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RetroVirox offers a menu of cell-based antiviral services to evaluate experimental therapies and vaccines against coronaviruses, including SARS-CoV-2. The company offers in vitro testing with SARS-CoV-2 pseudovirions and with live SARS-CoV-2 viruses to evaluate entry inhibitors, neutralizing antibodies, and antivirals against the novel coronavirus causative agent of COVID-19. Multiple viral strains are available for testing, including the most recent Omicron variants of concern (XBB.1.5, XBB.1.16, XBB.2.3.2, EG.5.1 JN.1, KP.2, and KP.3). Pseudoviruses coated with the viral spike (S) protein of SARS-CoV-2 are also used to recapitulate the mode of entry of the novel coronavirus. Over 50 spike mutant and variants are available as pseudoviruses. These assays can be used for the following purposes: - To determine the neutralizing activity of therapeutic antibodies and antisera
- To test experimental COVID-19 vaccines using antisera from inoculated animals or humans
- To evaluate small-molecule and other entry inhibitors targeting the S viral protein, the ACE-2 viral receptor, or host proteases and other targets involved in SARS-CoV-2 viral entry
Assays with live replicating SARS-CoV-2, and milder forms of seasonal human coronaviruses (hCoV-OC43 and 229E) allow for the evaluation of inhibitors at all stages of the coronavirus life cycle. Additional Information about the coronavirus assays and many other cell-based antiviral assays offered at RetroVirox is available here. Request additional information by email at info@retrovirox.com
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June 7, 2024—CDC has completed its initial study of the effects of the A(H5N1) bird flu virus from the human case in Texas on ferrets, a model used to assess potential impact on people. What you need to know - The A(H5N1) virus from the human case in Texas caused severe illness and death in ferrets. A(H5N1) infection in ferrets has been fatal in the past. This is different from what is seen with seasonal flu, which makes ferrets sick, but is not lethal.
- The A(H5N1) virus from the human case in Texas spread efficiently between ferrets in direct contact but did not spread efficiently between ferrets via respiratory droplets. This is different from what is seen with seasonal flu, which infects 100% of ferrets via respiratory droplets.
- These findings are not surprising and do not change CDC’s risk assessment for most people, which is low. The results do reinforce the need for people who have exposure to infected animals to take precautions and for public health and agriculture communities to continue to work together to prevent the spread of the virus to additional dairy herds and people.
CDC researchers used a ferret model[1] to better understand the severity of illness and efficiency of transmission of A/Texas/37/2024. For decades, CDC has conducted these types of studies to inform risk assessments of influenza viruses with pandemic potential. CDC used the virus from the human case in Texas which was reported on April 1, 2024, and was associated with sick dairy cow exposure. These are the first publicly reported animal model findings from a virus that infected a human as part of the current multistate outbreak of A(H5N1).
Summary of study findings The study, completed on Friday, May 31, found that A/Texas/37/2024 virus caused severe disease (100% lethal) in all six ferrets that were infected. This is consistent with what has been found recently in ferret studies with A(H5N1) viruses, including two published studies conducted in the past year. Ferrets infected with A(H5N1) viruses from mink in Spain (A/mink/Spain/3691-8_22VIR10586-10/2022) and from a person in Chile (A/Chile/25945/2023) had severe illness that was either fatal or required euthanasia. In terms of spread, the CDC ferret study found that the A/Texas/37/2024 virus spread easily among ferrets (3 of 3 ferrets, or 100%) in direct contact with infected ferrets (placed in the same enclosure). However, the virus was less capable of spreading by respiratory droplets, which was tested by placing infected ferrets in enclosures next to healthy ferrets (with shared air but without direct contact). In that situation, only 1 of 3 ferrets (33%) became infected, and there was a one- or two-day delay in transmission with the A/Texas/37/2024 virus compared to transmission with seasonal flu viruses. This suggests that A/Texas/37/2024-like viruses would need to undergo changes to spread efficiently by droplets through the air, such as from coughs and sneezes. CDC is repeating the experiment to confirm the findings and the results of these experiments will be used to inform an ongoing, broader CDC-led influenza risk assessment (IRAT) on A/Texas/37/2024. In terms of direct contact spread, the mink virus from Spain caused efficient spread (100%) among ferrets. The study using the Chile virus found 75% spread by direct contact among ferrets. While the findings related to respiratory transmission were similar in that there was no efficient respiratory spread, there were differences in terms of whether any respiratory spread was observed or not. The study cited previously using A/mink/Spain/3691-8_22VIR10586-10/2022 found 37.5% transmission by respiratory droplets. The study using A/Chile/25945/2023 found no transmission by respiratory droplets. The most recent CDC findings are more consistent with the findings with the mink virus from Spain than the virus from Chile. (Additional information about ferret transmission findings with avian influenza is available below.) Conclusion and risk assessment Taken together, these findings underscore that the A(H5N1) viruses spreading in poultry, dairy cows, and other animals with sporadic human infections pose a serious potential public health risk and could cause serious illness in people. While the three cases of A(H5N1) in the United States have been mild, it is possible that there will be serious illnesses among people. Findings from this study are largely consistent with recent A(H5N1) studies in ferrets, as well as past reports of serious human illness resulting from this virus. These findings also suggest; however, that current A(H5N1) viruses would need to undergo genetic changes to spread more easily via respiratory droplets, which is reassuring. Efficient respiratory droplet spread, like what is seen with seasonal influenza viruses, is needed for sustained person-to-person spread to happen. These findings do not change CDC’s immediate risk assessment for the general public who do not have animal exposures, which is low. Respiratory droplet spread compared There have been several prior respiratory droplet spread in ferrets with avian influenza viruses. Selected studies: - A study done using the avian influenza A(H7N9) virus (which has the highest pandemic risk assessment score on CDC’s Influenza Risk Assessment Tool (IRAT)) found that “A/Hong Kong/125/2017” spread easily among ferrets in the same enclosure but only 1 of 3 ferrets in the adjacent enclosure became via respiratory droplets in that study.
- A 2006 CDC study summarized results of a ferret study on A/Hong Kong/486/97, an A(H5N1) virus isolated from a human case in 1997. That study found respiratory droplet spread occurred in 2 of the 3 ferrets (66%). At that time, A(H5N1) viruses had caused probable person-to-person spread. That older 1997 A(H5N1) virus did not emerge to spread efficiently among people. Person-to-person spread has not been observed with A(H5N1) viruses since 2007.
- The previously mentioned 2024 study evaluated an A(H5N1) virus that caused an outbreak among mink at a mink farm in Spain (“A/mink/Spain/3691-8_22VIR10586-10/2022”) and found that respiratory droplet spread occurred in 3 out of 8 ferrets (37.5%). Of note, this study used a side-to-side airflow methodology; by contrast, CDC uses a top-to-bottom airflow approach. Despite the differences in methods, the results from this study were similar to those found in the CDC study.
- The most recently published CDC A(H5N1) ferret study was conducted on a virus from a human A(H5N1) case in Chile. Investigators found efficient direct contact spread, but no respiratory droplet spread.
- On the lowest end of the pandemic risk assessment scale, another ferret study looked at the effects of a low pathogenic avian influenza A(H7N9) virus (A/chicken/Tennessee/17-007431-3/2017) isolated from a multistate poultry outbreak in the United States with no human infections. There was inefficient spread in the direct contact model, with only 1 of 3 co-housed ferrets becoming infected. Because spread in the direct contact model was inefficient, spread by respiratory droplets was not studied.
Background on Ferret Studies Ferrets are considered the best small mammal for studying influenza virus infection and transmission and are commonly used as a tool to inform public health risk assessments of emerging influenza viruses. In these studies, ferrets are experimentally infected and followed to assess severity of illness. To test the ability of the virus to spread, infected ferrets are exposed to healthy ferrets in different settings. Understanding the disease characteristics of novel influenza viruses and their capacity to spread is a critical component of any public health response.
