A study in twins has revealed the importance of a person’s genetic makeup in determining their level of protection with seasonal flu vaccination, which could lead to better defenses against pandemic viruses.
The findings, published in Science, suggest the immune system may not be locked into a particular immune trajectory that is determined by the initial viral strain it comes across, as has been believed.
This greater potential for flexibility has led researchers to design a more effective vaccine that can trick the body into responding to multiple subtypes of a virus.
It means the immune system would not simply mount a response to one subtype and remain exposed to others, but instead gain greater protection against the different versions in circulation.
“Overcoming subtype bias this way can lead to a much more effective influenza vaccine, extending even to strains responsible for bird flu,” explained senior author Mark Davis, PhD, a professor of microbiology and immunology at Stanford University. “The bird flu could very likely generate our next viral pandemic.”
Flu kills up to 650,000 people worldwide annually, and a seasonal vaccine is formulated each year based on predictions as to which viral strains are most likely to be in circulation.
The virus uses a molecular “hook” called hemagglutinin to attach to vulnerable cells in the airways and the standard flu vaccine includes four versions of this antigen, one for each of the most common circulating viral subtypes.
However, the efficacy of the vaccine can vary dramatically year on year, mostly because people do not mount a response to all viral subtypes included in its design.
It had been thought that a concept of “original antigenic sin” (OAS) was responsible, where immune response is set but the first exposure to a viral subtype, leaving the body exposed to others.
But after analyzing antibody responses in monozygotic twins and vaccinated newborns, Davis and the team found that prior exposure was not the most important factor at play.
Instead, biased responses toward particular flu strains were mostly driven by genetics, particularly major histocompatibility complex (MHC) class-II polymorphisms.
The team used this information to couple antigens from four viral flu strains together using a molecular matrix scaffold and tested this in mouse models and tonsil organoids, created from lymph tissue that originated from extracted human tonsils.
The novel construction resulted in immune recognition of all four antigens, increasing antibody production to each strain. The broader response correlated with greater diversity of the helper T cells of the immune system, which aid B cells in antibody production.
“For many decades, the OAS hypothesis has influenced the explanation of subtype bias. However, it suggests no practical way for influenza vaccines to be altered to overcome this problem,” the investigators noted.
“By contrast, our study shows that coupling heterologous antigens may broaden T cell help and improve vaccine efficacy. This strategy to augment T cell help is readily applicable to vaccines for other pathogens for which multistrain coverage is needed.”
