第 11 回次世代アジュバント研究会
11th Meeting of the Japanese Vaccine Adjuvant Research Consortium<同時開催>

2nd ISV Asia Vaccine and Immunotherapeutic Symposium

2018 年 1 ⽉ 23 ⽇(⽕)/ January 23, 2018
千⾥ライフサイエンスセンター / Senri Life Science Center, Osaka, Japan主 催：国⽴研究開発法⼈医薬基盤・健康・栄養研究所
次世代アジュバント研究会
AMED 創薬基盤推進研究事業「⾰新的技術に裏打ちされた有効かつ安全な次世代
アジュバント開発」研究班 (研究代表者 国⽴研究開発法⼈医薬基盤･健康･栄養研究所 理事⻑ ⽶⽥ 悦啓)
共 催：⽇⽶医学協⼒研究会免疫専⾨部会<Organizer>◆National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN)◆Japanese Vaccine Adjuvant Research Consortium◆Research Committe"Development of the next-generation adjuvants with innovativeevaluation systems for safety and efficacy" supported by Japan Agency for Medical
Research and Development (AMED) Grant<Supporting organization>◆U.S.-Japan Cooperative Medical Science Program Immunology Board週刊 医学のあゆみ 第264巻 5号（2018年 2月 3日号）

近未来のワクチン
─開発研究の潮流と課題企画石井健 医薬基盤・健康・栄養研究所 ワクチン・アジュバント研究センターC O N T E N T S

総論

近未来ワクチン：開発研究の新展開
わが国の感染症ワクチンにおける 真の ワクチンギャップの解消とアンメットメディカルニーズ

ワクチン技術とサイエンスの新潮流

抗体医薬の代替としての治療ワクチン
がん抗原探索技術の基礎と臨床──次世代シーケンサーを活用したがん抗原の同定
ワクチンアジュバントと粘膜ワクチンの基盤となる自然免疫細胞解析
免疫・ワクチン応答を左右する腸内環境因子としての栄養と腸内細菌
粘膜ワクチンの潮流と課題
エボラ出血熱に対するワクチン開発の進展
ウイルスベクターを用いたワクチン開発

各種ワクチン開発の潮流と課題

ノロウイルスワクチン開発
新しいインフルエンザワクチン開発
多剤耐性緑膿菌に対する免疫療法──緑膿菌V抗原ワクチンの開発
粘膜免疫誘導型の結核ワクチン開発
──ワクチンベクターとしてのヒトパラインフルエンザ2型ウイルスの可能性
グローバルに開発が進むNPC-SE36マラリアワクチン
──BK-SE36マラリアワクチンの臨床開発
2018 年 2 月3日発売
グローバルHIVコントロールに向けたワクチン開発
定価（本体 2,400円＋税）
生活習慣病に対するワクチンの開発

最新トピック

ワクチンの安全性試験の理論的構築
ワクチンの有効性・安全性のバイオマーカー
ワクチン接種と稀ながら発生する副反応
感染症新薬・ワクチン開発におけるGHIT Fundの取組み●弊社の全出版物の情報はホームページでご覧いただけます. https://www.ishiyaku.co.jp /Conteents / 目次
m / プロググラム･････････････････････････････････････････････ ･･･････P2
2 ~ProgramP66

al presen
ntation / 講演要旨
旨･･･････････････････ ･･【O-01】】~【O-14】】
Abstractts for ora

oster pressentationn / ポスタター発表要要旨･･････ ･･【P-01】】~【P-24】
Abstractts for poVennue / 会場会

Li fe HallR
Reception/ 受付付

Receptionn

Science Hall

受付

Venue for oral preesentation
Januaryy 23

10:00
0-17:25

Venue ffor poster presentation
pnJanuaryy 23

10:00
0-14:00

Notice / 注
注意(1) Smoking is allow
wed only in the designnated roomm on the 6tth floor.
喫煙される方は、6 階の喫煙場所でお願いしします。館内ののそれ以外のの場所での喫喫煙は禁じられれています。

e turned off
ff your cell phone or p
put them ono vibrate duringdthe ppresentatio
ons.
(2) Please
講演中はは、携帯電話
話は電源を切切るかマナーモ
モードにしてくください。

1Program for oral presentation / 講演プログラム■ Registration (9:30)
1. Asia Vaccine and Immunotherapeutic Symposium(10:00 ～ 12:10)◆Opening remarks (10:00~10:05)
Margaret Ann Liu / International Society for Vaccine◆Part 1 （10:05 ~ 11:40）＜session chair＞

Shan Lu / University of Massachusetts Medical School
Yasunori Yasutomi / NIBIOHN【O-01】 10:05~10:30「Adjuvants improve the magnitude and durability of HIV vaccine-induced immune correlates」
Jerome H. Kim / International Vaccine Institute【O-02】 10:30~10:55「Development of adjuvanted vaccines: from an empirical to an evidence-based approach」
Arnaud Didierlaurent / GlaxoSmithKline Vaccines, Belgium【O-03】 10:55~11:20｢Mucosal Vaccines for the Prevention of Aero-digestive Infection｣
Hiroshi Kiyono / The University of Tokyo and Chiba University【O-04】 11:20~11:40「Towards formulating an atherosclerosis vaccine」
Kouji Kobiyama / La Jolla Institute for Allergy and Immunology, USA◆Part 2 （11:40 ~ 12:10）＜session chair＞

Joon Haeng Rhee / Chonnam National University
Ken J. Ishii/ NIBIOHN【O-05】 11:40~11:55｢Squalene-Adjuvanted H7N9 Virus Vaccine Induces Robust Humoral Immune Response against H7N9and H7N7 Viruses」
Juine-Ruey (JR) Chen / Adimmune Corporation, Taiwan【O-0６】 11:55~12:10「Intelligent emulsion functioned as potent adjuvant for prophylactic and therapeutic vaccinations」
Guanghui Ma / Chinese Academy of Sciences, China
2. Lunch Break（12:10 ~ 13:15）
3．Poster session ＆ Coffee break (13:15 ～ 14:00)◆Please feel free to come to Science Hall. Poster presenters will stand by their poster and be
prepared to answer questions from attendees.
◆Please help yourself to some coffee at the lobby.

2

4. Meeting of the Japanese Vaccine Adjuvant Research Consortium (14:00 ～ 17:25)◆Opening remarks (14:00~14:05)
Koichi Yamanishi / The research foundation for microbial disease of Osaka University◆Part 1 （14:05 ~ 15:20）＜session chair＞ Yumiko Imai / NIBIOHN【O-07】14:05~14:30「Development of mycobacterial glycolipids-based adjuvants using nanoparticle technology」
Sho Yamasaki / Osaka University and Kyushu University【O-08】14:30~14:55「Intestinal dendritic cell and mucosal vaccine development」
Satoshi Uematsu / Chiba University and The University of Tokyo【O-09】14:55~15:20「Hydroxypropyl-β-Cyclodextrin, as a novel safe and effective adjuvant for seasonal influenza vaccine」
Etsushi Kuroda / National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN) andOsaka University◆Part 2 （15:35 ~ 16:30）＜session chair＞

Jun Kunisawa / NIBIOHN【O-10】15:35 ~16:00「Recognition of nanoparticles and crystals by scavenger receptors」
Masafumi Nakayama / Tohoku University【O-11】16:00~16:15「Construction of a cell-based assay system to develop high throughput screening system for vaccine
adjuvant」
Eita Sasaki / National Institute of Infectious Diseases【O-12】16:15~16:30「Design, Synthesis and Biological Evaluation of Novel CD1d Ligands Containing Modified
LipidMoieties」
Shinsuke Inuki / Keio University and Kyoto University◆Part 3 （16:30 ~ 17:20）＜session chair＞

Ken J. Ishii / NIBIOHN【O-13】16:30~16:55「Possibilities of adjuvants use for allergen specific immunotherapy」
Katsuyo Ohashi-Doi / Torii Pharmaceutical Co. Ltd【O-14】16:50~17:15｢Development of Therapeutic Vaccines for hypertension and diabetes｣
Hironori Nakagami / Osaka University Graduate School of Medicine◆ Closing remarks (17:20~17:25)
Yoshihiro Yoneda / National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN)

3

Program for poster presentation / ポスター発表プログラム【 January 23, 2018 (10:00 ～ 14:00)】■ Poster session : Poster presenters will stand by their poster and be prepared to answer
questions from attendees from 13:15 to 14:00.
＜Poster Layout ＞Science Hall
Screen
P-10
P-09
P-08
P-07
P-06

P-11 P-12 P-13 P-14 P-15

P-05
P-04
P-03
P-02
P-01

P-16
P-17
P-18
P-19
P-20
P-21
P-22
P-23
P-24
Entrance【P-01】Development of Safe and Non-self Immunogenic Mucosal Adjuvant by Recombinant Fusion of Cholera
Toxin A1 Subunit with Protein Transduction Domain
Man Ki Song / International Vaccine Institute,Republic of Korea【P-02】
Harnessing Chaperna for the Assembly of Virus-like Particles as Recombinant Vaccines
Baik L. Seong / Yonsei University, Korea【P-03】
Modification of HA glycosylation for better immunogenicity of avian influenza H7N9 vaccine
Man-Seong Park / Korea University College of Medicine, Republic of Korea,Man-Seong Park
【P-04】
Staphylococcal particulate cell wall releasing neutrophil-calprotectin has adjuvant activity as likealuminum salt
Bok Luel Lee / Pusan National University,South Korea【P-05】
Neuropeptides control the pathology of severe influenza virus infection
Yumiko Imai / National Institute of Biomedical Innovation, Health and Nutrition (NIBIOHN)【P-06】
Assessment of K3-SPG, nano-particulate CpG DNA, as an immunotherapeutic agent in non-humanprimate models in vivo
Yuji Masuta / National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka
University and Nippon Shinyaku Co., Ltd4【P-07】
An approach to establish an in vitro assay system for the safety control of influenza vaccines andadjuvants
Haruka Momose / National Institute of Infectious Diseases【P-08】
Enhancement of avidity and ADCC activities of virus-specific antibodies by TLR agonists improved
vaccine efficacy of influenza split vaccines
Kayoko Sato /National Institute of Infectious Diseases【P-09】
Serum bactericidal assay for the evaluation of typhoid vaccines using a semi-automated colony counting
methodJae Seung Yang / International Vaccine Institute, Republic of Korea【P-10】
Relationship between the inducibility of the IFN-β production in Sendai virus Cantell strain and theantagonistic action toward the IFN-α/β signal transduction by the C protein
Kosuke Oda/ Graduate School of Biomedical and Health Sciences, Hiroshima University【P-11】
Th17 promotes the induction of antigen-specific gut-mucosal cytotoxic T lymphocytes following
intramuscular vaccination of an adenovirus vector
Masashi Tachibana / Osaka University【P-12】
Organogenesis of inducible bronchus-associated lymphoid tissue plays an essential role in
Ag85B-rhPIV2-based anti-tuberculosis respiratory vaccine in mice
Takahiro Nagatake / National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN)【P-13】
Prime-boost Vaccination with CpG ODN and curdlan strongly induces both systemic and mucosal
immunity
Naoki Takemura / Chiba University and The University of Tokyo【P-14】
T cell response analysis against human herpesvirus 6B glycoprotein complex vaccination
Mie Okutani / Osaka University【P-15】
Cooperative Adjuvant Effect of Combination of 2-Hydroxypropyl-β-Cyclodextrin and CpG-ODN
Tomoya Hayashi / National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN) andKumamoto University【P-16】
Adjuvant X can induce both cellular and humoral immunity even at very low antigen dose
Yasunari Haseda /Osaka University5【P-17】
Induction of IL-12p70 by a novel oligonucleotide in human PBMC
Jie Meng / Osaka University【P-18】
Vaccine adjuvant effects of dendritic cell-targeting peptides
Kazuki Misato / Osaka University【P-19】
Efficient induction of CD8+ cytotoxic T lymphocytes response by mutant dendritic cell-targeting peptide
Yuki Kanai/ Osaka University【P-20】
Activation of CD4+ T cell response by using dendritic cell-targeting peptide
Seiki Shirai / Osaka University【P-21】
Mechanism of synthetic hemozoin adjuvanticity
Michelle Sue Jann Lee/ Osaka University【P-22】ZBP1 governs neutrophil-mediated inflammation in influenza virus infection via IL-1a
Masatoshi Momota / National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN) andOsaka University【P-23】The role of Interleukin-1a and DNA in the particles-associated inflammation
Kou Hioki / Osaka University【P-24】
Immunological mechanism of synergistic anti-cancer activities by activation of TLR9 and STING
Burcu Temizoz/

Osaka University and National Institute of Biomedical Innovation, Health andNutrition (NBIOHN)

6

Abstract of oral presentation / 講演要旨

【O-01】

Adjuvants improve the magnitude and durability of HIV vaccineinduced immune correlates
Jerome H. Kim, MD
International Vaccine Institute
The RV144 HIV vaccine trial with ALVAC-HIV prime and gp120 B/E boost showed 31%
protection from HIV acquisition at 42 months. Correlates analysis revealed that
antibody to the V1V2 region of HIV-1 Env was associated with a decreased risk ofinfection whereas IgA to Env was associated directly with infection risk. anti-V1V2
responses were important in selection of gp120 subtype C antigens for efficacy trials in
the Republic of South Africa that are now under way. Post-hoc analysis ofsimultaneous vaccine efficacy (VE) suggested that efficacy was 60% at month 12, anddeclined steadily thereafter. In light of these findings we looked to different approaches
to improve the magnitude and durability of anti-V1V2 responses. Data suggested that alate dose of gp120 B/E – given more than 7 years after the primary series was
associated with striking V1V2 responses, exceeding that seen in RV144. When tested
formally, 12 and 15 month "booster" doses were associated with prolonged elevation of
V1V2 antibody. Older unpublished data suggested that adding monophorphoryl lipid A
liposomes to alum-adjuvanted gp120 resulted in significant increases in magnitude anddurability of anti-V1V2 responses. In NHP, SIV challenge studies using SIV cognates ofthe vaccines from RV144 showed that alum adjuvanted gp120 as a boost to ALVACSIV was associated with the same level of protection seen in RV144, however,adjuvanting in MF59 resulted in no evidence of protection from SIV acquisition despite
higher levels of antibody. These data are discussed in the context future trial design.