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Mexico reports the death of a man from a strain of bird flu not seen in humans before. A 59-year-old man in Mexico has died with a type of bird flu - H5N2 - never recorded in people before now. There is no risk to the wider public, say authorities, and none of the man's close contacts have caught the virus. It is unclear how he got it, although there have been cases in some poultry farms in Mexico. Infections like this can sometime pass from animals to humans. The man had other underlying health issues that likely made him vulnerable. He had been bedridden for weeks before getting sick with fever and shortness of breath from bird flu, according to officials. There is no evidence that the virus could start spreading between people and cause an outbreak, they say. The World Health Organization and other authorities monitor strains of flu, like this one, that could have the potential mutate and become a threat. What is bird flu? There are many types or strains of avian or bird flu. As well as birds, some wild mammals - such as seals, otters, wild dogs and foxes - can catch them too. Cases do occur in people from time to time and patients usually get better. One type of bird flu, called H5N1, has been spreading for weeks among dairy cow herds in the US, with a small number of cases reported among humans. The UK recently declared itself bird-flu-free after recording no new cases of H5N1, following outbreaks in poultry and other captive birds. Responding to the news from Mexico, Prof Ian Brown, Avian Virology Group Lead, Pirbright Institute, said: "The prompt follow up in healthcare professionals and family members in contact with the infected patient provides reassurance at present this is an isolated case." Dr Ed Hutchinson from the University of Glasgow said it looked likely that the man's infection was a spillover event - meaning he had probably caught it from an infected animal somehow. "At the moment surveillance is taking place, including testing people who may have been exposed to the virus but fought off the infection to see if they show any signs of an immune response. If there are more human infections with this virus it would become of wider concern.”
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SARS-CoV-2 infections worldwide led to a surge in cases of Long COVID, a post-infectious syndrome. It has been hypothesized that autoantibodies play a crucial role in the development of Long COVID and other syndromes, such as fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In this study, we tested this hypothesis by passively transferring total IgG from Long COVID patients to mice. Using Glial Fibrillary Acidic Protein (GFAP) and type-I interferon expression, we stratified patients into three Long COVID subgroups, each with unique plasma proteome signatures. Remarkably, IgG transfer from the two subgroups, which are characterized by higher plasma levels of neuronal proteins and leukocyte activation markers, induced pronounced and persistent sensory hypersensitivity with distinct kinetics. Conversely, IgG transfer from the third subgroup, which are characterized by enriched skeletal and cardiac muscle proteome profiles, reduced locomotor activity in mice without affecting their motor coordination. These findings demonstrate that transfer of IgG from Long COVID patients to mice replicates disease symptoms, underscoring IgG's causative role in Long COVID pathogenesis. This work proposes a murine model that mirrors Long COVID's pathophysiological mechanisms, which may be used as a tool for screening and developing targeted therapeutics. Preprint in bioRxiv (May 31, 2024): https://doi.org/10.1101/2024.05.30.596590
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A third person in the US has tested positive for H5 bird flu in connection to an ongoing outbreak in dairy cattle, the Michigan Department of Health and Human Services said Thursday. This is the second human case reported in the state and the fourth ever in the US. This time, in addition to some of the eye symptoms seen with previous H5N1 cases, the farmworker reported a cough and other respiratory symptoms that are more typical of human influenza infections, the health department said. “This individual had respiratory symptoms, including a cough, congestion, sore throat and watery eyes,” Dr. Nirav Shah, the principal deputy director of the US Centers for Disease Control and Prevention, said at a briefing Thursday. “What the respiratory symptoms tell us, more than anything, is that this virus, like many viruses, can present in more than one way, and for that reason, we should remain alert, not be alarmed,” he added. Experts said that the addition of respiratory symptoms doesn’t necessarily indicate that the virus has become more dangerous or that it may transmit more easily from person to person. Instead, they say, the person probably developed lung symptoms because of the route of infection, perhaps by breathing in infectious aerosols in the milking parlor instead of rubbing their eyes with contaminated hands. “With the first case in Michigan, eye symptoms occurred after a direct splash of infected milk to the eye. With this case, respiratory symptoms occurred after direct exposure to an infected cow,” Dr. Natasha Bagdasarian, chief medical executive for Michigan, said in a news release. “Neither individual was wearing full personal protective equipment (PPE). This tells us that direct exposure to infected livestock poses a risk to humans, and that PPE is an important toolin preventing spread among individuals who work on dairy and poultry farms. We have not seen signs of sustained human-to-human transmission, and the current health risk to the general public remains low.”.... CDC Statement (May 30, 2024): https://www.cdc.gov/media/releases/2024/p0530-h5-human-case-michigan.html
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This is a technical summary of an analysis of the genomic sequence of the virus identified in the Michigan case of highly pathogenic avian influenza (HPAI) A(H5N1) virus infection. This analysis supports the conclusion that the overall risk to the general public associated with the ongoing HPAI A(H5N1) outbreak has not changed and remains low at this time. The genome of the virus identified from the patient in Michigan (A/Michigan/90/2024) is publicly posted in GISAID (EPI_ISL_19162802) and has been submitted to GenBank (PP839258-PP839265) May 24, 2024 – CDC has sequenced the influenza virus genome identified in a conjunctival specimen collected from the person in Michigan who was identified to be infected with HPAI A(H5N1) virus and compared each gene segment with HPAI A(H5N1) sequences from cows, wild birds and poultry and the first human case in Texas. The virus HA was identified as clade 2.3.4.4b with each individual gene segment closely related to genotype B3.13 viruses detected in dairy cows available from USDA testing. No amino acid changes were identified in the HA gene sequence from the Michigan patient specimen compared to the HA sequence from the case in Texas and only minor changes were identified when compared to sequences from cows. These data indicate viruses detected in both cows and the two human cases maintain primarily avian genetic characteristics and lack changes that would make them better adapted to infect or transmit between humans. The genome of the human virus from Michigan did not have the PB2 E627K change detected in the virus from the Texas case, but had one notable change (PB2 M631L) compared to the Texas case that is known to be associated with viral adaptation to mammalian hosts, and which has been detected in 99% of dairy cow sequences but only sporadically in birds[i]. This change has been identified as resulting in enhancement of virus replication and disease severity in mice during studies with avian influenza A(H10N7) viruses[ii]. The remainder of the genome of A/Michigan/90/2024 was closely related to sequences detected in infected dairy cows and strongly suggests direct cow-to-human transmission. Further, there are no markers known to be associated with influenza antiviral resistance found in the virus sequences from the Michigan specimen and the virus is very closely related to two existing HPAI A(H5N1) candidate vaccine viruses that are already available to manufacturers, and which could be used to make vaccine if needed. Overall, the genetic analysis of the HPAI A(H5N1) virus detected in a human in Michigan supports CDC’s conclusion that the human health risk currently remains low. More details of this and other viruses characterized in association with the dairy cow outbreak are available in a previous technical summary.
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The US Department of Agriculture (USDA) Animal and Plant Health Inspection Service (APHIS) today announced that tests have confirmed highly pathogenic H5N1 avian influenza in alpacas at an Idaho farm where the virus had struck a poultry flock. The detection marks the first positive findings in alpacas, which are members of the camelid family. Detection of the virus in the alpacas isn't unexpected due to the high amount of virus in the environment and the comingling of multiple livestock species on the farm, APHIS said. The detection of the virus in farm animals on an affected poultry farm is similar to the H5N1 detection in baby goats at a Minnesota farm that experienced a poultry outbreak. Virus found in 4 of farm's 18 alpacas Genetic sequencing at the USDA's National Veterinary Services Laboratory (NVSL) reveals that the virus that infected the alpacas is the same B3.13 H5N1 genome circulating in dairy cows and is also the same genotype that infected poultry at the Idaho farm. APHIS said the poultry on the Idaho farm were depopulated this month. According to a notification from the World Organization for Animal Health, the alpacas and poultry were from a backyard farm in Jerome County. The virus was detected in 4 of the farm's 18 alpacas. The report said the alpacas had close contact with the infected birds. USDA Press Release (May 28, 2024): https://www.aphis.usda.gov/livestock-poultry-disease/avian/avian-influenza/hpai-detections/mammals/highly-pathogenic-avian
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An avian influenza outbreak in Victoria prompts the US Department of Agriculture to ban all poultry products until further notice. In short: An outbreak of avian influenza in Victoria has prompted the US to ban all Victorian poultry products. The restrictions apply to fresh poultry, commercial birds, eggs and poultry by-products. What's next? In an effort to contain the outbreak, Agriculture Victoria has placed the two farms impacted by the outbreak in a control zone. The United States Department of Agriculture has banned imports of all Victorian poultry products following an avian influenza outbreak. The H7N3 strain of the virus commonly known as bird flu was found on an egg farm in Meredith, west of Melbourne, on Wednesday and has since been linked to another site 130 kilometres south-west in Terang. The two properties share joint management, staff and machinery. More than 500,000 birds have had to be euthanased this week. The H7N3 is a high pathogenic strain of avian influenza and resulted in 400,000 chicken deaths at the Meredith farm in a bid to control the spread of the virus...
