In the current study, nanopore direct RNA sequencing and liquid chromatography-tandem mass spectrometry (LCMS/MS) analysis were employed to examine whether DVGs can encode proteins in infected cells. With the protein databases generated by nanopore direct RNA sequencing, six DVG-encoded proteins were identified by LCMS/MS based on the featured fusion peptides caused by recombination during DVG synthesis. The limitations and the biological significance of the study are discussed.
Below, we explain why 34,104 (by total cell lysates) and 34,056 (by cell lysates derived from RNAprotein pull-down assay) protein species were identified by LCMS/MS analysis. First, coronavirus DVGs are recombination products and thus contain ORFs of various lengths from one or more portions of ORFs in the full-length genome. As a result, many DVG species (145,015) are identified by nanopore direct RNA sequencing, and thus, many potential DVG-encoded protein sequences (189,221) can be used as protein reference databases for LCMS/MS. Second, the diverse genome structures of DVGs may encode in-frame peptides that have the same amino sequences as those encoded from the full-length genome. Consequently, if the peptides determined by LCMS/MS analysis match the amino acid sequences of the DVG-encoded proteins and the protein scores are higher than 41, the DVG-encoded protein species can be identified based on the provided protein reference databases. Consequently, many DVG-encoded protein species (34,104 from total cell lysates, and 34,056 from cell lysates by RNAprotein pull-down assay) were identified by LCMS/MS analysis. However, this may lead to false-positive results because the peptides that match the amino acid sequence of DVG-encoded proteins may also be encoded from the full-length coronavirus genome, as described above, and thus cannot be used as markers to determine whether the identified proteins are encoded by coronavirus DVGs. That is also the reason why we propose that if the peptides contain discontinuous in-frame amino acid sequences derived from different portions of amino acid sequences from full-length genome-encoded proteins or contain out-of-frame amino sequences, the peptides are fusion peptides encoded from DVGs because DVGs are synthesized by recombination of the viral genome. Therefore, these fusion peptides can be used as markers to identify the proteins actually encoded by coronavirus DVGs. Consequently, 6 DVG-encoded proteins were identified through the identification of 6 fusion peptides, as shown in Figs.1, 2 and 3.
In addition, because the read number for the 6 DVGs is low (only 1), whether there is a correlation between the abundance of DVGs identified by nanopore direct RNA sequencing and that of their encoded proteins identified by LC-MS/MS remains unknown. Our explanation for the results is as follows. Because coronavirus DVGs are recombination products and thus contain ORFs of various lengths from one or more portions of ORFs derived from the full-length genome, the diverse genome structures of DVGs may encode in-frame peptides that have the same amino sequences as those encoded from the full-length genome. Consequently, if the peptides determined by LC-MS/MS analysis match the amino acid sequences of DVG-encode proteins and the protein scores are higher than 41, the DVG-encoded protein species are identified based on the provided protein reference databases. However, the peptides which match the amino acid sequence of DVG-encoded proteins may also be encoded from full-length coronavirus genome, and thus we cannot determine whether the identified peptides and thus the proteins are encoded from coronavirus DVGs or full-length genome. Consequently, DVG species with higher read numbers may encode more proteins, but without the featured fusion peptides as markers, whether there is a correlation between the abundance of DVGs identified by nanopore direct RNA sequencing and that of their encoded proteins identified by LC-MS/MS still cannot be determined. That is also the reason why we propose that, as described above, if the peptides contain discontinuous in-frame amino acid sequences derived from different portions of amino acid sequences from full-length genome-encoded proteins, or contain out-of-frame amino sequences, they are fusion peptides encoded from DVGs. Thus, at the current stage, we can only conclude that DVG can encode protein, and whether there is a correlation between the abundance of DVGs and that of their encoded proteins remains unknown. However, since the identified 6 DVGs with read number of 1 have the capability to encode proteins as determined by the current study, we can speculate that other DVG species with higher read numbers may also have the capability to encode protein although they cannot encode featured fusion peptide as markers to determine the proteins-coding capability.
