Stitching together four molecules found in the standard flu vaccine guarantees an immune response to all of them, as demonstrated by scientists.
Researchers from Stanford Medicine have developed an approach aimed at enhancing the effectiveness of seasonal flu vaccinations and possibly providing protection against emerging flu variants that could cause pandemics. Their findings, set to be published on December 20 in Science, were confirmed using cultured human tonsil tissues.
Flu season is here, and it poses a serious threat. Each year, the influenza virus claims the lives of hundreds of thousands and sends millions to hospitals. To counter this, the seasonal flu vaccine is designed to prepare our immune system, allowing it to respond rapidly to the virus. A crucial aspect of this immune response is the creation of antibodies—specialized proteins that attach to specific viruses, functioning like a puzzle piece that blocks the virus from entering and replicating in our cells.
Traditional vaccines present one or more synthetic features, known as antigens, of a pathogen to immune system cells. This process allows those cells to learn and remember the specific antigens related to the pathogen targeted by the vaccine. When the actual virus appears, this immunological memory activates dormant immune cells to spring into action, effectively neutralizing the threat before it can infect additional cells.
The influenza virus uses a unique protein called hemagglutinin as a molecular hook to attach to susceptible cells in our respiratory system. Hemagglutinin serves as the primary antigen in the influenza vaccine.
The standard flu vaccine includes a blend of four types of hemagglutinin—one corresponding to each of the four prevalent influenza subtypes. The objective is to safeguard us against whichever subtype manages to enter our bodies.
However, the vaccine’s efficacy is not always optimal. Recent effectiveness rates have fluctuated between around 20% and 80%, according to Mark Davis, PhD, a professor of microbiology and immunology at Stanford.
This variability largely stems from the fact that many vaccinated individuals do not produce enough antibodies against every subtype included in the vaccine, as highlighted by Davis, the study’s senior author. The lead author, Vamsee Mallajosyula, PhD, is a research associate in Davis’s lab.
Interestingly, most people tend to generate strong antibody responses to only one subtype, Davis noted. However, he and his colleagues have discovered the reasons behind this phenomenon and developed a method to encourage our immune systems to respond vigorously to all four subtypes. This could significantly enhance the vaccine’s effectiveness in preventing even mild cases of influenza, let alone severe infections.
Mechanism of Action
Experts commonly refer to the concept of “original antigenic sin,” which suggests that our immune responses are shaped by our first encounter with a flu virus. According to Davis, “The premise is that the first flu infection sets a person’s immune response toward that specific subtype. Subsequent infections will likely trigger a response primarily aimed at that initial subtype, regardless of the current prevailing strain.” This belief suggests that one’s immune system is essentially fixed from that first infection.
However, research by Mallajosyula has shown that our genetic makeup, rather than our first exposure, primarily influences which subtype our immune systems respond to after vaccination. His findings revealed that a majority of people exhibit an uneven immune response to different influenza subtypes, known as “subtype bias,” affecting 77% of identical twins and 73% of newborns, who have had no prior flu exposure.
Davis’s team has devised a method to effectively engage our immune systems with all four vaccine subtypes. Here’s how it works:
B cells—the immune cells responsible for producing antibodies—are extremely selective about the antibodies they generate. A single B cell makes antibodies specific to only one or a few variants of an antigen. When an antigen enters the body, the B cell recognizes and absorbs it.
That’s the first step.
Next, the B cell fragments the antigen into tiny pieces called peptides, which are then displayed on its surface for assessment by helper T cells. These T cells play a crucial role in stimulating B cells into antibody-producing factories.
Similar to B cells, helper T cells are also selective. They will only activate B cells that present specific peptides they are programmed to recognize, and only if those peptides are held by compatible molecular structures, often referred to as “jewel cases.”
Each peptide necessitates a different type of jewel case. Due to genetic variances, people’s collections of these specialized jewel cases differ widely, leading to a situation where many of us have an abundance of cases compatible with one subtype of hemagglutinin yet far fewer for another subtype.
In the standard flu vaccine formulation, each of the four antigens is delivered as distinct particles. To address the subtype bias, Davis, Mallajosyula, and their collaborators linked all four antigens together. They created a vaccine in which the four types of hemagglutinin are chemically connected within a molecular framework. This approach ensures that when a B cell consumes any of the hemagglutinin types, it ingests the entire framework and thus presents bits from all four antigens, prompting the immune system to respond to each one.
This strategy forces B cells to engage with all four hemagglutinin subtypes, rather than favoring just the one they prefer. As a result, more B cells can display peptides from each subtype on their surfaces, albeit in a ratio that still reflects the B cells’ hereditary inventories of jewel-case molecules.
The increased variety of displayed peptides enhances the likelihood that helper T cells will encounter the antigen they are designed to combat. Activated T cells will proliferate, seek out B cells displaying those antigens, and encourage them to generate antibodies. This leads to a surge in antibody production that can effectively thwart the influenza virus, regardless of its subtype.
Testing with Human Tonsil Organoids
Davis, Mallajosyula, and their team evaluated their four-antigen vaccine construct using cultures of human tonsil organoids—living lymphatic tissue derived from tonsils of tonsillitis patients. In lab settings, this tissue reconstructs into small masses that simulate lymph nodes, providing an ideal environment for antibody production.
Indeed, B cells in these organoids that recognized the combined hemagglutinin molecules absorbed the entire construct, potentially displaying fragments from all four subtypes, thereby attracting more helper T cells to activate. The outcome was a strong antibody response to all four influenza strains.
Concerns remain regarding a viral strain that could lead to another significant pandemic, specifically avian influenza, which has been detected recently in wastewater and milk samples across several U.S. states. While this variant does not yet transmit easily between humans, it could mutate to acquire that capability, posing a serious risk.
The research team demonstrated that they could significantly enhance the immune response to bird flu by vaccinating tonsil organoids with a five-antigen construct—linking four seasonal antigens alongside the bird flu hemagglutinin—compared to standard vaccination with just the bird flu hemagglutinin alone or mixing it with seasonal antigens in separate constructs.
“By overcoming subtype bias in this way, we can potentially create a much more effective influenza vaccine, even against strains like bird flu,” Davis noted, emphasizing the threat that bird flu poses for future viral pandemics.
Davis and Mallajosyula hold a patent filed by Stanford’s Office of Technology Licensing for their new coupled-antigen strategy.
Researchers from the University of Cincinnati College of Medicine also contributed to this project.
This study received funding from several NIH grants and support from the Howard Hughes Medical Institute.
