Daily update Covid - 19

Daily update Covid - 19

This chart neatly explains why Austria and the Netherlands are taking action now, and I read that Germany will restrict the movement of unvaccinated people (<70% are fully vaccinated in Germany which is less than Italy, Spain and the UK), and Slovakia will follow. The Robert Koch Institute, recorded a seven-day incidence rate of 312 cases per 100,000 people, with several areas at more than 1,000, though cases fell nicely yesterday. A year ago, before the vaccine was introduced, the rate stood at 139. There were 265 deaths reported yesterday, much fewer than the pre-vaccine peak. Regardless, the Munich Christmas market has been cancelled. Clearly, deaths in Austria and the Netherlands will follow this, but less so than previous pandemic peaks due to vaccinations:

https://ourworldindata.org/grapher/biweekly-covid-cases-per-million-people?tab=chart&country=ESP~GBR~FRA~DEU~ITA~SWE~USA~AUT~NLD

Only a small fraction of attendees at the Cop26 climate summit in Glasgow tested positive for Covid during the eventat a rate of around 1 in 250 people, Public Health Scotland said. Test positivity remains my favourite metric as mobility in central and eastern Europe falls (Romania, Bulgaria mobility is down 25% - see graphs at end). Mobility in France/Italy is 5% below prepandemic levels but prepandemic was colder in February 2020. We should see behavioural adaptations in coming weeks, but now the sharpest downturns are in Austria vs France/Italy/Spain. Reports of increased mobility on Ukraine’s eastern border aren’t COVID related, but this is only test positivity:

https://ourworldindata.org/grapher/biweekly-covid-cases-per-million-people?tab=chart&country=ESP~GBR~FRA~DEU~ITA~SWE~USA~AUT~NLD~SRB~POL

Walvax, the Chinese mRNA company, is just beginning trials as a booster dose in Indonesia and Mexico. As you would expect, they are recruiting the trial population among people who got Chinese vaccines for doses 1 and 2, like the Chinese population did. If successful, they will roll it out in China, which will give them cover to deny Pfizer's application. A lot is riding on this trial. As this Global Times article makes clear, the Chinese authorities have been stirring up public doubt about Pfizer for months:

https://www.globaltimes.cn/page/202111/1238684.shtml

It would be extremely embarrassing to turn around at this point and demand that the population all get Pfizer boosters. Other Chinese pharma companies are also trying to make mRNA vaccines, but Walvax is way out ahead of them. As for timeline, I still think this rules out reopening before the party congress in October/November 2022. Indonesia is reporting only 368 cases per day in a population of 273 million. China really wants to know is how well the booster protects against severe disease, which requires a lot of breakthrough cases to quantify. At this rate, they will need to wait many months before they have statistical confidence in an efficacy number. At which point, even if they produce 2 billion doses in advance, it will still take them several months to do the rollout. The precise timing will depend on how they design the trial (how powered it is) and the base prevalence of COVID in the regions where the participants live. 

In the meantime, the headlines coming out of Europe right now are all vindicating the arguments of the "never-reopeners" inside China. Even though deaths in the well-vaccinated European countries are very low, it's still a reminder that no matter how well China does in its booster rollout, the result of opening up is going to be a big wave of people getting sick—and getting mad at the government for letting them get sick. 

In the US, Arkansas joined Colorado, California, and New Mexico in broadening access to Covid-19 booster shots before federal regulators expanded eligibility. New York City became the first major city to tell all adults to get a booster shot if they want one regardless of official eligibility. “What we’re finding is that we want more people to get their booster shot and that this is somewhat confusing and limiting as to the eligibility,” Arkansas’s Gov. Asa Mr. Hutchinson said, adding, “we’re changing that.” Last week, the governors of Colorado and New Mexico signed executive orders that expanded booster eligibility to all adults. California’s public health director issued a letter last week that expanded eligibility to anyone over 18. And authorities in New York state and West Virginia encouraged all adults to get a booster shot but didn’t issue a formal policy change.

Research on the long-term effects of Covid-19 (PASC, post-acute sequelae of COVID) found that at least 50% of people who survive infection experience a variety of physical and psychological health issues for six months or more after their recovery. The research was based on data from 250,351 adults and children and found that over half experience a decline in general well-being, resulting in weight loss, fatigue, fever, or pain. “About 20% have decreased mobility, 25% have trouble thinking or concentrating (called “brain fog”), 30% develop an anxiety disorder, 25% have breathing problems, and 20% have hair loss or skin rashes. Cardiovascular issues — chest pain and palpitations — are common, as are stomach and gastrointestinal problems.” Those who suffer with longer term symptoms include anyone who had Covid-19, even if they had no symptoms initially or just mild ones:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2784918?