It has been known that (i) coronavirus DVGs can be packaged [31], (ii) coronavirus N protein can inhibit host innate immunity [32] and (iii) innate immunity is the first line of host defense against virus infection [33]. In addition, based on the protein databases derived from the results of nanopore direct RNA sequencing in the current study, it is suggested that some DVG-encoded fusion proteins contain part or complete N protein. It is therefore speculated that one of the functions for coronavirus DVG-encoded fusion proteins is to regulate innate immunity, affecting virus replication and subsequent pathogenicity. On the other hand, coronavirus N protein has also been suggested to be important for replication and transcription (synthesis of coronavirus sgmRNAs including sgmRNA N) [34, 35]. However, N protein can only be synthesized from sgmRNA N, and consequently, the question is how coronavirus genome replicates and transcribes sgmRNAs before N protein is synthesized. As described above, because (i) coronavirus DVGs can be packaged [31], (ii) some DVGs contain partial or complete N protein ORF and (iii) DVGs can be translated as evidenced by the results of the current study, it is also argued that, after entry into the cells, the released DVGs with partial or complete N protein ORF can be immediately translated into N-containing fusion proteins, which in turn can facilitate the full-length coronavirus genome for subsequent replication and transcription before N protein is synthesized from sgmRNA N. According to the argument above, the DVG-encoded fusion proteins in coronaviruses including SARS-CoV-2 may have impact on pathogenesis through affecting innate immunity and replication. Lastly, it is also proposed that other coronavirus DVGs which encode other species of fusion proteins or out-of-frame novel proteins (when compared with the original ORFs in the full-length genome) may have different effects from those described above on pathogenesis although the functions of their encoded proteins remain to be determined. It is worth noting that, based on the previous study [26], the species and amounts of DVGs can be altered under different infection conditions such as in different infected cells and under different selection pressures. Since DVGs can encode various proteins, such alterations in the amounts and species of DVGs and thus the encoded proteins may be a way for coronavirus to respond to environmental changes, also contributing to the coronavirus pathogenesis.
The possible reasons why the featured fusion peptide was not detected in the total cell lysates by LCMS/MS are as follows. First, because there are too many species of DVGs in cells, the amount of each DVG-encoded protein (especially the protein with the featured fusion peptide) in a fixed amount of cell lysate may not be sufficient to be detected by LCMS/MS. Second, not every DVG-encoded protein contains the featured fusion peptides (based on the protein reference databases generated by nanopore direct RNA sequencing for BCoV), further limiting the identified number of protein species. Third, because SuperScript III reverse transcriptase (cat No. 18,080,044, Thermo Fisher Scientific, Waltham, USA), which is optimized to synthesize first-strand cDNA up to ~12kb, was used for nanopore direct RNA sequencing, the identified coronaviral RNA species, including DVGs, may not cover all coronavirus transcripts, especially those of longer size. Thus, the protein reference databases may not contain the full information of the DVG-encoded proteins, limiting the number of protein species identified by LCMS/MS analysis.
As shown in Figs.1, 2 and 3, it is suggested that DVGs have the capability to encode proteins as determined by RNAprotein pull-down assay followed by LCMS/MS. The results indicate that other DVGs may also have the capability to encode proteins. Consequently, the DVG-encoded proteins may play important roles during coronavirus infection. Thus, the current results may suggest an attractive field of study regarding the biological functions of proteins encoded by DVGs. Determining the function of DVG-encoded proteins is a priority to understand their roles in coronavirus pathogenesis. The outcomes of these studies may contribute to the development of antiviral strategies.
Merideth Schlader of Summerhill said she learned a valuable lesson during the COVID-19 pandemic shell carry with her to the next one.
You have to make an effort to stay connected, she said.
Schlader practiced what she preached recently, drinking coffee with two friends, Cathy Smith of Cortland and Shannon Eggleston of McGraw, discussing a faith-based book theyd read together.
Jeri Shirk of Cortland said she was disappointed by how political the COVID-19 pandemic became, and hopes the next one wont be the same.
And there will be a next one, experts said. Another pandemic, whether a new strain of COVID or otherwise, is inevitable.
The last pandemic, the Spanish flu of 1918 to 1920, killed 50 million of the worlds 1.9 billion people about 2.6% of the world population, historians estimate.
World War I slowed response. The first cases were actually reported in Kansas, and migrated to Europe, and the trenches thereof, with U.S. soldiers heading to war. But nervous nations didnt want an international panic, so widespread awareness came only after the flu was reported in Spain, a non-combatant.
The coronavirus pandemic has several parallels. It has killed nearly 7 million of the worlds 8 billion people since 2020, about 0.09%, a number achieved with a fast-paced vaccine program, better drug treatment and better technology in respirators than a century ago.
HEALTH OFFICIALS PREPARING
The COVID-19 pandemic showed a public health threat can affect the whole world, said Nicole Anjeski, Cortland County public health director. COVID had profound effects on not only physical health, but the health of economic and political systems worldwide.
We may not understand the full impact of this pandemic for years to come, Anjeski said. Individuals, local and federal governments, medical professionals, nonprofits and businesses had to work together to mitigate the effects of the pandemic.
Communication, Anjeski said, is among the most important tools of dealing with mass health events, a hard lesson learned early when miscommunication, unclear messaging and uncertainty marred health departments ability to communicate with communities.
For future pandemics, the health department annually reviews and updates emergency preparedness plans. It has yearly drills, too.
We actively explore the most appropriate and efficient ways to provide transparent communication with the community, and we continue to foster relationships we have built with our local health systems, physicians, community organizations and agencies, local leaders and state partners, Anjeski said.
IT TAKES ALL OF US
Frank Kruppa, commissioner of Tompkins County Whole Health, that countys public health department, said after 9/11 and the 2001 anthrax attacks when letters laced with toxic anthrax went out across the country Tompkins and health departments across the country began constant planning for public health threats.