Abstract of oral presentation / 講演要旨

【O-02】Development of adjuvanted vaccines: from an empirical to anevidence-based approach
Dr. Arnaud Didierlaurent
Senior Director, Head of adjuvant platform
GlaxoSmithKline Vaccines, Belgium
Adjuvants are now being used in licensed vaccines with proven clinical benefits andestablished safety. Several recent studies on their mode of action have provided
insight into how adjuvants impact the immune response. Specific molecular andcellular signatures associated with improved immunogenicity of adjuvanted vaccines
are now emerging from those studies, in particular from system vaccinology
approaches conducted in humans or relevant animal models. This provides novel
targets for the development of new generation adjuvants based on synthetic
molecules and improved formulations. The presentation will provide examples on
those immune signatures that are associated with improved potency and how they
can be used to develop new adjuvants in the future.

Abstract of oral presentation / 講演要旨

【O-03】

Mucosal Vaccines for the Prevention of Aero-digestive Infection
Hiroshi Kiyono
Division of Mucosal Immunology
International Research and Development Center for Mucosal Vaccine
The Institute of Medical Science, The University of Tokyo
Department of Immunology, Graduate School of Medicine, Chiba University
Mucosal vaccines induce antigen-specific immune responses at mucosal sites
including the respiratory, digestive, and reproductive tracts, and also inducing
immunity in the systemic compartment. Especially nasal and oral vaccinations are
effective mucosal immunization routes to prevent infectious pathogens invade thebody through the respiratory and digestive mucosa. Moreover, it is also attractive
method because the physical and psychological discomfort associated with injection
methods could be eliminated. Based on the advantages, we have been developing
novel nasal vaccination system using cationic cholesteryl group–bearing pullulan(cCHP) nanogels. Vaccine antigens incorporated into cCHP nanogels induced potent
antigen-specific mucosal and systemic immune responses and have exhibited nobrain deposition of antigen via olfactory bulb after nasal administration in mice andnonhuman primates. Thus, cCHP based nanogel is a safe and effective nasal vaccine
delivery system. For the intestinal infectious disease, our efforts have been aiming
the development of oral vaccine using the rice transgenic system, MucoRice
expressing vaccine antigen or neutralizing antibody for the prevention and/or
treatment of gut pathogen induced diarrheal disease. We will present and discuss ourprogress on our efforts for the development of mucosal vaccines against respiratory(e.g., Streptococcus pneumonia) and intestinal (e.g., Vibrio cholerae) infectious
diseases.
References:
1) Nochi, T., et al: Nat. Mater. 9: 572-578. 2010.
2) Kong, IG., et al: Infect. Immunol. 81:1625-34.2013.
3) Fukuyama. Y., et al: Mucosal Immunol. 8: 1144-1153.2015.
4) Joo, S., et al: Mucosal Immunol. 10: 901-911.2017.
5) Azegami, T., et al: Mucosal Immunol, 10: 1351-1360.2017.
6) Azegami, T., et al: J Hypertens, Advance online publication, 34 Suppl. 1:e42.2017.
7) Nochi, T., et al: Proc. Jpn. Soc. Immunol. 37: 159.2007.
8) Nochi, T. et al: J. Immunol. 183: 6538-6544.2009.
9) Tokuhara, D. et al: Proc. Natl. Acad. Sci. USA. 107: 8794-8799.2010.
10) Tokuhara, D., et all: J. Clin. Invest. 123: 3829-3838.2013.
11) Kashima, K., et al: BMC Genomics 16: 48.2015.
12) Nakahashi-Ouchida, Expert Rev. Vaccines. 27:1-10. Dec.2017.

Abstract of oral presentation / 講演要旨

【O-04】

Towards formulating an atherosclerosis vaccine
Kouji Kobiyama, Takayuki Kimura, Holger Winkels, Klaus Ley
La Jolla Institute for Allergy and Immunology, USA
Atherosclerosis is an inflammatory disease of the arterial wall. Its sequelae including
myocardial infarctions, strokes, and peripheral artery disease, are the leading causeof death worldwide. The development of an effective atherosclerosis vaccine is analluring medical technology that has the potential to prevent atherosclerosis andatherosclerosis-dependent diseases. We recently showed that vaccination withimmunogenic major histocompatibility complex class II (MHC-II)-restricted peptides of
apolipoprotein B (ApoB)-100 - the major antigen in atherosclerosis - induced IL-10 by
T cells and conferred atheroprotection. However, most studies so far used a clinically
non-translatable adjuvant, complete and incomplete Freund’s adjuvants (CFA and
IFA).
Thus, to develop an atherosclerosis-specific vaccine we aim to find 1) an effective
and clinically acceptable vaccine adjuvant and to identify 2) candidate epitopes ofhuman ApoB-100. We found that immunization of atherosclerotic mice with an
MHC-II-restricted mouse ApoB-100 peptide (P6) in Addavax effectively reduced
atherosclerotic burden. Addavax is a squalene-based adjuvant similar to MF59, whichis FDA approved and licensed in Europe. Mechanistically, mice immunized with P6 in
Addavax induced IL-10 production without eliciting an antibody response. These datasuggest that an antigen-specific antibody may not be required for atheroprotection by
vaccination and highlights MF59 as a candidate adjuvant.
In an effort to prioritize candidate epitopes of human ApoB-100, we discovered an
ApoB-100 peptide, P18, whose sequence is identical in mice and humans and whichbinds both mouse and human MHC-II. Immunization with this peptide conferred
atheroprotection and was accompanied by expansion of P18-specific regulatory T
cells (Tregs). Of note, P18-specific CD4+ T cells were detectable by HLA-DR1/P18
peptide tetramer in human PBMCs. Furthermore, P18-specific CD4+ T cells from
subclinical cardiovascular disease patients exhibited a higher frequency of
FoxP3+RORγt+ cells as compared to healthy donors, indicating that ApoB-specificTregs lose their anti-inflammatory phenotype in cardiovascular disease.

Abstract of oral presentation / 講演要旨

【O-05】

Squalene-Adjuvanted H7N9 Virus Vaccine Induces Robust Humoral
Immune Response against H7N9 and H7N7 Viruses
Dr. Juine-Ruey (JR) Chen
R&D Deputy Director, Adimmune Corporation, Taiwan.
Recent cases of avian influenza H7N9 have caused great concerns that virus may
become transmittable between humans. It is imperative to develop an effective
vaccine to fight against the pandemic potential of this H7N9 influenza virus to protect
human from the disease. Our study aims to investigate an optimized formulation forthe development of H7N9 vaccines. Various doses of H7N9 inactivated whole or split
virus antigens (0.5, 1.5, or 3μg based on hemagglutinin content) combined withsqualene based adjuvant (AddaVAX), aluminum hydroxide Al(OH)3 or without
adjuvant were evaluated for the efficacy of low immunogenic H7N9 vaccine in miceand ferret. With either H7N9 whole or split-virus based vaccines,
AddaVAX-adjuvanted formulations were the most immunogenic in eliciting significant
humoral immune response against H7N9 virus and exhibited strong cross-reactive
response in hemagglutination inhibition (HAI) and viral-neutralization assays against
H7N7 virus as well. In contrast, formulations with Al(OH)3 or without adjuvant wereless immunogenic and elicited lower titers of HAI and microneutralization assays
against both viruses. Protection experiments demonstrated that the formulation of
0.004μg to 0.5μg of split virion vaccines with AddaVAX conferred full protection
against viral challenge up to 100 LD50 of wild-type H7N9 virus. The reduction of virus
titers in different respiratory tissues by split virion combined with AddaVAX also
provide better protection from the virus challenge in ferrets than split virion combinedwith Al(OH)3. Taken together, our study demonstrates that squalene based adjuvant
can significantly enhance the protective efficacy of H7N9 virus vaccine and provides
a useful strategy to confront the potential pandemic outbreaks of H7N9 virus.

Abstract of oral presentation / 講演要旨

【O-06】

Intelligent emulsion functioned as potent adjuvant for prophylactic
and therapeutic vaccinations
Guanghui Ma*
State Key Laboratory of Biochemical Engineering, Institute of Process
Engineering, Chinese Academy of Sciences, Beijing 100190, PR China*Email: ghma@ipe.ac.cn
There is an urgent need to develop potent adjuvant for both humoral and cellularresponses. “Bio-mimicking” is considered as the golden role in the adjuvant design.
Previous attempts have focused on mimic the sizes, shapes, charges andcompositions of pathogens. However, it is neglected that these microbes are actually
soft materials, which demonstrate the force-dependent deformation and antigen
mobility during cellular encounter. In light of these concerns, we designed intelligent
emulsion which was stabilized by PLGA nanoparticle instead of conventionalsurfactant. It was demonstrated that the emulsions pliability during cellular encounterincreased the contact area, and the adsorbed antigens among nanoparticles
experienced lateral mobility to intensively interact with the receptors on the antigen
presenting cells. These features significantly promoted antigen uptake among therecruited immunecytes. As charge-reversal effect in lower pH environment oflysosomes, PLGA nanoparticle-stabilized emulsions presented positive charges tocause the destabilization of lysosomes and thus triggered cytosolic delivery ofantigens. Compared with solid particles and conventional surfactant-stabilize
emulsions, the intelligent emulsions enhanced activation of the draining lymph nodes,
and potently stimulated both humoral and cellular adaptive responses. The novel
adjuvant was further employed for prophylactic and therapeutic vaccinations, which
increased the survival of mice upon lethal challenge of H1N1 viruses andB16/MUC1melanoma. Accordingly, the pliability and lateral mobility of antigen-loaded
PLGA nanoparticle-stabilized emulsions may offer an effective, safe and broadly
applicable strategy to enhance adaptive immunity against infections and diseases.
Keywords Pickering emulsion, adjuvant, tumor immunotherapy.

