COVID fatality ratio ~ 1% in high-income countries, lower in low-income

The COVID infection fatality ratio is around 1% in high-income countries, but substantially lower in low-income countries with younger populations. 

These are the findings of a new report from the Imperial College London COVID-19 Response Team.

The report reveals that:

• In high income countries, the estimated overall infection fatality ratio (IFR) is 1.15% (95% prediction interval 0.78-1.79).
• In low-income countries, the estimated overall IFR is 0.23% (95% prediction interval 0.14-0.42).
• Risk of death from COVID-19 doubles for approximately every eight years of aging.
• Age-specific IFRs increased from 0.1% and below for individuals under 40 years to greater than 5% among individuals over 80 years.

The infection fatality ratio (IFR) is a key statistic for estimating the burden of COVID-19 and has been continuously debated throughout the current pandemic.

This ratio represents the proportion of deaths among all infected individuals.

This report covers a screening of 175 studies and identified 10 antibody surveys to obtain updated estimates of the IFR using a modeling framework.

This specific framework addresses several limitations of previous estimates which have relied on data early in the epidemic, and have not fully accounted for uncertainty in serological (antibody) test characteristics, and delays from onset of infection to seroconversion (specific antibody becoming detectable in the blood), death, and antibody waning.

The researchers find that age specific IFRs follow a pattern, with the risk of death doubling approximately every eight years of age.

Age-specific IFRs increased from 0.1% and below for individuals under 40 years to greater than 5% among individuals over 80 years

Using these age-specific estimates, the team estimates the overall IFR in a low-income country, with a population structure skewed towards younger individuals, can be expected to be approximately 0.23% (95% prediction interval 0.14-0.42).

In contrast, in high income countries, with a greater concentration of elderly individuals, the report estimates that the overall IFR can be expected to be approximately 1.15% (95% prediction interval 0.78-1.79).

In addition, the report takes seroreversion into account. Seroreversion is the waning of antibodies, leading to a negative serological result in people who were previously infected with coronavirus and would have tested positive at an earlier time.

Not accounting for seroreversion can overestimate the IFR among serosurveys conducted longer after the first wave of the outbreak (such as Italy), because we would underestimate the true number of people who had been infected.

New treatments for COVID-19

Researchers explain that it will be important to continue to monitor the IFR as new treatments are introduced and population immunity increases.

The study did not find a large effect of possible waning of antibodies on our IFR estimates at the times the serosurveys were done, but it will become increasingly important to account for potential declines in antibody levels to avoid overestimating the IFR in future.

In addition, the researchers did not find evidence that the IFR was higher in regions with larger epidemics.

The report publishes estimates for IFR per age group without seroreversion and with seroreversion, in addition to overall IFR for low income countries, low to middle income countries, upper middle-income countries and high-income countries.

The work is presented in the latest report from the WHO Collaborating Center for Infectious Disease Modeling within the MRC Center for Global Infectious Disease Analysis, Jameel Institute (J-IDEA), Imperial College London.

Since the emergence of the new coronavirus (COVID-19) in December 2019, the Imperial College COVID-19 Response Team has adopted a policy of immediately sharing research findings on the developing pandemic.

The code for reproducing these results is available on GitHub.

COVID-19 has high fatality rate

Dr. Lucy Okell, a co-author of the study from Imperial College London, said: "Although the elderly are by far at the highest risk of dying due to COVID-19, the risk in middle age is still high. For example, we estimate that around one in 260 people aged 50-55 years die if infected. We calculated COVID-19 fatality largely based on the first wave of the epidemic in a number of countries and we hope and expect to see some reduction in fatality now due to new clinical knowledge and treatment, but this remains a dangerous virus."

Dr. Nicholas Brazeau, a co-author of the study from Imperial College London, said: "Estimates of the IFR are difficult given the many biases of data collected during an outbreak. Using a statistical model, we partly reconcile these biases and help to explain country-specific differences. Overall, we suggest that age differences will have the largest effects, as regions that were hit hardest by the pandemic did not necessarily have higher IFRs."