COVID-19 strained that preparedness, Kruppa said. Before COVID, health departments prepared for shorter-term, acute events, not widespread crises.
The pandemic taught Tompkins to build its resources, with more vaccines, with partners and with connecting with the public and media, he said. Communication is vital to navigating a mass public health event.
Whether its county government, the community, nonprofits, businesses, we need to see how we make sure we all understand or have some understanding of a plan, and where everyone might fit in, Kruppa said. One of the positives out of this is a broader understanding with governments, businesses, nonprofits, of how it takes all of us to respond.
NOT THE FIRST RODEO
Nellie Brown, director of workplace health and safety programs for the Buffalo Co-Lab of Cornell Universitys School of Industrial and Labor Relations, said many factors could aggravate the next pandemic.
Our diseases over the centuries tend to indicate they jump from animals to people, the next one will probably be something similar, Brown said.
Climate change and human development exacerbate their spread, Brown said.
Were seeing huge amounts of extremes in our climate. That can cause a lot of animals to move. When you have animals that are forced to move or chased out, then animals we may not have had contact with are driven into contact with humans, Brown said.
Theres debate on the matter, but Brown said most evidence indicates droughts facilitate diseases.
When water dries up, organisms become more concentrated, and at the same time you have people unable to clean things or bathe. That makes things a lot more difficult, she said.
In 2009, with the H1N1 epidemic, the U.S. attitude was that it didnt need to plan because its medical system could handle anything, Brown said.
Now look at what happened in 2020, she said. Failure to plan is a huge issue.
Brown said the country shouldnt rely on the marketplace to provide treatments and vaccines.
Yes, it takes money to research and develop drugs and antivirals. It takes a lot of money, she said, but profit shouldnt be a major motive. Dont let the marketplace drive this because we need to be on the watch all the time, not just wait and see what drug will be profitable.
NONPROFITS ADAPT
If theres another situation like COVID, I think were pretty well prepared, said Jackie Leaf, executive director of Seven Valleys Health Coalition. Whether were helping with clinics or materials we would be there to back them up. As things wound down, I think we had pretty good systems, Im not sure what we would do differently.
Seven Valleys has a food rescue program. When farmers were told to dump milk, even as there were shortages on store shelves because production lines geared for single-serving and commercial containers couldnt be converted to half-gallon and gallon jugs fast enough the organization received excess milk and passed it out for free.
Were more prepared than we were the first time as far as food assistance, Leaf said. With its new food rescue facility, Seven Valleys can store and refrigerate fresh food.
FOOD SYSTEMS
Cortlandville dairy farmer Paul Fouts said theres only so much farmers can do to untie tangles in the food processing and distribution system. Dairy farmers, if they have the space and resources, could add storage tanks, a short-term solution not accessible to every dairy, especially smaller operations.
I dont know how they would do it, but there really needs to be some flexibility in the processing sector, Fouts said. The plants set up to process milk appropriate for food service suddenly couldnt process milk because it had nowhere to go.
Buying from local farms, Fouts said, could relieve supply issues.
Local food suppliers are more resilient against supply chain disruptions, shows a 2021 study by the World Economic Forum. Large, pervasive food systems are more vulnerable to supply shocks, whereas local producers are less dependent on large-scale labor, transportation or distribution.
STEPPING UP
Christella Yonta, president of the Cortland County United Way, said in the event of another global outbreak, the organization would do just what it did the first time to help distribute food.
At the time of the pandemic, the United Way was uniquely positioned to manage through it, and by that I mean we already had a well-established network of community partners, Yonta said.
Normally, United Way acts strictly as a fundraising distributor. During COVID, Yonta and her staff distributed food and masks instead of money. Yonta arranged with DoorDash to deliver food, a relationship Yonta says will continue.
Today, she said, the United Way and its counterparts are better connected and know more about what to expect.
We just had to step up, Yonta said And well do it again.
A systematic review and meta-analysis estimates a nearly 50% long-COVID rate months after infection in Africa, with psychiatric conditions the most common manifestations.
Published today in Scientific Reports, the February 2023 literature search and analysis involved 25 observational, English language long-COVID studies with 29,213 infected African patients.
Nearly half (48%) of the studies were from Egypt, the average patient age was 42years (range, 7 to 73 years), 59.3% were females, and the median follow-up was 3 months.
"In low-income countries, the estimates of its [long COVID's] incidence vary greatly due to a significant number of hidden infections (i.e., asymptomatic or undisclosed) and difficulties in accessing testing," the study authors wrote.
The team, led by researchers from the University of Bari in Italy, found a long-COVID rate of 48.6%, with a predominance of psychiatric conditions, especially post-traumatic stress disorder (25.8%).
The most common neurologic symptom was cognitive impairment (15%), and shortness of breath was the most common respiratory symptom (18.3%), followed by cough (10.7%). Other notable symptoms were loss of appetite (12.7%), weight loss (10.4%), fatigue (35.4%), and muscle pain (15.5%). A quarter (25.4%) of patients reported poor quality of life.