Abstract of oral presentation / 講演要旨

【O-07】Development of mycobacterial glycolipids-based adjuvants
using nanoparticle technology
結核菌糖脂質-レクチン受容体相互作用を活用した新規ナノ粒子アジュバントの創成

Sho Yamasaki, Ph.D. / 山崎晶

1 Department of Molecular Immunology, Research Institute for Microbial Diseases,
Osaka University / 大阪大学 微生物病研究所 分子免疫制御分野
2 Department of Molecular Immunology, Immunology Frontier Research Center(IFReC), Osaka University / 大阪大学 免疫学フロンティア研究センター 分子免疫学
3 Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu
University / 九州大学

生体防御医学研究所

免疫制御学分野

Rational design of adjuvants and delivery systems will promote development of
next-generation vaccines to control emerging and re-emerging diseases. To
accomplish this purpose, understanding the immune enhancing properties of new
adjuvants relative to those induced by natural infections can help with thedevelopment of pathogen mimicking materials that will effectively initiate innate
immune signaling cascades.
Mycobacterium tuberculosis, a causative agent of tuberculosis, has been known topossess potent adjuvant activities. Freund’s complete adjuvant (CFA), whichefficiently stimulates cell-mediated immunity, is composed of heat-killed M.
tuberculosis. However, the precise molecular mechanisms by which M. tuberculosis
exerts adjuvanticity have not been clearly understood for a few decades.
Among
patternrecognition
receptors(PRR)
for
pathogen-associatedmolecular patterns (PAMPs), C-type lectin receptors (CLRs) comprise a large familyof proteins that share a common structural motif and are involved in various immune
responses. We found that three ITAM-coupled CLRs, Mincle (Clec4e), MCL (Clec4d),
Dectin-2 (Clec4n) and DCAR (Clec4b1), act as pattern recognition receptors (PRRs)
for mycobacteria. Characteristic mycobacterial glycolipids, such as trehalosedimycolate (TDM) and lipoarabinomannan (LAM) and phopshatidylinositolmannoside(PIM), were identified as ligands for these receptors (Yamasaki, Nat. Immunol. 2008;
Ishikawa, J. Exp. Med. 2009; Miyake, Immunity 2013; Yonekawa, Immunity 2014;
Toyonaga, Immunity 2016). These findings shed light on CLRs as emerging immune
receptor family for glycolipids derived from pathogens, particularly mycobacteria, andthus CLRs could be attractive targets for the development of novel adjuvants. To
administrate these “water-insoluble” glycolipids in vivo, we hypothesized that recently
developed nanoparticles could be useful as effective and safe delivery systems.
In this symposium, we will introduce our approach to develop novel adjuvant bydecorating the surfaces of nanoparticles with those immunostimulatory glycolipids toconfer “pathogen-like” properties and enhance adjuvanticity.

Abstract of oral presentation / 講演要旨

【O-08】

Intestinal dendritic cell and mucosal vaccine development
Satoshi Uematsu, M.D., Ph.D.
1

Professor Department of Mucosal Immunology, Graduate School of Medicine, Chiba

University Project Professor
2

Division of Innate Immune Regulation, International Research and Development

Center for Mucosal Vaccines, Institute of Medical Science, The University of Tokyo
Vaccines are effective prophylaxis against infectious diseases. Conventionally, vaccine
antigens (Ag) are injected intramuscularly or subcutaneously to induce Ag-specific IgG and
Th1 responses, which prevent disease exacerbations through elimination of invading
pathogens and infected cells. However, injectable vaccines poorly induce mucosal immunity,
such as Ag-specific secretary (s)IgA and Th17 responses, which exert barrier functions toblock pathogen entry and colonization at mucosal surfaces. Because such responses are
regulated by unique subset of dendritic cells (DCs) that reside only in mucosa, topicalapplication of vaccine is necessary to deliver Ag to mucosal DCs for inducing Ag-specificmucosal immunity. However, the efficiency of mucosal vaccines in inducing systemic
immunity is relatively low, because of physical disturbance of Ag delivery to mucosal DCs byepithelial barriers. Furthermore, immune tolerance induction is a big problem especially in gut.
Co-administration of toxin-based adjuvants has been tested to overcome these difficulties but
are unavailable for humans due to their toxic side effects. Thus, development of an innovative
vaccination method which can induce both systemic and mucosal immunity adequately has
been aspired. Our previous reports showed that CD103+CD11b+ DCs in small intestinal
lamina propria (siLPDCs) induced intestinal mucosal immunity by Toll-like receptor ligands
stimulation such as flagellin and CpG oligodeoxynucleotides (CpG-ODN). Unlike splenic(SP)DCs, they specifically expressed retinoic acid-converting enzyme retinal dehydrogenase
isoform 2 (RALDH2) and could induce Ag-specific sIgA and Th17 responses in addition to
IgG and Th1 responses. Here, we find that SPDCs co-stimulated by CpG-ODN and curdlan
induce similar immune responses to those induced by activated siLPDCs. This adjuvant
combination not only induces activation but also up-regulates the expression of RALDH2 andtransforming growth factor-β in SPDCs, respectively, critical for IgA and Th17 inductions.
Intramuscular Ag injection with CpG-ODN and curdlan induces Ag-specific systemic
responses such as IgG and Th1. Surprisingly, the priming immunization also induces
Ag-specific sIgA in stool, which protects cholera toxin-induced diarrhea. Although Ag-specificsIgA induction is transient after the priming, oral Ag administration induces high levels of
Ag-specific IgA in stools for over 3 months. Moreover, Ag-specific Th1 and Th17 responses
are induced in intestine after the boosting. Boosting effect is also induced in lung byintranasal Ag administration, thereby effectively inhibiting the colonization and invasion ofStreptococcus pneumoniae. Collectively, this new prime-boost vaccination is the hybrid
method of injectable and mucosal vaccines and will be an innovative technique to effectively
prevent both invasion and disease progression of pathogens at the target mucosal tissues.

Abstract of oral presentation / 講演要旨

【O-09】

Hydroxypropyl-β-Cyclodextrin, as a novel safe and effective
adjuvant for seasonal influenza vaccine.
Etsushi Kuroda1,2, Takato Kusakabe1,2, Shingo Kobari1, Motoyasu
Onishi1 and Ken J. Ishii1,2
1

Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research(CVAR), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN)
2Laboratory of Vaccine Science, Immunology Frontier Research Center (IFReC),

Osaka University
Adjuvants are often used to improve the effectiveness of vaccines for initiating theprotective immunity. Although alum is the most widely used adjuvant in humanvaccines, alum has certain limitations; low potency for cellular immune responses,
IgE induction, formation of granuloma and long-term local inflammation at the site of
injection. Therefore, there are needs for an alternative adjuvant with even better
safety and efficacy than Alum.
Recently we found that hydroxypropyl-β-cyclodextrin (HP-β-CD), a widely usedpharmaceutical excipient to variety of drugs, can function as potent adjuvant for Flu
vaccines by enhancing antigen-specific IgG, but not IgE responses via similar
mechanism of Alum adjuvant.1 Furthermore, we also observed that HP-β-CD isapplicable to mucosal vaccine adjuvant for the induction of antigen-specific mucosal
immune responses by intranasal administration.2 Since HP-β-CD is an approved
pharmaceutical excipient, these findings indicate that HP-β-CD can be a safe andeffective adjuvant for human vaccines.
In this presentation, we will talk about the mode of action of HP-β-CD and theapplication as a novel flu vaccine adjuvant.
1: Onishi M, Ozasa K, Kobiyama K, Ohata K, Kitano M, Taniguchi K, Homma T, Kobayashi M, Sato A,
Katakai Y, Yasutomi Y, Wijaya E, Igarashi Y, Nakatsu N, Ise W, Inoue T, Yamada H, Vandenbon A,
Standley DM, Kurosaki T, Coban C, Aoshi T, Kuroda E, Ishii KJ. Hydroxypropyl-β-cyclodextrin spikes
local inflammation that induces Th2 cell and T follicular helper cell responses to the coadministeredantigen. J Immunol. 2015 194(6):2673-82. doi: 10.4049/jimmunol.1402027.
2: Kusakabe T, Ozasa K, Kobari S, Momota M, Kishishita N, Kobiyama K, Kuroda E, Ishii KJ.
Intranasal hydroxypropyl-β-cyclodextrin-adjuvanted influenza vaccine protects against
sub-heterologous virus infection. Vaccine. 2016 34(27):3191-3198. doi:
10.1016/j.vaccine.2016.04.001.

Abstract of oral presentation / 講演要旨

【O-10】

Recognition of nanoparticles and crystals by scavenger receptors
スカベンジャー受容体によるナノ粒子および結晶粒子の認識機構
Masafumi Nakayama / 中山 勝文
Frontier Research Institute for Interdisciplinary Sciences, Tohoku University /東北大学

学際科学フロンティア研究所

新領域創成研究部

Nanoparticles and crystals such as silica, alum, and monosodium urate crystalscause inflammation, which is triggered by phagocyte NLRP3 inflammasome
activation

and

cell

death.

Whilethemolecular

mechanisms

underlying

particle-induced NLRP3 inflammasome activation have been extensively studied, it ispoorly understood how macrophages recognize these particles on their cell surface.
Given the negatively charged surface, inorganic particles may be also recognized byreceptors for organic particles such as bacteria in a charge-dependent manner.
Indeed, the class A scavenger receptors such as SR-A1 and MARCO bind silica andtitanium particles as well as bacteria; however, these receptor-deficient mice andmacrophages have still shown inflammatory responses to these inorganic particles,
suggesting that additional receptor(s) may be involved. Using unbiased functional
screening, we have recently identified the class B scavenger receptor member 1(SR-B1) as a novel silica receptor. Both mouse and human SR-B1-mediated tetheringof silica to macrophage surface and the subsequent phagocytosis cause NLRP3
inflammasome activation and cell death. I here focus on the role of scavenger
receptors in nanoparticles and crystal-induced inflammation.

Abstract of oral presentation / 講演要旨

【O-11】

Construction of a cell-based assay system to develop highthroughput screening system for vaccine adjuvant
ワクチンアジュバントのハイスループットスクリーニング系構築を目指した培養細胞による in vitro 評価系の構築
Eita Sasaki / 佐々木 永太
Department of Safety Research on Blood and Biological Products, National Instituteof Infectious Diseases / 国立感染症研究所 血液・安全性研究部
In recent years, adjuvanted vaccines have been licensed and developed in order toincrease the effectiveness of the vaccine. Since the mechanism of action of adjuvants
are diverse, development studies are vigorously undertaken to develop and explore
more effective and safety adjuvants. In recent years, by rapidly evaluating the efficacy
and safety of candidate compounds at the early stages of drug development by
utilizing high throughput screening (HTS), shorten development time and efficient
strategies for seeds screening has been possible. However, in vaccine’s adjuvants,
such a HTS applicable for adjuvants has not been existed, and efficiency indevelopment is considered to be lower than that of synthetic drugs. Thus, we haveattempted to construct an in vitro HTS system useful for evaluating the efficacy andsafety of vaccine adjuvant. Previously, we identified the lung biomarker genes usefulfor evaluating the bioactivity of vaccines and adjuvants. Among the biomarker
genes, the genes have been considered involving "effectiveness" (infection
prevention) and "toxicity" of vaccines. This lung biomarker genes is also expressed insome cultured cell lines, therefore construction of an HTS system using cultured cells
is expected. Here we present an attempt to construct a vaccine and adjuvant
biological activity evaluation method using the biomarker genes, alveolar
epithelium/bronchial epithelial cell lines and human peripheral blood mononuclear
cells (PBMC). Regarding alveolar epithelium/bronchial epithelial cell lines, increased
expression levels of the biomarker genes and cytokines secretions response toinactivated influenza vaccine stimulation were observed. These reactions werestrongly observed in a whole-virion inactivated influenza vaccine (WPV), which has
high reactogenicity in humans. On the other hand, no responses to adjuvant
supplementation such as toll-like receptor (TLR) agonist were observed. In human
PBMC, WPV stimulation-dependent increases of the biomarker genes and cytokines
secretions were observed. Notable cell death and cell proliferations by vaccine
stimulations were not observed in T cells, B cells, NK cells and dendritic cells (DC).
Furthermore, when PBMC enriched with plasmacytoid DC (pDC) was used,sensitivities to biomarker genes expressions against WPV stimulation were improved,
suggesting that the biological activities assessed by the marker genes in PBMC
would captures the reaction derived from pDC.

