Molnupiravir is being developed for the treatment of COVID, which has been submitted for review by the US Food and Drug Administration, but large-scale production to treat COVID is still a challenge. Now, researchers have engineered enzymes to help manufacture the pill, resulting in a much shorter synthesis with a higher yield than current methods. The details of their work are reported in ACS Central Science.
The oral antiviral molnupiravir was originally developed to treat influenza, and works by causing viruses to make errors when copying their own RNA, introducing mutations that inhibit replication. Recently, interim phase 3 clinical trial findings indicated that molnupiravir reduced the risk of hospitalisation and death from COVID for newly diagnosed, at-risk patients, and that it had equal effectiveness against different SARS-CoV-2 variants. Researchers set out to develop a shorter, higher-yielding and sustainable way to synthesise the molecule.
The team came up with a three-step synthesis of molnupiravir from ribose, a sugar molecule. They identified enzymes or chemical treatments to sequentially add the appropriate chemical groups to ribose to generate the molecule. For the second step of the synthesis, the team identified bacterial enzymes that weakly catalysed the desired reactions. Using in vitro evolution, they greatly enhanced these enzymes’ activities. The new synthetic route, which also included a phosphate recycling strategy, was 70% shorter and had a seven-fold higher overall yield than the original route.
Over 28 million more years of life were lost than expected in 2020 in 31 upper-middle and high-income countries, according to a University of Oxford-led study published in the BMJ.
Save for a handful of exceptions, 37 countries examined including the US had more premature deaths than expected in 2020, with a higher rate in men than women.
Understanding the full impact of the COVID pandemic requires counting excess deaths, and analysing how premature those deaths are. Years of life lost (YLL) is a more detailed assessment of COVID’s impact on populations as it measures both the number of deaths and the age at which death occurs.
Researchers used this measure to estimate the changes in life expectancy and excess years of life lost from all causes in 2020. They compared the observed life expectancy and years of life lost in 2020 with historical trends in 2005-19 in 37 upper-middle and high-income countries.
Between 2005 and 2019, life expectancy at birth rose for both men and women in all the countries studied. In 2020, a drop in life expectancy was seen in both men and women in all countries save New Zealand, Taiwan, and Norway, where there was a life expectancy gain and Denmark, Iceland, and South Korea saw no change.
The biggest life expectancy drop was in Russia (−2.33 years in men and −2.14 in women), the US (−2.27 and 1.61), Bulgaria (−1.96 and −1.37), Lithuania (−1.83 and −1.21), Chile (−1.64 in men), and Spain (−1.11 in women). Years of life lost declined in most countries in both men and women between 2005 and 2019, except Canada, Greece, Scotland, Taiwan, and the US.
In 2020, years of life lost were higher than expected in all countries except Taiwan and New Zealand, where there was a reduction in years of life lost, and Iceland, South Korea, Denmark, and Norway, where there was no evidence of a change in years of life lost. In the remaining 31 countries, more than 222 million years of life were lost in 2020, which is 28.1 million more than expected (17.3 million in men and 10.8 million in women).
The highest excess years of life lost (per 100 000) were in Russia (7020 in men and 4760 in women), Bulgaria (7260 and 3730), Lithuania (5,430 in men and 2,640 in women), and the US (4,350 in men and 2,430 in women).
Overall, excess years of life lost in 2020 were over five times greater (2510 per 100 000) than those associated with the seasonal influenza epidemic in 2015 (458 per 100 000).
The excess years of life lost were relatively low in people under 65 years, except in Russia, Bulgaria, Lithuania, and the US where the excess years of life lost was more than 2 000 per 100 000.
Most countries in Asia, Africa, and Latin America were excluded due to insufficient data, and researchers could not account for other factors, such as socioeconomic status, regional disparities, and race or ethnicity. However, the findings are largely in line with previous studies, and the use of authoritative national mortality data, together with a validated analytical approach, suggests that the results are robust.
“Our 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,” the researchers wrote. “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.”
Despite high hopes, the first placebo controlled trial of inhaled steroids for COVID suggests that ciclesonide, an inhaled and nasal steroid drug commonly used for asthma and rhinitis, does not help young healthy people with COVID and respiratory symptoms improve earlier.
The study, published in the BMJ, was motivated by research showing that ciclesonide, which is safe, inexpensive and widely available, could decrease viral replication of SARS-Cov2 in mouse models of COVID. A randomised, double-blind, placebo-controlled trial of inhaled ciclesonide was designed to evaluate the resolution of symptoms in adults with COVID presenting with respiratory symptoms.