HHS has withdrawn a controversial Trump-era rule that effectively prevented the FDA from regulating some diagnostic tests for Covid-19 — a move that President Trump’s first FDA commissioner, Scott Gottlieb, slammed. It’s the latest development in a decades-long controversy over whether the FDA has the power to regulate lab-developed tests. For now, though, the agency says it will likely focus its reviews on emergency use authorizations for take-home and point-of-care diagnostic tests, antibody tests, and lab-based diagnostics that use strategies like “pooling” specimens to increase overall testing capacity. This week the FDA announced the recall of over 2.2 million of Ellume’s over-the-counter coronavirus tests due to “higher-than-acceptable false positive test results”. “In recent weeks, we noted an increased chance that Ellume COVID-19 Home Tests from specific product lots may provide an incorrect positive result,” the company’s chief executive officer, Sean Parsons, said. “Following a thorough investigation, we isolated the cause and confirmed that this incidence of false positives is limited to specific lots.” Ellume’s at-home coronavirus test was the first rapid home test authorized by the FDA. The Biden administration purchased millions of the Australian company’s products in a $232 million contract as part of efforts to scale up testing kit availability in the U.S. The recall comes as at-home tests have become increasingly difficult to find in recent months as demand has skyrocketed. 

Brazil was a pandemic hot spot for much of the past year, but now, the country has edged past the U.S. in fully vaccinating its population. Over 60% of Brazilians are fully immunized; in the U.S. the rate is about 59%. The achievement reflects the public’s trust in a healthcare system that has a track record of responding quickly to crises and comes in spite of the President’s poor handling of the pandemic and continual dismissal of the dangers of the virus. President Jair Bolsonaro has so far refused to get vaccinated himself.

An antibody-based Covid-19 drug developed by GSK and Vir works as well as an injection as it did as an infusion. This could make the drug, which is meant to prevent mild or moderate cases of Covid-19 from worsening, far more convenient for patients to receive. The drug, called sotrovimab, or Xevudy, has already been granted emergency use authorization from the FDA as an infusion, but the companies are hoping to win the same status for an intramuscular formulation. Notably, the Phase 3 trial testing the drug as an injection was underway when the Delta variant was at its height, and a large proportion of enrolment was in Florida. That said, antibody drugs may ultimately have a smaller market than expected, thanks to the efficacy of oral antivirals that are coming to the market. 

When it comes to the new anti-virals, 2 different oral treatments have proved effective at both preventing people newly diagnosed with Covid-19 from entering the hospital and from dying. “We’re accelerating our path out of this pandemic,” President Biden said after data on the second Covid pill became available. The wide availability of oral drugs could make Covid-19 less lethal, making it less risky for people to return to in-person work and to their normal lives. The first results, from Merck and Ridgeback Therapeutics, were released in October and will be considered by an advisory panel to the FDA in December. That could lead to an emergency use authorization in the U.S. by the end of the year. That drug, molnupiravir, reduced hospitalizations by 50% and prevented deaths entirely a large randomized clinical trial when it was given within five days of when symptoms began. The pill is given as a five-day course during which patients take a total of 40 pills. In November, Pfizer announced that its Covid pill, Paxlovid, reduced hospitalizations by 89% and also prevented deaths in its own large randomized study. As with the Merck drug, Paxlovid is given as a five-day course. It must be given with a second medicine, a booster, called ritonavir, which is made by AbbVie. The Pfizer regimen involves taking 30 pills over a five-day period.

Pfizer also just signed an agreement that will make generic versions of its investigational pill for Covid-19 available in low-income countries agreeing to waive royalties on sales in some of the world’s poorest nations. The agreement follows a similar deal between the Medicines Patent Pool and Merck, which authorized generics of its antiviral pill.

Though the topline results are similar, the medicines could have different risks and benefits. The companies have only issued data in press releases, not scientific articles, and doctors need to know a lot more about both. Here is an overview of what we still don’t know about the Covid pills and when we might learn it.

Which one works better?