Dr. Robert Verity, a co-author of the study from Imperial College London, said: "We know that antibody tests are not perfect, and there may be a considerable number of people who do not mount a detectable antibody response to SARS-CoV-2. However, even when this uncertainty is taken into account, we still find that COVID-19 has a high fatality rate—on the order of 1% for a typical high-income country. This risk is concentrated in older ages, with the probability of dying from COVID-19 doubling approximately every eight years." 

More information: The full report is available online: imperial.ac.uk/mrc-global-infe … 19/covid-19-reports/

https://medicalxpress.com/news/2020-10-covid-deaths-infection-fatality-ratio.html

Coronavirus mutation may have made it more contagious: study

The number of virus strains present in each zip code in Houston during the second wave of COVID-19 cases in summer 2020. Number of strains is represented by a spectrum of colors from blue (0 strains) to red (50 strains). Credit: Houston Methodist/University of Texas at Austin.

A study involving more than 5,000 COVID-19 patients in Houston finds that the virus that causes the disease is accumulating genetic mutations, one of which may have made it more contagious. According to the paper published in the peer-reviewed journal mBIO, that mutation, called D614G, is located in the spike protein that pries open our cells for viral entry. It's the largest peer-reviewed study of SARS-CoV-2 genome sequences in one metropolitan region of the U.S. to date.

The paper shows "the virus is mutating due to a combination of neutral drift—which just means random genetic changes that don't help or hurt the virus—and pressure from our immune systems," said Ilya Finkelstein, associate professor of molecular biosciences at The University of Texas at Austin and co-author of the study. The study was carried out by scientists at Houston Methodist Hospital, UT Austin and elsewhere.

During the initial wave of the pandemic, 71% of the novel coronaviruses identified in patients in Houston had this mutation. When the second wave of the outbreak hit Houston during the summer, this variant had leaped to 99.9% prevalence. This mirrors a trend observed around the world. A study published in July based on more than 28,000 genome sequences found that variants carrying the D614G mutation became the globally dominant form of SARS-CoV-2 in about a month. SARS-CoV-2 is the coronavirus that causes COVID-19.

So why did strains containing this mutation outcompete those that didn't have it?

Perhaps they're more contagious. A study of more than 25,000 genome sequences in the U.K. found that viruses with the mutation tended to transmit slightly faster than those without it and caused larger clusters of infections. Natural selection would favor strains of the virus that transmit more easily. But not all scientists are convinced. Some have suggested another explanation, called "founder's effects." In that scenario, the D614G mutation might have been more common in the first viruses to arrive in Europe and North America, essentially giving them a head start on other strains.

The spike protein is also continuing to accumulate additional mutations of unknown significance. The Houston Methodist-UT Austin team also showed in lab experiments that at least one such mutation allows spike to evade a neutralizing antibody that humans naturally produce to fight SARS-CoV-2 infections. This may allow that variant of the virus to more easily slip past our immune systems. Although it is not clear yet whether that translates into it also being more easily transmitted between individuals.

The good news is that this mutation is rare and does not appear to make the disease more severe for infected patients. According to Finkelstein, the group did not see viruses that have learned to evade first-generation vaccines and therapeutic antibody formulations.

"The virus continues to mutate as it rips through the world," Finkelstein said. "Real-time surveillance efforts like our study will ensure that global vaccines and therapeutics are always one step ahead."

The scientists noted a total of 285 mutations across thousands of infections, although most don't appear to have a significant effect on how severe the disease is. Ongoing studies are continuing to surveil the third wave of COVID-19 patients and to characterize how the virus is adapting to neutralizing antibodies that are produced by our immune systems. Each new infection is a roll of the dice, an additional chance to develop more dangerous mutations.

"We have given this virus a lot of chances," lead author James Musser of Houston Methodist told The Washington Post. "There is a huge population size out there right now."

Several other UT Austin authors contributed to the work: visiting scholar Jimmy Gollihar, associate professor of molecular biosciences Jason S. McLellan and graduate students Chia-Wei Chou, Kamyab Javanmardi and Hung-Che Kuo.

