A trial has begun into whether three potential bird flu vaccines could protect farmed animals from a disease that is now a year-round threat.
Wageningen Bioveterinary Research (WBVR) in Lelystad has been asked by the Dutch agriculture minister to conduct trials into vaccines for the H5 avian flu virus in laying hens. The first results from the three-month trial are expected in December.
Expert Nancy Beerens said that the virus, which typically arrived with migrating water birds from Siberia, has now spread to other breeds and is present in the summer months when it used to disappear.
Our summers used to be free of bird flu infections, she said in a press release. This year we saw for the first time that the bird flu season did not end with the departure of migratory birds in April. The virus has been infecting birds that summer in our country, which means that poultry farms started the summer with bird flu.
Largest cull
Despite culling more than four million birds, transport bans and orders to keep birds inside across the Netherlands since last October, each week new infections are discovered. On Monday, another 200,000 chicks were culled after bird flu was found on a poultry farm in Nieuw-Weerdinge in Drente the largest single cull yet.
The virus affects farmed turkeys, chickens, ducks and geese and despite heightened biosecurity measures, experts and farmers believe only a vaccination and new rules on European transport of vaccinated birds can combat the deadly disease.
The first Dutch trials will take place in a high containment unit at the WBVR lab. The new types of vaccine that we are testing in this study are expected to provide better protection against spread of the virus, added Beerens.
The results of [this and other European] studies are very important to get all EU member states on track for vaccination.
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Campylobacter gastroenteritis is an infection in your gut caused by Campylobacter bacteria. The infection often leads to inflammation in your stomach and intestines.
Each year in the United States, Campylobacter bacteria cause an estimated 1.5 million stomach illnesses.
Eating raw or undercooked poultry, seafood, or meat is a common source of infection. The illness can also be transmitted via produce, milk, or water that has come into contact with the campylobacter bacteria.
In this article, we take a look at the symptoms of campylobacter gastroenteritis, as well as how best to treat and prevent this common stomach illness.
Campylobacter gastroenteritis is an intestinal infection that occurs when Campylobacter bacteria is present in your food or water.
According to the Centers for Disease Control and Prevention (CDC), Campylobacter bacteria is the most common bacterial cause of diarrhea in the United States. The bacteria can be found in a wide range of animals, particularly poultry. It can also be transmitted through water that hasnt been properly treated.
Campylobacter gastroenteritis occurs more often in the summer than in winter. The Foodborne Diseases Active Surveillance Network suggests that for every 100,000 people, approximately 20 cases of Campylobacter infection are diagnosed each year in the United States.
Its estimated that many more cases are undiagnosed or go unreported.
If you have campylobacter gastroenteritis, you may experience symptoms such as:
Because campylobacter gastroenteritis affects the lining of the stomach and intestines, nausea and vomiting can often occur.
Symptoms generally start within two to five days of coming in contact with the bacteria and typically last one week.
Campylobacter causes gastroenteritis, which means the stomach and intestines are inflamed and irritated.
Oftentimes when people have symptoms of gastroenteritis, they refer to it as the stomach flu. But gastroenteritis is not related to the flu at all.
It can take as little as a single drop of juice from raw chicken that has the Campylobacter bacteria to cause an infection.
Most infections are caused by eating raw or undercooked poultry or consuming food or water that has been contaminated with the Campylobacter bacteria.
Campylobacter can contaminate food and water in different ways:
To diagnose campylobacter gastroenteritis, a doctor will first talk with you about your symptoms and how long you have been experiencing them.
If campylobacter gastroenteritis is suspected, they may use a laboratory test to detect the Campylobacter bacteria in your stool (poop), body tissue, or other bodily fluids.
Because symptoms of vomiting and diarrhea can lead to dehydration and depletion of minerals and electrolytes, a doctor may also check for signs of dehydration.
Symptoms of dehydration include:
Most people recover from campylobacter gastroenteritis with rest and by drinking extra fluids. They generally start to feel better within three days without seeing a doctor.
However, if dehydration is suspected or if symptoms dont ease after two to three days, you should seek medical help. This is especially true for young children, the elderly, and those with weakened immune systems.
To prevent you or your family from getting campylobacter gastroenteritis, its important to be cautious when handling chicken, meat, and seafood.
Here are some ways to prevent coming into contact with the bacteria:
Symptoms of campylobacter gastroenteritis can begin to resolve as early as three days and generally do not last longer than one week.
Campylobacter gastroenteritis comes from bacteria that attack the stomach and intestines. Symptoms include diarrhea, stomach cramping, nausea, and vomiting.
Influenza, or the flu, is a respiratory virus that attacks your nose, throat, and lungs. Symptoms include muscle aches, runny or stuffy nose, and sore throat. Both can cause fever and headaches.
Campylobacter bacteria are passed in the feces (poop), which means people who have diarrhea should be isolated and excluded from childcare, patient care, and handling food for others.
That said, the illness is not contagious like an airborne flu virus and is not typically spread from one person to another.
Complications from campylobacter gastroenteritis are rare, but they can occur.
Some people may develop arthritis and others may develop a rare disease called Guillain-Barr syndrome. Guillain-Barr syndrome happens when the bodys immune system starts to damage nerves in the body. It can cause muscle weakness and sometimes paralysis.
Campylobacter gastroenteritis is generally a mild illness. Symptoms typically dont last for longer than one week. However, it can be fatal among young children, the elderly, and people with weakened immune systems.
See a doctor if symptoms linger for more than three days, particularly if youre in a high risk category.
Campylobacter gastroenteritis is a type of food poisoning caused by Campylobacter bacteria. Symptoms are generally considered to be mild and include:
Most people recover with rest and hydration. However, if symptoms do not ease within two to three days, its important to see a doctor.
Concerned about a bird flu outbreak, the Palo Alto Junior Museum and Zoo has removed its birds from public viewing and canceled all bird interactions, including the popular flamingo feeding activity, until further notice.