At the headline level, Pfizer’s pill reduced the risk of hospitalization and death by 89% while Merck showed a reduction of 50%. But neither firm has disclosed detailed data from its pivotal studies, and the trials were not identically designed. The studies enrolled similar populations, unvaccinated people with mild to moderate Covid-19 and at least one risk factor for severe disease, but they had slightly different measures of efficacy. Pfizer’s 89% figure comes from patients who started getting its pill, Paxlovid, within three days of their first Covid-19 symptoms, which was the study’s primary endpoint. Merck’s 50% applies to patients who began treatment within five days. In the Paxlovid study, patients who started treatment within five days saw an 85% improvement in hospitalization or death versus placebo. Merck has not shared data on patients who got its drug within three days of symptom onset.

What the studies had in common was 100% efficacy against death, regardless of when patients started treatment. Merck’s study counted eight deaths among patients on placebo, and Pfizer’s observed 10.

On the safety side, the rate of side effects in both studies was similar between the treatment groups and placebo groups. In each study, fewer patients in the treatment group left the study due to side effects compared to those in the placebo group. Neither company has disclosed detailed data on the type and severity of side effects. Each treatment is administered twice a day for five total days, amounting to 10 doses in total. Pfizer’s drug is co-administered with a common antiviral called ritonavir, meaning treatment entails more pills.

Would they work better in combination? And would the companies allow that to happen?

Theoretically, yes. And it’s unlikely.

Combinations of antiviral drugs are the standard treatment for people with HIV because it reduces the risk of resistance caused by mutations in the virus. Since the Pfizer and Merck pills attack SARS-CoV-2 differently, using them in combination might offer the same protective benefit for patients with Covid, said Céline Gounder, an infectious disease expert at New York University’s Grossman School of Medicine. “The challenge is that since these drugs are developed by different companies, neither Merck nor Pfizer is incentivized to run a combination therapy trial,” said Gounder. “However, the National Institutes of Health or others could do that, and I think it’s really important that they start to develop a combination therapy.”

The short-lived nature of SARS-CoV-2 infection, unlike the persistence of HIV, means a combination regimen involving two antivirals may not be necessary for people with Covid. You need combination therapy in HIV because you’re treating patients for a long time, so you may see evolution of the virus. We don’t see the same long-term infection with SARS-CoV-2, as far as we know. People clear the virus.

Will the antiviral be available for vaccinated patients with breakthrough infections?

Both companies conducted their studies entirely in patients who were at high risk of complications if they caught Covid and who also had not been vaccinated. That leads to a big question for policymakers: Should those who have been vaccinated, but who develop a breakthrough infection of SARS-CoV-2, be given the pills?

Right now that is a question without data. A third antiviral pill, from the biotech firm Atea and Roche, failed to prove it was effective in its own study, and analysts suspect the reason is that the companies included vaccinated patients in the research. For those who have received the vaccine, hospitalization and death are much less likely. This means that it is harder for a drug to show efficacy, because there are fewer infections to prevent. So, regulators and public health officials will have to make a judgement on the risks and benefits of the Covid pills for people with breakthrough infections — without direct data in these populations. Pfizer is running a clinical trial, with results due next year, that does include vaccinated patients, and the company’s executives have expressed confidence based on the results so far that the treatment should work. Both Merck and Pfizer are also running studies to show that the drugs can prevent people from developing symptoms if they take the antivirals after they are exposed to the virus.

Do the drugs work the same way?

No, not really. While both drugs interfere with the process the coronavirus uses to reproduce itself, each drug interferes at a very different point.

Merck’s drug throws a wrench into the works quite early. After someone takes molnupiravir, the drug is transformed into something uncannily similar to one of RNA’s chemical building blocks. The modification is so subtle that not only will the coronavirus use molnupiravir in place of other building blocks when it replicates itself, but coronaviruses’ unusual proofreading mechanism can’t even pick up on the imposter compound. Over time, the drug will encourage the virus to introduce even more mistakes. Ultimately, this leads to what’s known as error catastrophe. It’s introducing so many different mutations that, eventually, nothing further can happen. You’ve got this completely mutated RNA. Pfizer’s drug, Paxlovid, acts at a completely different point in the virus’ reproductive process.

Unlike molnupiravir, Paxlovid allows the strings of viral RNA to be assembled correctly. It even allows those strings to be used to create viral proteins, which are initially produced in one big chunk. Like a bolt of fabric before it’s cut to a clothing pattern, this protein needs to be chopped down to size before it can work. That cutting is what Paxlovid prohibits. The drug is designed to bind to a particularly important point in an enzyme called a protease which slices up proteins. Without a functioning protease, the virus can’t create functional copies; no working virus, no problem.