Abstract of oral presentation / 講演要旨

【O-12】

Design, Synthesis and Biological Evaluation of Novel CD1d Ligands
Containing Modified Lipid Moieties
脂質部位の構造展開を基盤とする新規 CD1d リガンドの創製研究
Shinsuke Inuki1,2, Emi Kashiwabara1, Natsumi Hirata1, Junichiro
Kishi1 and Yukari Fujimoto1
井貫晋輔 1,2, 平田菜摘 1, 柏原瑛美 1, 岸惇一郎 1, 藤本ゆかり 1
1

Faculty of Science and Technology, Keio University, 2 Graduate School of

Pharmaceutical Sciences, Kyoto University / 1 慶大理工, 2 京大院薬CD1d is a non-polymorphic MHC class I-like molecule, whose ligands include
glycolipids such as α-GalCer (KRN7000).1) Complexes of glycolipid ligands and CD1d
can be recognized by T cell receptors (TCR) found on natural killer (NK) T cells andthereby induce the secretion of various cytokines, including Th1 and Th2 cytokines.2)
The control over the cytokine levels and balance is important for the development ofeffective immunotherapies. Thus, in an effort to identify novel immunomodulators,
several structure-activity relationship (SAR) studies of CD1d ligands have been
conducted to date.3) Intriguingly, these SAR studies revealed that the production andbalance of cytokine levels are dependent on CD1d ligand structures.3)
The CD1d contains a large hydrophobic lipid binding pocket: the A’ pocket of CD1d,which recognizes hydrophobic moieties of the ligands, such as long fatty acyl chains.
The A’ pocket is a large hydrophobic lipid binding groove surrounded by apolar aminoacid residues. However, the pocket includes a few polar amino acid residues (eg.
Ser28). We focused on the polar residues in the A’ pocket of CD1d, and designed
CD1d ligands that can interact with the hydrophilic residues through hydrogen bonds.
A series of the ligands, α-GalCer derivatives containing polar groups in the acyl chain,
was synthesized, and the structure-activity relationship studies demonstrated that
simple modification from a methylene to an amide group in the long fatty acyl chain,
when introduced at optimal positions, enhanced the CD1d recognition of theglycolipid ligands. Taken together, we demonstrated that confined polar residues in
the large hydrophobic area of the lipid binding pockets of CD1d could be targeted tosignificantly influence the affinity between the protein and its ligands. These findings
could provide a practical guide to designing lipid ligands and expanding opportunities
to utilize these ligands as pharmaceuticals and adjuvants.4)
1) Morita, M.; Motoki, K.; Akimoto, K.; Natori, T.; Sakai, T.; Sawa, E.; Yamaji, K.; Koezuka, Y.;
Kobayashi, E.; Fukushima, H. J. Med. Chem. 1995, 38, 2176.
2) Brennan, P. J.; Brigl, M.; Brenner, M. B. Nat. Rev. Immunol. 2013, 13, 101.
3) Laurent, X.; Bertin, B.; Renault, N.; Farce, A.; Speca, S.; Milhomme, O.; Millet, R.; Desreumaux, P.;
Hénon, E.; Chavatte, P. J. Med. Chem. 2014, 57, 5489.
4) Inuki, S.; Aiba, T.; Hirata, N.; Ichihara, O.; Yoshidome, D.; Kita, S.; Maenaka, K.; Fukase, K.; Fujimoto,
Y. ACS Chem. Biol. 2016, 11, 3132-3139

Abstract of oral presentation / 講演要旨

【O-13】

Possibilities of adjuvants use for allergen specific immunotherapy
Katsuyo Ohashi-Doi, Ph.D.
Research Laboratory, Torii Pharmaceutical Co. Ltd.
Allergen specific immunotherapy (AIT) has been used for more than 100 years as adesensitizing therapy for IgE-mediated allergic diseases and represents the only
potentially curative way of treatment. AIT is currently administered via either the
subcutaneous (SCIT: subcutaneous immunotherapy) or sublingual (SLIT: sublingual
immunotherapy) route and is recognized as the only treatment option with thepotential to provide long-term post-treatment benefits and alter the natural course ofallergic disease. The prevalence of Japanese cedar pollinosis in Japan is very high as
36.7% of the populations suffer from clinical allergy and 56.3% are sensitized withJapanese cedar pollen-specific IgE. However, even though SCIT has been available
in Japan for many years it is not widely practiced thus far because of thedisadvantages of SCIT, such as the need for frequent hospital visit, pain caused byinjections, and the risk of systemic reactions. Therefore most of the patients havebeen treated with pharmacotherapy such as anti-histamine tablets. In 2014, a newtreatment option with the introduction of SLIT-drop product for Japanese cedar
pollinosis, a new treatment option for Japanese cedar pollinosis was presented, and a
HDM SLIT-tablet for HDM-induced allergic rhinitis was approved in 2015. Both are
based on SLIT and do not have the same disadvantages as SCIT.
The goal of successful AIT is to relieve symptoms by modulating the immunologicalmechanisms related to allergy. Our current understanding of the AIT mechanism ofaction emphasizes a prominent role for CD4+ cells in controlling effector immune
mechanisms linked with allergic inflammation. Particularly, most allergic patients
exhibit allergen-specific Th2 responses, and CD4+ T cell responses are redirected
toward the Th1 type with an increased production of IFNγ as well as towards IL-10
producing regulatory T cells. Tolerance induction also requires allergen-specificregulatory B cells as well as a decreases in allergen-specific IgE levels over time
followed by increasing of blocking antibodies levels (i.e., IgG and IgA). Although AIT
has proven to be clinically effective and the more convenient SLIT-tablets weredeveloped, AIT remains underused and is estimated to be used in less than 10% ofallergic patients in worldwide. This is mainly due to several important drawbacks,
including safety concerns or requirement for long term treatment and low patientadherence. Therefore, benefit of adjuvant in AIT has received much attention in thisfield, in order to help lowering the allergen dose, improving the safety profile with lesslocal reactions and maintain or increase robust immunomodulation. In mypresentation, the benefit of adjuvant use for next generation of AIT drug development
will be discussed.

Abstract of oral presentation / 講演要旨

【O-14】Development of Therapeutic Vaccines for hypertension and diabetes

生活習慣病を標的とした治療ワクチンの開発
Hironori Nakagami, M.D.,Ph.D. / 中神啓徳
Department of Health Development and Medicine, Osaka University Graduate Schoolof Medicine
大阪大学大学院医学系研究科健康発達医学寄附講座
Recent research on vaccination has extended its scope from infectious diseases tochronic diseases, including Alzheimer’s disease, hypertension and diabetes. We
have recently reported that angiotensin II vaccine for hypertension or DPP4 vaccine
for diabetes successfully attenuated the high blood pressure or hyperglycemia ineach mice model, respectively (PNAS 2014, Hypertension 2015, Sci Rep 2017). The
immunogenic molecule (i.e. KLH) is used to provide an antigen that supports theactivation of helper T-cells in this vaccine system with co-treatment of
Freund's adjuvant. Anti-angiotensin II antibodies has been induced by two or threetimes injection of vaccine at two weeks intervals and sustained for several months,
which can efficiently ameliorate angiotensin II-induced high blood pressure andperivascular fibrosis in mice. We have also attempted to develop a therapeutic
vaccine against DPP4. As a result, the vaccine-induced anti-DPP4 antibodies canefficiently ameliorate hyperglycemia in diabetic mice without any immunogenic side
effects. From the clinical point of view, increasing the effectiveness of drug adherence
interventions may have a great impact on the health of the population, because it isreported that approximately 50% may not take medications among patients withchronic illness. This poor adherence to medication leads to increased morbidity anddeath. If the improvement of drug compliance has been achieved with vaccines inhypertensive patients, it may assist better control of blood pressure, leading to
reduced complications. We are now going to apply the therapeutic vaccine foranother chronic diseases under the collaboration with the physician-scientists fortranslational research. The potential of a therapeutic vaccine will give us a chance tochallenge to develop an innovative treatment for incurable diseases.

Abstract of poster presentation / 発表要旨

【P-01】Development of Safe and Non-self Immunogenic Mucosal Adjuvant
by Recombinant Fusion of Cholera Toxin A1 Subunit with Protein
Transduction Domain
Byoung-Shik Shim, In Su Cheon, Eugene Lee and Man Ki SongLaboratory Science Division, International Vaccine Institute, Seoul 08826,
Republic of Korea
Abstract
Potential use of cholera toxin (CT) as a mucosal vaccine adjuvant has been
documented in a variety of animal models. However, native CT is highly toxic to be
used as a mucosal adjuvant in humans. Here, we demonstrate a new approach togenerate a mucosal adjuvant by replacing the B subunit of CT with HIV-1 Tat proteintransduction domain (PTD), which efficiently delivers fusion proteins into the cell
cytoplasm by unspecific binding to cell surface. We compared the adjuvanticity andtoxicity of Tat PTD-CTA1-Tat PTD (TCTA1T) with that of CT. Our results indicate that
intranasal (i.n.) delivery of ovalbumin (OVA) with TCTA1T significantly augments theOVA-specific systemic and mucosal antibody responses to levels comparable tothose seen with CT adjuvant. Moreover, in vivo cytotoxic T lymphocyte activity
elicited by TCTA1T was significantly higher than that elicited by a mutant TCTA1T(TmCTA1T) lacking ADP ribosyltransferase function. In addition, co-administration of
influenza M2 protein with TCTA1T conferred near complete protection against lethal
influenza virus challenge. Importantly, TCTA1T, in contrast to CT, did not induce
serum IgG antibody responses to itself and was shown to be non-toxic. These
results suggest that TCTA1T may be a safe and effective adjuvant when given bymucosal routes.

Abstract of poster presentation / 発表要旨

【P-02】

Harnessing Chaperna for the Assembly of Virus-like Particles
as Recombinant Vaccines
Young-Seok Kim1, Soon Bin Kwon1, Jemin Sung1, Ji Eun Yu1, ManSeong Park2, and Baik L. Seong1*
1

Department of Biotechnology, College of Life Sciences andBiotechnology, and Vaccine Translational Research Center, Yonsei
University, Seoul, Korea
2
Department of Microbiology, College of Medicine, Korea University,
Seoul, Korea
Significant advances have been made in the design and manufacture ofnanoparticle vaccine, as vital alternative to traditional cell-culture vaccines.
Assemblages of key immunologic features of viruses as highly repetitive particulate
structures are essential for inducing potent and long-lasting antibody responses. The
folding of monomeric antigens and their subsequent assembly into higher orderedstructure is crucially important for robust and faithful production in a timely andreproducible manner. E. coli expression system is easy to use and the least
expensive. A major drawback for bacterial host, however, is that it does not provide
optimal milieu for the folding and assembly of human infecting viral antigens andenveloped virus antigen. Capitalizing on a novel function of RNAs as molecularchaperone (Chaperna), here we provide a robust protein folding vehicle that could be
implemented for virus-like particle (VLP) or nanoparticle (NP) assemblies in bacterial
host. Thus, a viral target surface antigen is fused with and RNA-interaction domain(RID), and expressed in E. coli as soluble form. The removal of RID by site-specificprotease prompted the assemblage of monomers into regular multimeric complex, as
confirmed by EM and DLS. We confirm that RNA is crucial for the folding ofmonomers and subsequent assembly into VLPs. The mutations that affects the RNAbinding to RBD greatly increases the soluble aggregation into amorphous structures,
reducing the overall yield of nanoparticles of defined size, confirming the importanceof RNA interaction for the assembly into highly ordered complex. The results suggestthat RNA functions as a ‘pace-maker’ for the assembly by controlling the overall
kinetic network of antigen folding pathway into immunologically relevant
conformation. The Chaperna platform holds promise to develop and deliver VLP and
NP vaccines as a high-priority vaccine strategy against emerging viruses.
* Correspondence to Baik L. Seong(E-mail: blseong@yonsei.ac.kr; Tel.: +82 2-2123-2885; Fax: +82 2-362-7265

Abstract of poster presentation / 発表要旨

【P-03】

Modification of HA glycosylation for better immunogenicity of avian
influenza H7N9 vaccine
Sehee Park,1 Ilseob Lee,1 Jin Il Kim,1 Jun Heo,2 Joon-Yong Bae,1Kirim Yoo,1 Juwon Kim,1 Misun Nam,1 Miso Park,1 Soo-Hyeon Yun,1
Kee Bum Park,2 Yong Seok Kim,2 Jae Soo Shin,2 Dong-Yeon Kim,2Man-Seong Park1,*
Authors’ affiliation
1
Department of Microbiology, and the Institute of Viral Diseases, Korea
University College of Medicine, Seoul 02841, Republic of Korea, 2Il Yang
Pharmaceutical Co., Yongin 17096, Republic of Korea.
Abstract
Recent cases of human infection with an avian influenza A(H7N9) virus in China
have been a concern of public health. However, current vaccine candidates
appeared to be less efficacious. To address a threat of the virus, we investigatedmolecular signatures of N-linked glycosylation (NLG) in the HA of H7 subtype viruses
and their applicability for vaccine development. Based on the potential glycosites
identified, we generated NLG mutant viruses using the HA of H7N9 A/Anhui/01/2013
on the 2009 pandemic H1N1 backbone. Unlike a single NLG-removed mutant fromthe HA residue 249 (rH7-249), single NLG-added (rH7+141, rH7+167) and double
NLG-added (rH7+141+167) viruses produced similar or increased sizes of plaques in
MDCK cells and exhibited better growth rates in MDCK, A549, and Vero cells,
compared with a parental rH7 virus. Of the NLG mutants, rH7+141+167, whichshowed the highest replication property in the cells, appeared to induce the most
broad-spectrum antibodies in the assays using guinea pig antisera. In an inactivatedvaccine formulation, the double NLG-added vaccine protected mice from challenge
by resulting in better immune responses than a NIBSC-made H7N9 vaccine. Thesesuggest the strong potential of NLG modification for the development of a high yield,
broad-spectrum vaccine against avian influenza viruses.
Keywords
avian influenza virus, hemagglutinin, immunogenicity, N-linked glycosylation
Acknowledgments
This study was supported by a grant from the National Research Foundation of
Korea (NRF) funded by the Ministry of Science and ICT, Republic of Korea (Grant
No.: NRF-2017M3A9E4061995).