Avian influenza in wild birds and poultry is common in the U.S. but typically poses low risk to humans, according to the zoos website. The outbreaks do pose a threat to local birds, however, and the zoo, located at 1451 Middlefield Road, is taking precautions to protect its feathered inhabitants.
The current outbreak of avian influenza is highly pathogenic, according to a press release from Santa Clara Valley Audubon Society. Four cases were detected in Canada geese and red-tailed hawks in Santa Clara County in August and early September.
Avian influenza typically is restricted to aquatic birds.
"This is primarily because of the watery habitat they enjoy, which assists in the spread of the virus," Matthew Dodder, executive director of Santa Clara Valley Audubon Society, said in an emailed statement. "It is well known that wildfowl, particularly ducks and geese, will make use of small urban ponds and pools."
New Omicron-targeting COVID-19 vaccine boosters are available through Yale Health and local pharmacies. Heres what you need to know about getting a booster.
Alexandra Martinez-Garcia 11:25 pm, Sep 28, 2022
Contributing Reporter
Jessai Flores, Illustrations Editor
Search for vaccine availability in your area at vaccines.gov. You can also call the Campus COVID Resource Line (CCRL) at 203-432-6604.
New COVID-19 booster vaccines the first to specifically target the uniquely contagious Omicron variant are available at pharmacies on campus and in New Haven.
Campus and city officials are encouraging people to make appointments as soon as possible through Yale Healths clinic or local pharmacies. Appointments are currently available through Yale Health, with current wait times at around eight to ten days.
The newest boosters, produced by Pfizer and Moderna, were authorized by the U.S. Food and Drug Administration last month and became widely available soon after.
Known as bivalent boosters or updated boosters, the new shots contain mRNA components that protect against both the original strains of the COVID-19 virus as well as the newer, more contagious strains BA.4 and BA.5 that have become dominant in the United States.
Who should get a booster shot?
Boosters are recommended for all people who received their last shot either an initial two-dose series or a previous booster at least two months ago, according to the U.S. Centers for Disease Control and Prevention.
[The booster] helps to protect one not only from getting sick with COVID-19 but also prevents severe disease, said Richard Martinello, medical director of infection prevention at Yale New Haven Health. Everyones at risk, even if youve had COVID before.
Martinello said that all people, even those who have had COVID previously, are at risk for infection. Long-term post-COVID-19 conditions can be debilitating for students, he added.
Pfizers new bivalent booster is authorized for use in people 12 and older, and the Moderna booster is approved for those 18 and older. Boosters are not yet recommended for children younger than 12.
Martinello suggested that those infected with COVID-19 wait until one month after recovery before receiving a booster.
Where can I get the COVID-19 booster in New Haven?
Yale affiliates including students, staff, faculty and other Yale Health members can make appointments to receive the updated booster at Yale Healths vaccine clinic through MyChart or through the Yale COVID-19 Vaccine Program. Yale Health is currently offering updated Pfizer boosters.
In addition, appointments can be made through local pharmacies such as CVS and Walgreens. Available appointments can be found at the federal website vaccines.gov. Yale asks that students and faculty who choose off-campus options report their updates in vaccinations.
It was super easy to register and receive [the booster], Josh Guo 24 wrote to the News. I scheduled my appointment through MyChart, and the clinic is a little far but pretty accessible via the Yale Shuttle.
Yale Healths vaccine clinic at Science Park is at 310 Winchester Avenue, around a 20-minute walk from central campus. The facility is separate from its main location on Lock Street.
On the other hand, scheduling appointments for some people, like Isabella Walther-Meade 25, has not been as easy.
According to Walther-Meade, her appointment at Walgreens which she scheduled online ten days in advance ended up being pretty stressful as it took about two hours due to staffing shortages. Walther-Meade chose to register at Walgreens because she was not sure how to do so through Yale Health and Walgreens appeared to have more appointments available on earlier dates.
Patients should bring a photo ID and insurance card to vaccine appointments.
Can I get my COVID-19 booster shot and flu shot at the same time?
Public health officials have also been urging people to protect themselves against the more familiar influenza virus. Flu season in the United States typically occurs during the fall and winter months.
The CDC has recommended that those receiving two shots during the same appointment receive them in different arms.
Flu shots are free and available to all people six months and older. Individuals with scheduled appointments for COVID-19 boosters will have the opportunity to receive a flu shot during the same appointment.
Does the booster have side effects?
Students have reported only mild side-effects after receiving their updated boosters. Several said that their reactions were less severe compared to reactions from their first booster shots.
I only had arm soreness for a day or two, Walther-Meade wrote in a statement to the News. I had a relatively severe reaction to my first booster, so I was relieved.
Olivia Meisner GRD 25 said she experienced a headache, mild fatigue and body aches. Roy Kohavi 26 also experienced a decrease in the severity of his side effects, going from headaches and fatigue after his original booster to no symptoms at all after his updated booster.
Martinello mentioned that health professionals are not seeing any side effects outside of the realm of what [theyve] previously seen, meaning that students and faculty who get the bivalent booster should not expect symptoms they havent experienced or heard about before.
Hospital remains strained by COVID-19 infections
Martinello stressed the importance of getting boosted to protect the overall community, especially as Yale New Haven Hospital continues to admit a steady stream of COVID-19 patients.
One of the things I worry about on a daily basis is how full our hospital is, Martinello said. In the last few months weve had 65 to 100 patients in our hospital with COVID-19 that takes a lot of resources that are very important for other health needs that our community has.
The Yale Health vaccine clinic is located at 310 Winchester Avenue.
December 14, 2020
Rochester research into RNA structure and function provides key information for developing coronavirus treatments.
The US Food and Drug Administration recently approved emergency use authorization for a COVID-19 vaccine developed by Pfizer and the German pharmaceutical company BioNTech.
The vaccine made history not only because it reported a 95 percent efficacy rate at preventing COVID-19 in clinical trials, but because it is the first vaccine ever approved by the FDA for human use that is based on RNA technology.