Protease inhibitors have been used for decades to create more than a dozen drugs for HIV and hepatitis C; in some cases, they’ve also been used as cancer drugs. There’s a long history of medicinal chemistry targeting proteases. Paxlovid is designed with a SARS-CoV-2-specific protease in mind, so it works more specifically on this coronavirus than molnupiravir. But Paxlovid can’t work as well if it’s taken on its own. The body’s defence mechanisms will get rid of anything that it doesn’t recognise, including drugs, which can be digested by enzymes in a person’s liver. Another drug called ritonavir blocks the liver enzyme that would likely chew up Paxlovid, which gives the latter drug the space it needs to work.

How do they compare with monoclonal antibodies?

Regeneron and Lilly have each won FDA authorization for antibody combination therapies that keep recently diagnosed Covid-19 patients from hospitalization and death. In a Phase 3 study enrolling recently diagnosed patients at high risk for severe disease, Regeneron’s treatment reduced the risk of hospitalization or death by 70% compared to placebo. In a similar study, Lilly’s therapy showed an 87% reduction.

The biggest difference is one of convenience. The antibody treatments are administered intravenously in a one-time, roughly hour-long process (Regeneron’s is authorized for subcutaneous injection when an IV procedure is not feasible). That could make the treatments from Pfizer and Merck, taken orally at home, preferable to patients unable to visit an infusion centre. There’s also a difference in cost. Regeneron and Lilly have signed deals with the federal government to sell their treatments at about $1,250 per dose. Merck’s agreement with the U.S. works out to about $700 for a five-day course of molnupiravir. Pfizer is still negotiating contracts but is expected to set a similar price for Paxlovid.

How easy will they be to get?

A pill is a huge leap in terms of logistical ease over infused therapies like monoclonal antibodies. For those treatments, not only did people have to make their way to clinics for their infusions, but hospitals and other facilities had to set up places where people who were actively infectious could come get treated without risking others’ health. The other antiviral authorized to treat Covid-19, Gilead’s remdesivir, is an infusion and approved only for hospitalized patients, but some data indicate that if it were to be given to patients earlier in their infections, it could have a greater effect. If its approval ever covered outpatients, however, it would still run into the same logistical challenges of an infused therapy.

Still, the Covid pills come with a key challenge of their own. They’re most effective when given early in the infection, so people need to be able to get tested and get their prescription rapidly. And the U.S. testing landscape is still limited. PCR tests can take days to return a result, and though the Biden administration has upped its effort to expand the availability of at-home rapid tests, finding one at a store is still hit or miss — success feels like scoring this holiday season’s hottest gift. Any delay in getting diagnosed undercuts the power of these pills; even a day or two has real implications for a treatment meant to clear out an acute infection like Covid-19.

Will it affect a patient’s DNA?

This is really a question only for Merck’s molnupiravir, since it works by sneaking subtly corrupted parts into the coronavirus’s RNA sequence. Once the virus has mutated too much, it can’t work, mission accomplished. But there’s a theoretical chance that molnupiravir could also influence normal human DNA when it replicates, too. If mutations happen during that process, it could spell real trouble.

Merck did some tests during molnupiravir’s development to check this possibility out. In two different types of animal studies using higher and longer doses than are given to humans, Merck’s scientists didn’t see any increased risk of unwanted mutations.

But UNC’s Swanstrom isn’t completely convinced that the tests Merck did were sensitive enough. In August, he published a paper in the Journal of Infectious Diseases showing that a key metabolite of molnupiravir could mutate DNA in animal cells:

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8136050/

Given these results, Swanstrom said he would be particularly interested in seeing a long-term study of people who took molnupiravir to continue to monitor this potential effect over the next 10 or 20 years.

“This thing is going to go into thousands of people. And are we just going to ignore the fact that there’s this potential risk?” he said. “The risk could be zero. It could be no worse than going to get a dental X-ray, or it could do something more. But unless we find out, you know, we’re going to learn this lesson the hard way, way later than we should.”

What might the new antivirals mean for cancer patients?