The high incidence of fatigue is particularly worrisome because of its debilitating nature. "This is concerning because, in Africa, it has the potential to lead to important impairment in productivity and further loss of economic agency," the researchers wrote.
The study recommends identifying at-risk people and defining treatment strategies and recommendations for African long-COVID patients.
Likewise, the mental illness burden in long-COVID patients poses a challenge on a continent with few mental health resources: "These findings highlight the pressing need for immediate policy implementation and reallocation of resources to address this severely underestimated public health issue."
Risk factors for long COVID included older age and hospitalization during infection.
"The study recommends identifying at-risk people and defining treatment strategies and recommendations for African long-COVID patients," the authors concluded, noting that high-quality studies are urgently needed.
As the holiday and peak respiratory seasons collide, and COVID-19 cases continue a steady, weeks-long climb, doctors want high-risk people to remember: Should COVID catch them in the coming days, one call to the doctor could save Christmas or more.
Paxlovid, an antiviral COVID therapy given under emergency use authorization (EUA) during the pandemic and now approved by prescription, prevents hospitalization and death between 60% and 80% of the time. The Food and Drug Administration (FDA) approved the drug in May for mild to moderate COVID in adults at high risk of developing severe illness.
State Hospitalizations Since Oct. 1 (as of Dec. 5)
Over the past month, theres been a steady increase in both emergency room visits and hospitalizations for COVID, said Thomas Campbell, MD, a professor of infectious diseases at the University of Colorado School of Medicine. Yet uptake of Paxlovid remains relatively low, with experts attributing fears of a rebound effect and a long list of drug interactions.
Campbell advises people to at least make that call. Doctors can help weigh whether risks outweigh benefits, find alternatives to some drugs that have interactions and even offer alternative therapies in some cases, he said.
Its important that to have its maximum benefit, Paxlovid is started as soon as possible after the onset of symptoms not after diagnosis and no more than five days after onset, Campbell said. Anyone with at least one high-risk factor should talk with their doctors, he said.
Nearly three-quarters of Americans fall in that group, with risk factors including diabetes, obesity, asthma, heart disease and being 50 or older so prevalent. High-risk youth between 12 and 18 years old can still receive Paxlovid under the EUA, and adults can receive a prescription directly from a pharmacist supplied with required health information.
As all emerging variants still reside within the omicron family, the newest booster shot, which wholly targets omicron, remains the best defense, Campbell said. And Paxlovid has maintained its effectiveness against the new variants, he said.
In the following Q&A, Campbell discusses pros and cons of Paxlovid and its alternatives as well as potential new options on the horizon, including one new drug targeting non-high-risk patients undergoing a clinical trial he is currently leading at the CU Anschutz Medical Campus.
From infections with no symptoms to why men are more likely to be hospitalized in the ICU and die of COVID-19, new research shows that your genes play a significant role
Early in the pandemic, genetic research focused on the virus because it was readily available. Plus, the virus contains only 30,000 bases in a dozen functional genes, so it's relatively easy and affordable to sequence. Additionally, the rapid mutation of the virus and its ability to escape antibody control fueled waves of different variants and provided a reason to follow viral genetics.
In comparison, there are many more genes of the human immune system and cellular functions that affect viral replication, with about 3.2 billion base pairs. Human studies require samples from large numbers of people, the analysis of each sample is vastly more complex, and sophisticated computer analysis often is required to make sense of the raw data. All of this takes time and large amounts of money, but important findings are beginning to emerge.
Asymptomatics
About half the people exposed to SARS-CoV-2, the virus that causes the COVID-19 disease, never develop symptoms of this disease, or their symptoms are so mild they often go unnoticed. One piece of understanding the phenomena came when researchers showed that exposure to OC43, a common coronavirus that results in symptoms of a cold, generates immune system T cells that also help protect against SARS-CoV-2.
Jill Hollenbach, an immunologist at the University of California at San Francisco, sought to identify the gene behind that immune protection. Most COVID-19 genetic studies are done with the most seriously ill patients because they are hospitalized and thus available. But 99 percent of people who get it will never see the inside of a hospital for COVID-19, she says. They are home, they are not interacting with the health care system.
Early in the pandemic, when most labs were shut down, she tapped into the National Bone Marrow Donor Program database. It contains detailed information on donor human leukocyte antigens (HLAs), key genes in the immune system that must match up between donor and recipient for successful transplants of marrow or organs. Each HLA can contain alleles, slight molecular differences in the DNA of the HLA, which can affect its function. Potential HLA combinations can number in the tens of thousands across the world, says Hollenbach, but each person has a smaller number of those possible variants.
She teamed up with the COVID-19 Citizen Science Study a smartphone-based study to track COVID-19 symptoms and outcomes, to ask persons in the bone marrow donor registry about COVID-19. The study enlisted more than 30,000 volunteers. Those volunteers already had their HLAs annotated by the registry, and 1,428 tested positive for the virus.
