Drugs ～Infectious disease～
Clinical Development of NPC-BKSE36/CpG Malaria Vaccine
Department of Malaria Vaccine Development,
Research Institute for Microbial Diseases, Osaka University

Principal
Investigator

Endowed Chair Professor Toshihiro HORII

Project Outline
BK-SE36 malaria vaccine is a combina�on of recombinant SE36 protein and aluminumhydroxide gel (AHG). From a clinical study in Uganda, a 72% protec�ve eﬃcacy could beobtained, with children from 6-10 years old responding more to the vaccine. A study inchildren 1-5 years old was also successfully carried out in Burkina Faso. In further clinical
trials with Japanese adults, adding CpG-ODN(K3), a nucleic acid adjuvant, to BK-SE36malaria vaccine resulted in 3-4 �mes increase in the an�body �ter. We have completed aBK-SE36/CpG clinical trial in Burkina Faso from adults to 1 year-old child without vaccine
related severe side eﬀects and we are now under analysis of obtained data. We also plan tocarry out a Phase I/IIa trial u�lizing controlled human malaria infec�on to have suppor�ngeﬃcacy data. BK-SE36 was renamed as NPC-SE36, reﬂec�ng the development of thevaccine with Nobelpharma Co., Ltd. as sponsor.
Life cycle of the falciparum malaria parasite

Pa�ents inApac, Uganda.

In 2018, there were roughly 400,000 deaths
due to malaria.

Results of BK-SE36/AHG Phase Ib trial in Uganda
100 (%)
90

Suggested
Protective efficacy 72%

807060?

50403020
1000-5 6-10 11-15 16-20
Percentage of persons who respond to thevaccine in each age groupParasite prolifera�onIn erythrocy�c stagePalacpac et al. (2013) Plos Onean� SE36 an�body targets the late stages of the blood-stage life cycle.

In Uganda a promising 72% protec�veeﬃcacy against high parasitemia andfever was obtained. A larger number ofvaccine responders were observed in
the younger age group, sugges�ng
immune tolerance occurs withrepeated malaria infec�on. Children, 05 years old, the target age group underWHO, are expected to respondfavorably to the vaccine.

Results of BK-SE36/CpG Phase Ia clinical trial
100 mg
SE36AHG

50 mg
SE36CpG

6000

6000

2000

2000

1500

1500

1000

1000

500

500

0

placebo (saline)

n=7

n=11

A comparison of vaccine induced an�body �ters from Japanese male adults
vaccinated with BK - SE 36 and BK-SE 36/CpG (le� panel), highlights the increase inan�body �ter 3 weeks a�er the second vaccine dose. Combina�on of CpG
enhanced an�body �ter resulted in more than 3 �mes higher an�body �tercompared to BK-SE36 alone. Furthermore, using serum obtained from 1
volunteer vaccinated with BK-SE36/CpG, in vitro growth inhibi�on assay (GIA)
showed inhibi�on of parasite prolifera�on.

Parasite prolifera�on blocking
eﬀect by serum from BK-SE36/CpG
vaccinated individual100 mg
SE36CpG

1.Naïve Japanese control
2.Ugandan adult serum
3.Japanese vaccinee70

In vitro parasite growth inhibi�on (%)

An�-SE36 (IgG) �ter

50 mg
SE36
AHG

060

50
4030

Biological function of SE36 protein

201001Ezoe et al. (2020) Vaccine

2

Host vitronectin

1.0

NucleusDense
granulesMicronemes
Apical tubulin ring

Rhoptries

Tougan et al., SciRep. 2018

0.75

NPC-SE36/CpG
Control

V1V2V30.5

Long term follow-up

ISMC

V10.25V3V2ISMC

Cumula�ve incidence of clinical malaria

NPC-SE36/CpG in Burkina Faso Phase Ib clinical trial;
Protective efficacy and duration of vaccine-induced antibody titerover 3 years

0ThrombinAn�thrombin III
Complement C7
Complement C9SC5b-9 complex
etc.

SE36 protein

300.2

0.4

ISMC

0.6

V1

V2

Long term follow-up

V3Long term follow-up

0.8: YearIndependent Safety Monitoring Commi�eeSE36 protein �ghtly binds to host vitronec�n that binds toother host proteins, components of compliment. Thesecomplex camouﬂage the surface of merozoite to evade hostimmune a�ack. The complex of SE36 with host vitronec�ncauses immune tolerance against SE36. Thus resulted immune
tolerance causes low an�body response in the endemic area,
then the observed low gene�c polymorphism of SE36 gene isthought to be by this low host immune pressure.

In Phase Ib of NPC-SE36/CpG in Burkina Faso, no serious side eﬀects due to vaccina�on were reported. Malaria onset was measured for one yeara�er vaccina�on. As a result, a preven�on eﬀect of 74% (p=0.035) was obtained. Furthermore, a three-year follow-up study of the an�body �ters
induced by vaccina�on revealed that high an�body �ters were maintained even three years a�er vaccina�on.
Target disease: Malaria; Patent informa�on: (1) Patent No. 4145145 (June 27, 2008), (2) No. 4145348 (June 27, 2008), (3) Patent No. 5748658 (May 22, 2015);
Technical features: New malaria vaccine of plasmodium an�gen polypep�de SE36 and its variants combined with adjuvant CpGODN (K3); Marketability:
Falciparum malaria is an infec�ous disease that infects 200-300 million people annually and kills more than 400,000 people, mainly infants under the age of 5(WHO Report 2018). The development of a highly eﬀec�ve vaccine is expected as a dras�c measure. Development challenges: Obtaining funding to conduct
large-scale clinical trials in endemic areas. Informa�on to clarify the division of roles between companies and academia: Joint research agreement withNobelpharma Co.,Ltd. (concluded on March 18, 2019).

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