The development of RNA vaccines is a great boon to the future of treating infectious diseases, says Lynne Maquat, the J. Lowell Orbison Distinguished Service Alumni Professor in biochemistry and biophysics, oncology, and pediatrics at Rochester and the director of Rochesters Center for RNA Biology.
COVID-19, short for coronavirus disease 2019, is caused by the novel coronavirus SARS-CoV-2. Like many other viruses, SARS-CoV-2 is an RNA virus. This means that, unlike in humans and other mammals, the genetic material for SARS-CoV-2 is encoded in ribonucleic acid (RNA). The viral RNA is sneaky: its features cause the protein synthesis machinery in humans to mistake it for RNA produced by our own DNA.
For that reason, several of the leading COVID-19 vaccines and treatments are based on RNA technology.
A contingent of researchers at the University of Rochester study the RNA of viruses to better understand how RNAs work and how they are involved in diseases. This RNA research provides an important foundation for developing vaccines and other drugs and therapeutics to disrupt the virus and stop infections.
Understanding RNA structure and function helps us understand how to throw a therapeutic wrench into what the COVID-19 RNA doesmake new virus that can infect more of our cells and also the cells of other human beings, Maquat says.
RNA stands for ribonucleic acid.
RNA delivers the genetic instructions contained in DNA to the rest of the cell.
Covid-19 stands for coronavirus disease 2019.
In the past few decades, as scientists came to realize that genetic material is largely regulated by the RNA it encodes, that most of our DNA produces RNA, and that RNA is not only a target but also a tool for disease therapies, the RNA research world has exploded, Maquat says. The University of Rochester understood this.
In 2007, Maquat founded The Center for RNA Biology as a means of conducting interdisciplinary research in the function, structure, and processing of RNAs. The Center involves researchers from both the River Campus and the Medical Center, combining expertise in biology, chemistry, engineering, neurology, and pharmacology.
Our strength as a university is our diversity of research expertise, combined with our highly collaborative nature, says Dragony Fu, an associate professor of biology on the River Campus and a member of the Center for RNA Biology. We are surrounded by outstanding researchers who enhance our understanding of RNA biology, and a medical center that provides a translational aspect where the knowledge gained from RNA biology can be applied for therapeutics.
A graphic created by the New York Times illustrates how the coronavirus that causes COVID-19 enters the body through the nose, mouth, or eyes and attaches to our cells. Once the virus is inside our cells, it releases its RNA. Our hijacked cells serve as virus factories, reading the viruss RNA and making long viral proteins to compromise the immune system. The virus assembles new copies of itself and spreads to more parts of the body andby way of saliva, sweat, and other bodily fluidsto other humans.
Once the virus is in our cells, the entire process of infection and re-infection depends on the viral RNA, Maquat says.
One of the reasons viruses are such a challenge is that they change and mutate in response to drugs.
That means novel virus treatments and vaccines have to be created each time a new strain of virus presents itself. Armed with innovative research on the fundamentals of RNA, scientists are better able to develop and test therapeutics that directly target the RNAs and processes critical to a viruss life cycle.
Traditional vaccines against viruses like influenza inject inactivated virus proteins called antigens. The antigens stimulate the bodys immune system to recognize the specific virus and produce antibodies in response, with the hope that these antibodies will fight against future virus infection.
RNA-based vaccinessuch as those developed by Pfizer/BioNTech and American biotechnology company Modernado not introduce an antigen, but instead inject a short sequence of synthetic messenger RNA (mRNA) that is enclosed in a specially engineered lipid nanoparticle. This mRNA provides cells with instructions to produce the virus antigen themselves.
Once the mRNA from a vaccine is in our body, for example, it instructs the protein synthesis machinery in our cells, which normally generates proteins from the mRNAs that derive from our genes, to produce a piece of the SARS-CoV-2 virus spike protein. Since the SARS-CoV-2 virus spike protein is foreign to our bodies, our bodies will then make antibodies that inactivate the protein.
Should the virus enter our body from an infected person, these antibodies will bind to and inactivate the virus by binding to its spike proteins, which coat the outside of the viral capsule, Maquat says.
An RNA-based vaccine therefore acts as a code to instruct the body to make many copies of the virus proteinand the resulting antibodiesitself, resulting in an immune response.
Unlike more traditional vaccines, RNA-based vaccines are also beneficial in that they eliminate the need to work with the actual virus.
Working with a live virus is costly and very involved, requiring that researchers use special biosafety laboratories and wear bulky personal protective equipment so that the virus is biocontained, and no one gets infected, Maquat says.
Developing a vaccine from a live virus additionally takes much longer than generating an mRNA-based vaccine, but no one should think the process is simple, Maquat says of the Pfizer/BioNTech vaccine. Since it is the first of its kind, a lot had to be worked out.
Researchers Douglas Anderson, Dragony Fu, and Lynne Maquat are among the scientists at the University of Rochester who study the RNA of viruses to better understand how RNAs work and how they are involved in diseases. (University of Rochester photos / Matt Wittmeyer / J. Adam Fenster)
Maquat has been studying RNA since 1972 and was part of the earliest wave of scientists to realize the important role RNA plays in human health and disease.
Our cells have a number of ways to combat viruses in what can be viewed as an arms race between host and virus. One of the weapons in our cells arsenal is an RNA surveillance mechanism Maquat discovered called nonsense-mediated mRNA decay (NMD).
Nonsense-mediated mRNA decay protects us from many genetic mutations that could cause disease if NMD werenot active to destroy the RNA harboring the mutation, she says.
Maquats discovery has contributed to the development of drug therapies for genetic disorders such as cystic fibrosis, and may be useful in developing treatments for coronavirus.
NMD also helps us combat viral infections, which is why many viruses either inhibit or evade NMD, she adds. The genome of the virus COVID-19 is a positive-sense, single-stranded RNA. It is well known that other positive-sense, single-stranded RNA viruses evade NMD by having RNA structures that prevent NMD from degrading viral RNAs.