Analyzing five key HLAs, she found an allele in the gene HLA-B*15:01 that was significantly overrepresented in people who didnt have any symptoms. The effect was even stronger if a person had inherited the allele from both parents; these persons were more than eight times more likely to remain asymptomatic than persons who did not carry the genetic variant, she says. Altogether this HLA was present in about 10 percent of the general European population but double that percentage in the asymptomatic group. Hollenbach and her colleagues were able confirm this in other different groups of patients.
What made the allele so potent against SARS-CoV-2? Part of the answer came from x-ray crystallography. A key element was the molecular shape of parts of the cold virus OC43 and SARS-CoV-2. They were virtually identical, and the allele could bind very tightly to them, present their molecular antigens to T cells, and generate an extremely potent T cell response to the viruses. And for whatever reasons that generated a lot of memory T cells that are going to stick around for a long time, says Hollenbach. This T cell response is very early in infection and ramps up very quickly, even before the antibody response.
Understanding the genetics of the immune response to SARS-CoV-2 is important because it provides clues into the conditions of T cells and antigens that support a response without any symptoms, she says. It gives us an opportunity to think about whether this might be a vaccine design strategy.
Dead men
A researcher at the Leibniz Institute of Virology in Hamburg Germany, Guelsah Gabriel, was drawn to a question at the other end of the COVID-19 spectrum: why men more likely to be hospitalized and die from the infection. It wasn't that men were any more likely to be exposed to the virus but more likely, how their immune system reacted to it
Several studies had noted that testosterone levels were significantly lower in men hospitalized with COVID-19. And, in general, the lower the testosterone, the worse the prognosis. A year after recovery, about 30 percent of men still had lower than normal levels of testosterone, a condition known as hypogonadism. Most of the men also had elevated levels of estradiol, a female hormone (https://pubmed.ncbi.nlm.nih.gov/34402750/).
Every cell has a sex, expressing receptors for male and female hormones on their surface. Hormones docking with these receptors affect the cells' internal function and the signals they send to other cells. The number and role of these receptors varies from tissue to tissue.
Gabriel began her search by examining whole exome sequences, the protein-coding part of the genome, for key enzymes involved in the metabolism of sex hormones. The research team quickly zeroed in on CYP19A1, an enzyme that converts testosterone to estradiol. The gene that produces this enzyme has a number of different alleles, the molecular variants that affect the enzyme's rate of metabolizing the sex hormones. One genetic variant, CYP19A1 (Thr201Met), is typically found in 6.2 percent of all people, both men and women, but remarkably, they found it in 68.7 percent of men who were hospitalized with COVID-19.
Lung surprise
Lungs are the tissue most affected in COVID-19 disease. Gabriel wondered if the virus might be affecting expression of their target gene in the lung so that it produces more of the enzyme that converts testosterone to estradiol. Studying cells in a petri dish, they saw no change in gene expression when they infected cells of lung tissue with influenza and the original SARS-CoV viruses that caused the SARS outbreak in 2002. But exposure to SARS-CoV-2, the virus responsible for COVID-19, increased gene expression up to 40-fold, Gabriel says.
Did the same thing happen in humans? Autopsy examination of patients in three different cites found that CYP19A1 was abundantly expressed in the lungs of COVID-19 males but not those who died of other respiratory infections, says Gabriel. This increased enzyme production led likely to higher levels of estradiol in the lungs of men, which is highly inflammatory, damages the tissue, and can result in fibrosis or scarring that inhibits lung function and repair long after the virus itself has disappeared. Somehow the virus had acquired the capacity to upregulate expression of CYP19A1.
Only two COVID-19 positive females showed increased expression of this gene. The menopause status of these women, or whether they were on hormone replacement therapy was not known. That could be important because female hormones have a protective effect for cardiovascular disease, which women often lose after going through menopause, especially if they dont start hormone replacement therapy. That sex-specific protection might also extend to COVID-19 and merits further study.
The team was able to confirm their findings in golden hamsters, the animal model of choice for studying COVID-19. Testosterone levels in male animals dropped 5-fold three days after infection and began to recover as viral levels declined. CYP19A1 transcription increased up to 15-fold in the lungs of the male but not the females. The study authors wrote, Virus replication in the male lungs was negatively associated with testosterone levels.
The medical community studying COVID-19 has slowly come to recognize the importance of adipose tissue, or fat cells. They are known to express abundant levels of CYP19A1 and play a significant role as metabolic tissue in COVID-19. Gabriel adds, One of the key findings of our study is that upon SARS-CoV-2 infection, the lung suddenly turns into a metabolic organ by highly expressing CYP19A1.
She also found evidence that SARS-CoV-2 can infect the gonads of hamsters, thereby likely depressing circulating levels of sex hormones. The researchers did not have autopsy samples to confirm this in humans, but others have shown that the virus can replicate in those tissues.