Because the new antiviral Pfizer is developing is a protease inhibitor, infectious disease specialists are familiar with how it works. So, we already know: these drugs have the potential to interfere with many therapies used to treat cancer. They’re going to be very helpful in our armamentarium, but they will not substitute for prevention or vaccination efforts because these are not medicines that are completely benign and harmless in terms of their drug-drug interactions and toxicity. So we’re going to have to be careful and thoughtful about how we use our protease inhibitors.

Next, in other news, the WHO’s Scientific Advisory Group on the Origins of Novel Pathogens (SAGO) has recently been established to “define and guide studies into the origins [of Novel Pathogens]” and “advise WHO on prioritising studies and field investigations into [Novel Pathogens].” In both of these, an attention to political questions like “which pathogens deserve investigation?” and “how should countries’ possible pathogen origins be prioritised?” will need to be addressed.

However, arguments have been made by WHO that SAGO should “follow the science” and “avoid politicisation.” There is a clear tension here. The statement to “avoid politicisation” is a political act in itself. It is an act that suggests states, government, and citizens have no business in holding science to account. In turn it is an act that both recognises the role and importance of politics, but sees the answer as doing nothing about it. Politics is framed as a problem, a major stumbling block to both pandemic preparedness and response, and for science to do its work, but one best avoided rather than understood. Political expertise is reduced to the important work of diplomacy or political communication. There is also an assumption that all political engagement means partisan or geo-politics, which is a misnomer. Politics is located at all levels, from the micropolitics of the Wuhan laboratory to the geopolitics of the G7 and UN systems. The publication of the membership of SAGO shows a lack of attention to expertise in the social sciences, and politics in particular. This is sure to cause problems in two domains core to the functioning of SAGO: the politics of pathogenic origins, and the politics of global investigations.

Politics is core to pathogenic origins: the origins of novel pathogens is circumscribed by politics as much as it is by natural factors. First, human-animal interactions are driven by the political economy. A growing body of evidence shows that decreased biodiversity, changes in land use, and increased deforestation have a marked effect on the diversity of hosts and frequency of human-animal interactions with potential for pathogenic spillover. Importantly, these are not natural events, but changes in ecology driven by global political economic forces. This is furthered by understanding the local political economy of markets and the everyday engagement that individuals have with animal reservoirs, and in turn who they further expose. Without expertise in understanding these diverse drivers of land use change and local political economy, any understanding of pathogenic origins is incomplete.

Further to this and relating more closely to the political nature of SARS-CoV-2 investigations, the nature of any “lab leak” origin (be it accidental or deliberate) is inherently political in nature. The location of BSL-4 laboratories have been subject to political choices with implications at the local level. Much maligned “gain-of-function” research performed with an intent to create new vaccines have political implications in terms of their dual-use potential.5 Even the biosafety systems put in place to prevent laboratory accidents are determined by political and social factors. Investigating novel pathogen emergence therefore also requires an understanding of the politics of biosafety and biosecurity.

Beyond this, politics determines how SARS-CoV-2 was able to spread, and who knew about its emergence when. Structures of power within laboratories, public health systems, district, provincial and national government would have determined how the disease may have spread before national, and indeed global reporting. Unpicking these governance structures requires social science expertise, beyond understanding the virology.

Pathogenic origins, then, are replete with local, national, and global political dynamics with implications core to emergence and re-emergence of the pathogen. The political drivers of pathogen emergence and re-emergence are thus a fundamental part of understanding novel pathogens. Given everything we have learned about the role of social science in pandemic governance in the last 20 months (or indeed the last 20 years), the lack of political science (or social science more generally) expertise on SAGO represents a major gap in knowledge and membership of the group.

Politics is core to global investigations: politics is not only an object of investigation for SAGO, but it is a key facet of its organisation and activity. The origin of SARS-CoV-2 is a highly contested issue of global politics, with an increasing focus on “lab leak” hypotheses as an alternative to the traditional “spillover” hypothesis. Both the Chinese Government and the United States Government have commissioned investigations into the origins of SARS-CoV-2, while WHO itself commissioned an investigation which reported in March 2021. The second phase of WHO’s investigation, however, has been marred by a lack of Chinese cooperation precisely because of WHO’s politics; its nature as a consensus body rather than authoritative body means that it has no power to compel member states to participate in investigations, it can only persuade or incentivise. This is a common issue in international organisations and one that WHO has come up against repeatedly.7 Moreover, many states may use WHO’s role and the origins narrative as a smokescreen to obfuscate their own domestic failures in mitigating covid-19, making the process highly political at both global and domestic levels. However, limited political expertise in navigating these political spaces on the SAGO panel risks scuppering investigations before they get off the ground.