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LA JOLLA, CA—Currently availableflu medications only target the virus after it has already established an infection, but what if a drug could prevent infection in the first place? Now, scientists at Scripps Research and the Albert Einstein College of Medicine have designed drug-like molecules to do just that, by thwarting the first stage of influenza infection. The drug-like inhibitors block the virus from entering the body’s respiratory cells—specifically, they target hemagglutinin, a protein on the surface of type A influenza viruses. The findings, published in the Proceedings of the National Academy of Sciences on May 16, 2024, represent an important step forward in developing a drug that can prevent influenza infection. “We’re trying to target the very first stage of influenza infection since it would be better to prevent infection in the first place, but these molecules could also be used to inhibit the spread of the virus after one's infected,” says corresponding author Ian Wilson, DPhil, the Hansen Professor of Structural Biology at Scripps Research. The inhibitors will need to be further optimized and tested before they can be assessed as antivirals in humans, but the researchers say that these molecules ultimately have the potential to help prevent and treat seasonal flu infections. And, unlike vaccines, the inhibitors likely wouldn’t need to be updated yearly. The researchers had previously identified a small molecule, F0045(S), with a limited capacity to bind and inhibit H1N1 type A influenza viruses. “We began by developing a high-throughput hemagglutinin binding assay that allowed us to rapidly screen large libraries of small molecules and found the lead compound F0045(S) with this process,” says corresponding author Dennis Wolan, PhD, senior principal scientist at Genentech and former associate professor at Scripps Research. In this study, the team aimed to optimize F0045(S)’s chemical structure to design molecules with better drug-like properties and more specific binding ability to the virus. To start, the Wolan lab used “SuFEx click-chemistry,” which was first developed by two-time Nobel laureate and co-author K. Barry Sharpless, PhD, to generate a large library of candidate molecules with various tweaks to F0045(S)’s original structure. When they screened this library, the researchers identified two molecules—4(R) and 6(R)—with superior binding affinity compared to F0045(S). Next, Wilson’s lab produced X-ray crystal structures of 4(R) and 6(R) bound to the flu hemagglutinin protein so that they could identify the molecules’ binding sites, determine the mechanisms behind their superior binding ability, and identify areas for improvement. “We showed that these inhibitors bind much more tightly to the viral antigen hemagglutinin than the original lead molecule did,” says Wilson. “By using click-chemistry, we basically extended the compounds’ ability to interact with influenza by making them target additional pockets on the antigen surface.” When the researchers tested 4(R) and 6(R) in cell culture to verify their antiviral properties and safety, they found 6(R) was non-toxic and had more than 200-times improved cellular antiviral potency compared to F0045(S). Finally, the researchers used a targeted approach to further optimize 6(R) and develop compound 7, which proved to have even better antiviral ability. “This is the most potent small-molecule hemagglutinin inhibitor developed to date,” says corresponding author Seiya Kitamura, who worked on the project as a postdoctoral fellow at Scripps Research and is now an assistant professor at the Albert Einstein College of Medicine. In future studies, the team plans to continue to optimize compound 7 and to test the inhibitor in animal models of influenza. “In terms of potency, it will be hard to improve the molecule any further, but there are many other properties to consider and optimize, for example, pharmacokinetics, metabolism and aqueous solubility,” says Kitamura. Because the inhibitors developed in this study only target H1N1 strains of influenza, researchers are also working to develop equivalent drug-like inhibitors to target other strains of influenza such as H3N2 and H5N1. Research published in PNAS (April 19, 2024): https://doi.org/10.1073/pnas.2310677121
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Mice administered raw milk samples from dairy cows infected with H5N1 influenza experienced high virus levels in their respiratory organs and lower virus levels in other vital organs. Mice administered raw milk samples from dairy cows infected with H5N1 influenza experienced high virus levels in their respiratory organs and lower virus levels in other vital organs, according to findings published in the New England Journal of Medicine. The results suggest that consumption of raw milk by animals poses a risk for H5N1 infection and raises questions about its potential risk in humans. Since 2003, H5N1 influenza viruses have circulated in 23 countries, primarily affecting wild birds and poultry with about 900 human cases, primarily among people who have had close contact with infected birds. In the past few years, however, a highly pathogenic avian influenza virus called HPAI H5N1 has spread to infect more than 50 animal species, and in late March, the United States reported a viral outbreak among dairy cows in Texas. To date, 52 cattle herds across nine states have been affected, with two human infections detected in farm workers with conjunctivitis. Although the virus has so far shown no genetic evidence of acquiring the ability to spread from person-to-person, public health officials are closely monitoring the dairy cow situation as part of overarching pandemic preparedness efforts. To assess the risk of H5N1 infection by consuming raw milk, researchers from the University of Wisconsin-Madison and Texas A&M Veterinary Medical Diagnostic Laboratory fed droplets of raw milk from infected dairy cattle to five mice. The animals demonstrated signs of illness, including lethargy, on day one and were euthanized on day four to determine organ virus levels. The researchers discovered high levels of virus in the animals’ nasal passages, trachea and lungs and moderate-to-low virus levels in other organs, consistent with H5N1 infections found in other mammals. In addition to the mice studies, the researchers also tested to determine which temperatures and time intervals inactivate H5N1 virus in raw milk from dairy cows. Four milk samples with confirmed high H5N1 levels were tested at 63 degrees Celsius (145.4 degrees Fahrenheit) for 5, 10, 20 and 30 minutes, or at 72 degrees Celsius (161.6 degrees Fahrenheit) for 5, 10, 15, 20 and/or 30 seconds. Each of the time intervals at 63℃ successfully killed the virus. At 72℃, virus levels were diminished but not completely inactivated after 15 and 20 seconds. The authors emphasize, however, that their laboratory study was not identical to large-scale industrial pasteurization of raw milk and reflect experimental conditions that should be replicated with direct measurement of infected milk in commercial pasteurization equipment. In a separate experiment, the researchers stored raw milk infected with H5N1 at 4℃ (39.2 degrees Fahrenheit) for five weeks and found only a small decline in virus levels, suggesting that the virus in raw milk may remain infectious when maintained at refrigerated temperatures. To date, the U.S. Food and Drug Administration (FDA) concludes that the totality of evidence continues to indicate that the commercial milk supply is safe. While laboratory benchtop studies provide important, useful information, there are limitations that challenge inferences to real world commercial processing and pasteurization. The FDA conducted an initial survey of 297 retail dairy products collected at retail locations in 17 states and represented products produced at 132 processing locations in 38 states. All of the samples were found to be negative for viable virus. These results underscore the opportunity to conduct additional studies that closely replicate real world conditions. FDA, in partnership with USDA, is conducting pasteurization validation studies – including the use of a homogenizer and continuous flow pasteurizer. Additional results will be made available as soon as they are available. The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, funded the work of the University of Wisconsin-Madison researchers. Published in NEJM (May 25, 2024): https://doi.org/10.1056/NEJMc2405495
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Editor’s summary Currently approved antivirals for SARS-CoV-2 target one of two viral proteins. Remdesivir and molnupiravir target the RNA-dependent RNA polymerase (RdRp), whereas nirmatrelvir (the antiviral agent of Paxlovid) targets the main protease (Mpro). Although these drugs are effective, there continues to be room for improvement, especially for drugs targeting the RdRp. Here, Martinez et al. evaluated the efficacy of an orally available small-molecule targeting the RdRp of SARS-CoV-2 and other coronaviruses called GS-5245 or obeldesivir. The authors found that GS-5245 could reduce disease severity in mice infected with one of several different coronaviruses, including SARS-CoV-2, SARS-CoV, and MERS-CoV. Moreover, combining GS-5245 with nirmatrelvir further improved outcomes in mice infected with SARS-CoV-2. Together, these data support further development of GS-5245/obeldesivir as a broader anti-coronaviral drug. —Courtney Malo Abstract Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV–related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (Mpro) inhibitor nirmatrelvir improved outcomes in vivo against SARS-CoV-2 compared with the single agents. Together, our data support the clinical evaluation of GS-5245 against coronaviruses that cause or have the potential to cause human disease. Published in Science Translational Medicine (May 22, 2024):