A possible treatment
Back in the lab, substituting low and high doses of testosterone in SARS-COV-2 infected male hamsters had opposite effects depending on testosterone dosage used. Gabriel says that hormone levels can vary so much, depending on health status and age and even may change throughout the day, that it probably is much better to inhibit the enzyme produced by CYP19A1 than try to balance the hormones.
Results were better with letrozole, a drug approved to treat hypogonadism in males, which reduces estradiol levels. The drug also showed benefit in male hamsters in terms of less severe disease and faster recovery. She says more details need to be worked out in using letrozole to treat COVID-19, but they are talking with hospitals about clinical trials of the drug.
Gabriel has proposed a four hit explanation of how COVID-19 can be so deadly for men: the metabolic quartet. First is the genetic risk factor of CYP19A1 (Thr201Met), then comes SARS-CoV-2 infection that induces even greater expression of this gene and the deleterious increase of estradiol in the lung. Age-related hypogonadism and the heightened inflammation of obesity, known to affect CYP19A1 activity, are contributing factors in this deadly perfect storm of events.
Studying host genetics, says Gabriel, can reveal new mechanisms that yield promising avenues for further study. Its also uniting different fields of science into a new, collaborative approach theyre calling infection endocrinology, she says.
(Precision Vaccinations News)
The U.S. Centers for Disease Control and Prevention (CDC) today announced aHealth Alert Network (HAN) Health Advisoryabout the occurrence, geographic spread, and sexually associated human-to-human transmission of Clade I Monkeypox virus (MPXV) in the Democratic Republic of the Congo (DRC).
Since January 2023, the DRC has reported 12,569 suspected mpox casesand 581 related deaths from 22 regions.
The new HAN says cases of Clade I MPXV have not been reported in the United States as of December 7, 2023.The global outbreak ofClade II MPXV was initially reported in May 2022.
However, clinicians should be aware of the possibility of Clade I MPXV in travelers who have been in DRC.
Third-party dataindicate that the number of touristsarriving in the DRC wasabout 460,880in 2021.
The CDC recentlyissued aTravel Health Notice (Level 2 - Practice Enhanced Precautions) for people traveling to DRC. Furthermore,there are no direct commercial passenger flights from DRC to the U.S. as of December 2023.
U.S. FDA-approved vaccines (JYNNEOS, ACAM2000) are expected to be effective for both Clade I and II MPXV infections.
Vaccination or prior MPXV infection should provide antibodies that will provide cross-protection to other orthopoxviruses, including Clade I MPXV, says the CDC.
However, clinical verification is under review.
The CDC recommends clinicians encourage vaccination for eligible patients.
Eligible patients who have only received one dose ofBavarian NordicJYNNEOS (MVA-BN, IMVAMUNE) vaccine, which is based on a live, attenuated vaccinia virus,should receive the second dose as soon as possible, regardless of the time that has elapsed since the first dose.
Mpox vaccines have limited availability in the U.S.
Furthermore, clinicians should notify theirstate health departmentif they have a patient withmpox-like symptoms andshouldsubmit lesion specimens for clade-specific testing for these patients.
With the world still grappling with the devastating effects of the COVID-19 pandemic, another health crisis looms. Health officials and experts are increasingly worried about the spread of a lethal strain of monkeypox, particularly in the Democratic Republic of the Congo (DRC). The virus variant, known as Clade I, is more virulent and poses a risk of human-to-human transmission. The World Health Organization (WHO) has expressed grave concerns about the outbreak and its changing epidemiology in the DRC.
The Centers for Disease Control and Prevention (CDC) has issued a health alert regarding this more lethal strain of monkeypox. The outbreak in the DRC has sickened nearly 13,000 people and caused 581 suspected deaths. Cases are believed to be spread via sexual contact, raising fears about its potential for widespread transmission. The situation in the DRC has led to a significant increase in suspected monkeypox cases and deaths, blindsiding health experts globally.
In response to this health crisis, the CDC has instructed clinicians to be vigilant and notify state health departments of any travelers with symptoms similar to monkeypox. The CDC has also emphasized the need for enhanced surveillance and testing in the United States. While there is currently no known risk for Clade I monkeypox in the United States, the CDC is not ruling out the possibility of it emerging in the future.
Countermeasures for Clade II infections, a less severe strain of monkeypox, are expected to be effective against Clade I infections. However, vaccine coverage in the U.S. remains low, with only 1 in 4 eligible people receiving both doses required for full protection. The CDC recommends people at risk for monkeypox to be vaccinated with two doses of the JYNNEOS vaccine, as two doses provide greater protection.
The response to this outbreak is being hampered by stigma, regulatory barriers, and competing disease outbreaks. This lack of urgency in providing vaccines and treatments is reminiscent of the unequal access to vaccines experienced during the COVID-19 pandemic. Concerns about discrimination, particularly in the context of sexual transmission, also add to the complexity of the situation. Despite these challenges, the need for a swift and comprehensive response is imperative.