“Based on my experience treating asthma, I thought it made sense to see if it would decrease the lung inflammation in patients with COVID early in the disease, as lung disease has an important impact for patients and is a major effect of the virus,” explained Dr Nicole Ezer, the first and lead author of the study, who is a lung specialist and a researcher in the Translational Research in Respiratory Diseases Program at the RI-MUHC. “In addition, we felt it was important to study a drug for COVID that has a very good safety profile and could be used in high, middle and low-income countries safely to reduce respiratory symptoms. Access to affordable medications is very important to decrease disparities in health outcomes across the world.”
The importance of placebo control From Sept. 15, 2020 to June 8, 2021, the study recruited 215 symptomatic adults and randomly assigned them to either inhaled and intranasal ciclesonide or inhaled and intranasal placebo for 14 days. Participants were asked to complete a survey online on the day of enrollment and on six other occasions until day 14, with a follow-up survey at day 29.
Based on the assumption that treatment would be most effective if given early in the disease process, participants were recruited within five days of a positive PCR test result for SARS-CoV-2 and symptom onset and received the treatment at home by commercial courier. No vaccinated participants were included in the trial.
No significant difference was seen between the intervention and control group. After seven days of treatment, 40% taking ciclesonide had no more fever and respiratory symptoms, vs 35% taking placebo. At day 14, these figures amounted to 66% in the ciclesonide group compared with 58% in the placebo group.
Those results are disappointing, especially since two recent open label studies had raised hopes in the scientific community that inhaled steroids could alleviate respiratory symptoms associated with COVID, and one study demonstrated efficacy of dexamethasone in admitted patients with COVID.
“The previously published studies had a major limitation: they were open label with no placebo. Other studies have shown that inhalers have a strong placebo effect,” explained the study’s senior author, Dr Emily McDonald, associate professor of medicine at McGill University. “Here’s a strong reminder that any study of a medication, in particular of inhalers, needs to be controlled with a placebo before we rush to recommend them.”
In spite of the study’s outcome, researchers still believe there is potential for the treatment of COVID with inhaled steroids.
“It’s still possible that inhaled steroids might be beneficial for older at-risk populations,” said Dr Ezer, who is also an assistant professor of medicine at McGill University. “We need more research focused on older adults and people who are high-risk, but those studies must have a placebo arm to make sure they aren’t coming to a false conclusion of benefit.”
An international survey has found that people who do not believe that being infected with COVID could seriously threaten their health are both less likely to believe in the importance of preventing spread of the disease and less willing to get vaccinated.
To contain COVID, it may be critical for individuals to feel concern about taking action to prevent transmission within their community. However such concerns and actions could be impacted by a number of both individual and cultural factors. Leonhardt and colleagues hypothesised that one factor influencing pandemic concerns could be people’s perceived invincibility to COVID. The findings were presented in PLOS ONE.
To test this idea, the researchers analysed responses from over 200 000 people across 51 countries from an ongoing online survey. The survey included a question about how serious it would be to get infected with COVID, as well as questions about willingness to get vaccinated and taking action to reduce spread in one’s community. The researchers also accounted for participants’ overall health, age, sex, and level of education.
Respondents who reported feeling more invincibile to COVID were less willing to get vaccinated, the researchers found, and also less likely to believe in the importance of individual actions to reduce transmission.
The strength of this link varied between countries. Individuals with high perceived invincibility living in countries with a greater emphasis on individual freedoms and autonomy, such as the US, were less willing to get vaccinated and less willing to take action than individuals with high perceived invincibility living in cultures with greater emphasis on collective action.
The authors say their findings highlight the importance of considering both individual and cultural factors when addressing pandemics. They suggest that suppression efforts employ messaging underscoring the importance of collective action, especially in individualistic cultures. Meanwhile, future research could further explore the impact of cultural factors on health beliefs and behaviours.
The authors added: “While feeling invincible may be beneficial in overcoming economic hardships or during periods of war, the results of our study suggest that it threatens the likelihood that people get vaccinated against COVID, and this is especially the case in individualistic countries, such as the USA, where people tend to focus on their own health rather than the collective health of their community.”
People who adhered to masking outside of the home, but were more exposed to infection due to their circumstances, still had “significantly” lower COVID infection rates, according to research published in BMJ Open.
Although it has been widely asserted that face coverings serve to protect others, rather than the wearer, this large-scale study established a clear link between wearing a face covering outside the home and infection.
The Oxford-led study links individuals’ and households’ ability to follow non-pharmaceutical interventions (NPIs) often known as COVID behavioural interventions, using the largest and most representative dataset to date in the UK, including people from different ethnic and age groups.
