Scientists have discovered why older people are more likely to suffer severely from the flu, and can now use their findings to address this risk. In a new study published in PNAS, experts discovered that older people produce a glycosylated protein called apoplipoprotein D (ApoD), which is involved in lipid metabolism and inflammation, at much higher levels than in younger people. This has the effect of reducing the patient’s ability to resist virus infection, resulting in a more serious disease outcome.
The team established that highly elevated ApoD production with age in the lung drives extensive tissue damage during infection to reduce the protective antiviral type I interferon response.
The research was an international collaboration led by scientists from the China Agricultural University, University of Nottingham, Institute of Microbiology (Chinese Academy of Sciences), National Institute for Viral Disease Control and Prevention (Chinese Centre for Disease Control and Prevention) and the University of Edinburgh.
Aging is a leading risk factor in influenza-related deaths. Furthermore, the global population is aging at an unprecedented rate in human history, posing major issues for healthcare and the economy. So we need to find out why older patients often suffer more severely from influenza virus infection.”
Professor Kin-Chow Chang from the School of Veterinary Medicine and Science at the University of Nottingham, and co-author on the paper
In this new study, the team investigated the mechanisms behind increased severity of influenza virus infection with age using an aging-mouse model and appropriate donor human tissue sections.
They identified ApoD as an age-related cell factor that impairs the activation of the immune system’s antiviral response to influenza virus infection by causing extensive breakdown of mitochondria (mitophagy) resulting in greater production of virus and lung damage during infection. Mitochondria are essential for cellular production of energy and for induction of protective interferons.
ApoD is therefore a target for therapeutic intervention to protect against severe influenza virus infection in the elderly which would have a major impact on reducing morbidity and mortality in the aging population.
Professor Chang, added: “There is now an exciting opportunity to therapeutically ameliorate disease severity of the elderly from influenza virus infection by the inhibitory targeting of ApoD.”
Study finds sensory cells that detect tissue damage, irritants also rein in harmful immune responses to protect the lungs
Clusters of mouse vagus nerve sensory cells reveal the presence of TRPV1, a molecular sensor that detects irritants, heat, and inflammation. A new HMS study reveals nerve cells with this sensor play a central role in taming inflammation and tissue damage in the lung during flu infection. Image: Chiu Lab.
A group of nerve cells known for their role in detecting chemical irritation, tissue damage, heat, and pressure now emerge as critical defenders against the worst ravages of the flu caused by an overactive immune response, according to new research by scientists at Harvard Medical School and the Harvard T.H. Chan School of Public Health.
The cells, called TRPV1 vagal nociceptors, live in the vagus nerve, which sends signals from internal organs – including the heart, lungs, and gut – to the brain to help regulate heart rate, breathing, digestion, and other functions. In the lungs, these cells trigger the protective cough reflex that forces the airways to expel foreign particles, mucus, and other irritants.
But the new research, published in Science Immunologyand conducted in mice, shows that in the setting of flu, these cells do much more – they rein in the immune system and avert the smoldering inflammation that often occurs in the aftermath of a viral infection and can injure healthy tissue.
Each year, the flu sickens millions and kills between 290 000 and 650 000 people worldwide, according to the World Health Organization. While the immune system helps fight off the virus, an excessive inflammatory response can inflict tissue damage and worsen illness. The findings are especially relevant in the wake of the COVID-19 pandemic, which revealed how an aberrant immune response following viral infection can sometimes lead to serious organ damage and even organ failure.
“Our research shows that the infected lung is a battleground where nerves and immune cells engage in a delicate dance to safeguard our health,” said co-senior study author Isaac Chiu, professor of immunology in the Blavatnik Institute at HMS. “Understanding this powerful neuro-immune signaling axis will be increasingly important as we design better ways to prevent and treat immune-mediated damage in viral infections, which can sometimes be worse than the direct damage caused by the virus itself.”
The findings, he added, raise the possibility that vagus nerve function may be one variable that explains why some people with the flu go on to develop long-lasting and devastating immune-driven damage in their lungs while others recover once the initial infection is resolved.
“Flu infections are highly variable in severity and there is a need to understand why certain groups of people, such as the elderly, experience worse disease,” said study first author Nicole Almanzar, a doctoral student in the Chiu Lab. “Our study demonstrates that the nervous system is actively involved in regulating the response of the lungs to infection, offering a new perspective on viral infections that could help explain why particular factors increase risk of severe infections.”
