US 20130266612A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0266612 A1 FUKASAKA et al. (43) Pub. Date: Oct. 10, 2013 (54) VACCINE COMPOSITION Publication Classification (71) Applicants: NITTO DENKO CORPORATION, (51) Int. Cl. Osaka (JP): OSAKA UNIVERSITY, A 6LX39/39 (2006.01) Osaka (JP) A639/45 (2006.01) (52) U.S. Cl. (72) Inventors: Masahiro FUKASAKA, Osaka (JP): CPC ............... A61K 39/39 (2013.01); A61 K39/145 Arimichi OKAZAKI, Osaka (JP): (2013.01) Daisuke ASARI, Osaka (JP); Mitsuhiko USPC .................. 424/210.1; 424/184.1; 424/234.1; HORI, Osaka (JP); Shizuo AKIRA, 424/257.1; 424/258.1 Osaka (JP): Osamu TAKEUCHI, Osaka (JP) (57) ABSTRACT (73) Assignees: OSAKA UNIVERSITY, Osaka (JP); NTTO DENKO CORPORATION An intraorally administrable vaccine composition useful to Osaka (JP) s be a preventive or therapeutic agent for infectious diseases, and effectively induces a systemic immune response or a (21) Appl. No.: 13/856,002 mucosal immune response is provided. A vaccine composi tion for administration to the oral cavity of a human or an (22) Filed: Apr. 3, 2013 animal, the vaccine composition containing at least one anti gen derived from an infectious disease, and at least one (30) Foreign Application Priority Data selected from the group consisting of a toll-like receptor 4 (TLR4)agonist, a toll-like receptor 2/6 (TLR2/6) agonist, and Apr. 4, 2012 (JP) ................................. 2012-0858.39 cyclic dinucleotide, or a derivative or salt thereof. Patent Application Publication Oct. 10, 2013 Sheet 1 of 7 US 2013/0266612 A1 Fig. 1 19 7 Fig. 2 12 Patent Application Publication Oct. 10, 2013 Sheet 2 of 7 US 2013/0266612 A1 Fig. 3 17 1 5 8 5 4 2 Patent Application Publication Oct. 10, 2013 Sheet 3 of 7 US 2013/0266612 A1 Fig. 5 20 S. S. 8. t . Example 10 g 6. Comparative rummer s C Exampie li -- Comparative : Exampie 14 20 ------------------------------------------------------------------------------------------------------------------ C. 2. 4. s 8 i2 14 16 day Fig. 6 r 8) 17 k gC 15 13 f E 11 E 9 w 7 5 s s &s8. &&.s S$&- cSS& Patent Application Publication Oct. 10, 2013 Sheet 4 of 7 US 2013/0266612 A1 Fig. 7 8 Fig. 8 1 9 7 1 5 13 1 9 Patent Application Publication Oct. 10, 2013 Sheet 5 of 7 US 2013/0266612 A1 Fig. 9 12 1 68O 4 Fig. 10 7 915 Patent Application Publication Oct. 10, 2013 Sheet 6 of 7 US 2013/0266612 A1 Fig. 11 12 O 8 6 4 Fig. 12 17 35 1 9 Patent Application Publication Oct. 10, 2013 Sheet 7 of 7 US 2013/0266612 A1 Fig. 13 4 1. 2 O 8 8 4 C s s sky&S s N 3. (9&S s (S&S SS & & US 2013/0266612 A1 Oct. 10, 2013 VACCINE COMPOSITION the gastric juice by a large content of an antacid, or to protect an antigen using coating techniques such as microspheres, or TECHNICAL FIELD the like. 0008. However, the development was practically success 0001. The present invention relates to a sublingually ful only on vaccines intrinsically highly stable in the gastric administrable vaccine composition useful to be a preventive juice Such as live attenuated poliovirus vaccine and live or therapeutic agent for infectious diseases. The present attenuated rotavirus Vaccine. invention particularly relates to a vaccine composition 0009. Alternatively, an allergy vaccine is an example of capable of effectively inducing a systemic immune response the oral administration preparation to induce an immune and a mucosal immune response when at least one selected response via the oral cavity mucosa (particularly Sublingual from the group consisting of a toll-like receptor 4 (TLR4) mucosa) delivery without Swallowing. This vaccine is termed agonist, a toll-like receptor 2/6 (TLR2/6) agonist, and cyclic as Sublingual immunotherapy (SLIT) and works by continu dinucleotide, or a derivative or salt thereof is sublingually ously administering Sublingually a plant-derived extract con administered as an adjuvant together with an antigen derived taining a protein to be an allergy antigen (allergen) to boost from an infectious disease. the immunotolerance against the allergen and reduce the allergy reaction. In recent years, SLIT is now widely accepted BACKGROUND ART in Europe and many products are available in the market today. 0002 Currently, the commercial vaccine preparations are 0010. The therapy using such a preparation which induces mostly available in the injection form. The injection form the immune response via the oral cavity mucosa route, par vaccine induces the immune response (IgG antibody produc ticularly the Sublingual mucosa route, is the focus of attention tion) in blood (systemic) but does not induce the mucosal because it provides better patient’s QOL and has a lower risk immune response (IgA antibody production), and thus pre of anaphylactic shock, critical adverse effect, than the con vents the post-infection pathogen growth but has a problem in ventional therapy which required the Subcutaneous injection the protection against the pathogen infection by mucosal of an allergen (Subcutaneous immunotherapy). rOute. 