Abstract of poster presentation / 発表要旨

【P-04】

Staphylococcal particulate cell wall releasing neutrophilcalprotectin has adjuvant activity as like aluminum salt
Byun Hyun Kim1, Jun Hyun Bae Byung1, Ji Yoon Jung, Sun Hwa
Kim, Seong Han Jang1 and Bok Luel Lee1
1

Host Defense Protein Laboratory, College of Pharmacy, Pusan National
University, Busan 46241, South Korea
Abstract
Nutritional immunity is a host defense response sequestrating host trace metals
using neutrophil-derived calprotectin (S100A8/A9) to modulate bacterial growth andpathogenesis. But, the triggering signal(s) inducing release of calprotectin fromneutrophils is not determined yet. Here, we found that both staphylococcal insoluble
particulate cell wall (PCW, 1 μm particle size) and aluminum salt functioned as
triggers for releasing calprotectin, but not by silica particle or staphylococcal soluble
cell wall (SCW) that was prepared from PCW by treatment of peptidoglycanhydrolyzing enzymes. Upon injection of PCW or alum into murine peritoneal cavity,
maximal large numbers of antigen presenting cells and high levels of neutrophil
chemotaxin KC and monocyte chemotactic protein (MCP1) are detected after 12 h
injection. Further, PCW- and alum-pre-injected mice, but not by silica- or SCWinjection, were highly protected from USA300 methicillin-resistant Staphylococcus
aureus (MRSA) infection. As expected, PCW- or alum-injected peritoneal lavage
fluids showed antibacterial activity in the presence of paraquat, but this activity wasabolished by addition of manganese ion. Upon I.P. injection of PCW, bothneutrophils and monocytes were recruited on the mediastinal lymph node after 6 h,while alum recruited monocytes only. Injection of ovalbumin/alum or ovalbumin/PCW
mixture induced higher numbers of germinal centers in the nymph node andproduced robust serum ovalbumin specific IgGs. Taken together, these results
demonstrate that both staphylococcal PCW use calprotectin for induction of nutrition
immunity and showed adjuvant activity as like aluminum salts.
Keywords
particulate cell wall, alum, calprotectin, adjuvant, nutrition immunity, Staphylococcus
aureusAbstract of poster presentation / 発表要旨 【P-05】
Neuropeptides control the pathology of severe influenza virus
infection
Yu Ichida1, Kenichiro Matsushita1, Midori Hoshizaki1, Seiki Fujiwara1,
Etsushi Kuroda2, Ken Ishii2, and Yumiko Imai1
1

Laboratory of Regulation of Intractable Infectious Diseases, National
Institute of Biomedical Innovation, Health and Nutrition, 2 Laboratory of
Adjuvant Innovation, National Institute of Biomedical Innovation, Healthand Nutrition
Severe influenza virus infection is characterized by extremely high cytokine
production and virus replication with high mortality rate. Catechlamines (CA) havebeen shown to modulate pulmonary inflammation and immune responses throughboth, neural and non-neural phagocyte-dependent mechanisms. Besides CA,
sympathetic nerves also release neuropeptide Y (NPY) upon stimulation. However,it remains unknown if any non-neural sources of NPY may also play a role in the
response to severe influenza virus infection. Here we show that de novo synthesisof NPY was increased in phagocytes including alveolar and interstitial macrophages,
and monocytes following influenza virus infection in lungs. Genetic deletion of Npy or
its receptor specifically in myeloid cells greatly improved the pathology of severe
influenza virus infection. NPY signalling on phagocytes impaired anti-viral response
and promoted pro-inflammatory cytokine production, and thereby enhancing thepathology of influenza virus infection. Thus, direct regulation of NPY-its receptor axis
in phagocytes could act as a fine-tuner of an innate immune response to virus
infection, which could be a novel therapeutic target for severe influenza virus
infection.

Abstract of poster presentation / 発表要旨 【P-06】
Assessment of K3-SPG, nano-particulate CpG DNA, as an
immunotherapeutic agent in non-human primate models in vivo
Yuji Masuta,1,2,3 Takuya Yamamoto,1,2 Ken J. Ishii1,2
1

Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant
Research, National Institutes of Biomedical Innovation, Health andNutrition
2
Laboratory of Vaccine Science, Immunology Frontier Research Center,
World Premier International Research Center, Osaka University
3
Laboratories of Discovery Research, Nippon Shinyaku Co., Ltd【Introduction】Priming, boosting and restoring memory cytotoxic T lymphocytes(CTLs) by vaccination or by immunotherapy in vivo have been actively investigated.
While immunostimulatory CpG DNA attract attention to elicit strong antigen-specific
CTL responses as a vaccine adjuvant, very few have been shown to act as ananti-cancer mono-therapeutic agent particularly in non-human primates (NHP). In thisstudy, we used cynomolgus macaques to estimate the potential of K3-SPG, thecomplex of CpG oligodeoxyribonucleotides (K3) and schizophyllan (SPG) for TLR9synthetic ligand, as an immunotherapeutic agent.
【Methods】We used 3 different nucleic acids-based adjuvants in this study; K3,
K3-SPG and poly (I:C) for TLR3, Retinoic acid-Induced Gene-I (RIG-I), Melanoma
Differentiation Associated gene 5 (MDA5) ligands. After administration of either K3,
K3-SPG or poly (I:C) in cynomolgus monkeys, a complete blood count wasdetermined. And we also measured the cytokines/chemokines production in serum
and analysed the frequencies and activation stats of neutrophils and T cells inperipheral blood mononuclear cells by flow cytometry.
【Results】We show that a single injection subcutaneously or intravenously of
K3-SPG significantly increased the frequencies of activated memory CD8+ T cells in a
NHP model. Vaccine-induced, antigen-specific memory CD8+ T cells were boosted byfollowing administration of K3-SPG alone, but not other agonists K3 or poly (I:C).
Although K3-SPG induced systemic inflammation, the levels of neutrophil influx in the
blood and proinflammatory cytokines in serum were lower than those induced by poly
(I:C) injection.
【Discussion】K3-SPG may represent a potent mono-immunotherapeutic agent toboost antigen-specific memory CTL responses even in the absence of specificantigen without robust systemic inflammation.

Abstract of poster presentation / 発表要旨

【P-07】

An approach to establish an in vitro assay system for the safetycontrol of influenza vaccines and adjuvants
Haruka Momose, Eita Sasaki, Yuki Hiradate, Hideki Kusunoki, Takuo
Mizukami, Isao Hamaguchi
Department of Safety Research on Blood and Biological Products,
National Institute of Infectious Diseases
BACKGROUND
The biological responses in the vaccinated animals are tested as indicators for thesafety of vaccines. With the recent development of cDNA microarray technology, it
has become possible to identify genes related to the safety of vaccines. We haveidentified 17 marker genes whose expression was enhanced in vaccinated animals’
lungs upon treatment of whole virion influenza vaccine, and found that these markers
could also be applied to the evaluation of influenza vaccines containing adjuvants.
For the next step, the establishment of an in vitro assay system would be desired as
an alternative to animal tests for the safety assessment of HA vaccines andadjuvants.
METHODS
Adjuvants were serially diluted, mixed with influenza HA vaccines, and added to celllines derived from lung tissue of rat, mouse and human origin. Reference influenza
vaccine (inactivated whole virion vaccine) was used as a positive control. After 24hours, the cells were lysed, and the expression levels of marker genes were
measured using branched DNA-based method. Cytokines/chemokines released fromthe cells were also analyzed.
RESULTS
Reference influenza vaccine induced the upregulation of marker genes in adose-dependent manner. The responsiveness to reference influenza vaccine variedin each cell line. HA vaccine containing Alum adjuvant could induced the moderate
upregulation of marker genes, whereas HA vaccines containing poly(I:C) or K3
adjuvants showed marginal or no significant effects on the expression profile ofmarker genes. It was consistent with the result that cell lines which were used in thisstudy expressed Toll-like receptor (TLR) 3, but not TLR9-specific mRNA. The releaseof chemokines was sometimes shown even when the upregulation of marker genes
was not obvious.
CONCLUSION
The expression analysis of marker genes in the in vitro assay system will be
expected to apply to the safety evaluation of influenza vaccines and adjuvants.
However, our assay system may not be optimal for adjuvants which were designed totarget TLRs, especially TLR9. Chemokines could be other markers for the safety
evaluation of influenza vaccines and adjuvants.

Abstract of poster presentation / 発表要旨

【P-08】

Enhancement of avidity and ADCC activities of virus-specificantibodies by TLR agonists improved vaccine efficacy of influenza
split vaccines
TLR アゴニストによる抗体の avidity の増強または ADCC 抗体の産生誘導
はインフルエンザスプリットワクチンの防御効果を増強する
Kayoko Sato1, Hideki Asanuma1, Manabu Ato2, Masato Tashiro1,
Takato Odagiri1, Shigeyuki Itamura1.
1

Influenza Virus Research Center, National Institute of Infectious
Diseases2
Department of Immunology, National Institute of Infectious Diseases
Influenza vaccines induce protective immunity via induction of antibody production
against subsequent infections, and a variety of different vaccine types are currently
available.

We have previously reported that split influenza vaccines induce higher

levels of virus-specific antibodies compared to whole-virion vaccines upon responses
to a booster immunization. To identify the mechanism of these antibody inductions,the effects of several TLR agonists were determined.

Mice were injected with split

vaccines with or without several TLR agonists twice with a 4-week interval and thesera were obtained 2 weeks after the last immunization.

Vaccine-specific IgG,

hemagglutination-inhibition antibody (HI) titers, microneutralization antibody (MN)
titers, avidity of vaccine-specific IgG, and ADCC activities in the sera were examined.
Split vaccines with TLR7 and TLR9 agonists induced significantly higher avidity ofvaccine specific IgG than those with TLR3 agonist or without adjuvant.

On the other

hand, vaccines with TLR3 and TLR9 agonists induced ADCC activities in sera but
those with TLR7 agonist did not.
vaccines with each agonist.

HI and MN titers were comparable among

In addition, split vaccines with all agonists significantly

decreased virus titer in the lung after subsequent infection, as compared with those in
the absence of TLR agonist.

Further studies are underway to clarify the mechanismof antibody induction by vaccines with TLR agonists and to identify the profile ofantibodies, which correlate to the virus elimination.

Abstract of poster presentation / 発表要旨

【P-09】

Serum bactericidal assay for the evaluation of typhoid vaccines
using a semi-automated colony counting method
Mi Seon Jang, Manki Song, Jae Seung Yang**Senior Research Scientist, Clinical Research Laboratory, Sciences Unit,
International Vaccine Institute, Seoul 08826, Republic of Korea
ABSTRACT
Typhoid fever, mainly caused by Salmonella enterica serovar Typhi (S. Typhi), is alife-threatening disease, mostly in developing countries. Enzyme-linked
immunosorbent assay (ELISA) is widely used to quantify antibodies against S. Typhi
in serum but does not provide information about functional antibody titers. Although
the serum bactericidal assay (SBA) using an agar plate is often used to measurefunctional antibody titers against various bacterial pathogens in clinical specimens, it
has rarely been used for typhoid vaccines because it is time-consuming and laborintensive. In the present study, we established an improved SBA against S. Typhi
using a semi-automated colony-counting system with a square agar plate harboring
24 samples. The semi-automated SBA efficiently measured bactericidal titers of serafrom individuals immunized with S. Typhi Vi polysaccharide vaccines. The assay
specifically responded to S. Typhi Ty2 but not to other irrelevant enteric bacteria
including Vibrio cholerae and Shigella flexneri. Baby rabbit complement was more
appropriate source for the SBA against S. Typhi than complements from adult rabbit,
guinea pig, and human. We also examined the correlation between SBA and ELISA
for measuring antibody responses against S. Typhi using pre- and post-vaccination
sera from 18 human volunteers. The SBA titer showed a good correlation with anti-Vi
IgG quantity in the serum as determined by Spearman correlation coefficient of
0.737 (P < 0.001). Taken together, the semi-automated SBA might be efficient,accurate, sensitive, and specific enough to measure functional antibody titers against
S. Typhi in sera from human subjects immunized with typhoid vaccines.

