Adaptation of muscle tissue to aerobic exercise alters the metabolism of muscle stem cells, helping them recover from injury. Credit: Phablo Sávio Abreu Teixeira
Researchers at the University of São Paulo (USP) in Brazil have discovered that the muscle regeneration promoted by aerobic exercise is mediated by changes in oxygen consumption by satellite cells, also known as skeletal muscle stem cells. The discovery is expected to be used to help people recover from injury and combat the loss of muscle mass associated with aging.
30 october 2020--Previous research showed that weight lifting and other kinds of strength training increase the number ofsatellitecells. Inaerobic exercise, muscle tissue is known to increase its capacity but the repair mechanisms associated with satellite cells had not previously been studied.
The USP group found that aerobic exercise boosted the growth of satellite cells and that significant metabolic alterations lay behind the phenomenon. The study was conducted during the Ph.D. research of Phablo Sávio Abreu Teixeira, with the support of a scholarship from São Paulo Research Foundation—FAPESP .
"We noted reduced oxygen consumption in satellite cells, whereas exercise raised the demand for oxygen in all other muscle tissue. This is the first time anyone has managed to observe how aerobic exercise influences mitochondrial metabolism in these cells and how this affects muscle regeneration," Abreu told.
To understand the mechanism, Abreu conducted a number of experiments with animals at USP's Chemistry Institute under the supervision of Professor Alicia Kowaltowski, who has continuously studied mitochondria since the 1990s and is affiliated with the Center for Research on Redox Processes in Biomedicine (Redoxome), one of the Research, Innovation and Dissemination Centers (RIDCs) supported by FAPESP.
The findings are reported in an article published in Journal of Cachexia, Sarcopenia and Muscle. "We discovered at least part of the mechanism that led to improved muscle regeneration. Fuller knowledge is the first step to being able to intervene in the regeneration process in future," Kowaltowski said.
Several stages
The study was performed in stages, comprising experiments with mice divided into two groups. One group was submitted to a battery of aerobic exercises on a treadmill for five weeks, while the control group remained sedentary.
At the end of this period the researchers tested the mice to see if the exercise had in fact improved their aerobic capacity. In the next stage, muscle tissue in both groups was injured and its regenerative capacity was analyzed.
"First we found that the trained animals had more recently formed muscle fibers, as well as less deposition of fibrous tissue and fewer signs of inflammation," Abreu said. "These findings confirmed that muscle tissue in the trained animals had in fact been better repaired."
After concluding that muscle repair capacity had improved, the researchers investigated the alterations to satellite cells isolated from the animals submitted to the exercise program. Proteins that regulate cell quiescence and activation, enabling self-renewal or differentiation, were augmented in these cells. "They also showed that differentiation had been inhibited, confirming our findings," Abreu said.
Satellite cells are responsible for muscle tissue regeneration and preservation, he explained, but to perform this function they have to remain quiescent in order to maintain tissue homeostasis. Throughout the subject's life, they are activated by injury or by wear-and-tear due to exercise. Some then differentiate into tissue cells, while others self-renew, giving rise to new satellite cells so that the cycle can continue.
"These cells are constantly activated, but over time they can become fatigued and stop self-renewing. This is what happens in muscular dystrophy and diseases involving loss of muscle mass such as cachexia or sarcopenia," Abreu said. "If we have more renewed cells, it means we have more cells capable of regenerating tissue."
In addition to concluding that exercise maintained muscle tissue regeneration capacity and contributed to recovery from injury, the researchers measured satellite cell oxygen consumption in search of an explanation for the phenomenon. "Surprisingly we found them to consume less oxygen, as if they had become more economical," Abreu said.
The findings refuted the researchers' initial hypothesis, which was that because aerobic exercise enhanced muscular oxidative capacity and satellite cells are anchored to the surface of skeletal muscle tissue (hence the name satellite), the oxidative capacity of satellite cells also ought to increase.
The role of mitochondria
Cellular respiration, the process by which chemical energy is released during the oxidation of organic molecules, occurs in mitochondria, organelles thought until recently to be responsible only for energy production. "Scientists have increasingly discovered the extent to which mitochondria are involved in various other processes," Kowaltowski said.
To confirm that mitochondrial oxygen consumption did indeed explain satellite cell self-renewal, Kowaltowski and Abreu performed two more experiments, using drugs to mimic the effect of reduced oxygen consumption on cells grown in the laboratory, and transplanting cells from exercised mice into sedentary mice. The reduction in oxygen consumption was indeed found to enhance satellite cell self-renewal. The rate of repair did not change in transplanted cells, but inflammation diminished, suggesting enhanced muscle recovery.
The researchers now plan to investigate the effects of reduced mitochondrial oxygen consumption and the pathways involved in satellite cell self-renewal. "In short, we need to understand why inhibition of cellular respiration enhances muscle recovery," Kowaltowski said.
It may be possible to replicate this phenomenon in future to treat age-related loss of muscle mass or the same problem resulting from cancer. The process is currently irreversible in many cases.
