Clinical development ofSE36 malaria vaccine

Prof. Toshihiro Horii
Department of Malaria Vaccine Development
Research Institute for Microbial diseases,Osaka University

1World Epidemic of Malaria tropica
Malaria, transmitted by Anopheles mosquito, is endemic in tropical and sub-tropical countries.
Annually, 250 million people are infected and 660 thousand are killed mainly in sub-SaharanAfrica. Majority of victims are children under 5 years old. In addition, in these regions, whenpregnant women became infected with malaria they suffer a serious condition of pregnancy
malaria, that may cause death of mothers and/or low birthweights of infants.
Infant patients in a malaria clinic
in Uganda

World epidemic regions ofMalaria tropica2

S. Casares et al. / Vaccine 28 (2010) 4880–4894

4881

ns. The most fundamental isuninterrupted transmission
ansmission in tropical areas
red to maintain the parasite
es a more effective and drasnate the parasite comparedegions. This barrier has been
elivery, weak environmental
Sporozoite vaccine
ourcing characterizing many
(RTS,S and R21)
enched. Unfortunately, dueational malaria eradication
Thesevaccinesprotect
against, such Transmissionthat malaria remains
infection
byintercepting
newly
blocking
invading
sporozoite
frommosquitobutortant infectious
vaccinedisease(Pfs25)forcould not protect from symptomatic
ntaged countries in tropicalmalaria caused by the escaped
sporozoite.
e poverty,
struggling
healthThis vaccine
providesno merit tovaccinee. Vaccine efficacy can beil.
measured but not
Erythrocytic stage
strainsexperimentallyof Plasmodium
falciin the field.
Vaccine (SE36)
sistant mosquitoes poses aAntibodies
ountries, even as recent eviAlmost all of erythrocytic antigen genes
rol in many areas. Moreover,except SE36 gene show strong genetic
polymorphism that disproportionately affects
t for travelers to and within
vaccine efficacies. Unlike vaccines based
sing economic developmentfrom the other life-cycle stages, SE36
alth of endemic populations.
vaccine-induced immunity is boosted bynatural malaria infection. Thus, SE36 vaccine
ne thus remains prioritized,
reduces the need for frequent vaccinations.
easons but to foster politi3-government organizations,ates Foundation, are suppleg for vaccine development
Fig. 1. The life cycle of Plasmodium falciparum. P. falciparum has a complex life cycle
w calls for elimination andthat involves an arthropod and a human host. In the human host, the cycle begins

Target stages of malaria vaccine candidates

with the bite of an infected Anopheles female mosquito that delivers sporozoites
into the skin. The sporozoites enter the blood circulation and migrate to the liverSE36 Malaria Vaccine
SE36 malaria vaccine is based on the recombinant protein derived from SERA5(Serine repeat antigen 5) that is expressed by the parasite at the schizont stage.
SE36 protein induces antibodies that attack merozoites.
セリンの繰り返し
Serinerepeat
P120 (SERA5)S-SS-SLife cycle at erythrocyte
S-S
P47
P47

SE36蛋白質

SE36 protein

Localization of full length (P120) SERA5 molecule in parasitized
red blood cell is shown in color. When the protein is processed theP47 molecule, green ball, surrounds the surface of the merozoite.
SE36 is genetically engineered from P47.

SE36 malaria vaccine
investigational product（SE36 protein adsorbed to Aluminumhydroxide gel and lyophilized ）4Clinical trials of SE36 malaria vaccine
Phase Ib
follow-up
research in
UgandaSE36/AHG
Pre-clinical

Phase Ia in
Japan

2003

2005

SE36/CpG

Phase Ib in
Burkina Faso

Phase Ib inUganda
2007

Early stage
development

2010 2011
Pre-clinical

2013
Phase Ia in
Japan

2015

2018

2022

Phase Ib in
Burkina Faso

Phase Ib
follow-up
research in
Burkina Faso

Clinical trials：show that the vaccine is well-tolerated with favorable
safety profile and is immunogenic.
5

