Stanford Medicine researchers have developed a new method for influenza vaccination that encourages a robust immune response to all four common flu subtypes, potentially increasing the vaccine’s efficacy.
In laboratory tests using human tonsil organoids, the modified vaccine showed promising results in combating both seasonal and bird flu strains. The approach involves a combined antigen methodology that might also protect against emerging flu variants with pandemic potential.
Innovative Flu Vaccine Development
Stanford Medicine scientists have developed a method to make seasonal flu vaccines more effective and potentially protect against emerging flu strains with pandemic potential. Their approach, demonstrated using cultured human tonsil tissue, was published in the journal Science on December 19.
Flu season is a serious health concern. Each year, influenza kills hundreds of thousands of people and hospitalizes millions worldwide. The seasonal flu vaccine helps by priming the immune system for a faster and stronger response. A critical part of this defense involves antibodies — specialized proteins that bind to the flu virus like puzzle pieces. When antibodies attach correctly, they block the virus from entering and multiplying in our cells.
Understanding Vaccine Antigens
Any classical vaccine displays, in a non-threatening way, one or more of a pathogen’s immune-system-arousing biochemical features, or antigens, to various cells of the immune system whose job is to carefully note and memorize particular antigens belonging to the pathogen of interest — the one the vaccine targets. When the real thing comes along, that memory will kick in and rouse those otherwise dormant immune cells to jump up, pump up, and punch out the pest’s lights — preferably before it can invade any cells.
Vaccine Design and Effectiveness
The influenza virus is studded with molecular hooks that it uses to latch on to vulnerable cells in our airways and lungs. This hook-like molecule, called hemagglutinin, is the principal antigen in the influenza vaccine.
The standard flu vaccine contains a mix of four versions of hemagglutinin — one for each of four commonly circulating influenza subtypes. The goal is to protect us from whichever of those subtypes eventually slips through our nostrils and takes up residence in our airways.
The vaccine’s efficacy isn’t as high as it could be, though. In recent years its effectiveness has ranged between about 20% and 80%, said Mark Davis, PhD, professor of microbiology and immunology and the Burt and Marion Avery Family Professor of Immunology.
That’s largely because many vaccinated people fail to develop enough antibodies to one or more of the subtypes represented in the vaccine, said Davis, the study’s senior author. The lead author is Vamsee Mallajosyula, PhD, a basic science research associate in Davis’ lab.
Strangely, most of us develop a robust antibody response to only one of them, Davis said. But he and his colleagues have figured out why that happens and have found a way to force our immune systems to mount a strong antibody response to all four subtypes. That could make a huge difference in the vaccine’s ability to keep us from suffering even mild consequences from influenza infections, let alone more severe ones.
Exploring Immune Response Mechanisms
It’s widely believed that individuals’ immune responses are partially due to what immunologists refer to, tongue in cheek, as “original antigenic sin,” Davis said. “The idea is that our first exposure to a flu infection predisposes us to mount a response to whatever subtype that infecting virus belonged to. Subsequent influenza exposures, regardless of which viral subtype is now assaulting us, will trigger a preferential or even exclusive response to that first subtype.” It’s been thought that we’re marked for life, immunologically speaking, by that initial encounter regardless of which subtype is bugging us now.
But that’s not true. An analysis conducted by Mallajosyula showed that it’s mostly our genes, not our first exposure, that push our immune systems to mount an antibody response to one or another of a flu shot’s four subtypes. Mallajosyula found this uneven immune response to different influenza subtypes (what immunologists call “subtype bias”) in most people, including 77% of identical twins — and 73% of newborns, who’ve had no previous exposure to the flu virus or the vaccine for it.
Davis’ group has found a way to trick our immune systems into paying attention to all four subtypes represented in the vaccine. Here’s how it works.
Overcoming Subtype Bias in Vaccines
B cells — the immune cells that serve as our body’s antibody factories — are ultrapicky about exactly which antibodies they make. An individual B cell will produce only a single species of antibody fitting a mere one or very few antigenic shapes. That B cell is just as picky about what antigen it will pay attention to: that is, precisely the antigen the B cell’s antibodies will stick to. When this antigen comes along, the B cell recognizes it and gobbles it up.
That’s step one.
Next, the B cell chops the antigen up into tiny strips called peptides, which it displays on its surface for inspection by roving immune cells called helper T cells, whose follow-on stimulatory services are critical for turning antigen-displaying B cells into antibody-spewing B cells.
