BK-SE36 malaria vaccine candidate for young children

Transcription

1 BK-SE36 malaria vaccine candidate for young children Toshihiro Horii, Ph.D RIMD, Osaka University 26 June. 2015, Save the date,tokyo, Japan

2 Structure of SERA5 protein and SE36 recombinant molecule 23 Serine repeat S H N 989 aa Trophozoite P a.a. 383 Ring P47 S-S P Schizont (Early) P47 (P25n + P25c) S-S P56 P18 P47 (P25n + P25c) P50 P6 P18 Invasion Merozoites Schizont (Rupture) Schizont (Mature) SE SE36 S-S SE36 protein is derived from P47 of SERA5. Serine repeats in P47 protein was removed because of its hydrophobic nature. Recombinant protein is produced in E. coli from a synthetic gene. Horii et al., Vaccine (2010)

3 Correlation of anti-se36 antibody levels with parasitemia in residents from the Solomon Islands Anti-SE36 IgG Anti-MSP-1 IgG (OD) (OD) Antibody level 0.5 Antibody level (N=57) 0<30 (N=32) 30<100 (N=10) 100< (N=16) 0 0 (N=57) 0<30 (N=32) 30<100 (N=10) 100< (N=16) Number of parasites per 200 white blood cells (Horii et al.,2010, Parasitol Int. )

4 Sero-positive rate against N-terminal domain of SERA is very low in younger generations and increases with age (%) Proportion of high responders SE36 (+) MSP (+) ~10 11~15 16~20 21~30 31~40 41~ (n=12) (n=25) (n=19) (n=20) (n=13) (n=26) Age Groups (yr.) (Horii et al.,2010, Parasitol. Int. )

5 Function of SERA5 Central domain, P50, is essential for schizont rupture, although mechanism is unclear. N-terminal and C-terminal domain binds to vitronectin for host immune modulation (unpublished data). N-terminal and C-terminal domain on merozoite has an essential function in RBC invasion (unpublished data).

6 Clinical trials of BK-SE36 in Uganda BK-SE36: GMP grade SE36 protein formulated with aluminum hydroxide gel 2010 Apr Aug Phase Ib in Uganda: Stage 1: malaria- exposed Ugandan adults (21-40 years old) - No severe adverse events 2010 Sep 2011 Feb 2011 Mar Nov Stage 2: Follow-up Phase Ib in Uganda: Stage 2: malaria- exposed Ugandan children and young adults (6-20 years old) - No severe adverse events Palacpac et al., PLoS ONE May 2013, Vol. 8

7 Phase 1b: Trial design Stage 1 Stage 2 safety approval Stage1, y: 56 subjects BK-SE36 Placebo 1 dose= 1.0mL (=100µg SE36 protein with 1mg aluminum hydroxide gel) Male Female Male Female Sero-negative Sero-positive Stage2, 6-20 y: 84 subjects 2 dose= 0.5 and 1.0mL BK-SE36 Placebo 0.5mL 1.0mL 0.5mL 1.0mL 6-10 y old y old y old

8 Stage1, y Administration site reactions Sero-negative (n=18) BK-SE36 (1.0mL) Sero-positive (n=18) Induration Pain/Tenderness Edema/Swelling Erthema/Redness (Other: Hyperpigmentation) 0 2 Stage2, 6-20 y 0.5mL (n=33) BK-SE36 1.0mL (n=33) Induration Safety and administration site reactions were similar to Phase 1a trial of this vaccine. Pain/Tenderness Edema/Swelling Erthema/Redness (Other: Hyperemia/ Hyperpigmentation) 0 2

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11 Immunogenicity of BK-SE36 Geometric mean fold increase in antibody titer y old y old y old BK-SE ml BK-SE ml Placebo Young children remarkably responded to BK-SE36.

