Abstract
Different diseases require different immune responses for efficient protection. Thus, prophylactic vaccines should prime the immune system for the particular type of response needed for protection against a given infectious agent. We have here tested fusion DNA vaccines which encode proteins that bivalently target influenza hemagglutinins (HA) to different surface molecules on antigen presenting cells (APC). We demonstrate that targeting to MHC class II molecules predominantly induced an antibody/Th2 response, whereas targeting to CCR1/3/5 predominantly induced a CD8+/Th1 T cell response. With respect to antibodies, the polarizing effect was even more pronounced upon intramuscular (i.m) delivery as compared to intradermal (i.d.) vaccination. Despite these differences in induced immune responses, both vaccines protected against a viral challenge with influenza H1N1. Substitution of HA with ovalbumin (OVA) demonstrated that polarization of immune responses, as a consequence of APC targeting specificity, could be extended to other antigens. Taken together, the results demonstrate that vaccination can be tailor-made to induce a particular phenotype of adaptive immune responses by specifically targeting different surface molecules on APCs.
Highlights
The introduction of mass vaccination represents a major breakthrough for modern medicine
Vaccine formulations with the adjuvant monophosphoryl lipid A (MPL), on the other hand, preferentially induce a Th1-like immune response[8], characterized by CD4+ T cells secreting the hallmark cytokine interferon c (IFNc), expression of the transcription factor T-bet[9], and Ig class switching to IgG2a[7]
Others have demonstrated that Th1/Th2 polarization of CD4+ T cells can be influenced by differences in vaccine particle size[37], vaccination with an antigen that has been conjugated to mannan under reducing or oxidative conditions[38], or co-delivery of antigens and cytokines in the form of DNA[39]
Summary
The introduction of mass vaccination represents a major breakthrough for modern medicine. Attenuated vaccines generally induce strong antibody and T cell responses, and a single immunization is often sufficient for obtaining life-long protection. The effect of subunit vaccines can be increased by adding adjuvants to vaccine formulations, thereby influencing the magnitude and phenotype of immune responses. Vaccine formulations with alum, for example, tend to induce Th2 responses[2], characterized by CD4+ T cells secreting interleukin-4 (IL-4), IL-5, IL-9 and IL-13 and expression of the transcription factor GATAbinding protein 3 (GATA-3)[3]. Vaccine formulations with the adjuvant monophosphoryl lipid A (MPL), on the other hand, preferentially induce a Th1-like immune response[8], characterized by CD4+ T cells secreting the hallmark cytokine interferon c (IFNc), expression of the transcription factor T-bet[9], and Ig class switching to IgG2a[7]
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