The UT Austin team tested different genetic variants of the virus's spike protein, the part that allows it to infect host cells, to measure the protein's stability and to see how well it binds to a receptor on host cells and to neutralizing antibodies. Earlier in the year, McLellan and his team at UT Austin, in collaboration with researchers at the National Institutes of Health, developed the first 3-D map of the coronavirus spike protein for an innovation that now factors into several leading vaccine candidates' designs.

The researchers found that SARS-CoV-2 was introduced to the Houston area many times, independently, from diverse geographic regions, with virus strains from Europe, Asia, South America and elsewhere in the United States. There was widespread community dissemination soon after COVID-19 cases were reported in Houston.

An earlier version of the paper was posted last month to the preprint server medRxiv. 

More information: Molecular Architecture of Early Dissemination and Massive Second Wave of the SARS-CoV-2 Virus in a Major Metropolitan Area, mBIO, DOI: 10.1128/mBio.02707-20 , mbio.asm.org/content/11/6/e02707-20

https://medicalxpress.com/news/2020-10-coronavirus-mutation-contagious.html

Masks good, ventilation better at cutting COVID risk at indoor events - study

Face masks and limits on numbers are important, but good ventilation technology is the most essential ingredient of all in reducing the risk of the coronavirus spreading at public events indoors, according to a German study.

And researchers say the study’s results have implications for containing the epidemic among the broader population too.

Around 1,500 volunteers with face masks, hand sanitiser and proximity trackers attended an indoor pop-concert in Leipzig in August to assess how the virus spreads in large gatherings.

Researchers simulated three scenarios with varying numbers of spectators and social-distancing standards, and created a computer model of the arena to analyse the flow of aerosols from infected virtual spectators.

“The most important finding for us was understanding how crucial it is to have good ventilation technology. This is key to lowering the risk of infection,” said Stefan Moritz, leader of the RESTART-19 study at the University Medical School in Halle.

The study also found that reducing venue capacity, having multiple arena entrances and seating spectators can have a major impact on the number of contacts people accumulate.

Its recommendations include only allowing food to be eaten at seats, open-air waiting areas, mask-wearing for the concert’s duration and employing stewards to make sure people stick to hygiene rules.

Researchers also developed an epidemiological model to analyse the impact of staging an event on the spread of the virus among the broader population.

They found hygiene measures such as mask-wearing and social-distancing should remain in place as long as the pandemic persists, while seating plans and number of guests should be adjusted based on the incidence of the virus.

“Events have the potential to fuel the epidemic by spreading pathogens, but if a hygiene concept is stuck to then the risk is very low,” said Rafael Mikolajczyk, from Halle University’s Institute for Medical Epidemiology.

The study’s results have not yet been peer-reviewed.

https://www.reuters.com/article/health-coronavirus-germany-concert-int-idUSKBN27E2AY

Covid Spike Proteins Disrupt Blood-Brain Barrier, Up Risk of Neurological Damage

Like a key, SARS-CoV-2 – the virus that causes coronavirus disease 2019 (COVID-19) – attaches to specific molecules on the host cell surface, opening gateways into the cell interior. Viral entry into host cells triggers a prodigious immune response. Much of this battle is waged within the lungs, which explains why many patients hospitalized with COVID-19 have severe respiratory symptoms. 

Respiratory symptoms, however, are only part of the story. Increasing evidence points toward blood vessel inflammation as having a crucial impact on the severity of COVID-19. In addition, anywhere from 30 to 80 percent of patients experience neurological symptoms, including dizziness, headache, nausea, and loss of concentration. These symptoms suggest that SARS-CoV-2 also affects cells of the central nervous system.

While there is no evidence yet that the virus invades the brain, new work by scientists at the Lewis Katz School of Medicine at Temple University shows that the spike proteins that extrude from SARS-CoV-2 promote inflammatory responses on the endothelial cells that form the blood-brain barrier. The study, published in the December print issue of the journal Neurobiology of Disease, is the first to show that SARS-CoV-2 spike proteins can cause this barrier to become “leaky,” potentially disrupting the delicate neural networks within the brain. 