Maquats lab has been collaborating with a lab at Harvard University to test how viral proteins can inhibit the NMD machinery.
Their recent work is focused on the SARS-CoV-2 structural protein called N. Lab experiments and data sets from infected human cells indicate this virus is unusual because it does not inhibit the NMD pathway that regulates many of our genes and some of the viruss genes. Instead, the virus N protein seems to promote the pathway.
SARS-CoV-2 reproduces its RNA genome with much higher efficiency than other pathogenic human viruses, Maquat says. Maybe there is a connection there; time will tell.
In the Department of Biology, Fu andJack Werren, the Nathaniel and Helen Wisch Professor of Biology, received expedited funding awards from the National Science Foundation to apply their expertise in cellular and evolutionary biology to research proteins involved in infections from COVID-19. The funding was part of the NSFs Rapid Response Research (RAPID) program to mobilize funding for high priority projects.
Werrens research will be important in ameliorating some of the potential side effects of COVID-19 infections, including blood clots and heart diseases, while Fus research will provide insight into the potential effects of viral infection on human cell metabolism.
Our research will provide insight into the potential effects of viral infection on host cellular processes, Fu says. Identifying which cell functions are affected by the virus could help lessen some of the negative effects caused by COVID-19. Green = said twice.
Douglas Anderson, an assistant professor of medicine in the Aab Cardiovascular Research Institute and a member of the Center for RNA Biology, studies how RNA mutations can give rise to human disease and has found that alternative therapeutics, such as the gene-editing technology CRISPR, may additionally usher in a new approach to how we target and combat infectious diseases, he says.
For the past few years, Andersons lab has developed tools and delivery systems that use the RNA-targeting CRISPR-Cas13 to treat human genetic diseases that affect muscle function. CRISPR-Cas13 is like a molecular pair of scissors that can target specific RNAs for degradation, using small, programmable guide RNAs.
When the health crisis first became apparent in Wuhan, China, researchers in Andersons lab turned their focus toward developing a CRISPR-Cas13 therapeutic aimed at SARS-CoV-2. Applying the knowledge already available about coronavirus RNA replication, they designed single CRISPR guide RNAs capable of targeting every viral RNA that is made within a SARS-CoV-2 infected cell. Using a novel cloning method developed in Andersons lab, multiple CRISPR guide-RNAs could be packaged into a single therapeutic vector (a genetically engineered carrier) to target numerous viral RNA sites simultaneously. The multi-pronged targeting strategy could be used as a therapy to safeguard against virus-induced cell toxicity and prevent escape of viruses which may have undergone mutation.
Infectious viruses and pandemics seemingly come out of nowhere, which has made it hard to rapidly develop and screen traditional small molecule therapeutics or vaccines, Anderson says. There is a clear need to develop alternative targeted therapeutics, such as CRISPR-Cas13, which have the ability to be rapidly reprogrammed to target new emerging pandemics.
While many new treatments for the novel coronavirus are being considered, there is one thing that is certain, Maquat says: Targeting RNA, or the proteins it produces, is essential for therapeutically combatting this disease.
Most people living in the United States today have only read about the 1918 flu pandemic and the relatively recent RNA viruses, such as Ebola or Zika, that are seen largely in other countries.
RNA treatments will most likely be a wave of the future for these and other emerging diseases, Maquat says. Epidemiologists know new infectious pathogens are coming given how small the world has become with international travel, including to and from places where humans and animals are in close contact.
Bats, in particular, are reservoirs for viruses. Many bat species are able to live with viruses without experiencing ill effects, given the bats unusual physiology. If these bat viruses mutate so they become capable of infecting humans, however, there will be new diseases, Maquat says.
It is just a matter of when this will happen and what the virus will be. The hope is that we will be ready and able to develop vaccines against these new viruses with the new pipelines that have been put in place for COVID-19.
This story was originally published on April 28, 2020, and updated on December 14, 2020.
FDA votes to approve emergency use of Pfizer coronavirus vaccineResearchers and volunteers in Rochester have been involved in the testing of the Pfizer/BioNTech vaccine since May, and technologies used in the development of the vaccine can trace their origins to decades of infectious disease research conducted at Rochester.
Tags: Arts and Sciences, Center for RNA Biology, COVID-19, Department of Biochemistry and Biophysics, Department of Biology, Douglas Anderson, Dragony Fu, featured-post, Lynne Maquat, medical center
Category: Science & Technology
For about 60 years, health authorities in the United States have been championing a routine for at least some sector of the public: a yearly flu shot. That recommendation now applies to every American over the age of six months, and for many of us, flu vaccines have become a fixture of fall.
The logic of that timeline seems solid enough. A shot in the autumn preps the body for each winters circulating viral strains. But years into researching flu immunity, experts have yet to reach a consensus on the optimal time to receive the vaccineor even the number of injections that should be doled out.
Each year, a new flu shot recipe debuts in the U.S. sometime around July or August, and according to the CDC the best time for most people to show up for an injection is about now: preferably no sooner than September, ideally no later than the end of October. Many health-care systems require their employees to get the shot in this time frame as well. But those who opt to follow the CDC current guidelines, as I recently did, then mention that fact in a forum frequented by a bunch of experts, as I also recently did, might rapidly hear that theyve made a terrible, terrible choice.
Theres no way I would do what you did, one virologist texted me. Its poor advice to get the flu vaccine now. Florian Krammer, a virologist at Mount Sinais Icahn School of Medicine, echoed that sentiment in a tweet: I think it is too early to get a flu shot. When I prodded other experts to share their scheduling preferences, I found that some are September shooters, but others wont juice up till December or later. One vaccinologist I spoke with goes totally avant-garde, and nabs multiple doses a year.
Read: Should your flu and COVID shots go in different arms?
