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Trial registered on ANZCTR

Registration number

ACTRN12607000552482

Ethics application status

Approved

Date submitted

12/10/2007

Date registered

26/10/2007

Date last updated

29/06/2012

Type of registration

Retrospectively registered

Titles & IDs

Public title

A Phase 1 randomised, double blinded within dose, controlled, dose- escalation, safety and immunogenicity study of a blood-stage vaccine (MSP2-C1/ISA 720) against Plasmodium falciparum MSP2 in healthy volunteers

Scientific title

Safety and tolerability trial of a randomised, placebo-controlled MSP2-C1/ISA720 malaria vaccine in healthy volunteers

Universal Trial Number (UTN)

Trial acronym

QP07C08

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Malaria

Condition category

Condition code

Infection

Other infectious diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The MSP2-C1/ ISA720 malaria vaccine is supplied as a milky white emulsion in single dose vials. Each 5 mL vial contains 0.8 mL, of which 0.5 mL is the intended volume to be injected. 0.5 mL of vaccine contains the equivalent of 0.15 ml of buffer containing antigen emulsified in Montanide® ISA720. The MSP2-C1/ ISA720 vaccine and ISA720 Control conforms to established requirements for sterility, safety and identity. The MSP2-C1/ISA720 malaria vaccine will be injected intramascularly into the 3 subgroups of participants within the intervention group. The vaccine will be provided in multiple doses, as three immunizations, twelve weeks apart. The first subgroup will receive 10 micrograms in each injection, the second subgroup will receive 40 micrograms in each injection, and the third subgroup will receive 80 micrograms in each injection.

Intervention code [1]

Prevention

Comparator / control treatment

Buffered ISA 720 adjuvant is the "placebo" and this is given in three doses, 12 weeks apart, in 0.5 ml volume, intramuscularly into the 3 subgroups of participants in the control group. The first subgroup will receive 10 micrograms in each injection, the second subgroup will receive 40 micrograms in each injection, and the third subgroup will receive 80 micrograms in each injection.

Control group

Placebo

Outcomes

Primary outcome [1]

Safety and tolerability

Timepoint [1]

Safety and tolerability of 3 vaccinations assessed from baseline by diary cards, telephone calls at days 0, 1, 21, 85, 105, 169 and 189 and by clinical evaluations at days 3,7,14,28,56,84,87,91,98,112,140, 168, 171, 175, 182, 196 and 336

Secondary outcome [1]

Humoral and cellular immune

Timepoint [1]

Humoral and cellular immune response assessed by blood analysis at baseline out to days 0, 28, 84, 112, 168, 196 and 336

Eligibility

Key inclusion criteria

Healthy, withhold donating blood.

Minimum age

18 Years

Maximum age

45 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

Malaria disease or exposure, intercurrent disease, recent illness, treatment with corticosteroids, anti-coagulant, anti-inflammatory or immunomodulator drugs, history severe allergic reaction or anaphylaxis, live vaccination within 4 weeks or dead vaccination within 2 weeks or participation in a clinical trial in the 4 weeks prior

Study design

Purpose of the study

Prevention

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Eligible patients assigned to cohorts and randomised and blinded within cohorts.
Blinded treatment provided by identical and blinded syringes prepared by unblinded pharmacist according to randomisation schedule provided by study statistician. The statistician is off-site.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Randomisation schedule provided by study statistician. Randomisation is based on a permuted block process, with the random numbers being generated by an application of the "Mersenne-Twister" algorithm from Matsumoto and Nishimura (1998). It involves a twisted General Functional System Requirement (GFSR) with period /2^19937 - 1/ and equidistribution in 623 consecutive dimensions (over the whole period). The "seed" is a 624-dimensional set of 32-bit integers plus a current position in that set.

Reference: Matsumoto, M. and Nishimura, T. (1998) Mersenne Twister: A 623-dimensionally equidistributed uniform pseudo-random number generator, Association for Computing Machinery (ACM) Transactions on Modeling and Computer Simulation, 8, 3–30.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Dose-escalating

Phase

Phase 1

Type of endpoint/s

Safety

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

15/10/2007

Actual

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment postcode(s) [1]

4006

Funding & Sponsors

Funding source category [1]

Other Collaborative groups

Name [1]

The PATH Malaria Vaccine Initiative

Address [1]

7500 Old Georgetown Rd, 12th Floor, Bethesda, MD, 20814 - 6133

Country [1]

United States of America

Primary sponsor type

Other

Name

The Queensland Institute of Medical Research

Address

300 Herston Rd, Herston, Queensland, 4006

Country

Australia

Secondary sponsor category [1]

Other Collaborative groups

Name [1]

The PATH Malaria Vaccine Initiative

Address [1]

7500 Old Georgetown Rd, 12th Floor, Bethesda, MD, 20814 - 6133

Country [1]