12 Follow-up study 84 administered subjects New subjects BK-SE36 (0.5 ml): n = 33 BK-SE36 (1.0 ml): n = 33 Placebo (0.5 ml): n = 9 Placebo (1.0 ml): n = 9 + Age, gender and locality matched Control: n = 50 Monthly visits + Any time when sick Serum sampling Active surveillance: monthly Passive surveillance: any time when a subject felt sick Detection of malaria infection and parasitemia

13 Vaccine efficacy Days to the first appearance of malaria parasites 5000/µL in control and vaccine groups (0.5mL ml) Protective efficacy against parasitemias 5000/µL+fever BK-SE36= 72%, p=0.003 Palcpac et al.,2013 PLOS ONE

14 Definition of responders to BK-SE Fold increase in antibody titer Responder (n=20) Non-responder (n=44) 1.92 Placebo (n=16) BK-SE36 Placebo

15 Responder to BK-SE36 Before 1st Before 2nd Post SE207 SE211 SE223 SE230 SE234 SE236 SE256 SE260 SE262 SE267 SE268 Percentile of population with 2 fold increase in antibody titers according to age group of vaccine cohort Dose 6-10y y y. 100 μg 72.70% 27.30% 18.20% 50 μg 36.40% 0% 27.30%

16 Non-Responder to BK-SE36 Before 1st Before 2nd Post SE238 SE251 SE271 SE243 SE275 SE264 SE279 SE233 SE250 SE263 SE237 SE255

17 Analysis of boosting effect by natural infection Vaccine response Fold increase 1.92 : Responder < 1.92 : Non-responder Infection: 100 parasites / µl blood i) Infection was found between monthly visits. ii) Infection was found at a monthly visit. Before After Before After Next visit Titer increase Titer increase

18 Boosting effect after natural infection Antibody titer Responder Non-responder Placebo/Control Geometric mean of fold increase P=0.0020** P<0.001*** P= Before After 1 Responder Nonresponder Placebo/ Control

19 Antibody titer Changes in antibody titer in responders ( >1.92 increase of titer by vaccination) Infection = 0 Infection 1 Antibody titer Boosting (*2 infection) * * 1 1 Initial Final Initial Before After Final 21 days after 2nd admin. 9 subjects 11 subjects 365 days after 2nd admin. 21 days after 2nd admin. malaria infection malaria infection 365 days after 2nd admin. Subjects in the responder group without infection have higher antibody titers at initial (21 days post vaccination). The antibody titers of subjects with infection were significantly boosted by natural infection.

20 Correlation between vaccine response and re-infection 30 Parasitemia 100 (detection limit) Number of subjects Number of infections Responder Non-responder Placebo/Control No. of infections Risk of 2 infections Responder ( 2/20) Non-responder (12/46) 70% reduction Placebo/Control (22/66) P=0.049* (by Fisher s exact test)

21 Nucleotide diversity (π) ama1 csp msp1 SERA-SE36 serca + adsl (n=459) (n=485) (n=404) (n=445) (n=453) The nucleotide diversities (π ) of SE36 are lower than those of ama 1, msp1 and csp genes Tanabe et al. (2012) Vaccine 30:

22 Phase 1a trial (2005) malaria-naïve Japanese adults Group 1: 50 µg SE36 (0.5mL ) Group 2: 100 µg SE36 (1.0mL ) Anti-SE36 (IgG) titer After 1 st administration After 2 nd After 3 rd After 1 st administration After 2 nd After 3 rd, placebo (saline) Horii et al., Parasitol Int. 2010

23 Phase Ib trial in Uganda; The highest response was observed in the youngest cohort. Proportion of subjects with >2-fold increase in antibody titers Age (y) Younger age group of 0-5 years old would be more responsive to BK-SE36 vaccination Follow-up study revealed the efficacy of BK-SE36 against several malaria endpoints Vaccine responders had lower risk of re-infection and did show boosting effects by natural infection

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25 Double blinded randomized Phase Ib clinical trial of BK-SE36 in Burkina Faso Months Cohort 1 (25-60 months) Weeks Dose 1 Dose 2 Booster Dose Cohort 2 (12-24 months) Dose 1 Dose 2 Booster Dose Treatment arms in each cohort 18 Vaccinees by intra-muscular 18 Vaccinees by subcutaneous 18 Placebo vaccinees (Synflorix) Endpoints Safety in young child Immunogenicity Exploratory efficacy