Abstract of poster presentation / 発表要旨 【P-10】
Relationship between the inducibility of the IFN-β production in
Sendai virus Cantell strain and the antagonistic action toward the
IFN-α/β signal transduction by the C protein
センダイウイルス カンテル株における IFN シグナル伝達阻害作用とIFN‐β 産生誘導能の関係性の解明
Kosuke Oda / 小田康祐
Graduate School of Biomedical and Health Sciences, Hiroshima
University / 広島大学大学院医歯薬保健学研究科ウイルス学研究室
Viral nucleic acids, which activate the innate immunity responses of the host, canbe used as a vaccine adjuvant to increase the immunogenicity. Sendai virus (SeV) is
known as a virus causing the acute respiratory infection in mice. Cantell strain of SeV
produces a large amount of defective interfering (DI) RNA, which is easily recognizedby host, inducing the production of IFN-β to activate the innate immunity (Yoshida et.
al., J. Virol., in press). There is no report that SeV infects human, although it exhibitsa high cell fusion activity. In addition, since SeV has little carcinogenic risk to humandue to the inability of the genome to invade the host nucleus during viral life cycle,
SeV is frequently used as a vector to express foreign proteins in the cell by using
genetic recombination. Therefore, Cantell strain has a potential as an excellent
vaccine adjuvant. In SeV, C protein is responsible for the suppression of IFN-α/βsignaling to the nucleus, since it inhibits the tyrosine phosphorylation of Signal
Transducer and Activator of Transcription 1 (STAT1) and STAT2. The C protein also
suppresses the IFN-γ signaling, by inhibiting the activation of the STAT1 homodimer.
On the other hand, production of IFN-β is known to be suppressed by negative
feedback (Jin and Cui, Autophagy, 2017; Jin et. al., Mol. Cell, 2017). Therefore,
inducible IFN-β production by DI RNA may be positively regulated by the inhibitory
action of the C protein to the IFN-α/β signal transduction.
C-terminal domain of the C protein, named Y3, binds to the N-terminal domain of
STAT1 (STAT1ND). Our X-ray crystallographic study demonstrated that the twomolecules of Y3 symmetrically bind to each niche created in the STAT1ND dimer. By
comparing with the structure of full-length STAT1, we can clarify the structural
mechanism underlying the STAT1 inactivation by the C protein (Oda et. al., J. Virol.,2015). On the other hand, N-terminal domains of the STAT family proteins are thought
to be unable to form heterodimeric structures. However, we revealed that STAT1ND
can associate with STAT2ND by SAXS analysis using a recombinant protein, in which
STAT1ND fuses with STAT2ND via a flexible linker peptide. Furthermore, we
demonstrated that one molecular of C protein associates with STAT1ND:STAT2ND
heterodimer. These results suggest that the binding of the C protein to the
STAT1:STAT2 heterodimer induces the change of the conformation to the antiparallel
form, leading to the dephosphorylation (Oda et. al., J. Biol. Chem., 2017).
In the future, we would like to create recombinants of the SeV Cantell strain as adesirable vaccine adjuvant by introducing the mutation into the C protein gene to alter
the inhibition activity against IFN-α/β signaling, which is expected to have a highinducibility of IFN-β production.

Abstract of poster presentation / 発表要旨 【P-11】
Th17 promotes the induction of antigen-specific gut-mucosal
cytotoxic T lymphocytes following intramuscular vaccination of an
adenovirus vector / アデノウイルスベクターワクチンによる腸管粘膜面での抗原特異的細胞傷害性 T 細胞の誘導は Th17 によって促進される○Masashi Tachibana1, 2, Masahisa Hemmi1, Natsuki Fujimoto1,
Masaki Shoji1, Fuminori Sakurai1, Kouji Kobiyama3, 4, Ken J. Ishii3, 4,
Shizuo Akira4, 5, Hiroyuki Mizuguchi1, 2, 3
○立花 雅史 1, 2、邊見 昌久 1、藤本 夏希 1、庄司 正樹 1、櫻井 文教 1、小檜山 康司
3, 4、石井 健 3, 4、審良 静男 4, 5、水口 裕之 1, 2, 3
1

Graduate School of Pharmaceutical Sciences, Osaka University, 2 Global Center for
Medical Engineering and Informatics, Osaka University, 3 National Institutes ofBiomedical Innovation, Health, and Nutrition, 4 Immunology Frontier Research Center,
Osaka University, 5 The Research Institute for Microbial Diseases, Osaka University1

大阪大学大学院薬学研究科、2 大阪大学国際医工情報センター、3 医薬基盤・健康・
栄養研究所、4 大阪大学免疫学フロンティア研究センター、5 大阪大学微生物病研究所
Most pathogens access the body through mucosal membranes; therefore it is a highpriority in global health to develop vaccines capable of establishing protective
immune responses at both systemic and mucosal sites. However, induction of
mucosal immunity by systemic administration of vaccines has proven difficult due tothe unique immunological features of the mucosal immune system. Reports showedthat intramuscular (i.m.) vaccination of an adenovirus vector (Adv) induces functionaland sustainable antigen (Ag)-specific cytotoxic T lymphocytes (CTLs) in gut-mucosal
compartments, as well as systemic compartments, in mice and rhesus macaques.
Therefore, an Adv has potential as a next-generation mucosal vaccine. Adv-derived
nucleic acids, adenoviral genomic DNA and noncoding RNA, trigger innate immune
responses through several pathways, resulting in robust production of type I
interferons (IFNs). We previously revealed, using Ifnar2−/− mice, that type I IFN
signaling is required for induction of gut-mucosal, but not systemic, CTLs following
vaccination; however, the molecular mechanism elicited by type I IFN signaling
remains unknown. In the present study, we revealed that Ag-specific T helper 17(Th17) cells were reduced in gut mucosa of Ifnar2−/− mice following i.m. Adv
vaccination. Here, we showed that transfer of Th17 cells into Ifnar2−/− mice prior to
Adv vaccination rescued the induction of Ag-specific gut-mucosal CTLs. Interestingly,
the transferred Th17 cells enhanced the induction of Ag-specific CTLs in gut mucosa,
but not in systemic sites in wild-type mice. These data suggested that Th17 cells
translate systemic type I IFN signaling into gut-mucosal CTL response following i.m.
Adv vaccination. We believe that our results will promote the development ofadvanced mucosal vaccines based on the novel concept of Th17 induction.

Abstract of poster presentation / 発表要旨

【P-12】

Organogenesis of inducible bronchus-associated lymphoid tissue
plays an essential role in Ag85B-rhPIV2-based anti-tuberculosis
respiratory vaccine in mice
Takahiro Nagatake1, Hidehiko Suzuki1, Ayaka Nasu1, Soichiro
Hirata1,2, Yasuko Wada1,3, Naomi Matsumoto1, Michiko Shimojou1,
Sakiko Morimorto1, Koji Hosomi1, Kentaro Ogami4, Yusuke
Tsujimura4, Mitsuo Kawano5, Tetsuya Nosaka5, Yasuhiro Yasutomi4and Jun Kunisawa1,2,3,6,7
1

Laboratory of Vaccine Materials, National Institutes of Biomedical Innovation, Healthand Nutrition, 2 Kobe University Graduate School of Medicine, 3 Graduate School of
Pharmaceutical Sciences, Osaka University, 4 Laboratory of Immunoregulation and
Vaccine Research, Tsukuba Primate Research Center, National Institutes ofBiomedical Innovation, Health and Nutrition, 5 Department of Microbiology andMolecular Genetics, Graduate School of Medicine, Mie University, 6 Division of
Mucosal Immunology, Department of Microbiology and Immunology / International
Research and Development Center for Mucosal Vaccines, The Institute of Medical
Science, The University of Tokyo, 7 Graduate School of Medicine, Graduate School of
Dentistry, Osaka University
Abstract
We previously reported that Ag85B-expressing human parainfluenza type 2 virus(Ag85B-rhPIV2) was useful as a nasal vaccine against tuberculosis; however, its
mechanism underlying immune induction remains to be investigated. In this study, we
found that the organogenesis of inducible bronchus-associated lymphoid tissue(iBALT) played an essential role in the induction of antigen-specific T and B immune
responses in the lung. Organogenesis of iBALT was induced by intranasal
administration of Ag85B-rhPIV2 or null-hPIV2 vector without excessive inflammation.
When iBALT genesis was disrupted by depletion of CD11b+ cells or impairing
lymphotoxin-signalling, Ag85B-specific immune responses (i.e., IFN-producing T
cells and IgA antibody) were diminished in the lung. These results suggest that iBALT
plays a key role in the induction of antigen-specific immune responses in
Ag85B-rhPIV2-based anti-tuberculosis vaccine as a safe and efficient nasal vaccine.

Abstract of poster presentation / 発表要旨

【P-13】

Prime-boost Vaccination with CpG ODN and curdlan strongly induces
both systemic and mucosal immunity / CpG ODN とカードランを用いたプラ
イム‐ブーストワクチン法は全身免疫と粘膜免疫の両方を強く誘導する

Naoki Takemura1,2, Satoshi Uematsu1,2 / 武村直紀 1,2、植松智 1,2
1

Department of Mucosal Immunology, Graduate School of Medicine,
Chiba University / 千葉大学大学院医学研究院・医学部 粘膜免疫学
2
Division of Innate Immune Regulation, International Research andDevelopment Center for Mucosal Vaccines, Institute of Medical Science,
The University of Tokyo / 東京大学医科学研究所 国際粘膜ワクチン開発研究センター

自然免疫制御分野

The injectable vaccines used today induce pathogen-specific IgG and Th1
responses to halt the progression of infectious diseases. However, most pathogens
enter the body through the mucosa, and the induction of pathogen-specific mucosal
immunity involving secretary IgA (SIgA) and Th17 responses is essential for inhibiting
their entry. Unfortunately, injectable vaccines are poor inducers of antigen(Ag)-specific mucosal immunity, because it is considered to be induced by uniquemucosal dendritic cell (DC) subsets. Our previous studies showed that
CD103+CD11b+ DCs in small intestinal lamina propria (siLPDCs) induce intestinal
mucosal immunity by Toll-like receptor ligand stimulation via flagellin or CpG
oligodeoxynucleotides (CpG-ODN). Unlike splenic DCs (SPDCs), they specifically
express retinoic acid-converting enzyme retinal dehydrogenase isoform 2 (RALDH2),and can induce Ag-specific SIgA and Th17 responses in addition to IgG and Th1
responses. Here, we show that SPDCs co-stimulated by CpG-ODN and curdlan
induce similar immune responses to those induced by activated siLPDCs.
Intramuscular Ag injection with CpG-ODN and curdlan induces Ag-specific systemic
responses (e.g., IgG and Th1 production). The priming immunization also induces
Ag-specific SIgA in stool, thereby protecting against cholera toxin-induced diarrhoea.
Although the Ag-specific SIgA induction is transient after priming, oral Ag
administration induces high levels of Ag-specific IgA in stools that exceeded 3 months.
Moreover, Ag-specific Th1 and Th17 responses are induced in intestine after boosting.
The boosting effect is also induced in the lungs and vaginas by intranasal andintravaginal Ag administration, respectively. This prime-boost method would provide
an innovative injectable hybrid mucosal vaccine capable of effectively preventing
pathogen invasion and disease progression in the targeted mucosal tissues.

Abstract of poster presentation / 発表要旨

【P-14】

T cell response analysis against human herpesvirus 6B glycoprotein
complex vaccination
ヒトヘルペスウイルス 6B の糖タンパク質複合体に対する T 細胞免疫応答

Mie Okutani1,2, Akiko Kawabata3, Mitsuhiro Nishimura3, Satoshi
Nagamata3,4, Yasuko Mori3, Taiki Aoshi1,2
奥谷三慧 1,2, 河端暁子 3, 西村光広 3, 長又哲史 3,4, 森康子 3, 青枝大貴 1,2
1

BIKEN Center for Innovative Vaccine Research and Development, The Research

Foundation for Microbial Diseases of Osaka University / (財)阪大微生物病研究会
BIKEN 次世代ワクチン開発研究センター, 2 Vaccine Dynamics Project, BIKEN
Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial
Diseases, Osaka University / 大阪大学微生物病研究所 BIKEN 次世代ワクチン協働研究所ワクチン動態プロジェクト, 3 Division of Clinical Virology, Center for Infectious
Diseases, Kobe University Graduate School of Medicine / 神戸大学大学院医学研究科感染症センター臨床ウイルス学分野,4 Department of Obstetrics and Gynecology,
Kobe University Graduate School of Medicine / 神戸大学大学院医学研究科外科系講
座産婦人科学分野
Human herpesvirus 6B (HHV-6B) belongs to betaherpesvirus subfamily which is acausative agent for exanthem subitum and is sometimes associated with severe
encephalopathy in immunosuppressed patients. A glycoprotein (g) H/gL/gQ1/gQ2
complex that is unique to HHV-6, is a viral ligand for its cellular receptor. In this study,
we examined this HHV-6B glycoprotein complex vaccination induced T cell
responses in mice by using a peptide library consisted of 162 peptides covering thewhole gH, gL, gQ1, and gQ2 sequences.
BALB/c mice and C57BL/6J mice were immunized intradermally with thegH/gL/gQ1/gQ2 complex and various vaccine adjuvants, and then splenocytes were
stimulated in vitro with 162 peptides and gamma interferon (IFN-γ) production wasdetermined. We found that adjuvant X induced strong T cell responses for thegH/gL/gQ1/gQ2 complex vaccination in mice. We further investigated the T cell
responses induced with gH/gL/gQ1/gQ2 complex plus adjuvant X by depleting CD4+
or CD8+ T cells with MACS system. Depletion experiment revealed that thegH/gL/gQ1/gQ2 complex vaccination with adjuvant x dominantly induced CD4+ T cell
response in both BALB/c and C57BL/6J mice. Only weak CD8+ T cell responses weredetected in C57BL/6J mice. These result suggested that the gH/gL/gQ1/gQ2 complex
vaccination can induce strong CD4 T cell responses in mice, and speculate to have asimilar result in human.

