Clinical Development of Malaria Vaccine BK-SE36
Toshihiro Horii PhD, RIMD, OU
Malaria
Malaria, a tropical disease transmitted by anopheles mosquito, causes over two hundred million clinical illness
and 438,000 deaths annually. Majority of the burden is in children under 5 years in sub-Saharan Africancountries. Pregnant women in the same region also suffer from pregnancy malaria. This disease is a serious
obstacle for economic development as well as health.

Mothers holding babies with severe malaria

Malaria endemic regions

Global death due to malariaIncreased with the spread of chloroquine resistant parasites (1980-2005) and decrease byintroduction of Coartem (2005-2010)
200Deaths (in 10,000)

160

Global (all ages)
Africa (<5 years)
Africa (>5 years)
Other (<5 years)
Other (>5 years)

120
80
400

Children from a village in
Burkina Faso, Africa

Year1

Rationales for malaria vaccine development✔️Serious obstacle for health and economic growth in sub-Saharan African countries.

✔️Protection for people who are dispatched to malaria endemic areas (businessmen, thosein humanitarian aid, embassy staff, national armed forces)✔️

Protection for migrant workers to Africa, for example Chinese and Indian workforce

Malaria parasites leave salivary glandof the mosquito during a mosquito
bite to invade man

Malaria parasites first
invade liver cells

Malaria parasites proliferate in
the mosquito, ready for thenext infection.

After liver stage, parasites
penetrate into the red bloodcells and grow exponentially.

Blood-sucking Anopheles
mosquito

BK-SE36 malaria vaccine
BK-SE36 malaria vaccine is a freeze-dried formulation of recombinant SE36 protein that was expressedin E. coli and adsorbed to aluminum hydroxide gel. The vaccine formulation is stable for half of year
under room temperature. SE36 protein is derived from SERA antigen gene of the malaria parasite,
Plasmodium falciparum. SERA is essential for parasite growth and is expressed in the red blood cellstage. SERA antigen functions during parasite egress and red blood cell invasion. The SE36 protein
induces antibodies that inhibits growth of the parasite.
セリンの繰り返し
Serine repeats

P120SERA(SERA5)
antigen
S-SS-S

Multiplication inred blood cells

S-SP47SE36蛋白質SE36protein

2Clinical trial of the BK-SE36 malaria vaccine in Uganda and follow-up research

Approved by Ugandan government authorities, the trial was conducted in compliance with theInternational Conference on Harmonization Good Clinical Practices and regulatory requirements from2010 to 2011. After safety assessment in men and women above 21 years old, vaccination in 6-20 years
old was carried out. Health and presence of blood stage parasites were further monitored in a followup research for over one year for 6-20 year olds.

Number of subjects
Cohort1
Sero negative to SE36
Sero positive to SE36

Cohort 2
6-10 y.
11-15 y.
16-20 y.

BK-SE36 vaccine 1.0 mL
malefemale
9999Control vaccine 1.0 mL
malefemale
5555

BK-SE36 vaccine
0.5 mL
1.0 mL
111111111111Control vaccine
0.5 mL
1.0 mL
333333

BK-SE36 malaria vaccine

Follow-up research was carried out for BK-SE36
vaccinees (66 people) and control people without
vaccination (66 people) for over 1 year. It wasobserved that the cumulative number ofsymptomatic malaria incidence in the vaccine group
was less than that in the control group withprotective efficacy of 72% (p=0.003). (PLOS ONE,2013)

3Comparison with other malaria vaccines
Nucleotide diversity (π)(index for genetic polymorphism)

RTS, S/AS01A vaccine is developed by GSK (GlaxoSmith Kline)
After three vaccinations, protective efficacy in one
year was 31.3% (NEJM, 2012). Approval is pending.

1

2Analysis of genetic polymorphism of a large number ofmalaria parasites collected in Tanzania. Column 1 showshigh diversity of the gene on which RTS,S vaccine is based;column 2 shows a much lesser diversity of the gene on
which SE36 is based. This is thought to be one of the major
causes for differences in vaccine efficacy.

Proceeding to the BK-SE36 clinical trial for 1-5year-old children in Burkina Faso

The first vaccination of cohort 1 was carried out in July, 2015 at Banfora, Burkina Faso. After safety
evaluation, the first vaccination of cohort 2 was carried out in October 2015.
Osaka University is collaborating
Number of subjects
with European Vaccine Initiative
CohortVaccineRoute of vaccination number (Heidelberg) and Burkina Faso
National Malaria Research and1. BK-SE 36
subcutaneous
18
Training Center for Phase Ib clinical
1: 25-60 month old
2. BK-SE 36
intra-muscular
18
trial of BK-SE36 (1-5-year-olds,
3. Control vaccine
intra-muscular
18children
2015-2017). This trial is supported
1. BK-SE 36
subcutaneous18
by GHIT Fund and Nobelpharma Co.
2: 12-24 month old
2. BK-SE 36
intra-muscular
18
toddlers

3. Control vaccine

intra-muscular

418108

BK-SE36/CpG, a novel formulation with CpG oligonucleotide as adjuvant
CpG (K3) ODN (ATCGACTCTCGAGCGTTCTC) is a novel adjuvant that is expected to have strong
immune enhancing effect.