More information: Phablo Abreu et al, Satellite cell self‐renewal in endurance exercise is mediated by inhibition of mitochondrial oxygen consumption, Journal of Cachexia, Sarcopenia and Muscle (2020). DOI: 10.1002/jcsm.12601
Provided by FAPESP
Monday, October 26, 2020
Coronavirus: Which treatments work and which don't?
Donald Trump's brief stay in hospital in early October raised awareness—once again—of the variety of treatments being investigated for COVID-19.\
26 october 2020--Some therapies the president received have been on the radar for a long time, others arenewto the list of potential treatments. Notably, drugs such as hydroxychloroquine that were once widely touted as a treatment weren't used, having beenshown to be ineffective.
Thanks to the Recovery trial, based at Oxford University, we're finding out more all the time about which therapies are useful. So, while the below won't be the definitive answer on how to treat COVID-19, nine months into the pandemic, this is what we know so far about what works.
Corticosteroids
As early as June 2020, there was evidence that dexamethasone, a cheap steroid, could reduce the risk of death in severely ill patients with COVID-19 by up to a third.
Later studies showed a similar reduction in death with another common steroid, hydrocortisone. It may be that these drugs are effective because they suppress severe inflammation in the lungs.
Interferon beta
We've known for some time that patients who don't produce enough interferon beta are susceptible to severe lung damage caused by viral infections, as it plays a key role in immunity to viruses.
In a small clinical trial, inhaled interferon beta reduced hospitalized COVID-19 patients' risk of developing severe respiratory disease by 79%. Patients treated with interferon beta were also twice as likely to recover fully over the 16-day treatment period.
While promising, these results need to be confirmed in larger studies comparing the drug with other treatments. Interferon beta is also being investigated in combination with other therapies, including remdesivir.
This antiviral drug, which stops certain viruses – including coronaviruses—from reproducing their genetic material, is already temporarily licensed in roughly 50 countries for treating COVID-19 patients with pneumonia who need supplemental oxygen.
The drug initially underwent trials for use against COVID-19 in China, but because the outbreak there was soon brought under control, not enough patients were enrolled to produce statistically significant results. Subsequent trials in the US were more positive, showing that it could shorten the recovery time of hospitalized COVID-19 patients with lower respiratory tract infections.
Other studies have not added much: COVID-19 patients with moderate pneumonia put on a five-day course of remdesivir fared better than those receiving standard care, but those put on a ten-day course didn't. This led the authors of the study to question the significance of the results. Disappointingly, a recent WHO study also showed no improvement in death rates or recovery time for hospitalized patients.
Nevertheless, remdesivir is the only antiviral drug shown to be effective against COVID-19. It is now part of most countries' standard treatment packages, despite the fairly weak evidence behind it.
Tocilizumab
Monoclonal antibodies—antibodies that have been artificially generated to target certain molecules—are already used to treat inflammatory diseases such as rheumatoid arthritis. One of these is tocilizumab, which blocks the actions of an inflammatory protein called interleukin 6.
In the US, tocilizumab is licensed for treating cytokine release syndrome – a severe side-effect of some cancer treatments that is similar to the serious inflammatory effects of COVID-19. Studies of tocilizumab's impact on COVID-19 have offered mixed results. Some have suggested that it reduces the likelihood of hospitalized patients needing mechanical ventilation, and it reduces the death rate of patients who do require ventilation. Others have shown that the drug has no effect on patient outcomes.
However, those studies were too small to allow for definite conclusions. One large observational study found positive effects, but other factors (such as differences in age, underlying health conditions and other treatments) may have influenced the results.
Larger, more robust studies are needed. Tocilizumab is now being investigated in Recovery and in another large randomized controlled trial in the US.
Convalescent plasma
Another antibody-based approach is to give patients blood plasma from people who have recovered from COVID-19. This plasma will contain natural antibodies produced by the donor during infection.
Convalescent plasma was authorized in the US for emergency use in COVID-19 patients in August, despite very limited evidence of benefit. Now that it has been authorized, doctors in the US aren't obliged to report on its effects, which has made it difficult to gather good data on its effectiveness. Large randomized controlled trials are needed.
REGN-COV2
REGN-COV2 is a mixture of two monoclonal antibodies directed against specific regions of the coronavirus's spike protein, which is the key structure that it uses to enter our cells.
Animal studies have shown promising results, but they can't reliably predict REGN-COV2's effects in humans. Its maker has requested emergency use authorisation in the US which, as with convalescent plasma, may make collecting reliable data more difficult. However, REGN-COV2 is also under investigation in the Recovery trial.
A rival product—LY-CoV555/LYCoV016—is under similar consideration for emergency use. There's very limited data on its benefits, but it too is being tested in a large clinical trial.
Other possible treatments
The one other treatment included in the Recovery trial is the antibiotic azithromycin. Given to treat a variety of infections, it has anti-inflammatory and antibiotic properties, and may also have antiviral actions. Trials so far show that there's no benefit when it's given to patients already admitted to hospital, but the Recovery trial is testing its effect during earlier stages of COVID-19.
