguson, whose modelling of the virus's likely spread at the outset of the pandemic in early 2020 alarmed governments across the world, told the BBC.

"I'm positive that by late September, October time we will be looking back at most of the pandemic."

ON THE WAY DOWN

Johnson lifted COVID-19 restrictions in England on July 19. New daily cases in the current wave peaked two days earlier at 54,674 and have since fallen dramatically, to 23,511 new cases on Tuesday.

The closure of schools for summer, the end of the Euro 2020 soccer championships and warmer weather are among factors epidemiologists say might have reduced social mixing indoors and therefore cases, even as England's economy has fully reopened.

Case numbers have been falling for longer in Scotland, where the recent peak in new infections was on July 1, than in England, corresponding to an earlier elimination from the Euros.

"Both of them seem to coincide in some ways with the end of activity in the Euro 2020 tournament," Rowland Kao, an epidemiologist at the University of Edinburgh, told Reuters, adding that changes in testing patterns might mean that the sharpness of the drop is overstated in daily testing figures.

"(Cases) may go up again, because we're only just going to be starting to see the effect of the complete release of restrictions associated with July 19 in England. So there may still be rises yet to come."

Britain has one of the highest official fatality rates from COVID-19 in the world, with 129,303 deaths, but vaccinations and lockdowns have greatly slowed the rate since March.

Scotland's National Clinical Director Jason Leitch said a gradual return to usual social activity would help smooth the end of the current wave, but that the next few weeks would be unpredictable.

"On the way down is always bumpier than the exponential rise on the way up," he told Reuters.

https://www.usnews.com/news/world/articles/2021-07-27/uk-pm-johnson-dont-get-carried-away-with-falling-covid-19-cases

CDC recommends masks indoors even for some vaccinated against Covid-19

 Federal health officials advised Tuesday that even people who’ve had their Covid-19 shots wear masks in public indoor settings in areas with widespread transmission of the coronavirus, a major setback in the progress in the U.S. epidemic that reflects a surging variant and the country’s ongoing struggles to increase vaccination rates.

The reversal to the Centers for Disease Control and Prevention’s earlier guidance comes as the Delta variant — the most transmissible version of the pathogen yet, by far — is igniting outbreaks and driving hospitalizations up in states with low vaccination rates, like Missouri, Arkansas, and Florida. The variant is responsible for seemingly increasing numbers of breakthrough infections.

The CDC also recommended that schools reopen in the fall with universal indoor masking for all students, teachers, and staff, even among people who are vaccinated — a policy decision that will ultimately be left up to state and local officials.

 

“Children should return to full-time, in-person learning in the fall with proper prevention strategies in place,” CDC Director Rochelle Walensky said during a press briefing.

In a statement, President Biden reiterated Walensky’s call that precautions would enable safer resumption of in-person schooling. “Masking students is inconvenient, I know, but will allow them to learn and be with their classmates with the best available protection,” he said.

Just two months ago, the CDC said that fully vaccinated people no longer needed to wear masks indoors, citing evidence that the immunizations prevented many cases entirely and left those who still got infected “less likely to … transmit [the virus] to others.”

But in addition to spreading more efficiently, Delta seems to have at least some ability to evade the immune response people generate after being vaccinated. Multiple studies have indicated that immunized people are still broadly protected against severe Covid-19 and death, but there is emerging evidence that Delta can cause breakthrough cases at higher rates than other virus versions — and that in some of those infections, people are still harboring large amounts of virus that could be passed to others.

Walensky said that new research indicates that vaccinated people are only contributing a small amount to overall transmission, the vast majority of which is occurring among people who haven’t received immunizations. But the data “unfortunately warrants” the updated recommendations.

“In those cases, those rare cases that we have breakthrough infections, we felt it important for people to understand that they have the potential to transmit virus to others,” she said.

Walensky called masks “a temporary measure” and urged people to get vaccinated, framing the shots as the tools that can suppress transmission rates in lasting ways.

“We really need to work to get these areas in the country that have substantial and high amount of transmission right now down to lower amounts of transmission,” she said.

