SFTSに関する治療薬・ワクチン開発

SFTSに関する治療薬・ワクチン開発

国立感染症研究所ウイルス第一部

吉河智城

Severe fever with thrombocytopenia syndrome (SFTS)

1. 特徴

2. 治療薬

3. ワクチン開発

発見

Mysterious diseases in mountainous regions Hubei and Henan provinces in China since

2008 – 2009

日本でのSFTS患者の確認

J Infect Dis. 2014 Mar;209(6):816-27.

臨床症状

高熱

血小板減少

リンパ球減少

消化器症状

血液凝固障害

神経症状

筋肉痛

致命率

中国の論文

21/171 (12%)

日本での研究

approx. 400 cases (2014-2019)

CFR 27%

韓国では

33%

媒介動物

Haemaphysalis longicornis

マダニ

但し、ダニ刺咬痕は患者の半数程度にのみ存在

伴侶動物を介した感染も報告されている

SFTSウイルス

(-)ssRNA

Enveloped

4 genes

L

RdRp

M

GPC (Gn, Gc)

S

N

NS

10.5 kb

Virion

Genome

Characters

Gn, Gc (GPC)

RdRp

N

SFTS患者が報告された国

安徽省

河南省

湖北省

日本

中国

台湾

ベトナム

SFTS患者の年齢分布

Hideki Tani

1

_{, Shuetsu Fukushi}

1

_{, Aiko Fukuma}

1

_{, Satoshi Taniguchi}

1

_,

Tomoki Yoshikawa

1

_{, Naoko Iwata-Yoshikawa}

2

_{, Noriyo Nagata}

2

_,

Akihiko Uda

3

_{, Shigeru Morikawa}

3

_{, Takashi Komeno}

4

_{, Yousuke}

Furuta

4

_{, Masayuki Shimojima}

1

_{, Masayuki Saijo}

1

Efficacy of favipiravir (T-705) against severe

fever with thrombocytopenia syndrome virus

infection

1

_{Department of Virology I ,}

2

_{Department of Pathology,}

3

_{Department of Veterinary Science,}

National Institute of Infectious Diseases, Tokyo

4

_{Research Laboratories, Toyama Chemical Co., Ltd.,}

T-705

(Favipiravir)

C

₅

H

₄

FN

₃

O

₂

➢

A novel antiviral drug (Avigan

®

) for

the treatment of influenza

➢

Developed in Japan by Toyama

Chemical Co., Ltd.

➢

Inhibits the RNA polymerase of

various RNA viruses

Virus titer (FFU/ml)

（SPL010 strain）

Cell viability

（Vero cells）

Inhibitory effects of T-705 and

ribavirin

on SFTSV infection in Vero cells

Ribavirin

1

2

3

0

Log

₁₀

conc (μM)

100

1

0.01

0.0001

EC

₅₀

: 49 μM

EC

₉₀

: 117 μM

T-705

100

1

0.01

0.0001

1

2

3

0

Log

₁₀

conc (μM)

(%)

EC

₅₀

: 6.0 μM

EC

₉₀

: 22 μM

(%)

15 100 10 5 0 50 100 80 60 110 90 70

60 mg

/kg/day

days 0 to 5

0 15 100 10 5 0 50 100 80 60 110 90 70

R

e

la

ti

v

e

w

e

ig

h

t

(%

)

Su

rv

iv

a

l

(%

)

Placebo

days 0 to 5

0

T-705

（Once/day/5days）

R

e

la

ti

v

e

w

e

ig

h

t

(%

)

Su

rv

iv

a

l

(%

)

15 100 10 5 0 50

300 mg

/kg/day

days 0 to 5

0

or

Treatment of SFTSV-infected IFNAR

-/-

mice with

T-705

Survival?

Dead?

SFTSV

（SPL010）

Day post infection

T-705 group

Day post infection

Day post infection

Placebo group

100 80 60 110 90 70

Intraperitoneal（i.p.)

administration

Subcutaneous

(s.c.) injection

15 100 10 5 0 50 100 80 60 110 90 70 15 100 10 5 0 50 100 80 60 110 90 70 15 100 10 5 0 50 100 80 60 110 90 70

R

e

la

ti

v

e

w

e

ig

h

t

(%

)

Su

rv

iv

a

l

(%

)

Placebo

days 0 to 5

25 mg

/kg/day

days 0 to 5

100 mg

/kg/day

days 0 to 5

Day post infection

0 0 0

Treatment of SFTSV-infected IFNAR

-/-

mice with

ribavirin

SFTSV

（SPL010）

Ribavirin

（Once/day/5days）

Survival?

Dead?

or

Ribavirin group

Day post infection

Day post infection

R

e

la

ti

v

e

w

e

ig

h

t

(%

)

Su

rv

iv

a

l

(%

)

Placebo group

s.c. injection

i.p.

administration

3

4

6

5

7

2

Placebo

25

mg

/kg/d

100 mg

/kg/d

300 mg

/kg/d

Ribavirin

T-705

60

mg

/kg/d

SFTSV RNA levels in the blood samples of

SFTSV-infected IFNAR

-/-

_mice

RNA copies

(log

₁₀

/ml)

RNA copies

(log

₁₀

/ml)

3

4

6

5

7

2

Placebo

25

mg

/kg/d

100 mg

/kg/d

300

mg

/kg/d

Ribavirin

T-705

60 mg

/kg/d

Day 2

Day 4

Day 7

Day 11

3

4

6

5

7

2

3

4

6

5

7

2

N.T.

N.T. : Not tested

N.T.