Despite early concerns that certain blood pressure drugs might increase the risk of COVID-19, large studies have shown that they are safe. Studies are now investigating whether they might have some protective effect.
Finally, several studies have shown that the antimalarial drug hydroxychloroquine and the antiviral combination lopinavir/ritonavir are ineffective against COVID-19. Derivatives of another (plant-derived) antimalarial drug, artemisinin, have antiviral activity and become concentrated in the lungs. In theory, they could have clinical benefits, but there's no data yet to show this.
Provided by The Conversation
Sunday, October 25, 2020
FDA approves first COVID-19 drug: antiviral remdesivir
by Marilynn Marchione
In this March 2020 photo provided by Gilead Sciences, rubber stoppers are placed onto filled vials of the investigational drug remdesivir at a Gilead manufacturing site in the United States. On Thursday, Oct. 22, 2020, the U.S. Food and Drug Administration has approved the first drug to treat COVID-19: remdesivir, an antiviral medicine given through an IV for patients needing hospitalization. The drug, which California-based Gilead Sciences Inc. is calling Veklury, cut the time to recovery by five days on average in a large study led by the U.S. National Institutes of Health. (Gilead Sciences via AP)
U.S. regulators on Thursday approved the first drug to treat COVID-19: remdesivir, an antiviral medicine given to hospitalized patients through an IV.
25 october2010--The drug, which California-based Gilead Sciences Inc. is calling Veklury, cut the time to recovery by five days—from 15 days to 10 on average—in a large study led by the U.S. National Institutes of Health.
It had been authorized for use on an emergency basis since spring, and now becomes the first drug to win full Food and Drug Administration approval for treating COVID-19. President Donald Trump received it when he was sickened earlier this month.
Veklury is approved for people at least 12 years old and weighing at least 88 pounds (40 kilograms) who are hospitalized for a coronavirus infection. For patients younger than 12, the FDA will still allow the drug's use in certain cases under its previous emergency authorization.
The drug works by inhibiting a substance the virus uses to make copies of itself. Certain kidney and liver tests are required before starting patients on it to ensure it's safe for them and to monitor for any possible side effects. And the label warns against using it with the malaria drug hydroxychloroquine, because that can curb its effectiveness.
"We now have enough knowledge and a growing set of tools to help fight COVID-19," Gilead's chief medical officer, Dr. Merdad Parsey, said in a statement.
The drug is either approved or has temporary authorization in about 50 countries, he noted.
Its price has been controversial, given that no studies have found it improves survival. Last week, a large study led by the World Health Organization found the drug did not help hospitalized COVID-19 patients, but that study did not include a placebo group and was less rigorous than previous ones that found a benefit. The FDA's approval statement noted that, besides the NIH-led one, two other studies found the drug beneficial.
Gilead charges $2,340 for a typical treatment course for people covered by government health programs in the United States and other developed countries, and $3,120 for patients with private insurance. The amount that patients pay out of pocket depends on insurance, income and other factors.
So far, only steroids such as dexamethasone have been shown to cut the risk of dying of COVID-19. The FDA also has given emergency authorization to using the blood of survivors, and two companies are currently seeking similar authorization for experimental antibody drugs.
2020 The Associated Press.
Thursday, October 22, 2020
Pastoral care shown to support older people at risk from COVID-19
by Staffordshire University
Volunteer Pastoral Agents provide a range of support to isolated elderly people in Brazil. Credit: Staffordshire University
Volunteers from the Catholic Church in Brazil helped to mitigate the impact of COVID-19 among the elderly, a new study shows.
22 october 2020--Peter Kevern, Professor Values in Health and Social Care at Staffordshire University, partnered with The Pontifical Catholic University of São Paulo to carry out the study which looked at the contribution of the Pastoral da Pessoa Idosa (PPI) program in Brazil.
And Professor Kevern suggests that the study findings may well assist the UK whose social care system has been severely tested during the pandemic.
PPI is a volunteer movement that uses the organizational structure of the Catholic Church of Brazil to provide a range of support to isolated elderly people right across the country. Anyone can be a volunteer in their community or in their building to support older people through the scheme.
Last year, approximately 25,000 'Pastoral Agents', provided home visits, personalized practical help and support to 164,000 older people. Pastoral Agents are also trained to measure and report indicators of wellbeing such as fragility, fluid intake, annual flu vaccination, and to refer people to government agencies.
Professor Kevern explained: "Brazil has a fragile social infrastructure so there are many unmet social needs to be addressed. The aim of this research was to estimate the contribution of the PPI program to the health and social support of older people. Almost 4,000 volunteers were interviewed over a one-week period using a 21-item telephone questionnaire to evaluate the impact of its activities during 'normal' times, and how they changed to address the challenge of COVID-19."
The arrival of COVID-19 led to a temporary stop in visits following recommendations by the World Health Organization but efforts to provide material and immaterial support and remote monitoring by phone calls were encouraged through a campaign.