As the world continues to reel from the impacts of one pandemic, the potential for another is a stark reminder of the interconnectedness of our global health landscape. The situation calls for increased vigilance, improved surveillance, and a renewed emphasis on vaccination. By learning from our experiences with COVID-19 and other infectious diseases, we can hopefully prevent this outbreak from escalating into a global crisis.
The Centers for Disease Control and Prevention (CDC) recently issued a health alert in response to the ongoing outbreak of a more severe and transmissible subtype of the monkeypox (mpox) virus, known as clade I, in the Democratic Republic of Congo (DRC). This alert seeks to prepare clinicians and public health officials in the U.S. for potential cases, despite no clade I cases being reported domestically at this time.
According to the CDC, the 2022-23 global outbreak of mpox was predominantly linked to the clade II monkeypox virus. Interestingly, this outbreak has largely affected gay and bisexual men, as well as other men who have sex with men. However, the clade I subtype, now spreading in the DRC, is raising serious concerns due to its increased transmissibility and severity.
This subtype of the disease has seen a significant surge in its suspected cases and related deaths in the DRC, primarily spreading through sexually associated human-to-human contact.
The CDC has emphasized that the Jynneos mpox vaccine should be effective against both clade I and clade II mpox viruses. However, vaccination coverage in the U.S. remains low. As of now, only one in four people eligible for the vaccine have received the two doses necessary for optimum protection.
Health authorities have recommended travelers to the DRC to be cautious. The CDC advises avoiding close contact with ill or dead animals and promotes enhanced surveillance efforts, especially if the clade I strain is detected in the U.S. Additionally, clinicians are urged to be alert for patients presenting with lesions consistent with mpox.
The World Health Organization (WHO) has expressed great concern over the ongoing outbreak in the DRC, which has proved fatal for nearly 600 people, primarily children, this year. The WHO, in collaboration with Congolese authorities, is currently working on the response and conducting a risk assessment.
Furthermore, CDC and WHO are increasingly concerned about an outbreak among sex workers in South Kivu, DRC. Efforts are being made to work with the Congolese government to procure or accept donations of mpox vaccines.
In light of this health alert, it is crucial that clinicians, public health officials, and individuals who are at risk or are traveling to the DRC remain vigilant. The importance of increasing vaccination coverage against the mpox virus cannot be overstated. By taking these steps, we can help to prevent the spread and severe impacts of this disease.
In the heart of the Democratic Republic of Congo (DRC), a deadly outbreak of a disease known as mpox is causing turmoil and distress. The disease, also known as monkeypox, has claimed many lives, with a reported 12,569 cases and nearly 600 fatalities between 1 January and 12 November 2023. Despite the availability of vaccines and treatments, stigma, regulatory impediments, and the presence of other concurrent disease outbreaks have hindered the response to this growing health crisis.
The ongoing mpox outbreak in the DRC is caused by the monkeypox virus, which is typically transmitted to humans through bites or direct contact with an infected animals blood, body fluids, or cutaneous/mucosal lesions. Interestingly, this outbreak involves a different clade of the mpox virus that reportedly causes more severe disease. For the first time, sexual transmission of this strain is playing a significant role, particularly among men who have sex with men.
The World Health Organization (WHO) has expressed concern about the situation in Congo, warning that the current outbreak presents a significant risk of international spread. The virus spread widely outside of Africa last year, primarily among men who have sex with men. Clade 1 mpox virus, which is currently prevalent in Congo, has a higher fatality rate than the version that spread internationally last year.
Unfortunately, the response to the outbreak has been hindered by several factors. The stigma associated with the disease, particularly due to its sexual transmission, has created barriers to prevention and control. The situation is further complicated by the fact that the DRC is described as hostile to homosexual activities, which could hamper efforts to curb the spread of the disease. Additionally, regulatory hurdles and the governments lack of urgency in responding to the outbreak have been widely criticized. The DRC has not requested to buy or applied for donations of vaccines and treatments, leaving these potentially life-saving resources unused outside the country.
SIGA Technologies, a leading pharmaceutical company, suggests that its antiviral drug TPOXX may be easier to deploy compared to the vaccine. However, this treatment has not yet been approved by the U.S. Food and Drug Administration (FDA), adding another layer of complexity to the situation.
The mpox outbreak in the DRC highlights the global issue of unequal access to vaccines, a concern that has been magnified during the COVID-19 pandemic. The DRCs struggle to utilize available vaccines and treatments underscores the critical importance of addressing these disparities and improving global health infrastructure.
As the mpox outbreak in the DRC continues to unfold, it serves as a stark reminder of the urgent need for global cooperation, accessible healthcare, and the dismantling of stigma and discrimination in the face of health crises. With the right actions and global support, it is hoped that the spread of this deadly disease can be curbed and countless lives saved.
Rare blood clots tied to some early COVID-19 vaccines that are no longer in use may have been the result of two out-of-control immune reactions happening at once.
One of these immune reactions was already known, but the second, reported Oct. 26 in the journal Blood, is a new discovery.