Further to this, once an investigation has begun it is conducted under the microscope. A useful analogue for this is investigations of alleged biological weapons use within the context of the United Nations Secretary General’s Mechanism. While the specific politics are slightly different, the lessons from those investigations remain the same: conducting an investigation under the microscope requires a myriad of both technical and political competencies. Not least, it requires an understanding of the politics of the institutions and states under investigation, to understand the context in which results are delivered. This extends to transparency of the investigation itself through extensive sample collection and record-keeping, parallel and independent laboratory analysis of samples, and clear testing of hypotheses; but also to the communication and reporting of the investigations’ results. Communicating to both a technical and a political audience is no mean feat and requires sensitivity to the use of narrative and how reporting demonstrates the veracity of findings while also being contextually sensitive.

SAGO needs a radical reframe: the idea that SAGO could ever be “apolitical” or that it could advise only “on technical and scientific considerations” is not only naive but ignores a key component of the work to be done in origins investigations. Fixing this requires, first and foremost, that the membership of the group include political and social scientific expertise; this is a minimum requirement. Once included, this expertise must not be side-lined, or viewed as secondary to the science. Going deeper, however, it needs to be acknowledged that SAGO is stepping into a space that is already politicised, and that inherently requires a sensitivity to politics. This has already been acknowledged by WHO itself, who reopened its call for membership “to encourage additional applications from the fields of social science/anthropology/ethics/political science and biosafety/biosecurity.” However, this was followed by the announcement of two more scientists to the panel, not social scientists, running contrary to the call for social science expertise. This flies in the face of the additional call and demonstrates something far worse of WHO’s intentions for SAGO. SAGO needs to see the political landscape, how it shapes it, and how it can navigate it, to not walk blindly into a minefield of its own making; but WHO’s call for social science expertise, only to appoint more scientists, shows at best wilful ignorance of politics and political expertise or, at worst, active contempt:

https://www.bmj.com/content/375/bmj.n2786

A paper in the BMJ aimed to estimate the changes in life expectancy and years of life lost. They used 37 upper-middle and high income countries or regions with reliable and complete mortality data. Reduction in life expectancy in men and women was observed in all the countries studied except New Zealand, Taiwan, and Norway, where there was a gain in life expectancy in 2020. No evidence was found of a change in life expectancy in Denmark, Iceland, and South Korea. The highest reduction in life expectancy was observed in Russia (men: −2.33, 95% confidence interval −2.50 to −2.17; women: −2.14, −2.25 to −2.03), the United States (men: −2.27, −2.39 to −2.15; women: −1.61, −1.70 to −1.51), Bulgaria (men: −1.96, −2.11 to −1.81; women: −1.37, −1.74 to −1.01), Lithuania (men: −1.83, −2.07 to −1.59; women: −1.21, −1.36 to −1.05), Chile (men: −1.64, −1.97 to −1.32; women: −0.88, −1.28 to −0.50), and Spain (men: −1.35, −1.53 to −1.18; women: −1.13, −1.37 to −0.90). Years of life lost in 2020 were higher than expected in all countries except Taiwan, New Zealand, Norway, Iceland, Denmark, and South Korea. In the remaining 31 countries, more than 222 million years of life were lost in 2020, which is 28.1 million (95% confidence interval 26.8m to 29.5m) years of life lost more than expected (17.3 million (16.8m to 17.8m) in men and 10.8 million (10.4m to 11.3m) in women). The highest excess years of life lost per 100 000 population were observed in Bulgaria (men: 7260, 95% confidence interval 6820 to 7710; women: 3730, 2740 to 4730), Russia (men: 7020, 6550 to 7480; women: 4760, 4530 to 4990), Lithuania (men: 5430, 4750 to 6070; women: 2640, 2310 to 2980), the US (men: 4350, 4170 to 4530; women: 2430, 2320 to 2550), Poland (men: 3830, 3540 to 4120; women: 1830, 1630 to 2040), and Hungary (men: 2770, 2490 to 3040; women: 1920, 1590 to 2240). The excess years of life lost were relatively low in people younger than 65 years, except in Russia, Bulgaria, Lithuania, and the US where the excess years of life lost was >2000 per 100 000. More than 28 million excess years of life were lost in 2020 in 31 countries, with a higher rate in men than women. Excess years of life lost associated with the covid-19 pandemic in 2020 were more than five times higher than those associated with the seasonal influenza epidemic in 2015:

