Flu viruses vary each year and although vaccines are also adapted depending on the viruses that scientists consider to be circulating, their effectiveness varies, so research continues with the aim of improving these drugs to better prevent influenza. disease. Now, a group of Stanford Medicine researchers have found a way to make seasonal flu vaccines more effective, and even potentially protect us from new flu variants with pandemic potential.
Hundreds of thousands of people die every year in the world as a result of the flu, while millions need to be hospitalized because of it. To prevent this, the flu vaccine stimulates our immune system so that it is better prepared to fight the virus.
A critical component of the immune response is the development of antibodies, which are specialized proteins that can selectively bind to a specific virus and, when the fit is tight enough and in the right place, prevent that virus from entering our cells. and is replicated inside.
Any classic vaccine presents one or more of the biochemical characteristics that stimulate the immune system, and the cells of the immune system are responsible for memorizing specific antigens that belong to the pathogen of interest (the one targeted by the vaccine). This way, when the real pathogen appears, that memory will kick in and awaken those otherwise dormant immune cells to activate and fight the microbes, preferably before they can invade any cells.
The standard flu vaccine contains a mixture of four versions of hemagglutinin, one for each of the four commonly circulating flu subtypes. The goal is to protect us from any of these subtypes. However, the vaccine’s effectiveness is not as high as it could be. In recent years its effectiveness has ranged between 20% and 80%, said Mark Davis, professor of microbiology and immunology and the Burt and Marion Avery Family Professor of Immunology and senior author of the study in a note published by Stanford Medicine. This is largely because many vaccinated people do not develop enough antibodies against one or more of the subtypes represented in the vaccine, Davis says.
Interestingly, most of us develop a robust antibody response to only one of them, Davis explained. But he and his colleagues have figured out why that happens and have found a way to force our immune systems to generate a strong antibody response to all four subtypes. That could make a big difference in the vaccine’s ability to prevent us from suffering even mild consequences from flu infections, let alone more serious consequences. The findings have been published in the journal Science.
‘Trick’ the immune system into detecting the four virus subtypes
It is widely believed that individuals’ immune responses are due in part to what immunologists call, tongue-in-cheek, “original antigenic sin,” Davis said. “The idea is that our first exposure to a flu infection predisposes us to generate a response to whichever subtype the infecting virus belongs to. Subsequent exposures to the flu, regardless of which viral subtype is attacking us at that time, will trigger a response. preferential or even exclusive to that first subtype”.
It has been thought that we are scarred for life, immunologically speaking, by that initial encounter, regardless of which subtype is bothering us now. But that’s not true. An analysis by Vamsee Mallajosyula, another of the lead authors of the work, showed that it is mainly our genes, not our first exposure, that drive our immune system to generate an antibody response against one or another of the four subtypes of the flu vaccine.
Mallajosyula found this unequal immune response to different subtypes of influenza (what immunologists call “subtype bias”) in most people, including 77% of identical twins and 73% of newborns who had not. had previous exposure to the flu virus or the flu vaccine.
Davis’ group has discovered a way to trick our immune system into paying attention to the four subtypes represented in the vaccine, which works as follows: B cells (the immune cells that act as the body’s antibody factories) They are extremely picky about exactly what antibodies they produce. Each individual B cell will produce only one species of antibody that fits one or very few antigenic forms.
“Overcoming subtype bias in this way may lead to a much more effective flu vaccine, extending even to the strains responsible for bird flu.”
The B cell is equally selective as to which antigen it will pay attention to: that is, precisely the antigen to which the B cell’s antibodies will bind. When this antigen appears, the B cell recognizes it and devours it. The B cell then cuts the antigen into small strips called peptides, which it displays on its surface for inspection by wandering immune cells called T helper cells, whose subsequent stimulatory services are critical in converting antigen-displaying B cells into B cells. antibody generators.
Helper T cells are just as finicky as B cells. A helper T cell will spread its stardust only on B cells that display peptides derived from antigens that a particular T cell is designed to respond to, and even then, only when that peptide is trapped in one of the compatible molecular jewel boxes that B cells produce in a myriad of varieties.
But each peptide requires a different jewelry box, and depending on how lucky they are in the genetic draw, the repertoires of those specialized jewelry boxes vary from person to person, leaving many of us with a lot of boxes. of jewelry that match peptides from one flu subtype, hemagglutinin, but far fewer that match peptides from another flu subtype.
In the standard influenza vaccine formulation, the four antigens corresponding to the four common subtypes are administered as separate particles in a mixture. To overcome subtype bias, Davis, Mallajosyula and their colleagues linked the four antigens and designed a vaccine in which the four varieties of hemagglutinin are chemically linked in a molecular matrix.
In this way, any B cell that recognizes and begins to ingest one or another of the four types of hemagglutinin in the vaccine ends up devouring the entire matrix and displaying fragments of the four antigens on its surface, persuading the immune system to react to all of them. despite his predisposition not to do so.
Forcing B cells to internalize all four hemagglutinin subtypes rather than just the best-tasting one effectively multiplies the number of B cells displaying hemagglutinin-derived peptides of each subtype on their surfaces, although still in a proportion skewed by the unequal inventories of jewel-shaped molecules of B cells.
This, in turn, makes the helper T cells much more likely to find a sample of the antigen they hate so much. They activate, begin to multiply, branch in search of any B cell that displays that antigen and stimulate the production of antibodies in them. These selected B cells also proliferate, culminating in massive production of antibodies that are likely to stop the flu virus, whatever its subtype.
Davis, Mallajosyula and their colleagues tested their four-antigen vaccine by placing it in cultures containing human tonsillar organoids (living lymphatic tissue that originates from tonsils removed from patients with tonsillitis and then disaggregated). In a laboratory dish, the tissue spontaneously reconstitutes into small tonsillar spheres, each a “mini-me” acting as a lymph node: the ideal environment for antibody manufacturing.
Indeed, B cells in these organoids that recognized any of the four bound hemagglutinin molecules engulfed the entire matrix and potentially displayed fragments of all four subtypes, thus recruiting many more helper T cells to initiate their activation. The result was robust antibody responses to all four influenza strains.
There is great concern about a viral strain that could cause the next devastating pandemic: bird flu, which has recently been detected in wastewater and milk in California, Texas and other parts of the United States. While this type of flu cannot yet be easily transmitted between humans, it could mutate to acquire this ability and is therefore considered a major looming risk.
The scientists further showed that they could substantially increase the antibody response to avian flu by vaccinating tonsil organoids with a five-antigen construct that connects the four seasonal antigens along with the avian flu hemagglutinin, rather than getting a lukewarm response. when vaccinated only with the avian influenza hemagglutinin or combined with the four seasonal antigens in different constructs.
“Overcoming subtype bias in this way may lead to a much more effective flu vaccine, extending even to the strains responsible for bird flu,” Davis said. “Avian flu could very likely generate our next viral pandemic,” concludes the researcher.