There is definitely such a thing as getting a flu shot too early, as Helen Branswell has reported for Stat. After people get their vaccine, levels of antibodies rocket up, buoying protection against both infection and disease. But after only weeks, the number of those molecules begins to steadily tick downward, raising peoples risk of developing a symptomatic case of flu by about 6 to 18 percent, various studies have found. On average, people can expect that a good portion of their anti-flu antibodies are meaningfully gone by about three or so months after a shot, says Lauren Rodda, an immunologist at the University of Washington.
That decline is why some researchers, Krammer among them, think that September and even October shots could be premature, especially if flu activity peaks well after winter begins. In about three-quarters of the flu seasons from 1982 to 2020, the virus didnt hit its apex until January or later. Krammer, for one, told me that he usually waits until at least late November to dose up. Stanley Plotkin, a 90-year-old vaccinologist and vaccine consultant, has a different solution. People in his age groupover 65dont respond as well to vaccines in general, and seem to lose protection more rapidly. So for the past several years, Plotkin has doubled up on flu shots, getting one sometime before Halloween and another in January, to ensure hes chock-full of antibodies throughout the entire risky, wintry stretch. The higher the titers, or antibody levels, Plotkin told me, the better the efficacy, so Im trying to take advantage of that. (He made clear to me that he wasnt making recommendations for the rest of the worldjust playing the odds given his age.)
Data on doubling up is quite sparse. But Ben Cowling, an epidemiologist and flu researcher at Hong Kong University, has been running a years-long study to figure out whether offering two vaccines a year, separated by roughly six months, could keep vulnerable people safe for longer. His target population is Hong Kongers, who often experience multiple annual flu peaks, one seeded by the Northern Hemispheres winter wave and another by the Southern Hemispheres. So far, getting that second dose seems to give you additional protection, Cowling told me, and it seems like theres no harm of getting vaccinated twice a year, apart from the financial and logistical cost of a double rollout.
Read: The strongest sign that Americans should worry about flu this winter
In the U.S., though, flu season is usually synonymous with winter. And the closer together two shots are given, the more blunted the effects of the second injection might be: People who are already bustling with antibodies may obliterate a second shots contents before the vaccine has a chance to teach immune cells anything new. That might be why several studies that have looked at double-dosing flu shots within weeks of each other showed no benefit in older people and certain immunocompromised groups, Poland told me. (One exception? Organ-transplant recipients. Kids getting their very first flu shot are also supposed to get two of them, four weeks apart.)
Even at the three-ish-month mark past vaccination, the bodys anti-flu defenses dont reset to zero, Rodda told me. Shots shore up B cells and T cells, which can survive for many months or years in various anatomical nooks and crannies. Those arsenals are especially hefty in people who have banked a lifetime of exposures to flu viruses and vaccines, and they can guard people against severe disease, hospitalization, and death, even after an antibody surge has faded. A recent study found that vaccine protection against flu hospitalizations ebbed by less than 10 percent a month after people got their shot, though the rates among adults older than 65 were a smidge higher. Still other numbers barely noted any changes in post-vaccine safeguards against symptomatic flu cases of a range of severities, at least within the first few months. I do think the best protection is within three months of vaccination, Cowling told me. But theres still a good amount by six.
For some young, healthy adults, a decent number of flu antibodies may actually stick around for more than a year. You can test my blood right now, Rodda told me. I havent gotten vaccinated just yet this year, and I have detectable titers. Ali Ellebedy, an immunologist at Washington University in St. Louis, told me he has found that some people who have regularly received flu vaccines have almost no antibody bump when they get a fresh shot: Their blood is already hopping with the molecules. Preexisting immunity also seems to be a big reason that nasal-spray-based flu vaccines dont work terribly well in adults, whose airways have hosted far more flu viruses than childrens.
Getting a second flu shot in a single season is pretty unlikely to hurt. But Ellebedy compares it to taking out a second insurance policy on a car thats rarely driven: likely of quite marginal benefit for most people. Plus, because its not a sanctioned flu-vaccine regimen, pharmacists might be reluctant to acquiesce, Poland pointed out. Double-dosing probably wouldnt stand much of a chance as an official CDC recommendation, either. We do a bad enough job, Poland said, getting Americans to take even one dose a year.
Read: Americas flu-shot problem is also its next COVID-shot problem
Thats why the push to vaccinate in late summer and early fall is so essential for the single shot we currently have, says Huong McLean, a vaccine researcher at the Marshfield Clinic Research Institute in Wisconsin. People get busy, and health systems are making sure that most people can get protected before the season starts, she told me. Ellebedy, whos usually a September vaccinator, told me he doesnt see the point of delaying vaccination for fear of having a lower antibody level in February. Flu seasons are unpredictable, with some starting as early as October, and the viruses arent usually keen on giving their hosts a heads-up. That makes dillydallying a risk: Put the shot off till November or December, and you might get infected in between, Ellebedy saidor simply forget to make an appointment at all, especially as the holidays draw near.
In the future, improvements to flu-shot tech could help cleave off some of the ambiguity. Higher doses of vaccine, which are given to older people, could rile up the immune system to a greater degree; the same could be true for more provocative vaccines, made with ingredients called adjuvants that trip more of the bodys defensive sensors. Injections such as those seem to maintain higher antibody titers year-round, says Sophie Valkenburg, an immunologist at Hong Kong University and the University of Melbournea trend that Ellebedy attributes to the body investing more resources in training its fighters against what it perceives to be a larger threat. Such a switch would likely come with a cost, though, McLean said: Higher doses and adjuvants also mean more adverse events, more reactions to the vaccine.
For now, the only obvious choice, Rodda told me, is to definitely get vaccinated this year. After the past two flu seasons, one essentially absent and one super light, and with flu-vaccination rates still lackluster, Americans are more likely than not in immunity deficit. Flu-vaccination rates have also ticked downward since the coronavirus pandemic began, which means there may be an argument for erring on the early side this season, if only to ensure that people reinforce their defenses against severe disease, Rodda said. Plus, Australias recent flu season, often a bellwether for ours, arrived ahead of schedule.