Using the COVID Infection Study (CIS), study participants were asked to complete a short questionnaire, as well as taking regular COVID tests. Respondents were asked to share how often they worked outside the home, how easy it was to keep social distance in their workplace, whether they took public transport and whether they had direct contact with others on a day-to-day basis.
According to the study, “Wearing a face covering outside was a significant predictor of a lower chance of infection before mid-December 2020 in the UK, when a stricter second lockdown was implemented.”
There was a higher rate of infections among those who lacked autonomy to follow COVID behavioural measures and did not comply with masking.
Author Professor Melinda Mills said, “Lack of compliance to COVID behavioural measures has often been positioned as an attitude or choice. Yet there are large groups of people who, due to their household or employment circumstances, cannot follow measures to work from home, engage in physical distancing at the workplace or avoid public transportation. This, in turn, means that they have a higher exposure to becoming infected.
“The inability for some groups of people to follow behavioural interventions exacerbates existing health inequalities and we showed that face coverings are one measure that can mitigate this unequal exposure.”
The team found, “The level of autonomy to adhere to behavioural interventions does not predict COVID infection alone, but rather the risk of infection is diminished when individuals wear face covering/masks.”
The study concluded that masking reduces the effects of unequal COVID exposure. Professor Mills added, “Using a very large individual and household sample and COVID swab tests, we showed that the inability for certain groups such as women in large households or those working in occupations where it is hard to maintain physical distancing were protected from infection during key periods in 2020 in the UK”.
SARS-CoV-2 virus. Source: Fusion Medical Animation on Unsplash
In an unexpected turn of events, the US National Institutes of Health (NIH) has acknowledged that it funded research into enhancing coronavirus infectivity, Vanity Fair reported.
The agency had last week sent a letter to the US House Committee on Energy and Commerce stating that its grant recipient, EcoHealth Alliance, enhanced a bat coronavirus to become potentially more infectious to humans. This was an “unexpected result” of the research, done in collaboration with Wuhan Institute of Virology.
The NIH letter also noted that EcoHealth Alliance violated terms of its grant conditions, which had stipulated that it was supposed to report to the agency if its work boosted viral growth by a factor of 10.
EcoHealth Alliance was supposed to submit a progress report at the end of the grant period in 2019 but it didn’t arrive at the NIH until August 2021, according to Vanity Fair. However, in a statement to Vanity Fair, EcoHealth Alliance said that it had reported the relevant information “as soon as we were made aware, in our four year report in April 2018.”
In that missing progress report (dated August 2021), lab mice infected with the enhanced virus became more ill than those infected with a wild one, reported Vanity Fair.
The Vanity Fair report also reveals a rather concerning detail contained in a leaked EcoHealth Alliance grant proposal submitted to the Defense Advanced Research Projects Agency in 2018. EcoHealth Alliance and the Wuhan Institute of virology proposed to engineer a furin cleavage site for the coronavirus to more easily enter humans cells. This matches a distinctive segment of SARS-CoV-2’s genetic code.
“If I applied for funding to paint Central Park purple and was denied, but then a year later we woke up to find Central Park painted purple, I’d be a prime suspect,” Jamie Metzl, a member of the WHO advisory committee on human genome editing, told Vanity Fair.
In its letter to US Congress, the NIH emphasised that the virus EcoHealth Alliance was studying could not have sparked the pandemic, as there was a vast genetic difference between it and SARS-CoV-2. NIH Director Francis Collins, MD, PhD, also issued a statement addressing the concerns raised by the letter, noting that such claims were “demonstrably false.”
“The scientific evidence to date indicates that the virus is likely the result of viral evolution in nature, potentially jumping directly to humans or through an unidentified intermediary animal host,” Dr Collins said in the statement.
Gilles Demaneuf, a data scientist in New Zealand, told Vanity Fair, “I cannot be sure that [COVID originated from] a research-related accident or infection from a sampling trip. But I am 100% sure there was a massive cover-up.”
In response to these criticisms of poor oversight and bad scientific judgment, the NIH has “circled its wagons”, Vanity Fair observed.
Though small studies have suggested that statins, which lower low-density lipoprotein (LDL), may also reduce COVID severity or mortality, findings from a large study suggest that it has no effect and may even worsen the disease.
In the effort to fight COVID, researchers have attempted to find existing medications that might have an effect on the outcome of the disease, and statins were one readily available candidate that appeared to have some effect. However, a new study published in the journal PLOS ONE suggests they may not be suitable.