The new study illuminates the complex interaction between body and brain and adds to a growing body of research showing that the nervous and immune systems engage in highly orchestrated crosstalk during infection to modulate body defenses.
One of Chiu’s earlier studies found that during bacterial infections of the lung, the same set of vagal nerve neurons suppressed the immune defences. In the new study, however, the immune-taming function of these cells worked to shield the lung from excessive damage during viral infection.
“Context clearly matters,” Chiu said.
Disabling the neurons worsened flu damage in the lungs
In a set of experiments, researchers exposed a group of mice with genetically disabled or chemically silenced TRPV1 neurons to influenza A virus. Mice without these nerve cells fared notably worse than mice with functioning TRPV1 cells. Even though the overall amount of virus in the lungs was the same in both groups, mice lacking TRPV1 neurons suffered more severe lung pathology, higher levels of harmful inflammation, and lower survival rates. Interestingly, Almanzar noted, even though the overall viral load remained the same, the spread of the virus within the lobes of the lungs was more pronounced in mice without these protective neurons.
The researchers also found that the absence of TRPV1 neurons altered the lung’s immune landscape. The lungs of mice lacking these neurons had an overabundance of neutrophils and macrophages – two types of immune cells that, in excess, can worsen tissue damage. At the same time, interferon signalling – one of the body’s most important viral-defence pathways – was seriously impaired in these immune cells.
In another experiment, the researchers used an antibody to deplete inflammation-driving cells in flu-infected mice lacking TRPV1 neurons. These animals had notably better survival than untreated mice lacking these protective neurons. The observation further underscores how nerve cells help prevent harmful immune reactions that can sometimes be more dangerous than the virus itself.
The researchers noted that they do not yet know precisely how TRPV1 neurons restrain the march of inflammatory cells at the molecular level – a question they plan to explore in subsequent work.
“The vagus nerve is powerfully controlling inflammation, but how it does so remains a mystery to be solved,” Chiu said. “But we’re excited that it plays such a strong role in viral infections.”
Harnessing the immune brake for therapy
Moving forward, this insight opens the door to exciting new avenues for therapy. Instead of only targeting the flu virus or dampening immune activity, the research team said, future treatments could mimic the function of nerve cells to ensure the delicate balance between protective and damaging immune responses is not thrown off.
The idea is not that far-fetched, the researchers said, noting that the FDA recently approved a therapy for rheumatoid arthritis by vagus nerve stimulation.
“Imagine if you could harness this brake to control inflammation in the lungs and beyond,” Chiu said. “By stimulating related circuits where the vagus nerve shuts down immune cells, one could envision treating immune-mediated dysfunction of many kinds, including that caused by viral infections.”
In a potential game-changer for how we treat the flu, scientists at the Hebrew University of Jerusalem have unveiled a new drug pairing that outperforms oseltamivir – the most widely used anti-influenza medication – against even the deadliest flu strains, including bird(avian) and swine flu.
The surprising duo? One of them is theobromine, a compound found in chocolate.
In a study recently published in PNAS, researchers, led by Prof Isaiah (Shy) Arkin, have developed a novel combination therapy that targets a key weakness in the influenza virus: its ion channel, a microscopic gate the virus uses to replicate and spread. By blocking this gate, the team effectively cut off the virus’s ability to survive.
Their study, conducted at Israel’s new Barry Skolnick Biosafety Level 3 facility, tested this combo, consisting of theobromine and a lesser-known compound called arainosine, against a broad range of flu viruses. In both cell cultures and animal trials, the treatment dramatically outperformed oseltamivir (Tamiflu), especially against drug-resistant strains.
“We’re not just offering a better flu drug,” said Prof Arkin. “We’re introducing a new way to target viruses – one that may help us prepare for future pandemics.”
Why It Matters
The stakes are high: Influenza continues to sweep the globe each year, with unpredictable mutations that challenge vaccines and existing drugs. In the U.S. alone, seasonal flu costs an estimated $87 billion annually in healthcare and lost productivity. Past pandemics – like the 2009 swine flu – have inflicted even deeper global costs, and the cost of future pandemics was estimated to rise even further up to $4.4 trillion.