The masking recommendations for vaccinated people applies to communities with “substantial” or “high” transmission rates, which together the CDC defines as 50 cases or more per 100,000 people over the past seven days. Transmission rates in nearly two-thirds of U.S. counties are in those categories, with wide swaths of Nevada, Utah, and many southern states experiencing those levels of spread, CDC data show. Some communities are reporting several hundred new cases per 100,000 people in the past week — what Walensky called “really an extraordinary amount of viral transmission.” 

Delta’s general transmissibility stems at least in part from changes in its genome that allow it to build up much higher levels of virus in the upper airway, leading to people emitting more virus for longer periods of time, meaning they are more likely to infect others.

An administration official, speaking on the condition of anonymity, told STAT that health experts do not have studies proving that fully vaccinated people are transmitting the virus. Rather, the official said, the updated guidance is based on studies showing that vaccinated people who contract the Delta variant have similarly high levels of virus in their airways, which suggested that they may be infectious to others. With other variants, vaccinated people had substantially lower levels of virus in their noses and throats compared to unvaccinated people.

The new masking guidelines provide an unwelcome turn in the pandemic. As vaccines started rolling out, it was clear they weren’t just protecting people from getting so sick they needed hospital care or they would die, but that they were also drastically cutting transmission. Experts say vaccines are still limiting transmission even with Delta, but not to the same level as before.

It’s taken some time for scientists to tease apart all that Delta can do in vaccinated people. Most concerningly, it has been ripping through unvaccinated populations, leading to another surge in hospitalizations in some states that are almost entirely among people who haven’t been immunized. Experts are still trying to determine if Delta causes more severe disease on average than other variants.

Recent infection clusters that included vaccinated people — and that broadly caused mild and asymptomatic cases — raised worries that Delta was potentially spreading among vaccinated people to an extent. Walensky said the CDC was conducting outbreak investigations of the clusters to determine whether and to what extent vaccinated people were passing the virus on to others.

If vaccinated people are transmitting the virus, masks could help in cases when people are asymptomatic or in the period when they are infectious but haven’t yet developed symptoms. Under existing CDC guidelines, vaccinated people who were showing symptoms were still urged to isolate.

Vaccinated people passing the virus to other vaccinated people isn’t ideal, but given how protective the shots are against the worst outcomes, the bigger concern right now is that vaccinated people could be contributing to the spread of the virus to unvaccinated people. Vaccinated people could also be transmitting the virus to individuals who didn’t mount robust responses to the shots because their immune systems are suppressed, including some with cancer or who have received organ transplants. Children under 12 are also not yet eligible for Covid-19 vaccines.

It’s unclear how the new CDC guidelines will land with an American public that seems eager to move on from the pandemic, even if the pandemic is not done with them. Many people who are vaccinated feel like they’ve done their part and might be unwilling to take a step back. And while health officials hope they can persuade some of the remaining unimmunized people to roll up their sleeves by improving access or addressing concerns, some portion of people have cemented their resistance to the shots.

Under the previous guidelines, unvaccinated people were still supposed to wear masks in public indoor settings.

The CDC says breakthrough cases still appear to be rare given how many people have been vaccinated, and the vast majority of infections are asymptomatic or mild. It’s also thought that because so many of those cases are so tame, many go undetected. However, many experts argue that breakthrough infections that cause no symptoms shouldn’t really be considered as cases. Mild or asymptomatic breakthrough infections are signs that the vaccines — whose top aim is to stave off death and severe illness — are doing their job, experts stress.

https://www.statnews.com/2021/07/27/cdc-recommend-masks-indoors-even-for-those-vaccinated-against-covid-19/

Europe approves a Covid-19 crystal ball

 A test that promises to predict which Covid-19 patients will go on to have severe disease has today become available in Europe. Made by the tiny private Israeli company Memed, the Covid-19 Severity assay measures a combination of biomarkers in a patient’s blood, assigning a score the company says correlates with the chances of the condition worsening. 

Clinical data on the product are indeed impressive at first glance. But there are reasons to suspect that the assay might not work quite so well in the real world, and questions over the level of demand for such a test remain.