“Despite the apparent beneficial effect of statins on the outcomes of various infectious diseases, our study revealed that their specific use to treat COVID is probably not merited,” said senior study author Petros Karakousis, MD, professor of medicine at the Johns Hopkins University School of Medicine. “Compared with earlier research, we looked at a larger and more widely varied inpatient population, and had better criteria for defining disease severity, thereby enabling our results to be more relevant for predicting the impact of statins on COVID outcomes in hospitalised patients.”
In the study, researchers reviewed the records of 4447 hospitalised patients, ages 18 years or older, who had been diagnosed with SARS-CoV-2 infection between March 1 and June 30, 2020. Of these, 594 (13%) were receiving statins at admission, with most statin users being men (57%) and older (ages 52–78 compared with ages 29–62) than the non-statin users. The highest percentage of statin users were black (47%), had hypertension (74%) or diabetes (53%), and were more likely to take medications for lowering blood pressure – along with statins to reduce their LDL cholesterol.
After accounting for confounding factors, statin use was found to have no significant effect on COVID mortality. However, they did find that patients hospitalised with COVID and taking statins had an 18% increased risk for having a more severe form of the disease.
“One plausible explanation for this finding is that statins increase cellular production of angiotensin-converting enzyme 2 [ACE2], the receptor on a cell’s surface through which SARS-CoV-2 gains entry,” said Prof Karakousis. “Therefore, statins may lower a cell’s resistance to infection and in turn, increase the odds that the patient will have a more severe case of COVID.”
Prof Karakousis said future studies should attempt to better define the relationship between statin use and COVID, noting that all previous ones were retrospective and had factors that could not be eliminated, such as many statin users being overweight.
The only way to definitively determine if statins have any benefit for patients with COVID is to conduct a randomised, placebo-controlled clinical trial.
A new study suggests that the sensitivity of tests for SARS-CoV-2 vary throughout the day according to the body’s circadian rhythm, which could have implications for how the disease is managed.
Carl Johnson, Cornelius Vanderbilt Professor of Biological Sciences, wondered how the virus might act differently depending on the time of day and the body’s circadian rhythms, and collaborated with colleagues to determine if the percentage of people testing positive for COVID varies based on time of day. They found that people were up to two times as likely to have an accurate positive test result if they tested in the middle of the day compared to at night. Their findings were published in the Journal of Biological Rhythms.
The data support the hypothesis that COVID acts differently in the body based on our natural circadian rhythm, which has also been implied by studies of other viral and bacterial infections. COVID virus shedding, when infected cells release infectious virus particles into the blood and mucus, appears to be more active around midday due to modulation of the immune system by our biological clock.
“Taking a COVID test at the optimal time of day improves test sensitivity and will help us to be accurate in diagnosing people who may be infected but asymptomatic,” Prof Johnson said. Their results indicate that viral load is lower after 8 pm. If people choose to get tested at that time, there could be a higher chance of a false-negative result. False negatives can be harmful to the community and for the patient, who might not seek additional care due to their negative test result.
A difference in COVID viral shedding throughout the day would help inform treatment for the disease. As Johnson and his co-authors report, the peak shedding in the afternoon, when patients are more likely to interact with others or seek medical care, could play a role in increasing the spread of the virus in hospitals and the wider community.
Further research is needed to confirm the diurnal nature of SARS-CoV-2. Experimentally testing COVID patients to see if individuals shed the virus differently throughout the day would have important public health implications, Prof Johnson said.
Fully vaccinated passengers arriving in England and most under 18s arriving from non red-list countries (which now includes South Africa) can use a lateral flow test (LFT) on or before day 2 of their arrival in England, the UK government has announced.
LFTs must be taken as soon as possible on the day of arrival in England or at the latest before the end of a passenger’s second day and can now be purchased from the list of private providers on GOV.UK from as little as £22 – significantly cheaper than PCR tests.
LFTs for international travel must be purchased from a private provider as NHS Test and Trace lateral flow tests cannot be used for international travel. Passengers who have already bought a PCR to use for travel do not need to buy another test as PCRs can still be used.
Passengers have to take a photo of their lateral flow test and booking reference supplied by the private provider, then send it back to them to verify the result. Failure to do so could result in a fine of £1000 (R20 000). It is also possible for passengers to book a test at some airport testing centres. People using PCR tests for travel will have their test reported by the company they purchase the test from.