Meanwhile, outbreaks of avian flu have devastated poultry industries and sparked fears of cross-species transmission to humans. Just one recent outbreak in the U.S. led to the loss of 40 million birds and billions in economic damage.
Current flu treatments, like oseltamivir, are losing ground as the virus adapts. Most drugs in use target a viral protein that mutates frequently, rendering treatments less effective over time. That’s where Arkin’s team saw an opening.
A New Strategy for Old Viruses
Instead of fighting the virus head-on with traditional antivirals, the researchers zeroed in on the M2 ion channel – a crucial viral feature that helps the virus replicate. Past efforts to block this channel have largely failed due to drug resistance. But the new theobromine–arainosine combo sidesteps this resistance, even neutralising hard-to-treat strains.
The team discovered the combo by scanning a library of repurposed compounds, many originally developed for other diseases, and testing their effects on both drug-sensitive and drug-resistant versions of the virus.
Broader Implications
The implications extend beyond influenza. Because many viruses, including coronaviruses, also rely on ion channels, this new approach could form the basis of future antiviral strategies.
The next steps include human clinical trials, but the early results offer hope not just for a better flu treatment, but for a smarter way to fight viral disease in general. ViroBlock, a startup company emanating from the Hebrew University, has been entrusted to develop the discoveries to reach the public.
For decades, medical professionals debated whether a common antiviral medication used to treat flu in children caused neuropsychiatric events or if the infection itself was the culprit.
Now researchers at Monroe Carell Jr. Children’s Hospital at Vanderbilt have debunked a long-standing theory about oseltamivir, known as Tamiflu.
According to the study, published in JAMA Neurology, oseltamivir treatment during flu episodes was associated with a reduced risk of serious neuropsychiatric events, such as seizures, altered mental status and hallucination.
“Our findings demonstrated what many pediatricians have long suspected, that the flu, not the flu treatment, is associated with neuropsychiatric events,” said principal investigator James Antoon, MD, PhD, MPH, assistant professor of Pediatrics in the Division of Pediatric Hospital Medicine at Monroe Carell. “In fact, oseltamivir treatment seems to prevent neuropsychiatric events rather than cause them.”
Key points:
Influenza itself was associated with an increase in neuropsychiatric events compared to children with no influenza, regardless of oseltamivir use.
Among children with influenza, those treated with oseltamivir had about 50% reduction in neuropsychiatric events.
Among children without influenza, those who were treated with oseltamivir prophylactically had the same rate of events as the baseline group with no influenza.
“Taken together, these three findings do not support the theory that oseltamivir increases the risk of neuropsychiatric events,” said Antoon. “It’s the influenza.”
The team reviewed the de-identified data from a cohort of children and adolescents ages 5-17 who were enrolled in Tennessee Medicaid between July 1, 2016, and June 30, 2020.
During the four-year period, 692 295 children, with a median age of 11 years, were included in the study cohort. During follow-up, study children experienced 1230 serious neuropsychiatric events (898 neurologic and 332 psychiatric).
The clinical outcomes definition included both neurologic (seizures, encephalitis, altered mental status, ataxia/movement disorders, vision changes, dizziness, headache, sleeping disorders) and psychiatric (suicidal or self-harm behaviours, mood disorders, psychosis/hallucination) events.
“The 2024-2025 influenza season highlighted the severity of influenza-associated neurologic complications, with many centres reporting increased frequency and severity of neurologic events during the most recent season,” said Antoon. “It is important for patients and families to know the true risk-benefit profile of flu treatments, such as oseltamivir, that are recommended by the American Academy of Pediatrics.”
“These flu treatments are safe and effective, especially when used early in the course of clinical disease,” added senior author Carlos Grijalva, MD, MPH, professor of Health Policy and Biomedical Informatics at Vanderbilt University Medical Center.
Investigators hope the findings will provide reassurance to both caregivers and medical professionals about the safety of oseltamivir and its role in preventing flu-associated complications.
A research team led by the University of Hong Kong have achieved an award-winning breakthrough in developing broadly protective, live-attenuated influenza vaccines (LAIV). These innovative LAIV platforms offer the potential to develop universal influenza vaccines that induce a more robust immune response against various virus subtypes, including both human and avian strains. Since they induce mucosal immune responses, they can also be administered nasally.