https://www.bmj.com/content/375/bmj-2021-066768

The above shows changes in life expectancy at birth associated with covid-19 pandemic in 2020. Change is calculated as the difference between observed and expected life expectancy, estimated using the Lee-Carter model. The below shows years of life lost (YLL) per 100 000 during 2005-20:

https://www.bmj.com/content/375/bmj-2021-066768

The below shows age components of the life expectancy losses in the US, Lithuania, Poland, and Spain in men and women produced by differences between the observed and expected age specific death rates by age intervals 0-14, 15-54, 55-64, 65-74, and ≥75. In the US and Lithuania, it appears that mortality excess in people younger than 65 years, particularly among men, was responsible for a high proportion of the total losses in life expectancy: the respective values for men and women were 62% and 42% in the US and 58% and 44% in Lithuania. Corresponding values in Poland were 27% and 8% and in Spain were 26% and 15%. These two countries, especially Spain, showed an expected pattern, with the dominating role of older ages as a driver of losses in life expectancy:

https://www.bmj.com/content/375/bmj-2021-066768

The results strongly justify a more nuanced estimation of the lives lost beyond excess mortality. For example, with a similar burden of excess deaths per 100 000 in Spain and the US (161 and 160, respectively), excess YLL (per 100 000) was substantially higher in the US (3400) than in Spain (1900), indicating higher numbers of deaths at younger ages in the US compared with Spain. Indeed, the ratio of YLL rate in people aged <65 and ≥65 years at death was 0.29 in the US, whereas it was only 0.07 in Spain. Despite a lower excess death rate than Lithuania, Poland, and Spain, the reduction in life expectancy in the US was higher than in these three countries. A full examination of this phenomenon is beyond the scope of the current study. Nevertheless, the decomposition analysis of the life expectancy losses in these four countries reveals particularly large contributions to the reduction of life expectancy from increases in mortality at ages younger than 65 years in the US. However, our analyses were not able to identify whether these excess deaths were directly caused by SARS-CoV-2 or were related to other causes of deaths. The highest reduction in life expectancy, and highest increase in YLL, largely occurred in countries where the baseline life expectancy was relatively low. Therefore, baseline health status could have contributed to these results. Widespread ethnic inequality in the US, as reported previously, might have contributed to high YLL in the US.

Their findings of a comparable or lower than expected YLL in Taiwan, New Zealand, Denmark, Iceland, Norway, and South Korea underscore the importance of successful viral suppression and elimination policies, including targeted and population based public health policy interventions. A comprehensive pandemic preparedness aimed at more resilient health systems could be key to tackling the impact of future pandemics. Quantifying the effects of specific policy interventions on the reduction of premature deaths will help inform future policy intervention. As many of the effects of the pandemic might take a longer time frame to have a measurable effect on human lives, continuous and timely monitoring of excess YLL would help identify the sources of excess mortality and excess YLL in population subgroups.

Snippets:

In other news, in a large, commercially insured population, overall use of outpatient visits after hospital discharge did not change significantly, even as telemedicine use increased. The percentage of patients completing a post-discharge visit stayed around 70%, consistent with findings prior to the pandemic, even as general ambulatory visits dropped significantly. Notably, although the mean number of visits after discharge did not change, telemedicine appeared to substitute for in-person visits. Pre-pandemic research suggested telemedicine was more likely additive to in-person care for certain clinical conditions. Data on outpatient visits early in the pandemic showed considerable declines in volume as discretionary care was deferred, with telemedicine compensating for some of this drop. Telemedicine offers added convenience for patients recovering from a hospitalization and post-discharge follow-up care is less likely to be considered discretionary, making it a useful case study in utilisation trends. As state and federal emergency waivers expire, policy makers will need to decide which telemedicine services deserve ongoing coverage, and at what level. Although there has been concern that payment parity may lead to overutilization, our research suggests that overall post-discharge utilisation has not been significantly affected, whereas nearly 30% of those discharged have continued to use telemedicine:

The Above is This is Trends in Discharged Enrolees Completing an Outpatient Evaluation and Management (EM) Visit During the 30 Days Postdischarge:

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2786179

The surge in breakthrough cases among vaccinated people highlights the extraordinary transmissibility of the delta variant. Now in a phase 3 trial of an inactivated SARS-CoV-2 vaccine (BBV152) based on an Asp614Gly variant, the authors found a substantial reduction in symptomatic COVID-19.