Professor Kevern added, "The striking thing about PPI was how quickly and flexibly the movement responded to the pandemic. Innumerable initiatives were undertaken by volunteers such as making masks, collecting food and other donations in order to make the lives of the elderly people monitored by the PPI better throughout Brazil. This was especially important for those who live in places far from urban centers, or in peripheries of large cities where access to social and health services is limited."
"I think we have some lessons to learn from PPI. In the UK, our social care system is also very fragile, and the experience of the early days of the lockdown, where older people were sent into care homes from hospital untested and many died from COVID-19, shows that the present system can't cope. Voluntary movements like PPI, supported and trained by the government, may be indispensable at times of population-level stress like a pandemic. There are some challenges coming down the line—possible future pandemics, Brexit, climate change—when again we might need to adjust to an unstable and rapidly-changing situation. Organizations like PPI might be part of the answer."
More information: Peter Kevern et al, The Contribution of Church-Based Networks to Social Care in the Coronavirus Pandemic and Beyond: The Case of Pastoral da Pessoa Idosa in Brazil, Religions (2020). DOI: 10.3390/rel11100486
In March, at the start of the COVID-19 pandemic, there was a consensus among health care providers and public health officials that a vaccine that provided complete immunity to SARS-CoV-2, the virus that causes COVID-19, would effectively end the pandemic.
21 october 2020--At the time, experts suggested that the development of a safe and effective COVID-19vaccinecould be accomplished in 12 to 18 months, even though vaccine development typically takes about 10 years. (In fact, the fastest vaccine ever developed—a mumps vaccine—still took four years.)
Yet, because of the urgency created by this global pandemic—and the serious illness and death rates associated with COVID-19—preclinical and clinical trials to test the efficacy and safety of COVID-19 vaccine candidates are happening at a rapid, almost frenetic, pace.
That leaves many Americans concerned about how safe a COVID-19 vaccine will be. According to a survey conducted by the Pew Research Center, the number of Americans who planned to get a COVID-19 vaccine has fallen from 72% in May to just 51% in September. What's more, according to the report, when asked about the pace of the vaccine approval process, 78% say their primary concern "is that it will move too fast, without fully establishing safety and effectiveness."
This fear was stoked in early September, when the Centers for Disease Control and Prevention (CDC) told state officials across the country to prepare for the distribution of a COVID-19 vaccine by November 1, just days before the presidential election. Whether this vaccine would be granted official licensure from the Food and Drug Administration (FDA) or be released by an emergency use authorization (EUA)—a tool by which the FDA can authorize use of medical products, including vaccines, that have not completed clinical trials—is unclear.
Nevertheless, the announcement raised concerns about undue political influence over the release of a COVID-19 vaccine, leading the chief executives of nine pharmaceutical companies to publicly pledge to "make the safety and well-being of vaccinated individuals" their "top priority," while stating that they would only seek approval of a vaccine if a Phase 3 trial establishes that it is both safe and effective. The pledge aimed to reassure the public that any vaccine that is approved will have passed all safety and efficacy checks.
But many remain skeptical—and confused.
With this in mind, we sat down with Saad Omer, MBBS, Ph.D., MPH, the director of the Yale Institute for Global Health. Dr. Omer leads a World Health Organization (WHO) group that evaluates the safety of COVID-19 vaccines.
He provided answers to our questions about COVID-19 vaccine development.
This interview—taken from three conversations—has been edited for length and clarity.
Q. Why do we need a COVID-19 vaccine?
A. Because it is the end game. If you want to resume the normal activities of life—eat at restaurants, go to theaters, all of the other things that you want to do without taking drastic actions—then you need a "population level" of immunity.
And there are two ways to achieve this. One is to let the whole population—or a large number of people—get infected with COVID-19. This would result in a great deal of mortality, a lot of people dying, which is obviously undesirable. The other way is through vaccination.
Q. Do you know if the vaccine will be similar to the annual flu vaccine, where we need to get it every year, or if it might provide immunity for life, like with the MMR vaccine?
A. We don't know yet. But, I would be surprised if it's a year-to-year vaccine. I expect the protection to last for at least a few years. Beyond that, we'll have to see.
Q. COVID-19 vaccines are being developed on a compressed timeline. Why won't that compromise safety?
A. Well, so far the speed is being gained due to process efficiencies rather than by cutting corners or eliminating the actual steps from development.
Q. What's an example of a process efficiency in this case?
A. Steps that are usually done sequentially are taken in parallel, while getting to the same end result of having good data. For example, running combined Phase 1 and Phase 2 trials, doing animal studies in parallel with human studies, doing quick target identification. And having vaccine development manufacturing facilities ready even before a vaccine is finalized.
Q. But if you're running combined trial phases, isn't there a greater risk for the people enrolled in a later-phase trial without first knowing the results of the earlier-phase trial?
A. No, there's really just a subtle difference in how the trials are run. If the trials were separate, you would publish the full data, and then recruit a new set of participants. For a combined trial, the data and safety monitoring board would look at the interim data and determine whether it's still worth continuing the trial. So, you're not stopping it and then taking a look. You're taking a look on an ongoing basis.