15 100 10 5 0 50 100 80 60 110 90 70 100 80 60 110 90 70 100 50 15 10 5 0 15 100 10 5 0 50 100 80 60 110 90 70 100 80 60 110 90 70 100 50 15 10 5 0 15 100 10 5 0 50 100 80 60 110 90 70 100 80 60 110 90 70 100 50 15 10 5 0 Rel a tiv e we ig h t (% ) Rel a tiv e we ig h t (% ) S u rv iv a l (% ) S u rv iv a l (% ) Placebo days 0 to 4 T-705 300 mg/kg/day days 1 to 6 T-705 300 mg/kg/day days 2 to 7 T-705 300 mg/kg/day days 3 to 8 T-705 300 mg/kg/day days 4 to 9 T-705 300 mg/kg/day days 5 to 10

Day post infection Day post infection Day post infection

0 0 ₀

0 0 0

Therapeutic efficacy of T-705 in SFTSV-infected IFNAR

ヒトでの臨床研究結果が掲載されます

A multicenter non-randomized, uncontrolled single arm

trial for evaluation of the efficacy and the safety of the

treatment with favipiravir for patients with severe fever

with thrombocytopenia syndrome

PLOS Neglected Tropical Diseases

in press

感染研ウイルス第一部を含む17のグループで行われた臨床研究

本臨床研究にてファビピラビルの経口投与を受けたSFTS患者の

投与開始後28日間での致命率は17.3%となり、国内の致命率27%

を下回った

Vaccinia Virus: A Recombinant Vaccine Vector

100nm

Surface tubules

Envelope

Lateral bodies

Outer membrane

Modified form Dubochet, et al., J. Virol. 1994

Core

Core envelope w/ palisade

dsDNA

A Smallpox Vaccine Strain, LC16m8 (m8)

A vaccinia virus strain

established in Japan

3rd generation

Effective

Can be lyophilized

3rd Generation is Highly Attenuated

Encephalitis

Systemic vaccinia

Pock

LD

₅₀

>10

8

m8

3rd generation

Encephalitis

Systemic vaccinia

LD

₅₀

= 10

6

Lister

2nd generation

Vaccine Target

Gn, Gc (GPC)

RdRp

N

Vaccine Efficacy of Recombinant m8s

B6-Ifnar

-/-2 weeks

4 weeks

SFTSV

YG-1

1x10

3

or 1x 10

5

TCID

₅₀

/100ul s.c.

m8-EGFP

m8-SFTSV-N

m8-SFTSV-GPC

m8-SFTSV–N+GPC

1x10

6

_{PFU/100ul/s.c.}

The Result

0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 7 0 8 0 9 0 1 0 0 1 1 0 D a y s p o s t c h a ll e n g e B o d y w e ig h t (% i n it ia l) 0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 0 2 0 4 0 6 0 8 0 1 0 0 D a y s p o s t c h a ll e n g e % s u r v iv a l N ( n = 1 0 ) G P C ( n = 1 0 ) N + G P C ( n = 1 0 ) E G F P ( n = 1 0 ) p < 0 . 0 0 0 1

SFTSV

10

5

TCID

₅₀

challenge

0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 7 0 8 0 9 0 1 0 0 1 1 0 D a y s p o s t c h a ll e n g e B o d y w e ig h t (% i n it ia l) 0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 0 2 0 4 0 6 0 8 0 1 0 0 D a y s p o s t c h a ll e n g e % s u r v iv a l N ( n = 9 ) G P C ( n = 8 ) N + G P C ( n = 9 ) E G F P ( n = 9 ) p < 0 . 0 0 1

SFTSV

10

3

TCID

₅₀

challenge

マウスを用いた研究成果が掲載されました

PLOS Pathogens

2021 Feb 3;17(2):e1008859.

PMID: 33534867

A highly attenuated vaccinia virus strain LC16m8-based

vaccine for severe fever with thrombocytopenia syndrome

m8-SFTSワクチンはどのような性状なのか？

ワクシニア事前接種済みのマウスにm8-SFTSワクチンは有効か？

m8-SFTSワクチンにより誘導される有効な獲得免疫は何か？

The Vaccine Efficacy in Monkeys

2 weeks

SFTSV

SPL10

1x10

9

_TCID

50

/5ml, i.v.

m8-EGFP (n=3)

m8-N+GPC (n=3)

1x10

7

PFU/100μl, i.d.

6 cynomolgus macaques

4 males, 2 females

6 weeks

SFTS Viral Load in Sera

1 3 5 7 9 3 4 5 6 7 8 D a y s p o s t in f e c tio n N g e n e c o p y n u m b e r (l o g 1 0 c o p ie s /m l s e r u m ) P r e U .D . n . s . p < 0 . 0 0 0 1 p < 0 . 0 0 0 1 n . s . n . s . 1 3 5 7 9 2 3 4 5 6 7 D a y s p o s t in f e c tio n S F T S V t it e r (l o g 1 0 T C ID 5 0 /m l s e r u m ) 2 3 6 4 5 7 P r e E G F P _{N + G P C} U .D . n . s . p < 0 . 0 0 0 1 p < 0 . 0 0 0 1 n . s . n . s .

Body Temperature

2

3

6

4

5

7

SFTSV

challenge

SFTSV

challenge

Euthanasia

Euthanasia

m8-EGFP

m8-N+GPC

3 4 3 5 3 6 3 7 3 8 3 9 4 0 4 1 B o d y t e m p e r a tu r e ( o C ) 3 4 3 5 3 6 3 7 3 8 3 9 4 0 4 1 B o d y t e m p e r a tu r e ( o C ) D a y s p o s t S F T S V in f e c t io n 1 2 : 0 0 0 :0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 3 4 3 5 3 6 3 7 3 8 3 9 4 0 4 1 D a y s p o s t S F T S V in f e c t io n B o d y t e m p e r a tu r e ( o C ) 1 2 : 0 0 0 :0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 1 2 : 0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 0 :0 0 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9

SFTS症例の推移