The trial followed a double-blind, randomised, placebo-controlled, phase 3 design in 25 hospitals in India to evaluate the efficacy, safety, and immunological lot consistency of BBV152. A total of 25,798 adult participants (aged >18 years) were randomly assigned, of whom 24,419 received two doses of BBV152 (n=12221) or placebo (n=12,198). The primary outcome was a first occurrence of laboratory-confirmed (RT-PCR-positive) symptomatic COVID-19, including severe disease, with onset at least 14 days after the second dose. As a case-driven study, 130 cases of symptomatic COVID-19 were required for efficacy analysis, which occurred in 16 973 initially seronegative participants who had at least 2 weeks of follow-up after the second dose. 24 cases occurred in the vaccine group (n=8471) and 106 in the placebo group (n=8502), providing an overall estimated vaccine efficacy of 77·8%, with efficacies of 79·4% in participants younger than 60 years (n=15 115) and 66·2% (33·8–84·0) in older participants (>60 years; n=1858). 16 cases of severe symptomatic COVID-19 were reported, one in the vaccine group and 15 in the placebo group, resulting in an efficacy of 93·4%. Vaccine efficacy against asymptomatic COVID-19 infections was 63·6%. Although the 95% CIs for efficacy against asymptomatic infections are wide, the lower limit of 29·0 still indicates clinically significant protection for public health. 50 samples overall tested positive for the delta variant, 13 in the vaccine group and 37 in the placebo group, giving a vaccine efficacy against delta variant disease of 65·2% (33·1–83·0). Nevertheless, further investigations are necessary to confirm this preliminary efficacy against the delta variant and other VOCs. In a different study, the neutralisation activity induced by BBV152 against the delta variant was 2·7-times lower than that against the Asp614Gly variant.

In the study, in all the delta-positive cases, the viral load in vaccine recipients was significantly lower than in placebo recipients. The concentrations of neutralising antibodies elicited by two doses of BBV152 were similar at day 56 (1 month after the second dose) in both younger and older participants or men and women. Additionally, BBV152 was well tolerated; the same proportion of participants (12·4%) reported adverse events in the vaccine group (1597 of 12,879 participants) and placebo group (1597 of 12,874), with no clinically significant differences in the distributions of solicited, unsolicited, or serious adverse events between the vaccine and placebo groups, and no cases of anaphylaxis or vaccine-related deaths. The authors concluded that the BBV152 vaccine had an acceptable safety profile, with similar safety results to other inactivated SARS-CoV-2 vaccine candidates.

This study was conducted in India, and only Indian participants were involved, making the study cohort less ethnically diverse, and limiting the generalisability of the results to other populations. Efficacy estimates for identified variants (n=79) were generated from the delta variant (n=50, 63·3%), kappa (B.1.617.1) variant (n=11, 13·9%), alpha (B.1.1.7) variant (n=4, 5·1%), and 14 other variants (n=14, 17·7%). In addition, the study provides evidence of protection against asymptomatic infection that might be of public health significance, which has not been reported in previous trials of other SARS-CoV-2 vaccines. Generally, the apparent protection against severe COVID-19 is most crucial, but the capability of preventing asymptomatic infection would also protect against mild disease, transmission, and eventually might lead to a reduction in subsequent cases of severe COVID-19. WHO issued an emergency use listing for BBV152 on Nov 3, 2021; the vaccine has already received emergency use authorisation in several countries, including India, Iran, Mexico, and the Philippines, which are currently experiencing high SARS-CoV-2 prevalence and low to moderate vaccination coverage. The roll-out of BBV152 might ease the ultra-cold chain requirements of other SARS-CoV-2 vaccine platforms, increase the finite global manufacturing capacity, and improve insufficient supply of vaccines which disproportionately affects low-income and middle-income countries.

The next step for studies of BBV152 should be a focus on monitoring for epidemiological variations in SARS-CoV-2 and the long-term vaccine efficacy against symptomatic COVID-19 and asymptomatic infection to identify whether the vaccine provides ongoing protection when any VOC replacement (other than by the VOCs investigated in this study) has occurred:

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02014-6/fulltext

 

Justin Stebbing
Managing Director

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