That means that whenever their Phase 1 and 2 trials are combined, for example, independent data review committees monitor the safety data in a blinded fashion. And these committees are appointed—usually, they are professors or other experts who are not related to the trial. They work directly with study statisticians, and the principal investigators of the study are not privy to those meetings. So, the committee monitors the trial on an ongoing basis. If they see concerning trends in the data, they can stop or pause the trial and then re-evaluate it, as necessary.
Q. Which is what happened with the AstraZeneca and Johnson & Johnson trials recently.
A. Yes.
Q. Many people are concerned about the shortened timeline of the Phase 3 trials. If those typically last 6 to 8 months, for example, but a vaccine is approved by November—in only a few months—how can we be confident that we're not missing data on side effects and efficacy?
A. The efficacy part is easier to answer. Essentially, there are two ways of running the trials: You can follow up with trial participants for a longer period of time, or you can have what are called "event-driven trials," where you enroll a ton of people so you can get events [people getting sick with COVID-19] from a large number of people. The event-driven trials are one way to find efficiency.
Q. How does that translate into an efficiency?
A. With these trials, the statistical information rather than the sample size is set in advance. In this case, this means that the trial enrollment size depends on the rate of events that have to occur to ensure the vaccine has an efficacy rate of at least 50%.
So, if you need 130 or 150 events to happen to confirm the vaccine's efficacy rate, you might enroll 30,000 participants. But, sometimes your events are accrued faster—if there's more disease in the community, as there would be in a pandemic, or if the vaccine isn't working as well, or a combination of both. The faster accruals mean you reach your events faster, which can save a significant amount of time.
Q. What about safety?
A. Safety comes down to oversight and transparency. Because this is a public health emergency, independent committees would be looking at the data earlier on in the process. That's where two committees, a trial DSMB [data and safety monitoring board] and what is called a VRBPAC [Vaccines and Related Biological Products Advisory Committee]—a standard committee that looks at the data before approval authorization licensure—come into play. The FDA commissioner has announced that they're going to have a meeting at the end of October—and that it will be open, meaning they recognize that transparency is important.
What's more, the FDA recently said that they're going to need to see at least two months of median follow-up safety data from vaccine manufacturers before they would even consider an EUA, and that's a good thing; it's more stringent criteria.
And there are other independent safeguards in place. Professional organizations like the American Academy of Pediatrics can issue or withhold their endorsement statements. If the data are not sufficient, they would point to that.
Also, from a data perspective, there is a process called post-marketing surveillance, where vaccines are followed carefully to see if there are early signals of adverse events. But even before that, there is some basic follow up that a large number of people will have to have to give us confidence in the safety of the vaccine. So, we as public health experts will want access to that data.
Q. Circling back to the condensed timeline question, is it fair to say that if there are no adverse events seen in these Phase 3 trials—however shortened they may be—we can assume there will likely be no long-term negative effects?
A. Well, we know that most of the adverse events that happen tend to cluster early on, usually within the first couple of months, so yes. And the idea is to be preemptive—to make sure that you're ready to detect any signals and mitigate and modify your recommendations.
So, you follow trial participants for anything that looks like disease or other things that are of concern, like autoimmune reactions, among others. If the committee thinks that there are no minimal or serious adverse events, it is reassuring.
But another consideration is that enough follow up has occurred so that we can say with confidence that it is okay to start vaccinating people. It's a risk–benefit situation, and the benefits should substantially outweigh the risks. Because it's a pandemic, we don't have the luxury of waiting years and years.
Q. We're testing new platforms that have not been used for approved vaccines before. You mentioned that, for traditional vaccines, the adverse events cluster in the first couple of months, which would alleviate fears about a compressed timeline. Do we know the same to be true for these new platforms?
A. We don't know, but they are new platforms, not new biology. They're using nature's own mechanisms to induce immunity. And we have experience from the early-phase trials. It's also important to recognize the distinction between serious adverse events and a subcategory of early events that are not serious and are fairly common for vaccines—things like injection pain or fever, which happen within one or two days of receiving the vaccine and then resolve. Those aren't typically related to serious events.
Q. Is it possible to know which vaccine candidates are more promising over the others?
A. No, not at this point. We have a broad category of the things that are in advanced stages. They all show promise, but which one of them would be more successful or more advanced and more efficacious remains to be seen.
Q. Why is representation of minorities—who have been disproportionately affected by COVID-19—in vaccine trials important? People with risk factors like obesity or advanced age might react differently to a vaccine, but it seems like we don't yet know if there is a genetic or biological link between these groups and severe cases of COVID-19.
A. We don't know about the genetic part of it. But we do know that there's a huge racial component to it. You need generalizable safety and efficacy data in all populations, but especially in the ones that are disproportionately impacted, because of biological, as well as social reasons—a vaccine's impact can vary. So, I couldn't overemphasize the importance of enrolling the populations that are most impacted by the outbreak; they should be reasonably well-represented.