Abstract of poster presentation / 発表要旨

【P-15】

Cooperative Adjuvant Effect of Combination of
2-Hydroxypropyl-β-Cyclodextrin and CpG-ODN
Tomoya Hayashi1,2, Takato Kusakabe1,3, Shingo Kobari1, Masatoshi
Momota1,3, Etsushi Kuroda1,3, Taishi Higashi2, Keiichi
Motoyama2, Ken Ishii1,3 and Hidetoshi Arima1,4
1

Adjuvant Innovation, National Institutes of Biomedical Innovation, Health andNutrition, 2 Department of Physical Pharmaceutics, Graduate School of
Pharmaceutical Science, Kumamoto University, 3 Laboratory of Vaccine Science,
Immunology Frontier Research Center (IFReC), Osaka University, 4 Program for
Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Glocal
Oriented) Program”, Kumamoto University, Japan
Adjuvants are used in vaccine formulations to induce potent immune responses
that cannot be obtained with antigen alone. However, sufficient immune responses
may not be shown with antigen and an adjuvant, thus the combination of multiple
adjuvants has also been developed. Recently, Onishi et al. reported that2-hydroxypropyl--cyclodextrin (HP--CyD) has Th2 adjuvanticity and produces low
IgE, which is involved in allergic reaction1, suggesting the possibility of HP--CyD as
a novel adjuvant with few side effects. However, there is no report on the combinationof HP--CyD and the other adjuvants. Meanwhile, Alum or CpG-ODN is known as
one of promising adjuvants for Th2 response or Th1 response, respectively.
Therefore, in the present study, we investigated the cooperative adjuvant effects of
HP--CyD in combination with Alum (Th2 response) and CpG-ODN (Th1 response).
C57BL/6 mice were administered ovalbumin (OVA) solutions containing HP--CyD
and Alum or CpG-ODN into the base of the tail on day 0 and 14. On day 21, the blood
was collected, and anti-OVA IgG1 (Th2 indicator) and IgG2c (Th1 indicator) in serum
were determined by ELISA. As a result, production of IgG1 after administration of
HP--CyD with Alum was almost comparable to that of Alum alone, and that afteradministration of HP--CyD with CpG-ODN was equivalent to that of HP--CyD alone.
Meanwhile, the production of IgG2c after administration of HP--CyD with CpG-ODN
was significantly increased, compared to that of HP--CyD alone and CpG-ODN
alone. In addition, we examined whether HP-β-CyD and CpG-ODN activate B cells
and dendritic cells in draining lymph node after co-administration in C57BL/6 mice.
Consequently, HP-β-CyD and CpG-ODN cooperatively upregulated the expression of
co-stimulatory molecules on CD19+ cells (B cells), whereas such effect was notshown on CD11c+ cells (dendritic cells). Taken together, these results suggest thatthe combination of HP--CyD and CpG-ODN induces both Th1 and Th2 responses
and particularly enhances Th1 response, due to the activation of B cells.
Reference:(1) M. Onishi et al., J. Immunol., 194, 2673-2682 (2015).

Abstract of poster presentation / 発表要旨

【P-16】

Adjuvant X can induce both cellular and humoral immunity even atvery low antigen dose
低抗原量でも細胞性および液性免疫を誘導するアジュバント X
Yasunari Haseda, Jie Meng, Taiki Aoshi / 長谷田泰成､ 孟潔､青枝大貴
Vaccine Dynamics Project, BIKEN Innovative Vaccine Research Alliance
Laboratories, Research Institute for Microbial Diseases, Osaka University
大阪大学微生物病研究所次世代ワクチン協働研究所ワクチン動態プロジェクト
Development of T cell response inducing vaccine is important, especially for a new
influenza virus pandemic such as H5N1 and H7N9, because most of people do nothave neutralizing antibody against these new viruses, and it has been shown that T
cells induced by seasonal influenza virus infection can be responding and protective
against these new virus infections. However, induction of T cell responses by current
protein vaccines are very limited even using a relatively strong adjuvant because
larger amount of antigen is required to induce detectable T cell responses thanantibody responses. We demonstrated that adjuvant X efficiently induced both
cellular and humoral immune responses upon very low dose of antigen
immunization(s), compared with other strong adjuvant such as cdiGMP and P-type
ODNs. These results indicated that adjuvant X is a promising future vaccine adjuvant
candidate to induce T cell responses against emerging infectious diseases withclinically applicable antigen dose.

Abstract of poster presentation / 発表要旨

【P-17】

Induction of IL-12p70 by a novel oligonucleotide in human PBMC
新規免疫賦活化核酸によるヒト PBMC における IL-12 の誘導メカニズムの解明

Jie Meng, Taiki Aoshi / 孟 潔, 青枝 大貴
Vaccine Dynamics Project, BIKEN Innovative Vaccine Research Alliance
Laboratories, Research Institute for Microbial Diseases, Osaka University
大阪大学微生物病研究所 BIKEN 次世代ワクチン協働研究所ワクチン動態プロジェクト

Vaccines need to initiate innate immune responses to induce protective adaptive
immune responses. Adjuvants are substances added to vaccines to induce innate
immune responses, activating antigen presenting cells (APCs), consequently
enhancing immunogenicity of highly purified vaccine antigens that have usually
insufficient immunostimulatory capabilities. CpG oligonucleotides (ODNs) have beenused as a vaccine adjuvant, and have been known to induce cytokines including
IFN-, IL-6, and IL-12p70 production, promoting Th1 type immune responses. IFN-
and IL-6 induction by CpG ODNs was well studied, however, there have been few
reports about CpG ODNs inducing IL-12p70 production in human PBMCs.
We screened more than 500 kinds of CpG related oligonucleotides, among these,
we found a ODN (ODN-I) which can uniquely induce strong IL-12p70 production inhuman PBMCs. Although previous report showed that human dendritic cells are themajor source of IL-12p70 production, our current result suggested that DCs (CD1c+
mDCs, CD141+ mDCs and pDC) were not a major source of IL12p70 after ODN-I
stimulation in human PBMCs.

Abstract of poster presentation / 発表要旨 【P-18】
Vaccine adjuvant effects of dendritic cell-targeting peptides
Kazuki Misato1, Yuki Kanai1,2, Taiki Aoshi3,4, Yasuo Yoshioka1,2,4
1

Vaccine Creation Project, BIKEN Innovative Vaccine Research Alliance
Laboratories, Research Institute for Microbial Diseases, Osaka University
2
Laboratory of Nano-design for Innovative Drug Development, Graduate
School of Pharmaceutical Sciences, Osaka University
3
Vaccine Dynamics Project, BIKEN Innovative Vaccine Research Alliance
Laboratories, Research Institute for Microbial Diseases, Osaka University
4
BIKEN Center for Innovative Vaccine Research and Development, The
Research Foundation for Microbial Diseases, Osaka University
Subunit vaccines are expected with improved safety compared with other vaccine
types. However, subunit vaccines must be delivered to dendritic cells (DC) more
efficiently and administered with an adjuvant, because the vaccine antigen alone
does not induce sufficient protective immunity. Our group is developing novel
targeting peptide as an antigen delivery carrier by using a phage display system,
which is an in vitro screening technique that uses a library of bacteriophages
displaying various peptides. In the present study, we tried to identify peptides thatbind dendritic cells (DC) as antigen delivery carrier for vaccine development bymeans of phage display system. A bacteriophage library was mixed with bonemarrow-derived DC and the bacteriophage clones that bound the DC were recovered.
The binding capacity of the recovered bacteriophage clones was determined by flow
cytometry: many of the peptides that bound the DC have a common sequence motif.
We examined the vaccine adjuvant effects of the DC-binding peptides in mice byusing recombinant fusion to conjugate the identified peptides with an antigen(antigen–peptide). The antigen-specific antibody response in mice administeredantigen–peptide was significantly higher than in mice administered the antigen alone
and comparable to in mice administered the antigen + adjuvant. Next we evaluatedthe usefulness of the peptide (FL4 peptide) as an antigen delivery carrier in mice tooptimize cancer vaccine. We used ovalbumin (OVA)-derived peptide (OVA257–264;
SL8) as antigen, and CpG oligodeoxynucleotide (ODN; a TLR9 ligand) as adjuvant.
SL8 or the fusion peptide SL8-FL4 without CpG ODN could not induce SL8-specificcytotoxic T lymphocytes (CTL). The SL8-specific CTL response in mice treated with
SL8-FL4 plus CpG ODN was significantly higher than that in mice treated with SL8plus CpG ODN. In addition, SL8-FL4 plus CpG ODN induced a strong antitumor
effect against OVA-expressing EG7 tumor cells. Together, these results suggest thatthe identified DC-targeting peptides are potentially useful antigen-delivery carrier for
vaccines.

Abstract of poster presentation / 発表要旨 【P-19】
Efficient induction of CD8+ cytotoxic T lymphocytes response by
mutant dendritic cell-targeting peptide
Yuki Kanai1, 2, Kazuki Misato2, Taiki Aoshi3, 4, Yasuo Yoshioka1, 2, 4
1

Laboratory of Nano-design for Innovative Drug Development, Graduate School of
Pharmaceutical Sciences, Osaka University
2
Vaccine Creation Project, BIKEN Innovative Vaccine Research Alliance Laboratories,
Research Institute for Microbial Diseases, Osaka University
3
Vaccine Dynamics Project, BIKEN Innovative Vaccine Research Alliance
Laboratories, Research Institute for Microbial Diseases, Osaka University
4
BIKEN Center for Innovative Vaccine Research and Development, The Research
Foundation for Microbial Diseases, Osaka University
It is believed that antigen specific CD8+ cytotoxic T lymphocytes (CTLs) play animportant role in preventing infectious diseases and cancer. However, most reported
vaccines cannot induce sufficient CTLs for rejection of infected or malignant cells,
because an efficient way to deliver the antigen to dendritic cells (DCs) is lacking. In aprevious study, we identified many peptides that bind to DCs. Furthermore, we
showed that one of these peptides (FL4 peptide) when fused with antigen, efficiently
promotes not only antigen specific antibodies but also CTLs responses. This finding
suggests that FL4 peptide might be an efficient way to deliver antigen to DCs to
induce antigen-specific CTLs. In this study, to develop more effective vaccine, we
assessed the capacity of FL4 mutant peptides to induce CTL responses. We used
ovalbumin (OVA)-derived peptide (OVA257–264; SL8) as antigen, and CpG
oligodeoxynucleotide as adjuvant. The SL8-specific CTL response in mice treatedwith a fusion peptide SL8-M6 (one of the FL4 mutant peptides) plus CpG ODN was
significantly higher than that in mice treated with SL8-FL4 or the other mutant fusion
peptides plus CpG ODN. In addition, SL8-M6 plus CpG ODN induced a strong
antitumor effect against OVA-expressing EG7 tumor cells. These results suggest that
M6 peptide has potential to induce CTLs effectively. We are currently assessing thatmechanism of CTL-induction by SL8-M6.