Current seasonal influenza vaccines protect primarily against three selected strains and require annual updates. Their efficacy can significantly decline if the circulating viruses do not match the strains chosen each year for each hemisphere. Moreover, these vaccines fail to guard against human infections caused by animal influenza viruses, such as avian strains, which pose a potential global pandemic threat. The World Health Organization (WHO) has underscored the urgent need for a new generation of universal influenza vaccines.
The research team developed two innovative approaches to create next-generation LAIVs. The first strategy involved engineering a human influenza virus with then gene for α-Gal, which is already targeted by human antibodies. Vaccine-infected cells then express α-Gal on their surfaces and boost vaccine-induced immune responses, including antibody-mediated cytotoxicity, opsonisation and phagocytosis.
The research data showed that the vaccine is attenuated in mouse models. Vaccinated mice showed strong innate and adaptive immune responses, including antibody and T-cell responses. These immune responses conferred broad protection against various influenza A virus subtypes, including human H1N1 and H3N2, and avian H5N1 strains.
The second approach to developing next-generation LAIVs involved introducing hundreds of silent mutations to a human influenza virus, shifting its codon usage from that of a human influenza virus to that of an avian influenza virus-like pattern. This shift resulted in the attenuation of the virus in mammalian cells, making it safe for use as an LAIV.
Additionally, the mutant virus replicated perfectly in chicken eggs, which is crucial for current effective vaccine manufacturing processes. With this approach, the viral protein expression of the LAIV remained identical to the original wild-type virus, providing a robust immune response against the viruses. The research team successfully generated several attenuated viruses with different human influenza virus backbones, including H1N1 and H3N2.
The development of these two award-winning LAIVs represents a significant advancement in the quest for broadly protective and efficient influenza vaccines. This new generation of LAIVs can both protect humans from seasonal influenza viruses and address the threat posed by emerging viruses, like avian influenza viruses.
“The advantages of LAIVs lie in their intranasal administration, which has been shown to induce mucosal immune responses along the respiratory tract, providing additional protection against infection,” highlighted Professor Leo Poon Lit-man, Chair Professor of Public Health Virology and Head of the Division of Public Health Laboratory Sciences, School of Public Health, HKUMed. “This needle-free delivery method alleviates the fear of vaccination, particularly in young children, so it will help mitigate vaccine hesitancy.”
Professor Luis Martinez-Sobrido, Ph.D., (left) and Staff Scientist Ahmed Mostafa Elsayed, PhD, (right) review test results for the presence of bird flu while wearing protective equipment required for biosafety level-3 laboratories.
One of the earliest strains of bird flu isolated from a human in Texas shows a unique constellation of mutations that enable it to more easily replicate in human cells and cause more severe disease in mice compared to a strain found in dairy cattle, researchers from Texas Biomedical Research Institute (Texas Biomed) report in Emerging Microbes & Infections.
The finding highlights a key concern about the H5N1 strains of bird flu currently circulating in the U.S.: the speed at which the virus can mutate when introduced to a new host.
Naturally found in wild birds and lethal in chickens, H5N1 has spread to a wide variety of mammals and began infecting dairy cows for the first time in spring 2024. As of early 2025, the outbreak had spread through herds across multiple states in the U.S. and infected dozens of people, mostly farm workers. So far, most people infected experience mild illness and eye inflammation and the virus is not spreading between people. The first H5N1 death in the U.S. was reported in January 2025 following exposure to infected chickens.
“The clock is ticking for the virus to evolve to more easily infect and potentially transmit from human to human, which would be a concern,” said Texas Biomed Professor Luis Martinez-Sobrido, PhD, whose lab specialises in influenza viruses and has been studying H5N1 since the outbreak began last year. The team has developed specialised tools and animal models to test prophylactic vaccines and therapeutic antivirals.
Human vs bovine
In the recent study, they compared H5N1 strains isolated from a human patient and from dairy cattle in Texas.
“There are nine mutations in the human strain that were not present in the bovine strain, which suggests they occurred after human infection,” Dr Martinez-Sobrido said.
In mouse studies, they found that compared to the bovine strain, the human strain replicated more efficiently, caused more severe disease and was found in much higher quantities in brain tissue. They also tested several FDA-approved antiviral medications to see if they were effective against both virus strains in cells.