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An HIV vaccine candidate elicited trace levels of HIV broadly neutralizing antibodies (bNAbs) and high levels of other key immune cells in an early-stage clinical trial. This immune response is an important signal that, if antibody levels can be further amplified, the vaccination strategy might be able to prevent HIV. The findings of this NIAID-supported trial were published in the journal Cell. HIV has genetic diversity that makes it difficult to target with a vaccine, but bNAbs are thought to be key to overcoming that hurdle because they bind to parts of the virus that remain relatively stable even when it mutates. Several classes of HIV-specific bNAbs have been identified, and each class binds to a different stable section of the virus’ surface. Some people with HIV generate bNAbs naturally through a process that typically occurs over years. For a preventive vaccine, researchers seek to accelerate the process by which the immune system generates bNAbs and to do so in people who do not have HIV. The clinical trial examined the ability of a vaccine concept to elicit bNAbs that bind to the membrane proximal external region (MPER) of an HIV surface protein. The study enrolled 24 participants, of whom 20 were randomly selected to receive vaccine doses. The remaining four participants received placebo injections. Fifteen participants in the vaccine arm received two doses, and five participants received three doses. The team then analyzed study participant blood samples. They found that 13 vaccine recipients generated early-stage MPER-directed antibodies after two doses. Among the five participants who received three doses, the antibodies in samples from two of them could neutralize many common globally circulating HIV strains in vitro, i.e., in a test tube or culture dish. One of those two participants had B cells—immune cells that produce antibodies—showing signs of maturing in such a way that they would be able to produce MPER-directed bNAbs if stimulated further. The other participant had started producing MPER-directed bNAbs. Vaccine recipients also had evidence of CD4+ T cell activity, which is a crucial step in enabling antibody development. One vaccine recipient experienced anaphylaxis, a known but rare allergy-related adverse event, which was promptly managed and resolved. The team investigated the cause of the event, which was likely from an additive used to help stabilize the vaccine contents. The trial was halted at that time. The research was sponsored by NIAID, co-funded by the Bill & Melinda Gates Foundation, and conducted by the Duke Consortium for HIV/AIDS Vaccine Development (CHAVD), one of two NIAID-supported HIV vaccine consortia, in collaboration with the NIAID-funded HIV Vaccine Trials Network. This study provided the proof of concept that a vaccine can induce bNAbs in people, which is a key question being pursued in the HIV vaccine research field. Moreover, bNAbs were detected within weeks, which is much faster than the antibody response in people with HIV. According to the authors, it is likely that an effective vaccine will need to build on and amplify the immune response that was observed in this study. Together, the clinical trial results identified ways that the vaccine’s safety and efficacy must be enhanced before it advances through further evaluation, and a new vaccine candidate is being developed based on these findings. Published in Cell (May 17, 2024): https://doi.org/10.1016/j.cell.2024.04.033
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The infection was detected in a farm worker who had been exposed to cows infected with the H5N1 virus, Michigan health officials said. A second human case of bird flu infection linked to the current H5N1 outbreak in dairy cows has been detected, in a farm worker who had exposure to infected cows, Michigan state health authorities announced on Wednesday. In a statement, health officials said the individual had mild symptoms and has recovered. Evidence to date suggests this is a sporadic infection, with no signs of ongoing spread, the statement said....
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A new study finds that taking the antiviral Paxlovid doesn't treat Long COVID symptoms better than a placebo. Taking the COVID-19 antiviral Paxlovid does not appear to improve Long COVID symptoms in a meaningful way, a new study finds. Those results are a blow to the millions of people living with the condition, which currently has no approved treatment or cure. Paxlovid has long been a source of hope for those with Long COVID. Scientists don’t know exactly what causes Long COVID, but many have hypothesized that viral material lingers in the body, potentially causing long-lasting symptoms including fatigue, the inability to exercise, brain fog, and more. Given that theory, a drug like Paxlovid, which stops the virus from multiplying and reduces the amount of it in the body, seemed to many like a promising treatment. But the new study, which was published June 7 in JAMA Internal Medicine, found that taking Paxlovid for 15 days was safe but did not improve key Long COVID symptoms better than a placebo. “I would have loved to bring forward a paper that said, ‘Great benefit,’” says senior author Dr. Upinder Singh, a professor of infectious diseases at Stanford University. Even though that wasn’t the result, Singh says, the study adds to scientists’ collective understanding of Paxlovid and Long COVID, and does not rule out the possibility of more positive results in the future. “Science is generative,” she says. “Data sometimes changes.” Study published in JAMA Internal Medicine (June 7, 2024): https://doi.org/10.1001/jamainternmed.2024.2007
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Juan Lama
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New findings point to the milking process as a possible route of avian-influenza spread between cows — and from cow to human. Milk from cows infected with bird flu contains astronomical numbers of viral particles, which can survive for hours in splattered milk, new data show1,2. The research adds to growing evidence that the act of milking has probably been driving viral transmission among cows, other animals and potentially humans. That’s a better scenario for public health than transmission through airborne particles, which would be more difficult to contain. “It’s good news it’s probably spreading by the milking process,” says Martin Beer, a virologist at the Federal Research Institute for Animal Health in Greifswald, Germany. This means that changes to milking procedures could help to bring the outbreak under control and prevent human infections. A virus that’s going places Since it was first isolated in 19963, the highly pathogenic bird-flu virus H5N1 has caused outbreaks in domestic and wild birds around the world, and it has occasionally infected mammals such as seals and foxes. On 25 March, US health officials announced that H5N1 had been detected in dairy cows for the first time. As of 5 June, infections have been confirmed in more than 80 dairy herds in nine states and in three dairy farm workers, all of whom had mild symptoms. Scientists had not previously suspected that cattle could easily become infected with bird flu, because the animals were thought to lack the receptor that allows the virus to enter their cells. But reports of sick cattle with inflamed udders raised suspicions that the virus can infect the animals’ mammary glands. New studies4,5 support this idea, showing that cells lining cows’ milk glands have abundant receptors for H5N1 and that this bird-flu strain proliferates in these cells rather than in the respiratory tract, which influenza viruses usually infect. “The mammary glands seem to be the main target of viral replication,” says Diego Diel, a virologist at Cornell University in Ithaca, New York, who co-authored one of the studies. But some infected cows also experience mild respiratory symptoms, Diel and his colleagues report. The studies were posted on the preprint server bioRxiv and have not yet been peer reviewed. Viral milkshake Diel and his colleagues examined the milk of cows with H5N1 and found astonishing amounts of virus: some samples contained hundreds of millions of infectious particles, a level “that is higher than we can grow in the lab” for experiments, says Seema Lakdawala, an influenza virologist at Emory University School of Medicine in Atlanta, Georgia. “In ideal conditions, we don’t get that — this is crazy high.” This abundance could help to explain why H5N1 viral fragments have been found in one in five retail milk samples6: a small number of infected cows could taint the milk supply with many particles. (Pasteurization inactivates H5N1 in milk, according to a preprint7 posted last week.) Beer sees opportunity in the sky-high numbers of infectious virus particles in milk. It means that testing milk pooled from all of a farm’s cows is likely to reveal the presence of even a few infected ones, and this is easier than testing individual animals. Pooled testing could inform workers on when to be on the lookout for sick animals, which could then be isolated. Spilt milk The findings suggest that minimizing exposure to raw milk could be an important way to prevent transmission. But the enormous scale of US milking operations means that stopping the spread will be complicated, says Juergen Richt, a veterinary virologist at Kansas State University in Manhattan. To begin with, the same milking equipment is used on many cows, offering the virus ample opportunity to spread. And milking is messy. Milk often spills onto the floor, and when equipment that suctions to cows’ udders is released, the liquid sprays out in every direction. This endangers dairy workers, Lakdawala adds. “That isn’t normally a big deal for people who work there — they’re used to it — but that means they’re bombarded with virus.” Data collected by Lakdawala and her colleagues support her worries: infectious virus can persist in milk droplets and on milking machines for hours, they found. On the basis of these data, she urges farms to consider disinfecting equipment between uses, installing proper ventilation and offering protective equipment, such as face shields, to farm workers to prevent further spread. To complicate matters, lactating cows — infected or not — must be milked regularly to avoid serious injury to the animal. That means that dairy farms, which typically send raw milk to large-scale facilities for processing, need money and equipment to inactivate the virus in milk from infected cows. Otherwise, it might be dumped it in a place where other animals, such as farm cats, could encounter it, Lakdawala says. Richt and his colleagues are collecting data to determine whether non-lactating cows and male cattle are also susceptible to the virus, but for now, he says that focusing on milking can help to control the outbreak. doi: https://doi.org/10.1038/d41586-024-01624-1
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Juan Lama
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In late 2023 an H5N1 lineage of high pathogenicity avian influenza virus (HPAIV) began circulating in American dairy cattle. Concerningly, high titres of virus were detected in cows’ milk, raising the concern that milk could be a route of human infection. Cows’ milk is typically pasteurised to render it safe for human consumption, but the effectiveness of pasteurisation on influenza viruses in milk was uncertain. To assess this, we evaluated heat inactivation in milk for a panel of different influenza viruses. This included human and avian influenza A viruses (IAVs), an influenza D virus that naturally infects cattle, and recombinant IAVs carrying contemporary avian or bovine H5N1 glycoproteins. At pasteurisation temperatures, viral infectivity was rapidly lost and became undetectable before the times recommended for pasteurisation. We then showed that an H5N1 HPAIV in milk was effectively inactivated by a comparable treatment, even though its genetic material remained detectable. We conclude that industry standard pasteurisation conditions should effectively inactivate H5N1 HPAIV in cows’ milk, but that unpasteurised milk could carry infectious influenza viruses. Preptint in medRxiv (May 31, 2024): https://doi.org/10.1101/2024.05.30.24308212