Helper T cells are just as finicky as B cells. A helper T cell will sprinkle its stardust only on B cells displaying antigen-derived peptides that particular T cell is designed to respond to — and even then, only when that peptide is gripped by one of the matching molecular jewel cases that B cells produce in myriad varieties.
But different peptides require different jewel cases. And depending on their luck in the genetic draw, people’s repertoires of those specialized jewel cases vary from one person to the next, leaving many of us with plenty of the jewel cases that match peptides from one influenza-subtype hemagglutinin but far fewer of those that match another flu subtype’s peptides.
In the standard flu vaccine formulation, the four antigens corresponding to the four common subtypes are delivered as separate particles in a mix. To overcome subtype bias, Davis, Mallajosyula, and their colleagues stitched all four antigens together. They designed a vaccine in which the four hemagglutinin varieties are chemically conjoined on a molecular matrix scaffolding. That way, any B cell that recognizes and begins ingesting one or another of the vaccine’s four hemagglutinin types ends up wolfing down the entire matrix and displaying bits of all four antigens on its surface, persuading the immune system to react to all of them despite its predisposition not to.
Forcing B cells to “eat their broccoli” — internalize all four hemagglutinin subtypes instead of just the one that tastes best — effectively multiplies the number of B cells displaying hemagglutinin-derived peptides from every subtype on their surfaces, albeit still in a ratio skewed by the B cells’ uneven inventories of jewel-case molecules.
This, in turn, makes helper T cells much more likely to stumble on a sample from the antigen they love to hate. They fire up, start multiplying feverishly, branch out in pursuit of any B cells displaying that antigen and spur antibody production in them. These selected B cells also proliferate, culminating in bulk production of antibodies that are likely to stop the influenza virus — whatever its subtype — in its tracks.
Testing the New Vaccine
Davis, Mallajosyula and their colleagues tested their four-antigen vaccine construct by putting it into cultures containing human tonsil organoids — living lymph tissue originating from tonsils extracted from tonsillitis patients and then disaggregated. In a laboratory dish, the tissue spontaneously reconstitutes itself into small tonsil spheres, each a “mini-me” that acts just like a lymph node — the ideal environment for antibody manufacturing.
Sure enough, B cells in these organoids that recognized any of the four conjoined hemagglutinin molecules swallowed the whole matrix and, potentially, displayed bits of all four subtypes, thus recruiting far more helper T cells to kick-start their activation. The result was solid antibody responses to all four influenza strains.
Addressing Pandemic Potential
There is considerable concern about a viral strain that could cause the next devastating pandemic: namely avian or “bird flu,” which recently has been detected in wastewater and milk in California, Texas, and other parts of the United States. While this type of flu is not yet able to be transmitted easily between human beings, it could mutate to gain this ability and thus is considered a major risk-in-waiting.
The scientists further showed that they could substantially boost the antibody response to bird flu by vaccinating tonsil organoids with a five-antigen construct connecting the four seasonal antigens along with the bird-flu hemagglutinin, as opposed to getting a tepid response when vaccinating with just the bird-flu hemagglutinin or combining it with the four seasonal antigens on different constructs.
“Overcoming subtype bias this way can lead to a much more effective influenza vaccine, extending even to strains responsible for bird flu,” Davis said. “The bird flu could very likely generate our next viral pandemic.”
For more on this research, see Unlocking the Genetic Code to Supercharge Flu Vaccines.
Reference: “Coupling antigens from multiple subtypes of influenza can broaden antibody and T cell responses” by Vamsee Mallajosyula, Saborni Chakraborty, Elsa Sola, Ryan Furuichi Fong, Vishnu Shankar, Fei Gao, Allison R. Burrell, Neha Gupta, Lisa E. Wagar, Paul S. Mischel, Robson Capasso, Mary A. Staat, Yueh-Hsiu Chien, Cornelia L. Dekker, Taia T. Wang and Mark M. Davis, 19 December 2024, Science.
DOI: 10.1126/science.adi2396
Researchers from the University of Cincinnati College of Medicine contributed to the work.
Davis and Mallajosyula are co-inventors on a patent Stanford’s Office of Technology Licensing has filed for intellectual property related to their coupled-antigen methodology.
The study was funded by National Institutes of Health (grants 5U19AI090019, 5U19AI057229, 5U01AI144673, 75N93019C00051 and U01AI144616) and the Howard Hughes Medical Institute.

