Life science
Medical & healthcare, Vaccine

Development of Next Generation Vaccines with High Efficacy and Safety by Utilizing the Excellent
Adjuvant Effect of Synthetic Alcaligenes Lipid A
Department of Chemistry, Graduate School of Science
Professor Koichi Fukase

Researchmap https://researchmap.jp/read0076573

Assistant Professor Atsushi Shimoyama

Researchmap https://researchmap.jp/ashimo_

Guest Professor Jun Kunisawa

Researchmap https://researchmap.jp/-9871▍ Significance of the research and Future perspective

Injection-type adjuvant activity

Intranasal-type adjuvant activity

IgG antibody levels increased in the blood.

Nasal IgA antibody levels increased.

1.52.01.5

1.0OD450

The importance of vaccines has been reaffirmed by the outbreakof new coronavirus infections. The challenges and efforts havebeen needed to develop vaccines, which are both safe and effective, against emerging and reemerging infectious diseases. To thisend, it is necessary to develop excellent adjuvants that can optimize the effectiveness of vaccines. Until now, aluminum salts havebeen widely used as vaccine adjuvants. Recently, GSK developeda monophosphorylated lipid A (MPL), which is a non-toxic formof a bacterial-derived glycolipid termed lipid A, as an excellent
adjuvant. MPL has been used in vaccines against viruses such as
human papillomavirus (cervical cancer prevention vaccine).
Since mucosal surfaces are the most important portals of entry
for pathogens, mucosal vaccines, which effectively enhance mucosal immunity as well as systemic immunity, are the next target for
the vaccine development. However, effective and safe adjuvants
for mucosal vaccines have not yet been developed. We developeda new mucosal vaccine adjuvant, lipid A from Alcaligenes faecalis,which symbiotically lives inside the intestine-associated lymphoidtissues, Peyer's patches. A. faecalis lipid A moderately activates
mucosal and systemic immunity without inducing excessive inflammation. The research group established the chemical synthesis of
A. faecalis lipid A and demonstrated that the synthetic lipid A effectively activates both mucosal and systemic immunity. Vaccines
containing A. faecalis lipid A adjuvant effectively induced the antigen-specific immune response without causing adverse reactions
such as inflammation. The intranasal vaccine consisting of pathogen antigen and A. faecalis lipid A showed excellent protection
against pathogens in a mouse model.

Remarkable adjuvant effect of lipid A
from symbiotic bacterium Alcaligenes faecalis;available for both injectable and intranasal vaccines

0.5

1.0

※Cholera toxin is
generally used inanimal experiments
as a potent mucosal
adjuvant.

0.5

00

11 12 13 14 15 16
Dilution (log2) Mice model

234567

Dilution (log2) Mice model

Non immunized（〇）OVA antigen alone （●）
OVA antigen + lipid A （●）

Pneumococcal antigen PspA alone （●）
PspA antigen + lipid A （●）
PspA antigen + cholera toxin （●）

Chemical structure of A. faecalis lipid A

Death of micefrom pneumococcal infection prevented.
100

Survival rate（（%））▍ Background & Results

A4英語

OD450

Adjuvant are substances administered together with antigens
in order to enhance vaccine effectiveness. We developed a new
glycolipid adjuvant, lipid A from Alkaligenes faecalis, which is a
symbiotic bacterium in Peyer's patch. We achieved the chemical
synthesis of A. faecalis lipid A and demonstrated that the synthetic lipid A shows effective immune activation in both mucosal andsystemic immunity without excessive inflammation. The intranasal
vaccine containing this adjuvant induced the excellent protective
effect against pathogens in a mouse model.

mucosal immunity to antigens without excessive inflammation.
Alcaligenes lipid A can be applied to the development of various
types of vaccines in the future.

PspA antigen + lipid A

100% alive

7550

PspA alone

25Non immunized0Neutrophil counts in the nasal （×105）

Life science

Abstract

012 3 4 5 6 7Days after infection

Induction of specific neutrophil responses only after infection
864Pre-infection
Non-specific response
induced by cholera toxin(Inflammation)

864220024 h after infection

Unlike cholera toxin,
A. faecalis lipid A did not
elicit local inflammation
by immunity, but induced
a rapid response only
upon infection.
Pneumococcal antigen PspA alone （●）
PspA antigen + lipid A （●）
PspA antigen + cholera toxin （●）

Since antigens alone do not effectively confer immunity, theaddition of adjuvants is necessary to increase the efficacy of vaccines. However, it is not easy to develop adjuvants that are botheffective and safe. The immunomodulating feature of commensal
Alcaligenes faecalis that resides in lymphoid tissues inspired theuse of Alcaligenes lipid A as a safe vaccine adjuvant. The chemically synthesized Alcaligenes lipid A enhances systemic andP a t e n t Japanese Patent Application No. 2019-501132, No. 2017-30179
Shimoyama, A; Kunisawa, J; Kiyono, H; Molinaro, A; Fukase, K et al. Angew. Chem. Int. Ed. 2021; 60(18):10023-10031. doi: 10.1002/anie.202012374.
T r e a t i s e Liu, Z; Hosomi, K; Shimoyama, A; Fukase, K; Kunisawa, J et al. Frontiers in Pharmacology 2021; 763657. doi: 10.3389/fphar.2021.763657.
Yoshii, K; Hosomi, K; Shimoyama, A; Fukase, K; Kunisawa, J et al. Microorganisms 2020; 8(8): 1102. doi: 10.3390/microorganisms8081102.
https://www.nibiohn.go.jp/information/nibio/2021/09/007301.html
https://www.sci.osaka-u.ac.jp/ja/wp-content/uploads/2021/09/PRfukase_rev.pdf
URL
https://www.juntendo.ac.jp/graduate/laboratory/labo/seikagaku_seitaibogyo/jeiis/pdf/No20/No20-1.pdf
https://www.peptide.co.jp/new-product/4369.html
K e y w o r d adjuvant, vaccine, mucosa, immunity, antigen