Even so, people who vaccinate too early could end up sicker in late winterin the same way that people who vaccinate too late could end up sicker now. Plotkin told me that staying apprised of the epidemiology helps: If I heard influenza outbreaks were starting to occur now, I would go and get my first dose. But timing remains a gamble, subject to the viruss whims. Flu is ornery and unpredictable, and often unwilling to be forecasted at all.
The flu vaccine is updated every year to match the specific strains of the influenza virus experts predict will be most prominent during flu season. To determine this, the World Health Organization Global Influenza Surveillance Response System, made up of 144 influenza centers in 114 countries, conducts year-round surveillance to determine which flu strains are actively circulating around the globe.
Twice a year, representatives from five of the top participating centers come together to review data and recommend which strains to include in the upcoming flu vaccine.
These flu experts try to anticipate what the dominant strains are going to be nine months down the road, explains William Schaffner, MD, professor of infectious disease at Vanderbilt University School of Medicine in Nashville. They're often on target, but on some occasions, the flu virus that circulates varies from the vaccine. How effective the influenza vaccine is changes from year to year too.
In other words, flu virus experts have to base their recommendations on a moving target, which means the flu vaccine cant be perfect. Even so, according to the Centers for Disease Control and Prevention (CDC), the most recent research suggests the flu shot lowers the risk of illness from 40 to 60 percent.
As for the specific influenza strains included in the flu vaccine, for the 2022-2023 season, there are four: two influenza A strains and two influenza B strains. In previous flu seasons, most vaccines protected against only three strains.
Can you get the COVID booster and flu shot at the same time? For Dr. Ashish Jha, the White House COVID-19 response coordinator, the answer is simple.
I really believe this is why God gave us two arms one for the flu shot and the other one for the COVID shot, he quipped during a recent briefing.
As public health officials prepare for a possible rebound of the coronavirus this fall and winter, theyre also urging people to get vaccinated against the familiar, if recently quiet, foe of influenza.
But busy residents need not fret about booking a pair of appointments. Jha, along with other officials and experts, say its perfectly fine to roll up each of your sleeves during the same visit.
Healthcare providers should offer flu and COVID-19 vaccines at the same visit to people who are eligible, according to the U.S. Centers for Disease Control and Prevention.
Getting both vaccines at the same visit increases the chance that a person will be up to date with their vaccinations, the CDC said in a presentation.
The agency suggested administering each shot in separate limbs.
Other vaccines are fine, too, unless theres a specific reason not to administer them at the time of the healthcare visit.
Providers should offer all vaccines for which a person is eligible at the same visit, the CDC said.
Flu shots are now available for everyone age 6 months or older. Residents can visit Californias MyTurn platform to find a walk-in clinic or to book an appointment starting Thursday.
Getting the flu vaccine was an annual event for many Californians but, like most aspects of life, the practice has been upended and interrupted during the pandemic. However, because of other interventions in place to combat COVID-19, the flu has been relatively dormant.
Influenza mostly disappeared the past two winters, but it returned this past spring of 2022 when we stopped wearing masks, Los Angeles County Public Health Director Barbara Ferrer said. Because we anticipate more flu in the upcoming months, we do encourage everyone to take advantage of the many vaccination sites where youre going to be able to get your flu vaccine and your COVID fall booster at the same time.
Both shots, she added, provide protection against illness severity, increasing the likelihood of fewer disruptions for you and your family this fall and winter.
Some officials have likened the new COVID-19 boosters to the flu shot. Just as officials formulate the flu vaccine in an attempt to target that years version of the virus, the updated boosters are designed against both the original coronavirus strain and the Omicron subvariants that have dominated the U.S. in recent months, including BA.5.
Were all familiar with the annual updating of influenza vaccines every year. Scientists monitor flu strains around the world, and this data is used to inform how the annual vaccine should be updated, Ferrer said earlier this month. The same concept was used in updating the COVID booster.
Moving forward, some officials have speculated its possible residents might receive annual COVID-19 booster doses, much as they do flu shots.
Computer generated 3D model, showing a cross-section of the green RNP spirals, blue hemagglutinin, ... [+] red neuraminidase, and purple m2 ion channels that constitute the structure of the Influenza A Virus (Orthomyxovirus family) image courtesy CDC/Douglas Jordan, 2009. (Photo by Smith Collection/Gado/Getty Images)
This is the second of two articles on universal flu vaccines, both of which are part of a larger series on influenza vaccines and influenza treatments. Previous articles can be read here: Part 1, Part 2, Part 3, Part 4, Part 5.
For many years there has been an obvious need for an influenza vaccine that neutralizes not just one strain, but many different strains across both major influenza types. This includes providing protection against as-yet undiscovered strains. Current vaccines have not achieved this, requiring yearly administration to keep pace with viral mutations. But over the last decade there has been great effort to develop such a universal flu vaccine, with much of it now beginning to pay off.
Two Targets Are Better Than One
The key problem so far has been that flu vaccines provide a potent but highly specific immune response; they work decently well, but only against those strains that have been included in the vaccine. Should a new strain of influenza appear, or one that scientists hadnt predicted, then vaccine efficacy is left seriously jeopardized. To combat this issue, scientists have begun looking towards highly conserved regions of the viral genome. These are regions that are shared across many strains and that only very rarely mutate.
Two areas of the influenza virus particle are particularly promising targets: the stem portion of the influenza surface protein hemagglutinin (HA), and the extracellular region of the matrix-2 protein (M2e). Both of these proteins play a crucial role in viral replication M2 helps untether the viral RNA from the surrounding viral membrane, and HA stem (HA2) creates the opening through which the RNA can then enter the host cell cytoplasm. Antibodies that bind to and block either of these proteins impair viral replication. Here, we describe a new vaccine candidate developed by Subbiah et al. that combines these two attractive targets into a single, highly engineered protein.