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A new report reinforces that the virus is not going away. Even as national institutions struggle to coordinate meaningful trials for possible long COVID treatments, researchers continue to tally the damage. New findings suggest that the disease’s reach isn’t merely long—it’s still growing. Three years after their initial bouts with COVID-19, patients who’d once been hospitalized with the virus remained at “significantly elevated” risk of death or worsening health from long COVID complications, according to a paper published May 30 in Nature Medicine. Even among those whose initial cases didn’t require a hospital stay, the threat of long COVID and several of its associated issues remained real, the researchers found. And cumulatively, at three years, long COVID results in 91 disability-adjusted life years (DALY) per 1,000 people—DALYs being a measure of years lost to poor health or premature death. That is a higher incidence than either heart disease or cancer. “People are developing new-onset disease as the result of an infection that they had three years ago,” says Dr. Ziyad Al-Aly, a clinical epidemiologist at Washington University in St. Louis and lead author of the study. “It challenges the notion that these viruses are sort of self-contained or that after the acute first phase, they become inconsequential.” With more than 130,000 patients, the study is by far the largest so far to track the progress of the virus over a full three-year period. It expands on work by Al-Aly and others at the two-year mark that found patients had elevated risk for long-COVID-related conditions that included diabetes, lung problems, fatigue, blood clots, and gastrointestinal and musculoskeletal disorders. At three years, Al-Aly tells Fortune, the primary complications among those with mild initial COVID cases were found in the neurological, GI, and pulmonary systems. The persistent risk among those who’d been hospitalized, meanwhile, extended to seven organ systems and included severe conditions such as strokes, heart attacks, heart failure, and even Alzheimer’s disease. The study included nationally recognized researchers Al-Aly and coauthor Dr. Eric Topol, executive vice president and professor of molecular medicine at Scripps Research. It drew from patients within the Veterans Affairs St. Louis Health Care system. As such, the scientists note, the demography skews more male, white, and slightly older than other patient studies might. “The data are encouraging in that there were no new-onset adverse health problems found in the third year after infection,” says Akiko Iwasaki, director of the Center for Infection and Immunity at the Yale University School of Medicine. But Iwasaki, who was not involved in the study, cautioned that some post-acute infection illnesses can turn up years later: “We will need to keep this type of long-term follow-up studies for extended periods.” More health challenges for hospitalized patients Perhaps unsurprisingly, those whose initial COVID cases required hospitalization faced the greatest challenges over the course of the three-year study, a grim reminder that interventions like vaccinations and antivirals are critical, Al-Aly says. (Those in the study were all enrolled during 2020, meaning they were infected largely before vaccines and antivirals were available.) “The story in hospitalized people is more stark,” the researcher says. “They have greater risk and longer risk horizon, with a burden of disease that is astronomically higher than non-infected people and higher than non-hospitalized individuals. Preventing hospitalization is very important.” The risk of new long COVID complications declined over time for both hospitalized and non-hospitalized patients, the study found. “That’s the good news story,” says Al-Aly. The risk of death, meanwhile, became “insignificant” after the first year among those who didn’t have to go to a hospital—that is, most of us who’ve ever been infected by COVID. For those whose cases required hospitalization, though, the threat of death “remained persistently elevated even in the third year,” the researchers said. That group also faced far greater burden of health—about 90 DALYs per 1,000 people, compared to about 10 DALYs per 1,000 for the non-hospitalized group. (For context, both heart disease and cancer cause about 50 DALYs per 1,000 people.) “The difference in DALYs between the two groups should not be interpreted to mean that people with long COVID from less severe acute disease are not suffering greatly as a result of their long COVID symptoms,” says Dr. David Putrino, director of the Cohen Center for Recovery from Complex Chronic Illness at Mt. Sinai School of Medicine. “It only means that at three years out, they’re experiencing less overtly life-threatening sequelae” than those who initially required hospitalization. The stubborn presence of long COVID reinforces the notion that this is no ordinary virus. Viral persistence, chronic inflammation, and immune system dysfunction are all thought by scientists to come into play, though more study is needed. What is the outlook for tackling long COVID? As for the question of what the term long COVID actually means—that is, how long it lasts—the science is still developing, Al-Aly says. He describes long COVID as “this sort of complex web of 80 or more different health problems,” some of which, like stroke or heart disease, could negatively affect patients for the rest of their lives. “We don’t know what we don’t know,” says Al-Aly. “This is only at three years… We don’t know what’s going to happen at 10 years.” The research group is hoping to persuade its funders to continue following the patient cohort for at least that long, he said. For these and other reasons, researchers have led the charge to accelerate the pace of trials for long COVID treatments, the early efforts at which have been criticized for wasting money and critical time. Appearing before a U.S. Senate committee in January, Al-Aly told committee members that at least 20 million people in the country have been hit with long COVID. Globally, that number is estimated to be at least 65 million. That meeting was noteworthy in part because it represented the first Congressional hearing on long COVID since the start of the pandemic. Researchers hope that this latest study will again focus attention on a disease with a long tail and an unknowable future, and perhaps prod the National Institutes of Health to take a bigger swing at the issue. “We need to be much bolder and much more ambitious with our trials,” Al-Aly says. “At the glacial pace that they’re going, we’re unlikely to get any definitive answers for decades to come.” Published in Nat. Medicine (May 30 2024):
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Juan Lama
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May 24, 2024 USDA’s Food Safety and Inspection Service (FSIS), as part of its ongoing efforts to ensure the safety of the food supply, has conducted tests on beef tissue from 96 cull dairy cows condemned at select FSIS-inspected facilities. Meat from condemned cows is prohibited from entering the food supply. On May 22, 2024, viral particles were detected in tissue samples, including muscle, from one cow. To date, samples from 95 cows have tested negative for viral particles. No meat from these dairy cattle entered the food supply. As part of this study, FSIS collected multiple tissues, including muscle samples from the diaphragm, at FSIS-inspected slaughter facilities from cull dairy cattle that have been condemned for systemic diseases. The samples were analyzed by APHIS using PCR to determine presence of viral particles. PCR testing does not differentiate between live virus or fragments. FSIS and APHIS are working together to conduct traceback, including notification to the producer to gather further information. FSIS personnel identified signs of illness in the positive animal during post-mortem inspection and prevented the animal from entering the food supply. This type of inspection is part of routine FSIS operations. These actions provide further confidence that the food safety system we have in place is working. Further updates will be provided as testing is completed. Background USDA is confident that the meat supply is safe. USDA has a rigorous meat inspection process, which includes Food Safety and Inspection Service (FSIS) veterinarians who are present at all federal livestock slaughter facilities. FSIS personnel inspect each animal before slaughter, and all cattle carcasses must pass a second inspection after slaughter and be determined to be fit to enter the human food supply. While we have multiple safeguards in place to protect consumers, we continue to recommend consumers properly handle raw meats and cook to a safe internal temperature. Cooking to a safe internal temperature kills bacteria and viruses in meat. Specific recommendations are available online at: Safe Minimum Internal Temperature Chart | Food Safety and Inspection Service (usda.gov). Ongoing Research To verify the safety of the meat supply in the context of H5N1, USDA’s FSIS, APHIS, and Agricultural Research Service (ARS) are working on three separate beef safety studies related to avian influenza in meat from dairy cattle. These studies are taking place in the interest of scientific inquiry and reaffirm consumer confidence. - Beef muscle sampling of cull dairy cows condemned at select FSIS-inspected slaughter facilities: FSIS completed collection of muscle samples at FSIS-inspected slaughter facilities from cull dairy cattle that have been condemned for systemic disease. No meat from these dairy cattle entered the food supply. The samples were analyzed by APHIS using PCR to determine presence of viral particles. To date, testing has been completed on 96 out of 109 muscle samples that were collected. As of May 22, no viral particles were detected in 95 samples for which testing has been completed. NVSL reported that viral particles were detected in tissue samples, including diaphragm muscle, from one cow. FSIS and APHIS are working together to conduct traceback, including notification to the producer to gather further information. FSIS personnel identified signs of illness in the positive animal during post-mortem inspection and prevented the animal from entering the food supply – as is standard for the food inspection process. These actions provide further confidence that the food safety system we have in place is working. Further updates will be provided as testing is completed.
