Inherited Gene Variations Impact Antibody Response to Infections & Vaccines | Immunity

Designing effective influenza vaccines for a global population is a perennial challenge, complicated by the virus’s constant evolution. New research from Karolinska Institutet, published this week in the journal Immunity, suggests that inherited differences in our antibody genes may significantly influence how well we respond to both infection and vaccination. The studies highlight the role of specific gene variations – particularly deletions in IGHD genes – in shaping our immune response to influenza, potentially impacting vaccine efficacy across different populations.

Mapping Immune Gene Variation Worldwide

Researchers have long known that genetics play a role in immunity, but the extent of variation in antibody genes was previously underestimated. This latest work, led by Professor Gunilla Karlsson Hedestam at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, utilized a novel technique called ImmuneDiscover to map these genes in a diverse cohort of 2,486 individuals from 25 different population groups around the world. ImmuneDiscover allows for a more detailed analysis of genetically complex regions of the genome than previously possible, opening new avenues for understanding immune system diversity. The study focused on understanding how these genetic differences affect the body’s ability to create neutralizing antibodies – proteins that block the virus from infecting cells.

Antibodies, too known as immunoglobulins (IG), are produced by B cells, a crucial component of the immune system. They are designed to recognize and neutralize foreign invaders like viruses. The research revealed that the genes responsible for antibody production exhibit more variation than previously thought, encompassing both changes in the genetic code itself and differences in the number of copies of certain genes.

The Role of IGHD Gene Deletions

A particularly striking finding was the prevalence of a common deletion involving six consecutive IGHD genes. These IGHD genes encode the portion of antibodies that directly bind to the virus. The frequency of this deletion varied considerably between populations, with up to 30 percent of some East Asian populations carrying deletions on both chromosomes. This suggests that the type of antibodies produced – and therefore the effectiveness of the immune response – can be influenced by these inherited genetic differences. The deletion’s presence across all populations studied indicates a complex evolutionary history, but its higher frequency in East Asian populations raises questions about potential implications for vaccine design and efficacy in these groups.

While the study doesn’t directly link these deletions to increased susceptibility to influenza, it suggests a potential connection. Individuals with these deletions may produce a narrower range of antibodies, potentially making them less equipped to neutralize diverse strains of the virus. This is an area requiring further investigation.

What Does This Imply for Flu Vaccine Development?

Current influenza vaccines are designed to target the major circulating strains of the virus, relying on the assumption that most people will mount a similar immune response. Even though, these findings suggest that this assumption may not hold true across all populations. The genetic variations identified could explain why some individuals respond better to vaccines than others, and why vaccine effectiveness can vary from year to year and between geographic regions.

The implications for vaccine development are significant. A “one-size-fits-all” approach may not be optimal. Future vaccines could potentially be tailored to account for these genetic differences, perhaps by including antigens (the components of the virus that trigger an immune response) that are more likely to elicit a strong antibody response in individuals with specific IGHD gene profiles. This is a long-term goal, requiring further research to fully understand the relationship between these genetic variations and immune protection.

It’s important to note that this research doesn’t suggest current vaccines are ineffective. Rather, it highlights a layer of complexity that could be leveraged to improve vaccine design and broaden protection. The study also doesn’t address the impact of other factors influencing vaccine response, such as age, underlying health conditions, and prior exposure to influenza viruses.

Understanding Antibody Diversity

Antibodies aren’t a single entity; they arrive in a vast array of forms, each with slightly different binding properties. This diversity is crucial for recognizing and neutralizing a wide range of pathogens. The IGHD genes play a key role in generating this diversity. Deletions or variations in these genes can limit the repertoire of antibodies an individual can produce, potentially reducing their ability to respond to evolving viruses like influenza. Influenza virus, a common cause of respiratory infection, infects up to one billion people annually, underscoring the importance of understanding immune responses.

Next Steps: Refining Vaccine Strategies

The Karolinska Institutet research team is continuing to investigate the functional consequences of IGHD gene deletions and other antibody gene variations. Future studies will focus on determining how these genetic differences impact the breadth and durability of the immune response to influenza, and whether they can be used to predict vaccine effectiveness in different populations. Further research will also explore the potential for developing personalized vaccine strategies that grab into account individual genetic profiles.

Public health surveillance efforts will also be crucial. Monitoring the prevalence of IGHD gene deletions in different populations could help identify groups that may benefit from tailored vaccination approaches. Collaboration between researchers, vaccine manufacturers, and public health agencies will be essential to translate these findings into improved influenza prevention strategies. The World Health Organization (WHO) regularly updates its recommendations for influenza vaccine composition based on surveillance data and emerging viral strains, and these findings could inform future updates.