The finding could help to explain how other clotting conditions develop and point to better treatments, as well as suggest ways to make vaccines safer for people who are prone to the side effect.
"Understanding how a drug causes an adverse event allows us to design new approaches to make those treatments safer," said Ishac Nazy, an associate professor of medicine at McMaster University in Canada who studies the vaccine-related clotting disorder but was not involved in the current research.
The vaccine-related clotting disorder, known as vaccine-induced immune thrombotic thrombocytopenia (VITT), was rare and linked to two shots: the Johnson & Johnson (J&J) and AstraZeneca COVID-19 vaccines. Both shots contained common-cold viruses called adenoviruses that were tweaked so that they couldn't infect cells. Instead, the modified viruses carried DNA instructions for part of SARS-CoV-2, the coronavirus that causes COVID-19, into the body.
VITT was a sobering side effect of what many public health experts had hoped would be a promising technology. Unlike the Moderna and Pfizer-BioNTech COVID-19 shots, which contain RNA, the J&J and AstraZeneca vaccines did not need ultracold storage, making them more accessible where cold-chain storage is unreliable. Adenovirus-based vaccines have been investigated for other diseases, but very few have achieved approval. Exceptions are an adenovirus-based Ebola vaccine approved in China and another approved by the European Union, both used only in at-risk individuals.
Soon after rolling out the J&J and AstraZeneca vaccines, doctors began reporting cases of clotting that looked a lot like a previously known disorder called Heparin-induced thrombocytopenia (HIT). About 20 to 30 years ago, HIT affected 3.5% of patients who had knee or hip replacements, said Dr. Andreas Greinacher, a physician who specializes in clotting disorders at the Greifswald University Hospital in Germany and was not involved in the new research. In these patients, heparin, a blood thinner normally given to prevent blood clots, actually triggered runaway clotting instead.
The adenovirus-based COVID vaccines were triggering the same condition as HIT, though scientists gave it a new acronym to reflect the different origin. Researchers reported that about 1 in 50,000 people under 50 who received the vaccine were affected, as well as about 1 in 100,000 of those 50 and older.
Neither vaccine is currently administered in the U.S. (AstraZeneca's shot was never used in the country, and J&J's vaccine was authorized but then retired due to the clotting issue and availability of better vaccines.) However, learning what triggers VITT could still be useful.
Today, HIT is rare because doctors now understand what causes it and can prescribe different, safer versions of heparin, Greinacher told Live Science. Similarly, he said, studying the mechanisms behind HIT and VITT could make adenovirus vaccines safer.
"Our big aim currently is to find which factor in the vaccines is triggering it," Greinacher said. "If you know the factor, I'm certain there are very smart biotechnologists who can modify the adenovirus vector so this factor is no longer present."
When VITT was first observed in patients getting COVID-19 vaccines in February 2021, scientists soon discovered that it had to do with PF4, a chemical signal released by platelets, the blood cells that form clots.
In rare cases after vaccination with an adenovirus-based vaccine, the body would make antibodies to PF4. These antibodies would latch onto PF4 and form clumps that could then bind to receptors called Fc on other platelets. This would activate the platelets and lead to a runaway clotting response.
The new Blood study found that PF4 alone also activates a second set of receptors that cause platelets to accumulate, likely a second reason why clotting goes haywire in this disorder.
There is still a long way to go, Nazy told Live Science, whose team first reported in 2021 how antibodies against PF4 were causing VITT. The new research suggests that there are actually two different ways that PF4 acts in VITT, he said. These two pathways are not exclusive and may work in tandem.
In the new study, researchers tested blood from healthy individuals and people with VITT to trace the cascade of signals that leads to the overactive clotting. They found that the PF4 activates a receptor called c-Mpl on platelets, which causes them to clump together. This is in addition to the mechanism discovered in 2021, in which complexes of PF4 and PF4 antibodies activate platelets' Fc receptors.
"What we have shown is that as well as that antibody trigger, you've also got PF4 itself binding to platelets and activating them, providing a double whammy," Phillip Nicolson, an associate clinical professor of cardiovascular medicine at the University of Birmingham in the U.K. and the leader of the new study, told Live Science. "That may be why [the clotting] happens to a harmful degree."
Scientists have a few clues as to why adenovirus vaccines can trigger this response. PF4 carries a positive electrical charge on its surface, while adenoviruses are highly negatively charged, Nicolson said, so they may bind together easily. But even that is not confirmed, Nazy said, and has mostly been shown with computer modeling rather than with real molecules.
In rare cases, unusual clotting happens without vaccination or treatment with heparin. A recent paper published in the The New England Journal of Medicine, and co-authored by Nazy, found that in at least two of these unexplained clotting cases, the clotting disorder occurred after typical adenovirus infections. In many cases, the connection between unexplained clotting and a viral infection may be missed. And it's still a mystery why very few people are susceptible to these clotting conditions.
"That's the part we need to understand to prevent the disease from even happening," Nazy said.
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