“Previous studies have shown that SARS-CoV-2 infects host cells by using its spike proteins to bind to the angiotensin converting enzyme 2 (ACE2) on the host cell surface,” explained Servio H. Ramirez, PhD, Professor of Pathology and Laboratory Medicine at the Lewis Katz School of Medicine at Temple University and principal investigator on the new study. 

ACE2 is expressed on endothelial cells, which form the inner lining of blood vessels, and serves a central role in mediating different functions of the cardiovascular system. According to Dr. Ramirez, “since ACE2 is a major binding target for SARS-CoV-2 in the lungs and vasculature of other organs in the body, tissues that are behind the vasculature, that receive blood from affected vessels, are at risk of damage from the virus.”

It has been unclear, however, whether ACE2 is also present in the brain vasculature or whether its expression changes in health conditions that worsen COVID-19, such as high blood pressure (hypertension). To find out, the team began by examining postmortem human brain tissue for vascular ACE2 expression, using tissues from individuals without underlying health conditions and from individuals in whom hypertension and dementia had been established. Analyses showed that ACE2 is in fact expressed throughout blood vessels in the frontal cortex of the brain and is significantly increased in the brain vasculature of persons with a history of hypertension or dementia.

The researchers then investigated the effects of the SARS-CoV-2 spike protein on brain endothelial cells in cell culture models. Introduction of the spike protein, particularly a portion designated subunit 1, produced substantial changes in endothelial barrier function that led to declines in barrier integrity. The researchers also uncovered evidence that subunit 2 of the SARS-CoV-2 spike protein can directly impact blood-brain barrier function. “This is of importance because unlike subunit 1, subunit 2 of the spike protein doesn’t bind to ACE2, meaning that a breach to the blood-brain barrier could occur in a manner that is independent of ACE2,” explained postdoctoral fellow and first author on the new report Tetyana P. Buzhdygan, PhD. 

Dr. Ramirez's team further investigated the effects of SARS-CoV-2 spike proteins on tissue-engineered microfluidic constructs designed to mimic a human brain capillary. “The tissue-engineered microfluidic models allow recapitulation of the 3D cyto-architecture and mechanical forces caused by fluid movement, which the vasculature is continuously exposed to,” said Allison M. Andrews, PhD, Assistant Professor in the Department of Pathology & Laboratory Medicine at LKSOM and a co-author on the report. Experiments showed that binding of spike protein subunit 1 increased barrier permeability in the engineered vessel-like constructs.

“Our findings support the implication that SARS-CoV-2, or its shed spike proteins circulating in the blood stream, could cause destabilization of the blood-brain barrier in key brain regions,” Dr. Ramirez said. “Altered function of this barrier, which normally keeps harmful agents out of the brain, greatly increases the possibility of neuroinvasion by this pathogen, offering an explanation for the neurological manifestations experienced by COVID-19 patients.”

The long-lasting effects of altered blood-brain barrier function in the presence of SARS-CoV-2 are unknown. Moreover, as Dr. Buzhdygan explained, “the brain vasculature is extremely branched, so even a small amount of neuroinflammation can be very damaging.” Based on the team's observations of ACE2 expression in the brain, this neurological damage could be extensive in COVID-19 patients with pre-existing health conditions in which the vasculature has already suffered some amount of injury.

It also remains unknown whether the virus can actually get inside neurons or glial cells that lie beyond the barrier. “The viral genome has not been found yet in the specific cell types of the brain,” Dr. Ramirez noted. “The next steps in our work are to look for genomic viral copies in different parts of the brain using autopsy material from COVID-19 cases and to investigate the pathogen’s ability to neuroinvade using different cell culture and tissue-engineered constructs.”