News
The CDC buried a measles forecast that stressed the need for vaccinations
This story was originally published on ProPublica, a nonprofit newsroom that investigates abuses of power. Sign up to receive our biggest stories as soon as they’re published. ProPublica — Leaders at the Centers for Disease Control and Prevention [...]
Light-Driven Plasmonic Microrobots for Nanoparticle Manipulation
A recent study published in Nature Communications presents a new microrobotic platform designed to improve the precision and versatility of nanoparticle manipulation using light. Led by Jin Qin and colleagues, the research addresses limitations in traditional [...]
Cancer’s “Master Switch” Blocked for Good in Landmark Study
Researchers discovered peptides that permanently block a key cancer protein once thought untreatable, using a new screening method to test their effectiveness inside cells. For the first time, scientists have identified promising drug candidates [...]
AI self-cloning claims: A new frontier or a looming threat?
Chinese scientists claim that some AI models can replicate themselves and protect against shutdown. Has artificial intelligence crossed the so-called red line? Chinese researchers have published two reports on arXiv claiming that some artificial [...]
New Drug Turns Human Blood Into Mosquito-Killing Weapon
Nitisinone, a drug for rare diseases, kills mosquitoes when present in human blood and may become a new tool to fight malaria, offering longer-lasting, environmentally safer effects than ivermectin. Controlling mosquito populations is a [...]
DNA Microscopy Creates 3D Maps of Life From the Inside Out
What if you could take a picture of every gene inside a living organism—not with light, but with DNA itself? Scientists at the University of Chicago have pioneered a revolutionary imaging technique called volumetric DNA microscopy. It builds [...]
Scientists Just Captured the Stunning Process That Shapes Chromosomes
Scientists at EMBL have captured how human chromosomes fold into their signature rod shape during cell division, using a groundbreaking method called LoopTrace. By observing overlapping DNA loops forming in high resolution, they revealed that large [...]
Bird Flu Virus Is Mutating Fast – Scientists Say Our Vaccines May Not Be Enough
H5N1 influenza is evolving rapidly, weakening the effectiveness of existing antibodies and increasing its potential threat to humans. Scientists at UNC Charlotte and MIT used high-performance computational modeling to analyze thousands of viral protein-antibody interactions, revealing [...]
Revolutionary Cancer Vaccine Targets All Solid Tumors
The method triggers immune responses that inhibit melanoma, triple-negative breast cancer, lung carcinoma, and ovarian cancer. Cancer treatment vaccines have been in development since 2010, when the first was approved for prostate cancer, followed [...]
Scientists Uncover Hidden Protein Driving Autoimmune Attacks
Scientists have uncovered a critical piece of the puzzle in autoimmune diseases: a protein that helps release immune response molecules. By studying an ultra-rare condition, researchers identified ArfGAP2 as a key player in immune [...]
Mediterranean neutrino observatory sets new limits on quantum gravity
Quantum gravity is the missing link between general relativity and quantum mechanics, the yet-to-be-discovered key to a unified theory capable of explaining both the infinitely large and the infinitely small. The solution to this [...]
Challenging Previous Beliefs: Japanese Scientists Discover Hidden Protector of Heart
A Japanese research team found that the oxidized form of glutathione (GSSG) may protect heart tissue by modifying a key protein, potentially offering a novel therapeutic approach for ischemic heart failure. A new study [...]
Millions May Have Long COVID – So Why Can’t They Get Diagnosed?
Millions of people in England may be living with Long Covid without even realizing it. A large-scale analysis found that nearly 10% suspect they might have the condition but remain uncertain, often due to [...]
Researchers Reveal What Happens to Your Brain When You Don’t Get Enough Sleep
What if poor sleep was doing more than just making you tired? Researchers have discovered that disrupted sleep in older adults interferes with the brain’s ability to clean out waste, leading to memory problems [...]
How to prevent chronic inflammation from zombie-like cells that accumulate with age
In humans and other multicellular organisms, cells multiply. This defining feature allows embryos to grow into adulthood, and enables the healing of the many bumps, bruises and scrapes along the way. Certain factors can [...]
Breakthrough for long Covid patients who lost sense of smell
A breakthrough nasal surgery has restored the sense of smell for a dozen long Covid patients. Experts at University College London Hospitals NHS Foundation Trust successfully employed a technique typically used for correcting blocked nasal passages, [...]