Anyone who tests positive will need to isolate and take a confirmatory PCR test, at no additional cost to the traveller, which can be genomically sequenced to help identify new variants. PCR tests can be accessed free of charge by ordering in the usual way through NHS Test and Trace – via nhs.uk/coronavirus or by calling 119. Test providers will be expected to advise people to self-isolate and direct people towards the NHS Test and Trace booking page.
In addition, all travellers must complete a passenger locator form beforehand, including providing a test booking reference number supplied by a testing provider.
However, these new rules apply only to those arriving in England: anyone travelling on to Ireland, Northern Ireland, Scotland, Wales, the Channel Islands or the Isle of Man within 10 days after arrival in England have to follow the rules for testing and quarantine in those places.
Those passengers who are not fully vaccinated with an authorised vaccine returning from a non-red list destination must still take a pre-departure test (antigen/PCR), a PCR test on day 2 and day 8 test and complete 10 days’ self-isolation (with the option of doing Test to Release on day 5).
A case study details three teenagers with mild or asymptomatic COVID presented with suicidal thoughts, “paranoia-like fears,” delusions and “foggy brain”, which could be explained by anti-neural antibodies – ‘turncoat’ antibodies that may attack brain tissue.
Mounting evidence points to neurological and psychiatric effects of COVID, with a UK study finding a 13% risk of a first-time diagnosis after COVID. The study, published in JAMA Neurology, is the first to look at anti-neural antibodies in paediatric patients previously infected with SARS-CoV-2.
Over five months in 2020, 18 children and teens were hospitalised with confirmed COVID at UCSF Benioff Children’s Hospital San Francisco, three of whom were the patients in the study who underwent neurological evaluations.
The researchers examined the patients’ cerebrospinal fluid (CSF) and found that two of the patients, both of whom had histories of unspecified depression and/or anxiety, had antibodies indicating that SARS-CoV-2 may have invaded the central nervous system. They also had anti-neural antibodies in their CSF, suggesting a rampant immune system accidentally targeting the brain.
The research follows a previous UCSF study that also found a high level of autoantibodies in the cerebrospinal fluid of adult patients with acute COVID, who experienced neurological symptoms, including intractable headaches, seizures and loss of smell.
“It is way too soon to know whether COVID is a common trigger for neuropsychiatric illnesses, but it does seem to be a potent trigger for the development of autoantibodies,” said co-corresponding author Samuel Pleasure, MD, PhD. “It is currently totally unknown whether patients predisposed to neuropsychiatric illnesses are more likely to develop worsened symptoms after COVID, or whether COVID infection can act as an independent trigger.”
Unlike most psychiatric presentations, the three patients in the UCSF study had symptoms with sudden onset and rapid progression, representing a marked change from their baselines, said co-first author Claire Johns, MD. “The patients had significant neuropsychiatric manifestations despite mild respiratory symptoms, suggesting potential short and long-term effects of COVID.”
After hospitalisations lasting weeks and ongoing psychiatric medications, the two UCSF patients, whose cerebrospinal fluid tested positive for SARS-CoV-2 antibodies and anti-neural antibodies, were treated with intravenous immunoglobulin, an immunomodulatory therapy that curbs inflammation in autoimmune disorders. After five days, the first patient had “more organised thoughts, decreased paranoia and improved insight.”
Autoantibodies targeting the protein TCF4 were also found, which has genetic links in some schizophrenia cases. However, “we don’t know that the antibodies are actually interfering with the protein’s function,” said co-corresponding author, Michael R. Wilson, MD, noting that the diagnosis of schizophrenia is based on a constellation of symptoms, not a biomarker. The second patient partially responded to immunotherapy with improved cognition and working memory, but continued to have “impaired mood and cognitive symptoms” six months later. The third patient, with no psychiatric history and without SARS-CoV-2 antibodies or anti-neural antibodies in their cerebrospinal fluid, recovered with psychiatric medications. Their symptoms were attributed to recreational drug use.
In another case study, a 30-year-old patient with mildly symptomatic COVID who presented at a hospital emergency department with delusions, violent outbursts, hyper-anxiety and paranoia was unresponsive to antipsychotic medication but after being diagnosed with possible “autoimmune-mediated psychosis”, responded to intravenous immunoglobulin.
Nonetheless, the researchers agree it’s unlikely that there were pre-existing autoantibodies, and they point to other disorders with psychiatric symptoms, like anti-NMDAR encephalitis syndrome, that are caused by anti-neural antibodies and respond to treatment directed at these rogue antibodies.
The researchers agree that more study is warranted, although Dr Pleasure noted that the rarity of cerebrospinal fluid samples from paediatric patients is a challenge, as they rarely have severe enough COVID to warrant a lumbar puncture.