“Fortunately, the mutations did not affect the susceptibility to FDA-approved antivirals,” said Staff Scientist Ahmed Mostafa Elsayed, PhD, first author of the study.
Antivirals will be a key line of defence should a pandemic occur before vaccines are widely available, Dr Martinez-Sobrido said. This is especially true since humans have no preexisting immunity against H5N1 and seasonal flu vaccines appear to offer very limited protection, according to a separate study conducted in collaboration with Aitor Nogales, PhD, at the Center for Animal Health Research in Spain.
Dr Elsayed shows the host species of the four types of influenza viruses: A, B, C and D. Avian influenza is part of the influenza A group and has infected a wide range of species. Influenza A and B are responsible for seasonal flu in humans.
Next steps and recommendations
Texas Biomed is now exploring the human H5N1 mutations individually to determine which are responsible for increased pathogenicity and virulence. The team wants to figure out what allows H5N1 to infect such a wide range of mammal species; why H5N1 causes mild disease in cows but is lethal in cats; and why infections via cows are less harmful to people than infections from chickens.
In a third paper, Dr Elsayed and collaborators analysed the history of H5N1 in dairy cattle for the journal mBio and called for a One Health approach to protect both animals and people.
“A key priority will be to eradicate bird flu from dairy cows to minimise risk of mutations and transmission to people and other species,” Dr Elsayed said. “Steps that can be taken now include thorough decontamination of milking equipment and more stringent quarantine requirements, which will help eliminate the virus more quickly in cows.”
McGill University scientists have discovered that pregnancy may trigger a natural immunity to boost protection against severe flu infection. Contrary to the common belief that pregnancy increases vulnerability to infections, researchers found that it strengthened an immune defence in mice, blocking the Influenza A virus from spreading to the lungs, where it can cause severe infection.
“Our results are surprising because of the current dogma, but it makes sense from an evolutionary perspective,” said co-lead author Dr Maziar Divangahi, Professor in McGill’s Faculty of Medicine and Health Sciences and Senior Scientist at the Research Institute of the McGill University Health Centre (The Institute).
“A mother needs to stay healthy to protect her developing baby, so the immune system adapts to provide stronger defenses. This fascinating response in the nasal cavity is the body’s way of adding an extra layer of protection, which turns on during pregnancy.”
Exploring benefits for pregnancy and beyond
The researchers used a mouse model to observe how a certain type of immune cell activates in the nasal cavity of mice during pregnancy, producing a powerful molecule that boosts the body’s antiviral defenses, especially in the nose and upper airways.
“Influenza A virus remains among the deadliest threats to humanity,” said first author Julia Chronopoulos, who carried out the research while completing her PhD at McGill. “This natural immunity in pregnancy could change the way we think about flu protection for expectant mothers.”
The Public Health Agency of Canada recommends pregnant women and pregnant individuals get the flu vaccine, as they are at high risk of severe illness and complications like preterm birth. The new insights offer promise for more targeted vaccines for influenza, which is among the top 10 leading causes of death in Canada.
“The broader population could also benefit, as our findings suggest the immune response we observed could be replicated beyond pregnancy,” said co-lead author Dr James Martin, Professor in McGill’s Faculty of Medicine and Health Sciences and Senior Scientist at the RI-MUHC. This could mean new nasal vaccines or treatments that increase protective molecules, known as Interleukin-17.
The team’s next focus is on finding ways to reduce lung damage during viral infections like the flu or COVID. Rather than targeting the virus, as previous research has done, they aim to prevent dysregulated immune systems from overreacting, an approach that could lower the risk of serious complications associated with flu infection.
A world-first study has found low-dose aspirin may treat flu-induced blood vessel inflammation, creating better blood flow to the placenta during pregnancy. Animal studies examined whether the treatment for preeclampsia could be applied to flu infections – and the results, published in Frontiers in Immunology, were very promising.
Lead researcher and RMIT Post-Doctoral Research Fellow, Dr Stella Liong, said that flu infections during pregnancy can resemble preeclampsia, a pregnancy complication that causes inflammation to the aorta and blood vessels. Low-dose aspirin is commonly taken to prevent preeclampsia, as it stops the body from creating chemicals that cause inflammation.
“When the vascular system is inflamed, it leads to poor blood flow and affects the aorta’s function,” she said. “This is especially a problem during pregnancy where good blood flow to the placenta is crucial to the development of the foetus.”