Design of the Antigen: Perfecting the Headless HA Protein
Interest in the stem portion of HA has its roots in the discovery of human broadly neutralizing antibodies (bnAbs) that target the region. This discovery revitalized hopes of developing universal flu vaccines by giving researchers an entry point for the production of a universal antigen. Since the full HA protein only rarely elicits broadly neutralizing antibodies, various approaches have emerged to expose and properly present the stem domain to our immune system. One of the more successful strategies involves knocking off the HA head domain while ensuring structural stability of the leftover HA stem.
But this is easier said than done. The head of the HA protein stabilizes the prefusion protein resulting in a tightly coiled triplex of three proteins. Broadly neutralizing monoclonal antibodies only recognize this tightly coiled triplex and are lost once the fusion process commences or the head of the HA protein is removed.
To perfect the hemagglutinin portion of their antigen, Subbiah and colleagues drew upon previous research by Impagliazzo et al. and Yassine et al. Both groups managed to engineer stable, headless HA stem antigens called mini-HAs that exhibited structural and antibody binding properties similar to full-length HA. Antibodies produced in response to these mini-HAs managed to protect against a wide range of HAs in mice and nonhuman primates.
Figure 1 outlines the various stages of Impagliazzo et al.s design, culminating in the creation of a stable, headless "mini-HA" stem that retains all the relevant neutralizing binding sites. Figure 2 outlines the design stages of Yassine et al, who achieved great minimization of the HA protein, ultimately succeeding in having the stem domain contribute 94% of the total surface area of their antigen.
FIGURE 1. (A) The mini-HA design strategy is described in five stages, each characterized by ... [+] specific modifications leading to selection of the best construct for each stage. Key modifications for each stage are schematically depicted and color-coded. (B) Ribbon mini-HA model (from PDB ID 1RD8) with color-coded modifications (per stage, as in Fig. 1A) and putative N-glycosylation sites (CG1-3, CG7; taupe).
FIGURE 2. (A) Proggressive removal of the HA head domain to expose as much of the HA stem domain as ... [+] possible without losing structural stability. (B) Percentage of HA stem contribution to total antigen surface area: full HA protein (left), Gen4 of modified headless HA antigen (center), and Gen6 of modified headless HA antigen.
Forming a Stable Trimer and Preventing Protein Aggregation
Influenza hemagglutinin is naturally a trimeric molecule, meaning it is composed of three distinct hemagglutinin proteins bound together. In order to accurately mimic this three-part structure, Subbiah et al. excluded the C-terminus of the HA stem portion and instead replaced it with the foldon sequence of a virus that infects bacteria.
When added to the end of a monomer that has a propensity to dissociate, the foldon sequence stabilizes it and allows it to form a trimer (Figure 3). Failure to do so may lead the headless HA stem antigen to lose its structure, and by extension its epitope sites. If our antibodies cannot bind to the stem, they cannot learn about its structure and thus cannot take on the specific shape needed to protect us from future reinfection.
FIGURE 3. (A) A trimeric fiber loses its structure and breaks down into unfolded monomers, leading ... [+] to irreversible protein aggregation. (B) The addition of the foldon sequence allows monomers to return to their trimeric structure, preventing loss of structure and subsequent protein aggregation.
The researchers also added specific point mutations along HA1 head and HA2 stalk to prevent protein aggregation issues. All of the mutations were in regions outside of those recognized by broadly neutralizing antibodies. Each one of the mutations was in a long helical region with a tendency to self-aggregate. By changing the amino acids in these stretches, they substantially reduced non-specific aggregation and instead favored the stable form of the protein.
In addition to this, they mutated a cysteine residue and replaced it with a serine residue. Again strengthening the stability of the protein and minimizing the chance of any unwanted disulfide bonds from forming.
Addition of M2e
To broaden the neutralization of their antigen, and increase its potency, the researchers added in two identical segments of the M2 channel protein. The segments they chose correspond to a 23 amino acid-long sequence that encodes the epitopes for the extracellular region of the protein. This area protrudes from the viral membrane, allowing it to be bound by neutralizing antibodies.
Crucially, M2e has previously been shown to confer cross-group immunity. Influenza A viruses are split up into two groups according to phylogenetic differences in their HA protein. Usually immunity against group 1 HAs (H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, H18) does not confer immunity against group 2 HAs (H3, H4, H7, H10, H14, H15). This means that infection by an influenza A/(H3N2) virus, for example, generally does not confer protection against a strain of influenza A/(H1N1).
Finally, Subbiah et al. connected the various domains of the M2e-H3 construct using flexible linkers, which are small amino acids that function like bungee cords; they keep the proteins tethered together but are flexible enough not to interfere with the folding process.
The full genetic sequence of the M2e-H3 antigen can be seen in Figure 4, and the structure of the antigen as compared to wild type hemagglutinin can be seen in Figure 5.
FIGURE 4. M2e-H3 stalk vaccine construct with flexible and soluble linker sequences (AAAGGAA; ... [+] GGGGS; GSA; GSAGSA; QGTGG).
FIGURE 5. (LEFT) A schematic diagram of the H3 HA protein, derived from the H3N2 influenza virus. ... [+] (RIGHT) A schematic of the chimeric M2e-H3 stalk protein, with stabilizing point mutations marked in violet.
Production and Purification of the Antigen
For ease of purification of the antigen, the researchers added a histidine tag (6xHis) to the N-terminal of the M2e-H3 stem domain. A histidine tag is made up of a DNA sequence that encodes six to nine histidine residues. These histidine residues bind to several different types of immobilized metal ions. So, once a protein has been His-tagged it can be easily identified and separated from other proteins by exposure to such metal ions. The histidine tag can then be removed from the protein or it can be retained, either way it does not affect the antigenicity of the protein.
Next, Subbiah et al. synthesized a codon-optimized gene encoding the M2e-H3 stem protein. This gene is then inserted into escherichia coli (E.coli) for quick and easy mass production.
