Vaccine Self-Assembling Immune Matrix Is a New Delivery Platform That Enhances Immune Responses to Recombinant HBsAg in Mice

Abstract

bVaccination remains the most effective public health tool to prevent infectious diseases. Many vaccines are marginally effective and need enhancement for immunocompromised, elderly, and very young populations. To enhance immunogenicity, we exploited the biphasic property of the (RADA)4 synthetic oligopeptide to create VacSIM (vaccine self-assembling immune matrix), a new delivery method. VacSIM solution can easily be mixed with antigens, organisms, and adjuvants for injection. Postinjection, the peptides self-assemble into hydrated nanofiber gel matrices, forming a depot with antigens and adjuvants in the aqueous phase. We believe the depot provides slow release of immunogens, leading to increased activation of antigen-presenting cells that then drive enhanced immunogenicity. Using recombinant hepatitis B virus surface antigen (rHBsAg) as a model immunogen, we compared VacSIM delivery to delivery in alum or complete Freund's adjuvant (CFA). Delivery of the rHBsAg antigen to mice via VacSIM without adjuvant elicited higher specific IgG responses than when rHBsAg was delivered in alum or CFA. Evaluating IgG subtypes showed a mixed Th1/Th2 type response following immunization with VacSIM, which was driven further toward Th1 with addition of CpG as the adjuvant. Increased specific IgG endpoint titers were observed in both C57BL/6 and BALB/c mice, representative of Th1 and Th2 environments, respectively. Restimulation of splenocytes suggests that VacSIM does not cause an immediate proinflammatory response in the host. Overall, these results suggest that VacSIM, as a new delivery method, has the potential to enhance immunogenicity and efficacy of numerous vaccines. Vaccines remain the single greatest public health tool to combat infectious diseases. Vaccine formulation and delivery are key to the ability of vaccines to induce the desired immune responses. One goal of vaccine delivery is to present vaccine antigens in a manner that enhances antigen-presenting-cell (APC) activation, leading to antigen/organism uptake and processing of vaccine antigen(s). Delivery methods or adjuvants that safely enhance vaccine immunogenicity/efficacy are desirable for vaccines that are marginally effective and for vaccines administered to low responders or immunocompromised populations. Additional goals are to reduce the number of doses required to induce effective, vaccine responses and to reduce the amount of vaccine/dose, especially when a single dose of vaccine is administered, as with annual influenza vaccines. Lastly, in pandemics, a vaccine that produces high titers after a single administration would be beneficial. Recent advances in the understanding of how innate mechanisms influence adaptive immunity have led to more rational design in the development of new vaccine adjuvants and delivery systems.Aluminum salts were the first adjuvants licensed for human vaccines in the 1920s. The licensure of non-aluminum salt adjuvants took an additional 80 years (1). One reason for this long gap is that the principles of adjuvant activit...

Active immunotherapy for TNF-mediated inflammation using self-assembled peptide nanofibers

“…Platforms that share structural similarities with Q11 and which may be interesting to study in this regard include other peptides that form into long, high-aspect ratio nanofibers. For example the peptide KFE8 has been explored previously in vaccinations against cocaine addiction [43]; the peptide RADA4 has been explored as a depotforming material in vaccines against hepatitis B [44]; the peptide EAK16 has been investigated in vaccines against HIV [45]; the peptide Ac-AAVVLLLW-COOH has been explored in anticancer vaccines [46]; and Q11 has been explored in applications including malaria [47], influenza [19], S. aureus vaccines [20], and cancer [48]. Other fibrous self-assemblies include those composed of peptide amphiphiles, which have been explored in anticancer vaccines [49] and vaccines against group A streptococcus [50].…”

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“…The goal of this approach is to generate a persistent source of antigen for prolonged immunostimulation, a partial mechanism of action of alum and other current adjuvants used in the clinic [15] . This fiber-based approach was employed to deliver a hepatitis B antigen with CpG, which triggered enhanced humoral and cellular responses when compared with a formulation containing alum and an equivalent dose of EIII [122] . Together, these results support the potential to use self-assembled materials to generate in vivo depots of antigen and immunostimulatory cues that can enhance immunogenicity.…”