Number of subjects
K3 ODN (ATCGACTCTCGAGCGTTCTC)CpG K3 ODNCpG(ATCGACTCTCGAGCGTTCTC)
2020
Vaccine group
Dose

BK-SE36/CpG
Control
BK-SE36/CpG
Control

Cohort 1
Cohort 2

TLR9
TLR9SE36
amount Al
amount per CpG amountNo ofper dose
dose
per dose
vaccinees
0.05 mg
0.5 mg
0.5 mg70.0 mg
0.0 mg
0.0 mg30.1 mg
1.0 mg
1.0 mg110.0 mg
0.0 mg
0.0 mg50.5 mL
1.0 mL

antibody titer was induced by addition of CpG adjuvant.
CpG HigherCpG
100 mg SE36/AHG
50 mg SE36/AHG100 mg SE36/AHG
Dose 50 mg SE36/AHG

6000

6000

6000

2000

2000

2000000000

1000

1000

1000

500

500

500

5000000

2000001000

Sterile immunity could beobtained for 1 year when thevaccine induced antibody
titer is over this threshold.

placebo (saline)
placebo (saline)
In vitro parasite growth inhibition (%)

6000

Anti-SE36 (IgG) titer

Anti-SE36 (IgG) titeraddition
CpGCpG CpG

7060

1.Naïve Japanese control
2.Ugandan adult serum
3.Japanese vaccinee

504030201001253After a 24 hour assay, in vitro
parasite growth inhibition activity
was obtained with serum
collected from BK-SE36/CpG
vaccinee and pooled Ugandan
adult serum.
BK-SE36/CpG vaccination induced
parasite growth inhibitory
antibodies. The inhibition
observed was greater than thatobserved for people who haveexperienced infections for many
years in malaria endemic areas.

Future plans

2013
12

3

The expiration dateof the present stockof BK-SE36 forclinical trials

201441232015
41232016
41232017
41232018
4

Burkina FasoBK-SE36 Phase Ib(1-5 y. old)

660M ¥
Japan First-in-Man
BK-SE36/CpG
Phase Ia
(adults)

123

2019
4

12Burkina Faso
BK-SE36/CpG
Phase II/III(1-5 y. old)

32020
4

1

2

3

4Regulatory
Approval
application in Japan
Licensingapplication in USA

Burkina Faso
BK-SE36/CpG
Phase Ib
(adult→1-5 y. old)
230M ¥

Required Funds
6 months prior to start of clinical trial, ethics approval and regulatory requirements have tobe applied for in Burkina Faso. At this time it is necessary to specify source of funds for trial
conduct/activities.
After the expiration date of the current clinical batch of BK-SE36, it is necessary to build a new production
line which needs an additional investment of about ¥2 billion.

6-ConclusionWe have shown that BK-SE36 malaria vaccine has apromising protective efficacy (72%) in the 6-20 year-old
children and young adults in Uganda. Based on ouranalysis of the induced antibody response, even higher
protective efficacy (80%) can be expected in children
under 5-year-old, the WHO designated target population.
In addition, even higher efficacy can be expected by theaddition of CpG, especially for travelers to malaria
endemic areas.

Organizations involved in the development
・Research Institute for Microbial Diseases, Dept. of Mol. Protozoology Toshihiro Horii (Prof)
Basic research, Support for clinical trial, Monitoring
・The Research Foundation for Microbial Diseases of Osaka University
Koichi Yamanishi（President）
BK-SE36 GMP manufacturer, clinical trial design, implementation and supervision
・Osaka City University School of Medicine and Public HealthYoshio Hirota （Prof. Emeritus）
Statistical analyses of data・Osaka University Medical Center for Translational Research
Yoshiki Sawa（Dean, Med. Sch.）First-in-Man investigator initiated clinical trial for BK-SE36/CpG
・ (Ltd) GeneDesign , Inc
Kazuhiko Yuyama (President)
CpG GMP manufacturer
・Uganda BK-SE36 Malaria Vaccine Working GroupTom Egwang (Head)
Conduct of clinical trial in Uganda・(Ltd) Nobelpharma Co.
Jin Shiomura (President)
Clinical trial sponsor/partner
・Centre National de Recherche et de Formation sur le Paludisme
Sodiomon Sirima (Head)
Conduct of clinical trial in Burkina Faso
・European Vaccine Initiative (EVI)
Odile Leroy (Sec General)
Clinical Trial Coordination7

TOSHIHIRO HORII
BIOGRAPHYBIRTHYEAR: 1953
1976 B.A. Biology, Osaka University; 1980 Research Associate, Osaka University;
1984 Two years at Dartmouth Medical School, Hanover, NH for research on moleculargenetics and start of malaria research; 1991 Assistant Professor, Research Institute forMicrobial Diseases of Osaka University; 1999 Professor; 2005 Director, ResearchCenter for Infections Disease Control and International Research Center for Infectious
Diseases, Osaka UniversityAwards：

2004 The 51st Koizumi Prize, The Japanese Society of Parasitology
2004 The 50th Takeda Science Foundation Specific Research Grant
2014 Masamichi Aikawa Medal, Japanese Society of Tropical Medicine

Memberships：
The Japanese Society of Parasitology, President
The Japanese Society for Vaccinology, member of a board of trustees
The Japanese Society of Tropical Medicine
The Japanese Society of Molecular Biology

Major Grants for BK-SE36 Malaria Vaccine Development

Grant-in-Aid for Scientific Research on Priority Areas, MEXT（1996-1999, 2003～2007,2008-2012 ）Grant-in-Aid for Scientific Research (A), MEXT
（1999-2000、2012-2015）
Grant for the Knowledge Cluster Initiative, MEXT
（2002-2006、2007-2011）
Translational Research Promotion Project, NEDO (New Energy and Industrial Technology
Development Organization)（2009-2011）
Cost for follow-up research of BK-SE36 clinical trial(phase Ib), The Research Foundation forMicrobial Diseases of Osaka University（2011）
International Collaborative Research Program for Integrated Promotion of Social System Reformand Research（2011-2016）
Grant for Translational Research Network Program, MEXT （2012-2015）
GHIT Fund RFP Product Development Platform（2013-2015, 2014-2016）8

2015/11/12