Other key collaborators on the project include Dr. Raghava Potula, Department of Pathology and Laboratory Medicine at LKSOM, and Dr. Peter A. Galie, Department of Biomedical Engineering, Rowan University, New Jersey. 

https://www.templehealth.org/about/news/sars-cov-2-spike-proteins-disrupt-the-blood-brain-barrier-potentially-raising-risk-of-neurological-damage-in-covid-19-patients

Atea, riding interest in COVID-19 drugs, pulls off one of 2020's top biotech IPOs

• Boston biotech Atea Pharmaceuticals, a developer of small molecule drugs for infectious diseases, has raised $300 million in an initial public offering, selling 12.5 million shares at $24 apiece.
• The new funding will help Atea advance an antiviral to treat or potentially prevent COVID-19, as well as a portfolio of other medicines for viruses like Dengue and respiratory syncytial virus. The IPO comes seven days after Roche paid the firm $350 million for partial rights to the COVID-19 antiviral AT-527, which is currently in mid-stage testing and could advance to multiple Phase 3 trials next year.
• Atea's IPO is the fourth largest U.S. biotech stock offering of 2020 and the eighth biggest since the start of 2018, according to a database compiled by Biopharma Dive. Despite an initial slowdown at the beginning of the pandemic, biotech company IPOs are on a record-setting pace this year, reflecting excitement surrounding the industry's role in developing coronavirus treatments and vaccines.

Infectious disease drugs haven't generated nearly the type of interest from IPO investors in recent years as cancer drugs. Of the ten largest offerings in each of the last three years, for example, 14 of those 30 biotechs had an experimental or marketed cancer medicine as their lead program. Just one biotech — AlloVir, which raised $276 million in July — had an infectious disease drug at the forefront of its pipeline, according to Biopharma Dive's IPO database.

The coronavirus pandemic, however, increased interest in both vaccines and infectious disease drugs as the industry scrambled to respond. Shares of Moderna and BioNTech, for instance, have surged to all-time highs because of their progress with experimental coronavirus vaccines. CureVac, another developer of a coronavirus shot, has the second highest market value of any biotech to go public in the U.S. this year. Newcomers AlloVir and Vaxcyte, meanwhile, are among the year's better performers, climbing at least 54% from their offering price as of Thursday's market close.

Atea, then, appears to have gone public at the right time. Formed in 2014, the company was originally developing AT-527 for hepatitis C infections. In May, it was cleared to begin testing the drug, an oral small molecule that interferes with the RNA of several viruses, against SARS-CoV-2.

Atea has since started a Phase 2 trial of 190 patients with moderate disease and one or more risk factors for poor outcomes, with results expected next year.

The pivot to coronavirus research has been lucrative for Atea. Since then, the biotech has raised $215 million in a private funding round, added $350 million in cash through the partnership with Roche and now another $300 million through its IPO.

Atea claims its antiviral is easy to manufacture and less burdensome to administer earlier in a patient's disease course, when stopping the virus from spreading might help prevent the progression of COVID-19. Gilead's approved COVID-19 drug Veklury, by comparison, must be infused over several days, making it more difficult to administer when it might be most effective.

Other, larger companies are also seeking to improve on Veklury. Merck & Co. has an antiviral pill it licensed from Ridgeback Therapeutics in Phase 2 testing. And Pfizer is advancing an intravenously administered antiviral drug.

Engineered antibody drugs from Regeneron, Eli Lilly and others could also play a role in treating COVID-19 patients before they need to be hospitalized.

The Roche partnership, announced just a week before Atea's IPO, has given the company the backing to run a broad development program. Positive results in the ongoing mid-stage trial could lead to two Phase 3 tests in non-hospitalized patients and those newly exposed to infection.

In addition to the $350 million upfront, Roche could pay Atea another $650 million more under the agreement, with $330 million tied to regulatory development milestones. In return, Roche secured international rights to AT-527, and will help manufacture and distribute the drug overseas.

Cell therapy developer SQZ Biotechnologies also went public on Friday, raising $71 million. Sixty three biotechs — which Biopharma Dive defines as companies developing human medicines — have raised more than $50 million through a U.S. IPO this year.

https://www.biopharmadive.com/news/atea-pharma-prices-ipo-covid-19-drug/588101/