The research, led by RMIT University in collaboration with Trinity College Dublin, Ireland Professor John O’Leary and University of South Australia Professor Doug Brooks, found foetuses and placenta from mice with influenza A were smaller than those from uninfected mice.
Markers of low blood oxygenation and poor blood vessel development were also evident in the foetuses. The mice treated daily with low-dose aspirin had less inflammation and improved foetal development and offspring survival.
While the research was still awaiting human clinical trials, Liong said low-dose aspirin was already recognised as safe to take during pregnancy. The research team however recommended pregnant people seek medical advice before taking new medications.
Brooks said influenza A infections during pregnancy was a big concern as every pregnancy overlaps with part of a flu season.
“There are long term implications for both the mother and the foetus, and aspirin might provide a simple solution for preventing this influenza associated pathology,” Brooks said.
Why flu infection is dangerous during pregnancy
O’Leary said the research findings had huge implications for pregnancy and seasonal influenza virus infections for pregnant people.
“This study shines a light, for the first time, on the role of vascular inflammation associated with influenza virus and the potential dramatic effect of the disease-modifying drug aspirin, in low dosage, in pregnant women with co-morbid influenza,” O’Leary said.
While there weren’t many studies of the impacts of flu infections during pregnancy, project lead and RMIT Professor Stavros Selemidis said it was clear that pregnancy changed how the body responded to the virus.
Liong and Selemidis’ earlier breakthrough research found the flu virus during pregnancy could trigger a damaging hyperactive immune response, causing the virus to spread around the body from the lungs through the blood vessels.
“We used to think the flu virus just stayed in the lungs, but during pregnancy it escapes from the lungs to the rest of the body,” Selemidis said.
“This infection could set you up for cardiovascular disease later in life, but also set up cardiovascular disease in the offspring later in life.”
While vaccination was still the considered the best way to prevent flu infection during pregnancy, Selemidis pointed out vaccination rates were generally low in the pregnant population.
“Low vaccination rates aside, the flu shot may not generate the perfect immune response, especially if someone is pregnant or has an underlying medical condition,” he said.
“That’s why it’s useful to have a potential back up in low-dose aspirin to help prevent vascular dysfunction during pregnancy and improve foetal development.”
The new vaccine, tested in primates against the 1918 flu virus, would be a “one and done” shot
Photo by Mika Baumeister on Unsplash
New research led by Oregon Health & Science University reveals a promising approach to developing a universal influenza vaccine – one that also confers lifetime immunity against an evolving virus. The study, published in Nature Communications, tested an OHSU-developed vaccine platform against the virus considered most likely to trigger the next pandemic.
Researchers reported the vaccine generated a robust immune response in nonhuman primates that were exposed to the avian H5N1 influenza virus. But the vaccine wasn’t based on the contemporary H5N1 virus; instead, the primates were inoculated against the influenza virus of 1918 that killed millions of people worldwide.
“It’s exciting because in most cases, this kind of basic science research advances the science very gradually; in 20 years, it might become something,” said senior author Jonah Sacha, PhD, professor and chief of the Division of Pathobiology at OHSU’s Oregon National Primate Research Center. “This could actually become a vaccine in five years or less.”
Researchers reported that six of 11 nonhuman primates inoculated against the 1918 flu virus survived exposure to one of the deadliest viruses in the world today, H5N1. In contrast, a control group of six unvaccinated primates exposed to the H5N1 virus succumbed to the disease.
Sacha said he believes the platform “absolutely” could be useful against other mutating viruses, including SARS-CoV-2.
“It’s a very viable approach,” he said. “For viruses of pandemic potential, it’s critical to have something like this. We set out to test influenza, but we don’t know what’s going to come next.”
A senior co-author from the University of Pittsburgh concurred.
“Should a deadly virus such as H5N1 infect a human and ignite a pandemic, we need to quickly validate and deploy a new vaccine,” said co-corresponding author Douglas Reed, Ph.D., associate professor of immunology at the University of Pittsburgh Center for Vaccine Research.
Finding a stationary target
This approach harnesses a vaccine platform previously developed by scientists at OHSU to fight HIV and tuberculosis, and in fact is already being used in a clinical trial against HIV.