- Samples of ground beef obtained at retail in the affected States: Final results were posted on May 1, 2024. Samples were collected at retail outlets in the States in which dairy cattle herds have tested positive for H5N1 influenza virus. The samples were analyzed by APHIS using polymerase chain reaction (PCR), to indicate whether any viral particles were present. No virus particles were found to be present.
- Ground beef cooking study: Final results were posted on May 16, 2024. ARS inoculated a very high level of an H5N1 Influenza A virus into 300 grams ground beef patties (burger patties are usually 113 grams) to determine whether FSIS recommended cooking temperatures are effective in inactivating H5N1 virus. The burger patties were then cooked to three different temperatures (120, 145 and 160 degrees Fahrenheit), and virus presence was measured after cooking. There was no virus present in the burgers cooked to 145 (medium) or 160 (well done) degrees, which is FSIS’ recommended cooking temperature. Even cooking burgers to 120 (rare) degrees, which is well below the recommended temperature, substantially inactivated the virus.
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Juan Lama
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Background Molnupiravir and nirmatrelvir-ritonavir (Paxlovid) are oral antivirals that have been proposed as treatments for patients admitted to hospital with COVID-19. Methods In this randomised, controlled, open-label, adaptive platform trial, several potential treatments for patients hospitalised with COVID-19 pneumonia were evaluated. Molnupiravir and nirmatrelvir-ritonavir were assessed in separate comparisons in RECOVERY, both of which are reported here. Eligible and consenting adults could join the molnupiravir comparison, the nirmatrelvir-ritonavir comparison, or both. For each comparison, participants were randomly allocated in a 1:1 ratio to the relevant antiviral (five days of molnupiravir 800mg twice daily or nirmatrelvir-ritonavir 300mg/100mg twice daily) or to usual care without the relevant antiviral drug, using web-based unstratified randomisation with allocation concealment. The primary outcome was 28-day mortality, and secondary outcomes were time to discharge alive from hospital, and among those not on invasive ventilation at baseline, progression to invasive ventilation or death. Analysis was by intention-to-treat. Both comparisons were stopped by the investigators because of low recruitment. ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). Findings From 24 January 2022 to 24 May 2023, 923 patients were recruited to the molnupiravir comparison (445 allocated molnupiravir and 478 allocated usual care), and from 31 March 2022 to 24 May 2023, 137 patients were recruited to the nirmatrelvir-ritonavir comparison (68 allocated nirmatrelvir-ritonavir and 69 allocated usual care). More than three-quarters of the patients in both comparisons were vaccinated and had anti-spike antibodies at randomisation, and more than two-thirds were receiving other SARS-CoV-2 antivirals (including remdesivir or sotrovimab). In the molnupiravir comparison, 74 (17%) patients allocated to molnupiravir and 79 (17%) patients allocated usual care died within 28 days (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.68-1.28; p=0.66). In the nirmatrelvir-ritonavir comparison, 13 (19%) patients allocated nirmatrelvir-ritonavir and 13 (19%) patients allocated usual care died within 28 days (HR 1.02; 95% CI 0.47-2.23; p=0.96). In neither comparison was there evidence of a significant difference in the duration of hospitalisation or the proportion of patients progressing to invasive ventilation or death. Interpretation In adults hospitalised with COVID-19, neither molnupiravir nor nirmatrelvir-ritonavir were associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death although these comparisons had limited statistical power due to low recruitment. Preprint in medRxiv (May 24, 2024): https://doi.org/10.1101/2024.05.23.24307731
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Juan Lama
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WastewaterSCAN Data Dashboard tracks infectious diseases across the US via wastewater surveillance. Wastewater (sewage) is anything but waste. It can provide valuable insights. Scientific advances have made it possible to detect traces of infectious diseases in wastewater — everything from respiratory and gastrointestinal viruses to fungal infections. And the data collected from testing wastewater over time (called “wastewater monitoring”) can be used to inform public health or personal decisions. Wastewater monitoring is efficient, reliable, and anonymous. Samples are collected at sewage treatment plants, where everyone’s waste is combined. Testing these samples can detect infectious diseases even if people don’t feel sick. It can give public health officials a heads up before they start seeing positive tests or increases in people seeking treatment. In short, it can help inform what people do to protect their health.
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Juan Lama
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The aircraft-acquired transmission of SARS-CoV-2 poses a public health risk. Following PRISMA guidelines, we conducted a systematic review and analysis of articles, published prior to vaccines being available, from 24 January 2020 to 20 April 2021 to identify factors important for transmission. Articles were included if they mentioned index cases and identifiable flight duration, and excluded if they discussed non-commercial aircraft, airflow or transmission models, cases without flight data, or that were unable to determine in-flight transmission. From the 15 articles selected for in-depth review, 50 total flights were analyzed by flight duration both as a categorical variable—short (<3 h), medium (3–6 h), or long flights (>6 h)—and as a continuous variable with case counts modeled by negative binomial regression. Compared to short flights without masking, medium and long flights without masking were associated with 4.66-fold increase (95% CI: [1.01, 21.52]; p < 0.0001) and 25.93-fold increase in incidence rates (95% CI: [4.1, 164]; p < 0.0001), respectively; long flights with enforced masking had no transmission reported. A 1 h increase in flight duration was associated with 1.53-fold (95% CI: [1.19, 1.66]; p < 0.001) increase in the incidence rate ratio (IRR) of cases. Masking should be considered for long flights. Published in Int. J. Environ. Res. Public Health (May 21, 2024): https://doi.org/10.3390/ijerph21060654
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Juan Lama
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Spillover of highly pathogenic avian H5N1 into the cattle population poses a risk to humans through the close contact with farm workers. High viral loads of influenza viruses in the unpasteurized milk of infected lactating cows has the potential to contaminate equipment within milking parlors and create fomites for transmission to dairy workers. Cattle H5N1 and human 2009 H1N1 pandemic influenza viruses were found to remain infectious on surfaces commonly found in milking equipment materials for a few hours. The data presented here provide a compelling case for the risk of contaminated surfaces generated during milking to facilitate transmission of H5N1 from cattle-to-cattle and to dairy farm workers. Preprint at medRxiv (May 22, 2024): https://doi.org/10.1101/2024.05.22.24307745
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Juan Lama
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Infections with the highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b virus have resulted in the death of millions of domestic birds and thousands of wild birds in the U.S. since January, 2022. Throughout this outbreak, spillovers of the virus to mammals have been frequently documented. Here, we report the detection of HPAI H5N1 virus in dairy cattle herds across several states in the U.S. The affected cows displayed clinical signs encompassing decreased feed intake, altered fecal consistency, respiratory distress, and decreased milk production with abnormal milk. Infectious virus and RNA were consistently detected in milk collected from affected cows. Viral staining in tissues revealed a distinct tropism of the virus for the epithelial cells lining the alveoli of the mammary gland in cows. Analysis of whole genome sequences obtained from dairy cows, birds, domestic cats, and a racoon from affected farms indicated multidirectional interspecies transmissions. Epidemiologic and genomic data revealed efficient cow-to-cow transmission after healthy cows from an affected farm were transported to a premise in a different state. These results demonstrate the transmission of HPAI H5N1 clade 2.3.4.4b virus at a non-traditional interface and to a new and highly relevant livestock species, underscoring the ability of the virus to cross species barriers. Available in bioRxiv (May 22, 2024): https://doi.org/10.1101/2024.05.22.595317