Protection against malaria onset by SE36/AHG vaccination(Uganda)Cumulative events (%)

60

Days before onset of blood parasitemia >5000/μl
and axillary temperature >37.5℃, 6-20 years-old

40
Control group20

Protective efficacy:72%
p=0.003 by log-rank test

SE36 group
0130

194258322

Days after 2nd vaccination
Palacpac et al. (2013) PLOS ONE
6

Protection against malaria onset by SE36/CpG vaccination(Burkina Faso)

Cumulative events (%)

100

Days before onset of blood parasitemia >5000/μl andaxillary temperature >38℃, 5-10 years-old

75

SE36/CpG

Protective efficacy: 74%

Controlp=0.024 by log-rank test50Control group25

3rd vaccination

2nd vaccination

SE36/CpG group

000.2

0.4

0.60.8Year after 2nd vaccine administration
Ouédraogo et al (2023) Front. Immunol.
Nebie et al. (2024) Vaccine
7Persistence of SE36/CpG vaccine induced antibody

Antibody titer

Vaccine administrations

Vaccine group
Control group

Nebie et al. (2024) Vaccine

Long persistence of vaccine efficacy and booster effect by natural infection are best options toensure continuing immunity and support public health policy in endemic areas

8Critical data and detailed evidence: Part 1Comparison of protective efficacies by major vaccine candidates so far reported

A blood-stage vaccine is needed against malaria disease and death

1. Low efficacy of blood stage vaccines, except for SE36, is caused by genetic polymorphism of thetarget antigens
SE36 has undergone 3 Phase 1 clinical trials in Africa. Promising data
2. RTS,S and R21 in blue circles are pre-qualified by WHO.

••••

Protection from high parasitemia (≥5000 parasites/µL) and fever
Uganda

BK-SE36

6-20 y-old

PE = 72%

p = 0.0

Burkina Faso

BK-SE36/CpG

5-10 y-old

PEGHIT= Fund74%
p = 0.0| Management Team | 9Antibody titers can be boosted in vaccinees who experience malaria infection. Responders have lower risk
SERA nucleotide diversity is low and African-specific polymorphisms do not interfere with antibody respo
Induction of protective antibodies does not require strict conformational protein structure

Function of SE36/P47 protein in the parasite

Thrombin
Antithrombin IIISE36 protein
Host vitronectin

nucleusmicronemes

densegranules

apical tubulin ringrhoptries

Complement C7
Complement C9SC5b-9 complex
etc.

A merozoite.
1. SE36/P47 protein fully covers the surface of the merozoite and bind to host serum vitronectin. Vitronectin binds
to many host serum proteins including complements. This bound complex camouflages merozoite from hostimmune system. （Tougan et al., 2018 SciRep.）
2. SE36/P47 protein is presented to host immune system with vitronectin. Host immune system develops immune
tolerance against SE36/P47 protein through repeated malaria infection in endemic areas. （Bougouma et al.,2022 Front Immunol.）
3. Consequently, sero-conversion rate of people in endemic area is low, resulting in lesser genetic polymorphism(Arisue et al., 2022 Front Cell Infec Microbiol.）
10Perspectives of SE36 Malaria Vaccine
The WHO global strategy for malaria targets children under 5 years old inAfrica. SE36 malaria vaccine showed 74% protective efficacy in 5-10 yearold children. Immunogenicity of SE36 in 1.0 year-old infant was muchhigher than in 5-10 year-old children. Therefore over 90% protective
efficacy is expected in younger age groups.
The immunity in SE36 vaccinees was boosted by the natural malaria
infection, therefore in terms of vaccine cost, logistics/coordination andsustainability, SE36 is a promising vaccine in terms of public health policy.
Although the immune response of malaria naïve adults was a bit lower
than infants, travelers could still be protected by SE36 vaccine with over
80% efficacy.

Public health policy with SE36 malaria vaccine could
significantly reduce world malaria burden
11