Abstract of poster presentation / 発表要旨

【P-20】

Activation of CD4+ T cell response by using dendritic cell-targeting
peptideSeiki Shirai1, 2, Kazuki Misato2, Shigeyuki Tamiya1,2, Yasuo Yoshioka1, 2, 3
1

Laboratory of Nano-design for Innovative Drug Development, Graduate
School of Pharmaceutical Sciences, Osaka University
2
Vaccine Creation Project, BIKEN Innovative Vaccine Research Alliance
Laboratories, Research Institute for Microbial Diseases, Osaka University
3
BIKEN Center for Innovative Vaccine Research and Development, The
Research Foundation for Microbial Diseases, Osaka University
It is commonly believed that CD8+ T cell responses play a major role in antiviral
immunity. Although this remains true for many viruses, several studies recently haveshown that CD4+ T cells are also important in antiviral response. Therefore, thedevelopment of vaccine that can induce CD4+ T cell responses efficiently isnecessary. In this study, we tried to develop novel vaccine which could enhance CD4+
T cell response by delivering antigen to dendritic cells (DCs). To identify DC-targeting
peptides, we used a phage display system to screen a library of bacteriophages that
could bind DCs by displayed peptides and identified the DC-targeting peptide. Next,
we evaluated the usefulness of this DC-targeting peptide as an antigen delivery
vehicle in mice to induce antigen specific CD4+ T cell response. We used ovalbumin(OVA)-derived peptides (MHC class I epitope OVA257–264; SL8 and MHC class II
epitope OVA323-339; OTII) as antigens, and CpG oligodeoxynucleotide (ODN; a TLR9
ligand) as an adjuvant. OTII-specific CD4+ T cell response in mice treated with the
OTII fused with the DC-targeting peptide plus CpG ODN was significantly higher thanthat in mice treated with OTII or control fusion peptides plus CpG ODN. In contrast,
the SL8 fused with the DC-targeting peptide plus CpG ODN could not induce
SL8-specific CD8+ T cell response. These results suggest that our identified
DC-targeting peptide might be useful as an antigen-delivery vehicle to activate
antigen specific CD4+ T cell response.

Abstract of poster presentation / 発表要旨

【P-21】

Mechanism of synthetic hemozoin adjuvanticity
Michelle Sue Jann Lee,1 Yoshikatsu Igari,2 Toshihiro Tsukui,2 Ken J.
Ishii,3,4 Cevayir Coban1
1

Laboratory of Malaria Immunology, Immunology Frontier Research Center(IFReC), Osaka University, Osaka, Japan2

ZENOAQ – Nippon Zenyaku Kogyo Co., Ltd, Fukushima, Japan

3

Laboratory of Vaccine Science, IFReC, Osaka University, Osaka, Japan

4

Laboratory of Adjuvant Innovation, National Institute of Biomedical

Innovation (NIBIO), Osaka, Japan
GLP-manufactured synthetic hemozoin (sHZ) is a beta-hematin polymer produced
from hemin chloride that yields around 1 μm crystals with optimal antigen-specificadjuvant effects. This simple-to-produce adjuvant candidate has the added advantage
of stability and cost-effectiveness besides its known adjuvanticity and safety, making it
rational to further investigate its potential as vaccine adjuvant. Although sHZ behaves
like a type-2 adjuvant, the adjuvant effects of sHZ are dependent on the model antigens
and the host species. Several studies have suggested the benefits of sHZ as an
adjuvant, such as reduction of IgE production in dog allergy model immunized withallergen, and non-pyrogenic sterile protection against influenza when immunized with
HA split vaccine in ferrets. The potency of sHZ adjuvanticity and its safety as adjuvant
have been assessed, but the mechanism of action has not been investigated. Here wedemonstrate the mechanism of adjuvanticity and enhanced class-switching mediated bysHZ.

Abstract of poster presentation / 発表要旨

【P-22】ZBP1 governs neutrophil-mediated inflammation in influenza virus
infection via IL-1α
Masatoshi Momota1, 4, Patrick Lelliott5, Takato Kusakabe1, 4, Koji
Kobiyama6, Takuya Yamamoto3, Etsushi Kuroda1, 4, Yumiko Imai2,
Cevayir Coban5, and Ken. J. Ishii1, 3.
1

Laboratory of Adjuvant Innovation, and 2Regulation of Intractable
Infectious Diseases, and 3Translational Immunology, National Institutesof Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan;
4
Laboratory of Vaccine Science, and 5Malaria immunology, World
Premier International Immunology Frontier Research Center, Osaka
565-0871, Japan;
6
La Jolla Institute for Allergy and Immunology, La Jolla,
CA 92037.
Keywords: influenza, cell death, NLRP3 inflammasome, IL-1α/β,
neutrophils,
In influenza A virus (IAV) infection, IL-1 plays an important role in both protective
and pathological immunity, however, the precise immunological mechanism by which
the production of IL-1α and IL-1β is regulated during lethal and/or non-lethal IAV is
unknown. Recent evidence suggest that Z-DNA binding protein-1 (ZBP1) is involvedin IAV-induced cell death and IL-1β induction, however, the involvement of the
NLRP3 inflammasome is unclear, and ultimately it remains controversial if ZBP1
contributes toward protective, or pathological immunity.
Here, we show that ZBP1 is essential not only for IAV-induced cell death and IL-1βinduction, but also for IL-1α induction, which did not require the NLRP3
inflammasome pathway. Indeed, mice lacking NLRP3, ASC or Caspase-1/11 had no
phenotype, while those lacking either IL-1 receptor (IL-1R) or ZBP1 displayed higher
viral load and mortality than wild type mice. Conversely, when mice were infected
intratracheally, to mimic highly pathogenic infection, ZBP1 deficiency protected micefrom acute pulmonary inflammation. These reciprocal roles of ZBP1 mirrors its
essential role in recruitment and infiltration of neutrophils to the lung, and in resultant
inflammation and neutrophil extracellular trap (NET) formation.
Collectively, these results indicate that ZBP1 is essential not only for IAV-induced
cell death, but also IL-1α production in vitro and in vivo in the absence of NLRP3
inflammasome machinery. As a result, ZBP1 controls IL-1-dependent,
neutrophil-mediated pulmonary inflammation, leading to reciprocal outcomes,
protective immunity or immunopathology, depending on the type, kinetics, and target
host tissue of IAV infection.
1

Abstract of poster presentation / 発表要旨 【P-23】
The role of Interleukin-1α and DNA in the particles-associatedinflammation
Kou Hioki, 1,2 Burcu Temizoz,1,2 Etsushi Kuroda,1,2 Ken J. Ishii1,2
1

Laboratory of Vaccine Science, WPI Immunology Frontier ResearchCenter (IFReC), Osaka University, Japan
2
Center for Vaccine and Adjuvant Research (CVAR), National Institutesof Biomedical Innovation, Health and Nutrition (NIBIOHN)
E-mail address: khioki@ifrec.osaka-u.ac.jp
Abstract summary
Recently, the number of patients with allergic inflammation, including
allergic asthma or rhinitis have been increased. Although the reason is
unclear, many reports suggest that environmental factors are causing
allergic inflammations, one of well-known factors is particle pollution,such as particulate matter 2.5 (PM2.5). PM2.5 is a micro-sized particle
and these kind of fine particles are known to enter deep in the lung and to
induce pulmonary inflammation. In addition, recent studies have revealed
that these fine particle function as an adjuvant to induce allergic immune
responses.
Adjuvants are the reagents that enhance the immune response tocoadministered antigen(s). Once particle adjuavnts are inhaled, they aredeposited in the lung, and then induce in allergic lung inflammation,
which is characterized by increase serum immunoglobulin E (IgE) levels
against allergen. In general, IgE is a well-known mediator and an
important marker for allergic diseases.
Aluminium salts (referred to as Alum) are the mostcommonly-used-particle adjuvants, and are known to preferentially
increase the IgE level. However, underlying mechanisms of Alum’
adjuvanticity and induction of IgE responses are still unclear. One ofproposed mechanisms of action of Alum is reported thatdamage-associated molecular patterns (DAMPs), including DNA, arereleased under the cell death and activate the innate immune cells.
Furthermore, we previously showed that Interleukin-1 alpha (IL-1α)
works as a DAMP and is released under the cell death after Alumstimulation, in addition to host DNA release. We also observed that IL-1α
were released in the lung after administration of Alum into the lungs, andrelease IL-1α is involved in IgE production in vivo.
In this study, we investigated the role of IL-1α and DNA as DAMPs, andwe hypothesized that IL-1α bind to DNA and is released as a DNA- IL-1α
complex under cell death for effective activation of immune cells.
References
1) Kuroda et al. Immunity 45.6 (2016): 1299-1310
2) Marichal et al. Nature medicine 17.8 (2011): 996-1002.

Abstract of poster presentation / 発表要旨

【P-24】

Immunological mechanism of synergistic anti-cancer activities byactivation of TLR9 and STING
Burcu Temizoz1,2, Kou Hioki1,2, Shingo Kobari2, Etsushi Kuroda1,2 andKen J. Ishii1,2
1

Laboratory of Vaccine Science, WPI Immunology Frontier Research Center(iFReC), Osaka
University, Osaka, Japan
2

National Institute of Biomedical Innovation, Health and Nutrition (NBIOHN),
Osaka, JapanTLR9 and Stimulator of IFN Gene (STING) agonists are both potential anti-tumor
agents and vaccine adjuvants that have been used in clinical trials. However, several
concerns are raised as currently available TLR9 agonist, CpG oligodeoxynucleotide(ODN) (K-type), is a weak inducer of IFNs and STING agonists rather induce type-2
immune responses, limiting their potential therapeutic applications. Our previous reportdemonstrated that TLR9 and STING agonists synergize for the induction of innate andadaptive type-II IFN via the mechanisms involving type-I IFNs and IL-12. In addition,
together TLR9 and STING agonists become a potent type-1 adjuvant and an anti-tumor
agent that can elicit robust CTL- and NK cell-dependent anti-tumor immunity in mousetumor models of thymoma and melanoma, respectively. Here, we further show andcharacterize the anti-tumor effect of combination of K3 CpG (TLR9 agonist) and cyclic
dinucleotides (STING agonists) in the pancreatic cancer model using Pan02 cells. By
using the Pan02 peritoneal dissemination model, we found that local but not systemic
combination treatment exert a potent anti-tumor effect. Moreover, combination
treatment is superior to K3 CpG- and STING agonist-only groups in the induction of longterm survivors that recovered from cancer. Furthermore, these long term survivors arealso resistant to a secondary challenge with Pan02 cells, suggesting the development of
the tumor-specific memory responses by the combination treatment. Finally, wedemonstrated that co-ordinate action of IL-12 and type-I IFNs is required for the antitumor effect of the combination in the Pan02 peritoneal dissemination model, which isconsistent with or previous findings indicating that IL-12 and type-I IFNs produced by
APCs are necessary for mediating the synergistic effect of combination on innate andadaptive IFNg induction. Together, these data reveals the potential of the combinatorial
use of TLR9 and STING agonists in cancer immunotherapy for multiple cancer types.

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EntranceToday's Program○2

nd

ISV Asia Vaccine and Immunotherapeutic Symposium

10:00-10:05
10:05-10:30(25min)
10:30-10:55(25min)
10:55-11:20(25min)
11:20-11:40(20min)
11:40-11:55(15min)
11:55-12:10(15min)Opening remarks: Margaret Ann Liu /(10:00-12:10)

International Society for Vaccines

Jerome Kim / International Vaccine Institute, Korea
Arnaud Didierlaurent / Glaxo Smith Kline plc, Belgium
Hiroshi Kiyono / The Institute of Medical Science, the University of Tokyo(IMSUT)
Kouji Kobiyama / La Jolla Institute for Allergy and Immunology, USA
Juine-Ruey (JR) Chen / Adimmune Corporation，Taiwan
Guanghui Ma / Institute of Process Engineering, Chinese Academy of Sciences○Poster Session / Coffee-break(13:15-14:00)○11 Meeting of the Japanese Vaccine Adjuvant Research Consortium (14:00-17:30)
th

14:00-14:05 Opening remarks : Koichi Yamanishi / The research foundation for microbial
disease of Osaka University )14:05-14:30
Sho Yamasaki / Osaka University(25min)
14:30-14:55
Satoshi Uematsu / Chiba University・The University of Tokyo(25min)
14:55-15:20 Etsushi Kuroda / National Institutes of Biomedical Innovation, Health andNutrition（NIBIOHN）(25min)
15:35-16:00
Katsufumi Nakayama / Tohoku University(25min)
16:00-16:15
Eita Sasaki / National Institute of Infectious Disease (NIID)(15min)
16:15-16:30
Shinsuke Inuki / Kyoto University(15min)
16:30-16:55
Katsuyo Ohashi-Doi / Torii Pharmaceutical Co., Ltd.
(25min)
16:55-17:20
Hironori Nakagami / Osaka University(25min)
17:20-17:25 Closing remarks : Yoshihiro Yoneda / National Institutes of Biomedical
Innovation, Health and Nutrition（NIBIOHN）

第 11 回次世代アジュバント研究会

プログラム・講演要旨集

Program and Abstracts (January 23, 2018, Senri Life Science Center, Osaka,Japan)

Copyright Ⓒ 2018 All rights reserved(不許複製・禁無断転載) 出版：2018 年 1 月 23 日
発行：国立研究開発法人医薬基盤・健康・栄養研究所ワクチン・アジュバント研究センター事務局