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In new research, investigators at Massachusetts General Hospital (MGH) show that the 100-year-old Bacillus Calmette-Guérin (BCG) vaccine, originally developed to prevent tuberculosis, protects individuals with type 1 diabetes from severe COVID-19 disease and other infectious diseases. Two back-to-back randomized double-blinded placebo-controlled trials found that the BCG vaccine provided continuous protection for nearly the entire COVID-19 pandemic in the US, regardless of the viral variant. The 18-month Phase III trial, published in iScience, was conducted late in the US pandemic when the highly transmissible Omicron variant was circulating. A 15-month Phase II trial was conducted early in the pandemic; results of that trial were published in Cell Reports Medicine. During the COVID-19 pandemic, several international trials tested if BCG as a single shot, or booster, given to previously BCG-vaccinated adults protected them from infection and COVID-19. This research expanded the large global clinical trial database showing that BCG administered to newborns works as a platform for all infectious disease, maybe for decades. But results from these COVID-19 booster trials in people previously vaccinated with BCG were mixed, with five randomized trials showing efficacy and seven trials showing no benefit. The MGH Phase II and Phase III clinical trials testing BCG differed from other BCG trials in important ways. Instead of receiving one dose of BCG, participants received five or six doses of a particularly potent strain of BCG vaccine. The US participants were followed for a total of 36 months instead of weeks or months. "We know that in people who are naïve to BCG vaccine, the off-target effects can take at least two years to achieve full protection," said Faustman. "Giving multiple doses of the vaccine may speed up that process." And importantly, the US population had never received BCG vaccines, so these clinical trials were not booster trials. "The Phase II and Phase III trials conducted at MGH were unique in that they were the only COVID trials in the world in which the study population had never received a BCG vaccine and was never exposed to TB," said Faustman. "Trials conducted in countries where participants had previously received BCG vaccine as newborns or who had previous exposure to tuberculosis may have obscured any benefit from a BCG booster." The MGH trials enrolled 141 participants with type 1 diabetes; 93 people in the treatment group received five or six doses of BCG vaccine and the 48 individuals in the placebo group received sham vaccine and were followed for 36 months to capture diverse COVID-19 genetic variants and many infectious disease exposures. During the earlier Phase II trial (January 2020 to April 2021) when the virus was more lethal but less transmissible, the BCG vaccine's efficacy was 92%, comparable to the efficacy of the Pfizer and Moderna COVID-19 vaccines in healthy adults. Over the full 34 months of the US COVID-19 pandemic, the BCG vaccine had a significant efficacy of 54.3%. The investigators also found that the BCG-treated participants had lower rates of viral, bacterial, and fungal infections as well as COVID-19 disease itself. The BCG vaccine confers an immunity that likely lasts decades, a clear advantage to the COVID-19 vaccine and vaccines against other infectious diseases, such as influenza, where the duration of effectiveness is only two or three months. "The BCG vaccine offers the prospect of near-lifelong protection against every variant of COVID-19, the flu, respiratory syncytial virus, and other infectious diseases," said Faustman. Some of the BCG-treated participants also received the commercially available COVID-19 vaccines during the Phase III trial. The investigators observed that the Pfizer, Moderna, and Johnson & Johnson vaccines did not protect people with type 1 diabetes against COVID-19. "Our study showed that the BCG vaccine neither increased the efficacy of the COVID-19 vaccine, nor was it harmful to those who received the COVID-19 vaccine," said Faustman. "As the pandemic continues to evolve it will interesting to see if we can work with the FDA to allow access to BCG vaccine for type 1 diabetics, who appear to be particularly at risk for all infectious diseases." Research Cited Published in IScience (May 22, 2024): https://doi.org/10.1016/j.isci.2024.109881
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How easy is it to switch from seasonal to pandemic flu vaccine production? Does a bird flu vaccine for cows make sense? The answers are complicated. If the H5N1 bird flu virus ever acquires the ability to transmit easily to and among people — keep your fingers crossed that it doesn’t — the world is going to need serious amounts of vaccine. Like, lakes of the stuff. Some manufacturers have been working with H5N1 viruses for years, producing small batches of doses that have undergone preliminary human testing. Some millions of doses — in the low double digits — have even been stockpiled by the U.S. government. But deciding when to start producing H5 vaccine at scale, in the quantities needed to vaccinate the world, is no easy feat. It’s a high-cost, high-risk endeavor. Get it right and you save lives. Hesitate, and lives will be lost. But making the call if the vaccine turns out not to be needed is not a cost-free decision either. There are some obvious questions that come to mind when you start thinking about what might trigger mass production of H5N1 vaccine. Here are a few, and some things to think about to help make sense of a truly complicated situation. Given the concern about H5N1 in dairy cattle, why not just start making H5N1 vax now, in case we need it? The global capacity to make flu vaccine is in the range of about 1.2 billion trivalent (three components in one) doses of vaccine a year, according to a market assessment the World Health Organization published in January. Most of the year, that production capacity is in use doing what it was built to do, making seasonal flu vaccine for the Northern and Southern hemisphere flu seasons. In the weeks between those two runs, plant maintenance is typically done. In a flu pandemic, the output of all those production lines would shift to making pandemic vaccine to protect against the new strain of flu that would likely be triggering large waves of illness worldwide. Here’s the thing. The production lines can make seasonal flu vaccine. Or they can make pandemic flu vaccine. They cannot make both at the same time. That’s why deciding to make pandemic flu vaccine at scale is not a no-cost decision. “You can’t just press the button and begin producing pandemic H5 vaccines. You have to stop producing your seasonal vaccine, and all of you out there know how lifesaving that vaccine is,” Mike Ryan, head of the WHO’s health emergencies program, told reporters at a press conference earlier this month. “So, this requires a very careful consideration.” When decisions like these have to be made, it’s not clear how things are going to play out. A new virus might cause a devastating pandemic. Or, as was the case in the 2009 H1N1 pandemic, it might trigger an event that is so mild that politicians will later question whether an emergency response was needed. (In a recent interview, Tom Frieden, who was director of the Centers for Disease Control and Prevention during the H1N1 pandemic, called it “a pimple of a pandemic.”) In 2009, the world didn’t really have to make a tough decision about whether to stop seasonal flu vaccine production, said Marie-Paule Kieny, who was WHO’s assistant director-general for health systems and innovation at the time. (Kieny has since retired from the global health agency.) That’s because production of the seasonal vaccine for the 2009-2010 Northern Hemisphere winter was almost completed when it became clear the new virus had triggered a pandemic. But another time, a decision might have to be taken to abort the seasonal flu vaccine effort to switch to pandemic vaccine — a decision that would be costly for producers. In most cases, manufacturers only get paid for vaccines they deliver, and if they have to junk a run of seasonal flu vaccine because the client decides it wants pandemic, not seasonal flu vaccine, they have to absorb those costs, said Paula Barbosa, associate director for vaccine policy for the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA). Sure, they’d probably end up selling all the pandemic vaccine doses they could make, as quickly as they could make them. But the costs associated with the abandoned run would eat into those profits. “Individual companies might have specific agreements with certain countries, but overall, what is lost, it’s on the manufacturers,” Barbosa said. There can be opportunity costs as well. At a point during the Covid-19 pandemic, when global vaccine production was operating at full steam, there was a global shortage of glass for vaccine vials. Everything used in vaccine production — the eggs viruses are grown in for most of the traditional flu vaccine manufacturing, the equipment needed to administer vaccines — would likely be in short supply in a serious pandemic. Using any of this stuff to make or administer seasonal vaccine when pandemic vaccine is needed would be a wasted opportunity. “You have to be totally conscious that, especially when you get to a global scale, it’s syringes, it’s needles, vials. It’s the capacity to fill and finish the vaccine. We don’t have that at global scale and most of it, like the antigen, or much of it is concentrated in better-off countries. So yeah, there is a huge supply chain and logistics challenge if we have a global pandemic,” said Jesse Goodman, who was director of the Food and Drug Administration’s Center for Biologics Evaluation and Research during the 2009 pandemic. Goodman is now director of the Center on Medical Product Access, Safety and Stewardship at Georgetown University. Barbosa pointed out another cost of switching into pandemic vaccine production mode. Big manufacturers, like Sanofi and CSL Seqirus, run their flu vaccine production facilities year round, serving clients in both hemispheres. But some smaller companies that make flu vaccine for local markets make it half the year and produce pediatric vaccines the rest of the time. Switching to pandemic flu vaccine production could mean essential childhood vaccines aren’t available for some period of time, Barbosa said. “We really need a process to altogether take that decision and then for there to be a full understanding of what are the consequences, not only for manufacturers, but for worldwide vaccine production,” she said. Is there a process? Is it clear how a decision to make H5N1 vaccine will be made? “Nothing is clear,” said Kieny. After the 2009 pandemic, the WHO held a series of three meetings with industry, regulators, and national authorities to try to figure out whether a framework for making a switch from seasonal to pandemic production could be devised. Industry very much wanted to know they would be issued marching orders. They still do. “Manufacturers themselves cannot be responsible for this decision,” Barbosa said. “Right now there is no formal process to tell all manufacturers to switch from seasonal vaccine production to pandemic production. Industry does need a clear signal to do that switch even fully or partially,” she said. “WHO declaring a pandemic is helpful. But it might not be enough. For instance, if it’s a pandemic, and the pandemic virus causes milder disease … there may not be a need to manufacture a pandemic vaccine at all.” The WHO-led consultations, which were held from 2013 through 2017, did not result in a firm plan for how to do this. It wasn’t clear that anyone wanted to own this decision-making responsibility, Kieny said — “at least until the situation gets really bad.” Gary Grohmann, who used to be the head of immunobiology for Australia’s Therapeutic Goods Administration — its FDA-equivalent — was involved in those meetings. He suggested individual countries will give manufacturers they purchase from directions, based on the best advice available from their public health agencies, and from the WHO. When it perceives there is a need, the latter will make a recommendation that pandemic flu vaccine production begin, Grohmann said. “That will be only a recommendation. And it would be up to the individual countries to make the decision and then ask their manufacturers … to make their vaccines and to stop production, possibly, of other vaccines,” he said. Major manufacturers, though, sell to multiple clients. What if the country in which the plant is housed wants to start pandemic vaccine production, but another important client wants to proceed with seasonal production, in case the pandemic doesn’t take off? Kieny believes some big national governments may get the ball rolling when they decide it’s time to buy pandemic vaccine. “It depends when the big customers, and especially the U.S., will say, ‘We think that it’s worth putting the money on the table.’ Then everyone will rush and do the same,” she said. “It’s not a question of a switch. It’s a question of a decision. And it’s a financial decision to invest.” That could be particularly true in the wake of the Covid pandemic, when messenger RNA vaccines made their global debut, especially if a flu pandemic were to happen in the near term. A number of the mRNA manufacturers, Pfizer and Moderna among them, have been working on, but have not yet licensed, seasonal flu vaccines. Without a seasonal product line to disrupt, it would be easier for those players to make pandemic vaccine — should they choose to enter the market. But there would need to be the promise of sales. “For vaccine lines that aren’t used for flu now, the decision isn’t to switch, it’s whether to invest and when to start producing,” Kieny said. Wenqing Zhang, head of the WHO’s global influenza program, said after its 2017 consultation with stakeholders, the WHO revisited the whole question of how pandemic influenza vaccine production would be triggered, eventually coming up with a document called the Pandemic Influenza Vaccine Response-Operational Framework. The document, finalized in 2022, has not been published, she said, because some items in it touch on issues that are up for negotiation in the ongoing efforts to update the International Health Regulations. Zhang said the document, which is not available online, acknowledges that manufacturers would need a signal from the WHO that a pandemic may be underway. But the WHO declaration would be about the risk that the virus poses, she said. Whether the document will be published as is or will require revisions will depend on the outcome of the IHR negotiations. So watch this space. Flu vaccine manufacturers just took a component out of the seasonal vaccine, the influenza B/Yamagata virus that disappeared during the Covid-19 pandemic. Why not use that space in the seasonal shot to start protecting people against H5N1? Goodman actually advocates something similar: He’d like to see H5N1 vaccine made in a monovalent shot — in other words, not combined with vaccines targeting seasonal flu viruses — that people could opt to get if they wanted to start protecting themselves against this virus. He proposed it in an article in Clinical Infectious Diseases in 2016. Rather than stockpile vaccine against H5, stockpile immunity in people, he argues. “Even if this particular threat” — the H5N1 outbreak in cows — “doesn’t turn into a pandemic, I do think it should give further impetus to really thinking about doing that,” he told STAT. But the idea of bundling H5N1 vaccine into the seasonal flu shot would cause regulatory challenges. The virus is not very immunogenic, meaning it doesn’t trigger a strong immune response in people. Research done nearly 20 years agoshowed that in order to achieve what would probably be a protective response, the vaccine would need to be given in two massive doses; later research showed two regular sized doses with an adjuvant, a compound that boosts the immune response a vaccine generates, would likely provide protection. Most seasonal flu shots do not contain an adjuvant — the sole exception is a vaccine for seniors sold by Seqirus, which contains the company’s MF-59 adjuvant. Adding an adjuvant to the seasonal shots would change the vaccines enough that new licenses might be needed — a big lift for manufacturers. In addition, studies would be needed to make sure that the H5N1 component did not erode the immune response to the other components of the vaccines. Zhang said that before H5N1 or another potential pandemic vaccine could be used in this way there would need to be more research. There’s no data, she noted, on what happens after repeated vaccination against H5N1. And it’s not clear when would be the best time to give it, because immunity induced by vaccination will wane over time. “All these, I think, are research questions that need to be addressed,” she said. If vaccinating people is such a tough call to make, why not just vaccinate the cows? This may turn out to be something that happens, but it’s still very early days. Some makers of animal vaccines are reportedly working on developing H5N1 vaccines for cows. But there are still a lot of questions that need answering before farmers are likely to embrace this approach, said Meghan Davis, a dairy and mixed animal veterinarian who does “One Health” research in Johns Hopkins University’s department of environmental health and engineering and school of medicine. (One Health is a term that refers to the intersection of human and animal health.) “I think we do not have enough information right now to address the really pragmatic questions that dairy producers are going to have, if they’re going to spend money for this,” Davis told STAT. Farmers will want to know who is going to pay for a vaccine that they may be mainly using to lower the risk that H5N1 will spill over from cows to people. Though animal vaccines can be much less expensive than the human equivalents, the price of the serum itself is not the only cost of an immunization program. If a vaccine has to be administered by a veterinarian, that adds to the cost. If it has to be given more than once, the cost goes up. Will all cows need it, or could you target only lactating cattle? How long will the immunity the vaccine induces last? “Without the answers to those questions, you really can’t think about your cost benefit at all,” she said. But Davis said farmers may see advantages of vaccination. The impact of H5N1 in cows is still coming into view because farmers have been pretty close-mouthed about what they are experiencing when the virus moves into a herd. However, word is starting to emerge that some of the affected cows do not return to pre-infection milk production levels, that when they recover from the infection some experience a “deficit,” Davis said. “Now you’ve got a cow who’s not going to produce as much as she would have produced at that point in her lactation.” In such cases, farmers may decide to send cows like these to slaughter earlier than otherwise would have been the case, getting fewer years of production out of these animals. If a vaccine prevented infection and protected against a drop in production, that might change the economics of the approach, she said. Another issue related to vaccination of animals against H5N1 relates to international trade. Though the World Organization for Animal Health — the animal equivalent of the World Health Organization — recommends against it, some countries restrict imports of poultry that have been vaccinated against avian influenza strains, because testing can’t easily differentiate between antibodies that are the result of previous infection or vaccination. Davis said this may be less of an issue for dairy cattle, as milk sales are more local and regional than international, but she noted it might be an issue for cheeses.
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The case marks the first detection of the highly pathogenic strain of bird flu on the continent. Australia has reported its first human case of the H5N1 avian influenza in a child who recently returned from India. The case marks the first time the highly pathogenic strain of bird flu, which has killed millions of birds and mammals since it began circulating in 2020, has been detected on the continent. The child contracted the virus in India in March of this year - likely through contact with a sick bird - and experienced a “severe infection,” but has since made a full recovery, according to local health authorities. Officials said contact tracing has not identified any further infections and that the risk of transmission to others was “very low”, as the virus has not yet shown evidence that it can spread between people. The Department of Health in the Australian state of Victoria, where the human case was identified, are also responding to an outbreak of avian influenza at a poultry farm but has said that it is an unrelated incident. Although H5N1 infections in people are rare, the highly pathogenic virus carries an alarmingly high mortality rate. Of the 800 cases reported since the late 1990s, roughly 50 per cent resulted in death. The virus has recently broken out among dairy cattle in the US in an unprecedented outbreak. So far, 51 herds in nine US states have been affected, although experts think it is far more widespread. The apparent ability of the virus to spread between cows is significant because it provides more opportunities for it to evolve to better infect and spread between other mammals. Of particular concern is whether H5N1 might now be able to infect pigs, often described as ‘mixing vessels’ for influenza and making it more likely that the virus could adapt to spread between humans. So far this year, there have been two other confirmed human cases of H5N1. In Vietnam, a man died in March after direct contact with an infected bird, whilst in Texas a farm worker caught the virus from sick cattle – although his symptoms were mild. The US Centre for Disease Control is monitoring a further 300 people who have been exposed to the virus via cattle for signs of infection. The WHO still considers the risk to humans low but urged countries to rapidly share information to enable real-time monitoring of the situation to ensure preparedness as the virus continues to spread.
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