Q. The FDA has said that if a COVID-19 vaccine has an efficacy rate of at least 50%, they will approve it. 50% is also the minimum efficacy rate on the WHO target product profile, although they believe 70% is ideal. Can you reconcile that difference?
A. It speaks to why there are independent processes so that different bodies like the WHO or the U.S. government can arrive at their desired percentage—and often they will converge. But, the WHO is dealing with a larger population, where they need a more efficacious vaccine to provide broader immunity. I think it's reasonable for the U.S. to say that 50% is not ideal, but it's good enough.
Q. Would 50% be good enough to give us herd immunity?
A. It depends on the immunization rates and who gets vaccinated. People tend to think of herd immunity as binary—yes or no. But in these kinds of situations, even with a vaccine that is 50% effective, you start to see what are called "indirect effects" where you slow down the outbreak without extinguishing it.
Q. So we would still need to take precautions, like wear masks, wash our hands, and practice social distancing.
A. Yes. But it's important to remember that 50% is the floor that the FDA has set—the minimum. If there is an approved vaccine that is more effective than 50%, then there's more flexibility in terms of easing up restrictions. So, we shouldn't assume that it will be a 50% effective vaccine just because that's the FDA's minimum requirement for approval.
Q. Is there a risk, then, that if we have a vaccine that's at or around 50% effective, it will slow the development of a vaccine that is 100% effective?
A. Well, if you have a 50% effective vaccine that is widely used, then it becomes what's called the "standard of care." So, for ethical reasons, rather than giving a placebo to trial participants in the control arm, you have to give them the 50% effective vaccine.
Ultimately, it might impact future trial sizes—depending on if you're looking for efficacy and disease events (they would be larger) or instead for the type and level of immune response associated with protection (they might be smaller)—and recruitment efforts. But I don't see it as a concern.
Q. So, if a vaccine that is 50% effective doesn't completely prevent infection, could it offer protection against severe illness?
A. Yes, that's the main end point. The trials are not designed to measure the impact of the vaccine on transmission; they are designed to look at disease outcomes. So, it may very well happen that this is not stopping or reducing transmission, but instead reducing disease.
Q. Will people who have been infected with and recovered from the coronavirus need to get a vaccine?
A. I'm hoping to study that question myself, but at this point we don't know yet.
Q. In September, the FDA said it may approve a vaccine before Phase 3 trials are complete. This came on the heels of what some considered a questionable decision regarding the agency's EUA on convalescent plasma and its claims about it (which the agency eventually walked back). What do you make of these events, and what can we do to protect ourselves?
A. That's a really good question. In terms of convalescent plasma, experts raised their concerns vociferously. There was a lot of pushback. Most experts were okay with the EUA; they were uncomfortable with the over-interpretation of the data.
Recently, the FDA has insulated itself; they've sent good signals about following the accepted, mainstream process. The kinds of evidence they would expect to make decisions on are very encouraging. The signs are good that despite any political pressure, the career folks at the FDA are likely to follow the by-the-book procedures.
But, basically, the general public doesn't have to interpret this data on their own. Look at the people who have been studying this problem—and not through a Google search—look at the actual original researchers who have served on government advisory panels. See what they're saying. Similarly, watch for how the data is shared, how they're presented, and look for transparency.
Q. Is there a hopeful note you'd like to leave on?
A. The initial studies have shown that there could be a reasonable vaccine for this virus. I haven't seen any major dead ends in vaccine development so far. The animal studies and the data from humans in early trials are encouraging, though not definitive in terms of protection.
In other words—it's like we're going to be taking a long trip, and we're finding reasonable weather in the first part of the journey.
Provided by Yale University
Tuesday, October 20, 2020
Coronavirus survives on skin five times longer than flu: study
SARS-CoV-2 (shown here in an electron microscopy image). Credit: National Institute of Allergy and Infectious Diseases, NIH
The coronavirus remains active on human skin for nine hours, Japanese researchers have found, in a discovery they said showed the need for frequent hand washing to combat the COVID-19 pandemic.
20 The pathogen that causes the flu survives onhuman skinfor about 1.8 hours by comparison, said the study published this month in theClinical Infectious Diseasesjournal.
"The nine-hour survival of SARS-CoV-2 (the virus strain that causes COVID-19) october 2020--on human skin may increase the risk of contact transmission in comparison with IAV (influenza A virus), thus accelerating the pandemic," it said.
The research team tested skin collected from autopsy specimens, about one day after death.
Both the coronavirus and the flu virus are inactivated within 15 seconds by applying ethanol, which is used in hand sanitisers.
"The longer survival of SARS-CoV-2 on the skin increases contact-transmission risk; however, hand hygiene can reduce this risk," the study said.
The study backs World Health Organization guidance for regular and thorough hand washing to limit transmission of the virus, which has infected nearly 40 million people around the world since it first emerged in China late last year.
Journal information: Clinical Infectious Diseases
Friday, October 16, 2020
COVID-19 trial finds remdesivir, hydroxychloroquine, lopinavir and interferon don't save lives
by World Health Organization (WHO)
Credit: Unsplash/CC0 Public Domain
In just six months, the world's largest randomized control trial on COVID-19 therapeutics has generated conclusive evidence on the effectiveness of repurposed drugs for the treatment of COVID-19.