The method involves inserting small pieces of target pathogens into the common herpes virus cytomegalovirus, or CMV, which infects most people in their lifetimes and typically produces mild or no symptoms. The virus acts as a vector specifically designed to induce an immune response from the body’s own T cells.
This approach differs from common vaccines – including the existing flu vaccines – which are designed to induce an antibody response that targets the most recent evolution of the virus, distinguished by the arrangement of proteins covering the exterior surface.
“The problem with influenza is that it’s not just one virus,” Sacha said. “Like the SARS-CoV-2 virus, it’s always evolving the next variant and we’re always left to chase where the virus was, not where it’s going to be.”
The spike proteins on the virus exterior surface evolve to elude antibodies. In the case of flu, vaccines are updated regularly using a best estimate of the next evolution of the virus. Sometimes it’s accurate, sometimes less so.
In contrast, a specific type of T cell in the lungs, known as effector memory T cell, targets the internal structural proteins of the virus, rather than its continually mutating outer envelope. This internal structure doesn’t change much over time – presenting a stationary target for T cells to search out and destroy any cells infected by an old or newly evolved influenza virus.
Success with a century-old template
To test their T cell theory, researchers designed a CMV-based vaccine using the 1918 influenza virus as a template. In a highly secure biosafety level 3 laboratory at the University of Pittsburgh, they exposed the vaccinated nonhuman primates to small particle aerosols containing the avian H5N1 influenza virus – an especially severe virus that is currently circulating among dairy cows in the US.
Remarkably, six of the 11 vaccinated primates survived the exposure, despite the century-long period of virus evolution.
“It worked because the interior protein of the virus was so well preserved,” Sacha said. “So much so, that even after almost 100 years of evolution, the virus can’t change those critically important parts of itself.”
The study raises the potential for developing a protective vaccine against H5N1 in people.
“Inhalation of aerosolised H5N1 influenza virus causes a cascade of events that can trigger respiratory failure,” said co-senior author Simon Barratt-Boyes, PhD, professor of infectious diseases, microbiology and immunology at Pitt. “The immunity induced by the vaccine was sufficient to limit virus infection and lung damage, protecting the monkeys from this very serious infection.”
By synthesising more up-to-date virus templates, the new study suggests CMV vaccines may be able to generate an effective, long-lasting immune response against a wide suite of new variants.
“I think it means within five to 10 years, a one-and-done shot for influenza is realistic,” Sacha said.
Creative artwork featuring colourised 3D prints of influenza virus (surface glycoprotein hemagglutinin is blue and neuraminidase is orange; the viral membrane is a darker orange). Note: Not to scale. Credit: NIAID
Researchers at Vanderbilt University Medical Center have isolated human monoclonal antibodies against influenza B, a significant public health threat that disproportionately affects children, the elderly and other immunocompromised individuals, as they report in the journal Immunity.
Seasonal flu vaccines cover influenza B and the more common influenza A but do not stimulate the broadest possible range of immune responses against both viruses.
In addition, people whose immune systems have been weakened by age or illness may not respond effectively to the flu shot.
Small-molecule drugs that block neuraminidase, a major surface glycoprotein of the influenza virus, can help treat early infection, but they provide limited benefit when the infection is more severe, and they are generally less effective in treating influenza B infections. Thus, another way to combat this virus is needed.
The VUMC researchers describe how, from the bone marrow of an individual previously vaccinated against influenza, they isolated two groups of monoclonal antibodies that bound to distinct parts of the neuraminidase glycoprotein on the surface of influenza B.
One of the antibodies, FluB-400, broadly inhibited virus replication in laboratory cultures of human respiratory epithelial cells. It also protected against influenza B in animal models when given by injection or through the nostrils.
Intranasal antibody administration may be more effective and have fewer systemic side effects than more typical routes – intravenous infusion or intramuscular injection – partly because intranasal antibodies may “trap” the virus in the nasal mucus, thereby preventing infection of the underlying epithelial surface, the researchers suggested.
These findings support the development of FluB-400 for the prevention and treatment of influenza B and will help guide efforts to develop a universal influenza vaccine, they said.
“Antibodies increasingly have become an interesting medical tool to prevent or treat viral infections,” said the paper’s corresponding author, James Crowe Jr, MD. “We set out to find antibodies for the type B influenza virus, which continues to be a medical problem, and we were happy to find such especially powerful molecules in our search.”