Memed’s test can be run in 15 minutes on the company’s Memed Key platform. It measures levels of tumour necrosis factor-related apoptosis inducing ligand (Trail), interferon gamma-inducible protein-10 (IP-10) and C-reactive protein (CRP). 

Trail levels increase in viral infection but are believed to fall in severe viral infections, which could make this a particularly useful biomarker for severe cases. In Covid-19 specifically, low Trail levels are associated with inability to clear the virus and increased disease severity. IP-10 has been implicated in lung injury in severe viral infection, and CRP is a marker of inflammation.

Predicting survival

Trial data published as a preprint at the start of July give an idea of what the test might be able to achieve. The study recruited 394 eligible Covid-19 patients between March and November 2020 at the emergency departments, wards and intensive care units of six sites in Israel, Germany, and the US. All had PCR-confirmed Covid-19.

Based on these results, patients were assigned a score from 0-100, and using this, were stratified into four categories or bins. The likelihood of severe outcome – defined as ICU admission, non-invasive or invasive ventilation, or death – increased significantly (p<0.001) with higher scores. 

Distribution of patients across score bins
BinScoren Total% Patientsn Severen Non-Severe% Severe (PPV)% Non-Severe (NPV)
480-1007519.0542172.028.0
340-8011629.4467039.760.3
220-407920.1106912.787.3
10-2012431.531212.497.6
 Total394100113281  
PPV = positive predictive value; NPV = negative predictive value. Source: Medrxiv preprint.

The signature produced by Memed’s test also differentiated patients who further deteriorated after having a severe outcome from those who improved (p=0.004).

14-day survival distribution was significantly different between patients scoring less than 40, in bins 1 and 2, and those scoring 40 and above, in bins 3 and 4, with a p value of 0.001.

Kaplan-Meier survival estimates for signature score bins. Source: Medrxiv preprint.

All this points to a test that could be hugely useful in hospitals, not least because it might allow patients to be discharged if they are predicted to have a mild infection. 

But there are reasons for caution, most obviously that the study has not yet been peer reviewed. Moreover, the trial was retrospective: some of the patients enrolled in the trial had already been admitted into the ICU, and had thus already met one of the criteria for severe disease.

Lastly, the study was conducted in the spring, summer and autumn of 2020, before the emergence of Delta and other new coronavirus variants. Newer variants might produce slightly different biomarker signatures, rendering the test less accurate.

Merck spinout Organon bags preterm labor drug ahead of phase 3

 Women’s health specialist Organon has seen enough promise ObsEva's preterm labor prospect ebopiprant to acquire global rights in its first new deal since spinning out of Merck & Co. last month. The deal is back loaded, with $385 million tied to sales milestones and $90 million tied to development and regulatory events but comes with $25 million upfront.

Last month, ObsEva shared phase 2a data on the prostaglandin F2α receptor antagonist in the treatment of spontaneous preterm labor, an area with no approved therapy. The clinical trial linked the addition of oral ebopiprant to atosiban infusion to a reduction in the rate of women who delivered within 48 hours of starting treatment. 

When it disclosed the mid phase data, ObsEva outlined plans to move ebopiprant into a phase 2b/3 clinical trial in the fourth quarter. Organon is yet to provide an update on the plans, noting in its statement that it will “work with the scientific and medical communities and regulatory authorities in major markets ... to advance the clinical development and registration of ebopiprant.”


Picking up the rights to ebopiprant marks an early move in Organon’s efforts to build out its pipeline. The spinoff emerged from Merck with 64 products and the initial focus was more on the growth of approved medicines than new candidates. Organon, having identified more than 140 clinical-phase assets relevant to its focus, planned to kickstart its R&D work through business development.

The deal brings together companies spawned from the two Mercks. ObsEva was founded in response to the closure of Merck KGaA’s site in Geneva almost a decade ago. Since then, ObsEva has taken oral GnRH receptor antagonist linzagolix to the cusp of a filing for approval in uterine fibroids. ObsEva picked up linzagolix from Kissei Pharmaceutical, but ebopiprant was licensed from Merck KGaA.

https://www.fiercebiotech.com/biotech/merck-spinout-organon-bags-preterm-labor-drug-ahead-phase-3