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28 Development of Next Generation SE36 Malaria Vaccine For having a stronger immunogenicity. Formulation with innate immune adjuvant, CpG K3 ODN (TLR9 ligand adjuvant)

29 Comparison of vaccine induced antibody titers after 3 weeks of the second administration between BK-SE36 and BK-SE36/CpG in Phase Ia clinical trials of Japanese naïve adult (male) CpG 50 µg SE36/AHG (0.5mL) 100 µg SE36/AHG (1.0mL) Anti-SE36 (IgG) titer n=7 n=11 0 placebo (saline)

30 BK-SE36/AHG BK-SE36/AHG BK-SE36/AHG BK-SE36/AHG Phase Ia in Japan y 2005 Phase Ib in Uganda y, 6-20 y Phase Ib in Burkina 1-5 y Phase II/IIIb XXXX-XXXX Comparison of subclass, epitopes, protective ability and etc. of the induced IgG BK-SE36/CpG Phase Ia in Japan y BK-SE36/CpG Phase Ib XXXX-XXXX BK-SE36/CpG Phase II/IIIb XXXX-XXXX

31 Acknowledgement Department of Molecular Protozoology, RIMD, Osaka University: Nirianne M. Q. Palacpac, Ken J. Ishii, Nobuko Arisue, Takahiro Tougan, Sawako Itagaki, The Research Foundation for Microbial Diseases of Osaka University: Shigeharu Ueda, Ishikawa Toyokazu, Hiroki Shirai, Nahoko Suzuki, Takuya Okada, Department of Public Health, Faculty of Medicine, Osaka City University: Yoshio Hirota, Wakaba Fukushima, Kazuya Ito BK-SE36 Malaria Vaccine Working Group- MBL and LMC, Uganda: Thomas G. Egwang, AdokeYeka, Edward Ntege, Christopher Nsereko, Betty Balikagala, KaturoOsbert, Bernard Kanoi, OpioOtim William, Amina Ali Kheir, Adongo Faith Ayen, John Paul Bygamy, Godfrey Mujuzi Medical Center for Translational Research, Osaka University Hospital Akira Myoui, Sachiko Ezoe, Masanori Yagi Nirianne Palacpac

32 Gender Seroconversion Immunogenicity of BK-SE36 Phase 1b trial: malaria- exposed Ugandan adults Stage 1, yr. Administration No. of subject s Antibody titer Geometric mean (95% CI) Before 1st administration 3 weeks after 2nd administration Female Negative Positive BK-SE ( ) 34.5 ( ) Placebo ( ) 26.3 ( ) BK-SE ( ) ( ) Placebo ( ) ( ) Negative Male Positive BK-SE ( ) 59.1 ( ) Placebo ( ) 29.8 ( ) BK-SE ( ) ( ) Placebo ( ) ( ) In healthy adults, largest increase in mean anti-se36 protein antibody were observed in subjects with low baseline antibody titers to SE36. Palacpac et al., PLoS ONE May 2013, Vol. 8

33 Immunogenicity of BK-SE36 Phase 1b trial: malaria- exposed Ugandan children and young adults Stage 2, 6-20 yr. Antibody titer Geometric mean (95% CI) Age group Administration No. of subjects Before 1st administration 3 weeks after 2nd administration 6-10 y old y old y old BK-SE ml ( ) ( ) BK-SE ml ( ) 48.0 ( ) BK-SE ml ( ) ( ) BK-SE ml ( ) 63.5 ( ) BK-SE ml ( ) ( ) BK-SE ml ( ) ( ) 6-20 y old Placebo ( ) 53.8 ( ) Antibody titer is relative to 5,000 units assingd for high titer pooled Ugandan serum Palacpac et al., PLoS ONE May 2013, Vol. 8