The effectiveness of influenza vaccines varies considerably among individuals, typically ranging from 20% to 60%. Severe influenza-related complications occur particularly frequently in older adults. Understanding why some individuals develop strong protection after vaccination while others generate a substantially weaker response is therefore an important goal.
Researchers in the United States combined data from four vaccinated cohorts collected over five influenza seasons, totalling 581 participants. The study revealed that pre-vaccination levels of certain cytokines in the blood are associated with the magnitude of the subsequent antibody response to influenza vaccination. This relationship was especially evident among individuals with low baseline antibody titers against influenza viruses.
However, correlation alone does not establish causation. To determine whether these cytokines directly influence vaccine efficacy, the researchers employed human tonsil and spleen organoids – immune tissue models that retain memory T and B cells and recapitulate key stages of antibody response development.
Type I Interferon Functions as a Natural Vaccine Adjuvant
The researchers identified two cytokines – IL-18 and IFN-β (a type I interferon) – and one chemokine, GROα/CXCL1, whose pre-vaccination levels were associated with stronger antibody responses to influenza vaccination. This association was strongest in individuals with low baseline influenza antibody titers.
Previous studies have suggested that IFN-β acts as a natural vaccine adjuvant. Expression of genes stimulated by type I and type II interferons has been shown to correlate with antibody responses measured 28 days after vaccination.
The present study demonstrated that type I interferon is specifically responsible for enhancing vaccine-induced immunity. Neither type II interferon nor IL-18 – a potent inducer of type II interferon production – produced a similar effect.
Addition of type I interferon (IFN-β) reproduced many of the immune effects observed with live influenza vaccines and increased antibody production following inactivated vaccine administration to levels comparable to those observed with live vaccines.
The IL-21/IL-12 Pathway Enhances Antibody Production Independently of Type I Interferon Signaling
The researchers identified a second mechanism that enhances immune responses independently of type I interferons, involving the cytokines IL-12 and IL-21. In human spleen organoids, type I interferons did not stimulate IL-12 or IL-21 production; however, IL-12 promoted IL-21 production. In addition, IL-12 directly regulated B-cell function.
Further experiments in mice demonstrated that delivery of mRNA encoding either IFN-β or IL-21 via lipid nanoparticles increased the durability of antibody responses.
Conclusion
The cytokines IFN-β and IL-21 may serve as effective vaccine adjuvants for enhancing antibody responses. Delivery of mRNA encoding these cytokines through lipid nanoparticles could improve the immunogenicity of inactivated vaccines.
Reference
Human vaccine responses regulated by parallel cytokine pathways