16 october 2020--Interim results from the Solidarity Therapeutics Trial, coordinated by the World Health Organization, indicate that remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon regimens appeared to have little or no effect on 28-day mortality or the in-hospital course of COVID-19 among hospitalized patients.
The study, which spans more than 30 countries, looked at the effects of these treatments on overall mortality, initiation of ventilation, and duration of hospital stay in hospitalized patients. Other uses of the drugs, for example in treatment of patients in the community or for prevention, would have to be examined using different trials.
The progress achieved by the Solidarity Therapeutics Trial shows that large international trials are possible, even during a pandemic, and offer the promise of quickly and reliably answering critical public health questions concerning therapeutics.
Newer antiviral drugs, immunomodulators and anti-SARS COV-2 monoclonal antibodies are now being considered for evaluation.
The results of the trial are under review for publication in a medical journal and have been uploaded as preprint at medRxiv.
More information: undefined undefined et al. Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results, (2020). DOI: 10.1101/2020.10.15.20209817
Provided by World Health Organization (WHO)
Coronavirus reinfections are real. Here's what that means for controlling the pandemic
by Marie McCullough, The Philadelphia Inquirer
Credit: Pixabay/CC0 Public Domain
The first confirmed case of an American who got COVID-19 twice adds to scant but mounting evidence that people can be reinfected with the coronavirus—and get sicker than during the initial bout.
15 october 2020--The 25-year-old Nevada man, who had no known immune problems, got a mild case of COVID-19 in April. About a month later, he was diagnosed again and needed hospitalization and oxygen, according to the report published Monday inLancet Infectious Diseases.
The authors say at least three other confirmed cases have been published worldwide, including the first in Hong Kong barely two months ago. But the COVID-19 Reinfection Tracker of BNO News, an international news agency headquartered in the Netherlands, lists the Nevada case and 22 others, including one death.
To confirm reinfection, DNA sequencing of respiratory samples must reveal two slightly different variants of the virus, indicating the second infection was not just a remnant or reactivation of the first. That kind of analysis rarely occurs, partly because of the cost, but mostly because respiratory samples used for diagnosis are rarely preserved for later genetic analysis.
Although it is hard to say how rare reinfection may be, it complicates questions about the strength and length of natural protective immunity; the role of vaccines in strengthening immunity; and hopes for "herd immunity." Community-wide, or herd, protection happens when enough people become immune, either through infection or vaccination, to make disease spread unlikely.
"Reinfection cases tell us that we cannot rely on immunity acquired by natural infection to confer herd immunity," Akiko Iwasaki, an immunologist at Yale University School of Medicine, wrote in a commentary accompanying the new study. "Herd immunity requires safe and effective vaccines and robust vaccination implementation."
But the study authors, led by University of Nevada biostatistician Richard L. Tillett, point out that we may not be able to rely on vaccines for complete protection, either, "with influenza regularly showing the challenges of effective vaccine design." Recent studies show that the seasonal flu shot reduces the risk of illness by 40% to 60%.
Infection with certain viruses, such as the measles, causes lifelong immunity. In contrast, seasonal coronaviruses that cause common colds confer only short-lived protection, perhaps three or four months. Then, the disease-fighting antibodies made by the immune system to fight the invader fade away.
If the new coronavirus, which emerged 10 months ago in China, confers only limited immunity, then a vaccine might strengthen this protection by revving up other parts of the immune system. Some vaccines now in development have been shown to activate T cells, a more complex line of defense than antibodies.
Since the new coronavirus has mutated to have slightly different variations that can cause reinfection, does that mean we need a vaccine for each variant?
Iwasaki believes the answer is no because, at least so far, reinfected people have had an immune response to the second infection, suggesting the virus has not developed a way around immune defenses.
"There is currently no evidence that a variant has emerged as a result of immune evasion," she wrote. "For now, one vaccine will be sufficient to confer protection against all circulating variants."
The authors conclude with a sobering observation: Without "comprehensive genomic sequencing" of positive cases around the world, detection of cases of reinfection will be very limited. That, in turn, will "exacerbate the poor surveillance efforts ... not only to diagnose COVID-19, but also to" track genetic changes in the virus.
Journal information: Lancet Infectious Diseases
Wednesday, October 14, 2020
New blood test predicts which COVID-19 patients will develop severe infection
by RCSI University of Medicine and Health Sciences
Professor Gerry McElvaney (left), the study’s senior author and a consultant in Beaumont Hospital, and Professor Ger Curley (right) stand in front of the RCSI Education and Research Centre in Beaumont Hospital, Dublin. Credit: RCSI University of Medicine and Health Sciences
Scientists have developed, for the first time, a score that can accurately predict which patients will develop a severe form of COVID-19.
14 october 2020--The study, led by researchers at RCSI University of Medicine and Health Sciences, is published inThe Lancet's translational research journalEBioMedicine.