0011. However, SLIT has been to use preparations only for 0003. Under the circumstances, the vaccination via boosting a specific immunotolerance, but has been not a mucosal route has been drawing attention in recent years. In therapy to activate the immunity. The oral cavity mucosa is particular, the development of a vaccine containing an influ generally not likely to develop immunity, and the activation of enza virus as an antigen for mucosal administration (transna immunity, even if the immunotolerance is developed, has sal administration) has been in a high profile. been considered to be difficult. 0004. The mucosal administration vaccine induces the 0012 Examples of the induction of the mucosal immunity systemic immunity (IgG antibody production) and also and systemic immunity via the oral cavity mucosa route, induces the mucosal immunity (IgA antibody production). particularly the Sublingual mucosa route, are reported includ The IgA antibody does not strictly discriminate the pathogen ing the following. type of a disease to be targeted, is adaptable to ever-changing 0013 OVA-specific systemic immune response (IgG pro pathogen epidemic every year and is thus considered to be duction) and OVA-specific mucosal immune response (IgA effective for the pandemic prevention. production) are proposed to have been confirmed when OVA 0005. One of the reasons for the transnasal administration used as an antigen and cholera toxin used as an adjuvant were vaccine to attract attention is that the antigen administration administered Sublingually (see, for example, Patent Litera to the gastrointestinal mucosa is susceptible to the influences ture 1). However, in the proposal, highly neurotoxic cholera of gastric juice and proteases which are hardly evitable, toxin was used as the adjuvant and the safety issue was left to whereas the antigen administration to the transnasal mucosa be cleared. is free of these influences. Additionally, there is an antigen 0014. Using OVA as an antigen and 3 de-O-acylated recognition tissue called NALT on the nasal cavity mucosa monophosphoryl lipid A, a TLR4 agonist, as an adjuvant and which is beneficial for immune response. This is another administering them Sublingually have been proposed to bring reason for the transnasal administration vaccine to gain inter about OVA-specific systemic immune response (IgG produc eStS. tion) and OVA-specific mucosal immune response (IgA pro duction) as well (see, for example, Patent Literature 2). In this 0006. However, the antigen administration to the nasal proposal, a TLR4 agonist was Sublingually administered as cavity mucosa, while being highly effective, have had draw an adjuvant, however, no example regarding an antigen backs in that it is most likely to cause critical adverse effects derived from an infectious disease was presented and the Such as acute encephalopathy, or the like; the transnasal versatility of the effect to the antigen type was not evident. administration perse is cumbersome and difficult to practice Additionally, the comparatively large doses of OVA being 80 on the elderly, infant, or the like; and the stable effect is not to 160 g and 3 de-O-acylated monophosphoryllipid Abeing assured due to physical factors such as nasal mucus, or the 20 to 40 ug are not practical when considering the safety. like. 0015. A proposal on a method for synthesizing glucopy 0007. On the other hand, there have also been many ranosyl lipid, a synthetic adjuvant, (see, for example, Patent attempts to induce the systemic immunity and mucosal Literature 3) also describes the mucosal immune response immunity via oral administration of an antigen through the induction by the mucosal administration of an antigen in gastrointestinal mucosa (intestines), and the like, after Swal combination with the adjuvant. The inductions of serum IgG lowing. The concern here is how the antigen breakdown and IgA in a nasal wash are also proposed by the administra caused by the gastric juice or proteases is prevented. To solve tion of MALP-2, a TLR2/6 ligand, together with B-galactosi the problem, techniques have been developed to neutralize dase used as an antigen to the nasal cavity of a mouse (see, for US 2013/0266612 A1 Oct. 10, 2013 example, Patent Literature 4). However, no example regard 0027. The toll-like receptor 4 (TLR4) agonist preferably ing an antigen derived from an infectious disease or admin comprises at least one selected from the group consisting of istration thereof to the oral cavity mucosa was presented, and lipopolysaccharide,