Does it Retain Antigenicity?
After extraction and purification, Subbiah et al. began testing the M2e-H3 stalk molecule for its ability to be recognized by antibodies, known as antigenicity. They exposed the chimeric molecule to antibodies known to target the stem portion of the hemagglutinin protein as well as antibodies known to target M2e; in both cases they witnessed high reactivity. The scientists recorded similar results from antisera blood samples from mice that had previously been infected with an influenza virus and had built up a corresponding antibody response. Importantly, the construct retained its antigenicity when exposed to influenza A viruses belonging to different HA groups. And, even after storage at 122 degrees Fahrenheit for 11 days, the antigen continued to elicit strong antibody reactivity, suggesting solid thermostability.
Animal Models
Having confirmed that the M2E-H3 stem protein can be recognized and bound by antibodies, Subbiah and colleagues moved on to vaccination trials. Often, vaccines based on viral proteins instead of inactivated or attenuated viruses require an adjuvant to help stimulate a stronger immune response, and by extension, better protective efficacy. For their experiments, the researchers used a particularly strong adjuvant similar to the AS01 liposome adjuvant licensed for use in herpes Zoster vaccination. This is a double-edged sword: the adjuvant ensures a quick immune response, but because of its strength, it also comes at the cost of side effects. Although the side effects are not much cause for concern headache, fever, chills, and so on they are uncomfortable all the same. Using a different delivery platform, like mRNA technology, may help circumvent these issues in the future.
The adjuvanted M2e-H3 stalk vaccine was administered to mice as two doses, a primary vaccination followed by a boost two weeks later. Following the first dose, there was a noticeable increase in antibodies specific to M2e and HA stem regions. Addition of the boost further increased antibody titers 10 fold. Antisera built up in response to M2e-H3 exposure managed to protect against both group 1 and group 2 influenza A viruses. Subbiah et al. suspect this might be explained by antibody-dependent cellular cytotoxicity (ADCC), a mechanism of immune defense whereby effector cells recognize antibodies stuck to antigens and actively break down the foreign threat. Their suspicions were proven right by western blotting, which showed that M2e antibodies, in particular, raised ADCC activity 20 fold.
To compare protection against an M2e only vaccine, the group of researchers designed another chimera protein combining M2e fused with the receptor binding domain (RBD) of SARS-CoV-2 spike protein. When exposed to a lethal dose of influenza A/HK/H3N2 virus, all of the mice inoculated with M2e-H3 stem survived, suffering only moderate body weight loss of around 10%. On the other hand, none of the mice inoculated with the M2e-only vaccine survived the infection (Figure 6).
FIGURE 6. Protective efficacy comparison of M2e-H3 stalk and M2e only vaccines after A/HK/1968 H3N2 ... [+] (12xLD50, 1.4102 EID50) virus challenge.
Along with a robust antibody response, M2e-H3 stalk vaccination also triggered a strong T cell response. Where antibodies can bind to pathogens to prevent infection, T cells are in charge of getting rid of already-infected cells, curbing the spread of the virus. Indeed, the vaccine significantly reduced the amount of virus in the lungs of infected mice within a span of six days. Depleting T cell levels in vaccinated mice before exposing them to a lethal challenge with influenza A H7N9 produced twice as much weight loss (12%) than in mice that had not been depleted of their T cells.
Implications
The work by Subbiah et al. acts as a clear proof of concept: using M2e and HA stalk regions as antigens can stimulate broad neutralizing immunity. Crucially, this immunity should hold up to new strains, as it targets those viral regions that only very rarely mutate. Although their work focused specifically on influenza A viruses, there is no reason to think that, given enough time and research, we wont be able to produce a truly universal influenza vaccine.
The progress that has been made is in very large part due to the development of monoclonal antibodies that are broadly neutralizing against a wide array of influenza strains. These antibodies have provided a key guide to the design of vaccine antigens to help elicit immune responses with a similar breadth of neutralizing capabilities. This elegant work that has developed over the past ten years may prove to be a reliable framework for the development of similarly universal vaccines to some of our most vexing problems, including HIV and SARS-CoV-2. Such attempts are already underway for Covid-19, and proved to be the missing part of the puzzle for the design of effective vaccines against respiratory syncytial virus (RSV).
Influenza, more commonly known as flu, is a highly contagious viral disease. The influenza virus attacks with more intensity during the winter months. Symptoms can be mild, but the virus can also cause severe illness and even death, particularly for those in the high-risk groups (the very young, people over 55, those with an underlying health condition, those who are pregnant, overweight or who have a weakened immune system). Symptoms usually last between three and seven days, although in some instances they can persist for several weeks.
The virus spreads through water droplets, especially when an infected person coughs or sneezes, or via contaminated hands and surfaces.
Hygiene measures adopted during the COVID-19 pandemic, such as washing your hands, coughing into your elbow and keeping your distance, are good habits to keep up, as they are effective in helping to reduce the chance of contracting and/or spreading the flu virus.
The vaccine remains the best way to protect yourself against flu, to prevent the spread of the disease and to reduce its severity, in particular if youre part of a high-risk group.
An international panel of experts carefully reviews the strain composition of the vaccine annually based on data from epidemiological centres and then makes recommendations to countries accordingly as to what strains they might wish to include in their national flu vaccine programme.
It takes about two weeks for an adequate immune response and protection to develop, and immunity tends to decline over the course of a few months. It is thus important to get a flu vaccine every year.
The flu vaccine will be available free of charge to anyone working on the CERN site, including contractors. Practical details of this years flu vaccination campaign, which will run from 17 October until 11 November, can be found at https://hse.cern/fluvaccination.
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Further information:General information on Influenza | WHOGeneral information on Influenza in Switzerland | OFSP (available in French only)
Vaccination in France | Ameli (available in French only)Vaccination in Switzerland | HUG (available in French only)