The measurement, called the Dublin-Boston score, is designed to enable clinicians to make more informed decisions when identifying patients who may benefit from therapies, such as steroids, and admission to intensive care units.
Until this study, no COVID-19-specific prognostic scores were available to guide clinical decision-making. The Dublin-Boston score can now accurately predict how severe the infection will be on day seven after measuring the patient's blood for the first four days.
The blood test works by measuring the levels of two molecules that send messages to the body's immune system and control inflammation. One of these molecules, interleukin (IL)-6, is pro-inflammatory, and a different one, called IL-10, is anti-inflammatory. The levels of both are altered in severe COVID-19 patients.
Based on the changes in the ratio of these two molecules over time, the researchers developed a point system where each 1-point increase was associated with a 5.6 times increased odds for a more severe outcome.
"The Dublin-Boston score is easily calculated and can be applied to all hospitalized COVID-19 patients," said RCSI Professor of Medicine Gerry McElvaney, the study's senior author and a consultant in Beaumont Hospital.
"More informed prognosis could help determine when to escalate or de-escalate care, a key component of the efficient allocation of resources during the current pandemic. The score may also have a role in evaluating whether new therapies designed to decrease inflammation in COVID-19 actually provide benefit."
The Dublin-Boston score uses the ratio of IL-6 to IL-10 because it significantly outperformed measuring the change in IL-6 alone.
Despite high levels in blood, using only IL-6 measurements as a COVID-19 prognostic tool is hindered by several factors. IL-6 levels within the same patient vary over the course of any given day, and the magnitude of the IL-6 response to infection varies between different patients.
More information: Oliver J McElvaney et al. A linear prognostic score based on the ratio of interleukin-6 to interleukin-10 predicts outcomes in COVID-19, EBioMedicine (2020). DOI: 10.1016/j.ebiom.2020.103026
Tuesday, October 13, 2020
Protective antibodies persist for months in survivors of serious COVID-19 infections
Colorized scanning electron micrograph of a dying cell (blue) heavily infected with SARS-CoV-2 (yellow), the virus that causes COVID-19. Credit: NIAID Integrated Research Facility, Fort Detrick, Maryland.
People who survive serious COVID-19 infections have long-lasting immune responses against the virus, according to a new study led by researchers at Massachusetts General Hospital (MGH). The study, published in Science Immunology, offers hope that people infected with the virus will develop lasting protection against reinfection. The study also demonstrates that measuring antibodies can be an accurate tool for tracking the spread of the virus in the community.
13 october 2020--The immune system produces proteins called antibodies in response to SARS-CoV-2, the virus that causes COVID-19. "But there is a big knowledge gap in terms of how long theseantibody responseslast," says Richelle Charles, MD, an investigator in the Division of Infectious Diseases at MGH and a senior author of the paper. To find out, she and her colleagues obtained blood samples from 343 patients with COVID-19, most of whom had severe cases. The blood samples were taken up to four months after a patient's symptoms emerged. The blood's plasma was isolated and applied to laboratory plates coated with the receptor-binding domain (RBD) of the virus's "spike" protein, which attaches to cells, leading to infection. The team studied how different types of antibodies in the plasma bound to RBD. The results were compared toblood samplesobtained from more than 1,500 individuals prior to the pandemic.
The researchers found that measuring an antibody called immunoglobulin G (IgG) was highly accurate in identifying infected patients who had symptoms for at least 14 days. Since the standard PCR (nasal swab) test for SARS-CoV-2 loses sensitivity over time, augmenting it with a test for antibodies in patients who have had symptoms for at least eight days (at which time 50 percent are producing antibodies) will help identify some positive cases that might otherwise be missed, says Charles.
The researchers found that IgG levels remained elevated in these patients for four months, and were associated with the presence of protective neutralizing antibodies, which also demonstrated little decrease in activity over time. "That means that people are very likely protected for that period of time," says Charles. "We showed that key antibody responses to COVID-19 do persist."
In another finding, Charles and her colleagues showed that people infected with SARS-CoV-2 had immunoglobulin A (IgA) and immunoglobulin M (IgM) responses that were relatively short-lived, declining to low levels within about two and a half months or less, on average. "We can say now that if a patient has IgA and IgM responses, they were likely infected with the virus within the last two months," says Charles.
Knowing the duration of the immune response by IgA and IgM will help scientists obtain more accurate data about the spread of SARS-CoV-2, explains Jason Harris, MD, a pediatric infectious disease specialist at MGH and co-senior author of the study. "There are a lot of infections in the community that we do not pick up through PCR testing during acute infection, and this is especially true in areas where access to testing is limited," he says. "Knowing how long antibody responses last is essential before we can use antibody testing to track the spread of COVID-19 and identify 'hot spots' of the disease."
More information: Anita S. Iyer et al. Persistence and decay of human antibody responses to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 patients. Science Immunology 08 Oct 2020: Vol. 5, Issue 52, eabe0367 DOI: 10.1126/sciimmunol.abe0367