United States of America

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

The Queensland Institute of Medical Research Human Research Ethics Committee

Ethics committee address [1]

The Queensland Institute of Medical Research, Post Office Royal Brisbane, Q 4029

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

10/10/2007

Ethics approval number [1]

Summary

Brief summary

The goal of this Phase 1 vaccine trial is to demonstrate safety and immunogenicity of MSP2-C1/ISA720 malaria vaccine in healthy adult human volunteers.   The World Health Organisation reported in 2005 that malaria kills more than 1 million people annually and that approximately 3.2 million people living in 107 countries or territories are at risk of infection [1].  Most of the malaria mortality occurs in sub Saharan Africa and in children under 5 years of age.  Of the four species of malaria parasite that infect humans, Plasmodium falciparum is responsible for the majority of these deaths.  Mounting drug resistance of the malaria parasite, as well as widespread resistance of mosquitoes to insecticides, make these control strategies increasingly unrealistic.  A vaccine that would reduce both mortality and morbidity secondary to P. falciparum infection would be a valuable resource in the fight against this disease.

Trial website

www.qpharm.com.au/volunteer-advertisments.htm

Trial related presentations / publications

WHO and UNICEF World Malaria Report 2005.

Smythe JA, Coppel RL, Brown GV, et al. (1988). Identification of two integral membrane proteins of Plasmodium falciparum. Proc Natl Acad Sci. USA 85: 5195-5199.

Gerold P, Schofield L, Blackman MJ, et al. (1996) Structural analysis of the glycosyl-phosphatidylinositol membrane anchor of the merozoite surface proteins-1 and -2 of Plasmodium falciparum.

Cowman AF, Baldi DL, Healer J, et al. (2000) Functional analysis of proteins involved in Plasmodium falciparum merozoite invasion of red blood cells. FEBS Lett 476: 84-88.

Dubbeld MA, Kocken CH, Thomas AW. (1998) Merozoite surface protein 2 of Plasmodium reichenowi is a unique mosaic of Plasmodium falciparum allelic forms and species-specific elements. Mol Biochem Parasitol 92: 187-92.

Smythe JA, Coppel RL, Day KP. et al. (1991) Structural diversity in the Plasmodium falciparum merozoite surface antigen 2. Proc Natl Acad Sci USA 88: 1751-1755.

Fenton B, Clark JT, Khan CM, et al. (1991) Structural and antigenic polymorphism of the 35- to 48-kilodalton merozoite surface antigen (MSA-2) of the malaria parasite Plasmodium falciparum. Mol Cell Biol. 11: 963-71.

Al-Yaman F, Genton B, Anders RF, et al. (1994) Relationship between humoral response to Plasmodium falciparum merozoite surface antigen-2 and malaria morbidity in a highly endemic area of Papua New Guinea. Am J Trop Med Hyg 51: 593-602.

Taylor RR, Smith DB, Robinson VJ, et al. (1995) Human antibody response to Plasmodium falciparum merozoite surface protein 2 is serogroup specific and predominantly of the immunoglobulin G3 subclass. Infect Immun 11: 4382-8.

Lawrence N, Stowers A, Mann V, et al. (2000) Recombinant chimeric proteins generated from conserved regions of Plasmodium falciparum merozoite surface protein 2 generate antiparasite humoral responses in mice. Parasite Immunol 22: 211-221.

Taylor RR, Allen SJ, Greenwood BM, Riley EM. (1998) IgG3 antibodies to Plasmodium falciparum merozoite surface protein 2 (MSP2): increasing prevalence with age and association with clinical immunity to malaria. Am J Trop Med Hyg 58: 406-413.

Metzger WG, Okenu DM, Cavanagh DR, et al. (2003) Serum IgG3 to the Plasmodium falciparum merozoite surface protein 2 is strongly associated with a reduced prospective risk of malaria. Parasite Immunol 25: 307-312.

Polley SD, Conway DJ, Cavanagh DR, et al. (2006) High levels of serum antibodies to merozoite surface protein 2 of Plasmodium falciparum are associated with reduced risk of clinical malaria in coastal Kenya. Vaccine 24: 4233-4246.

Eisen DP, Saul A, Fryauff DJ, Reeder JC, Coppel RL. (2002) Alterations in Plasmodium falciparum genotypes during sequential infections suggest the presence of strain specific immunity. Am J Trop Med Hyg 67: 8-16.

Epping RJ, Goldstone SD, Ingram LT, et al. (1988) An epitope recognised by inhibitory monoclonal antibodies that react with a 51 kilodalton merozoite surface antigen in Plasmodium falciparum. Mol. Biochem. Parasitol. 1988, 28:1-10.

Clark JT, Donachie S, Anand R. et al. (1989) 46-53 kilodalton glycoprotein from the surface of Plasmodium falciparum merozoites Mol. Biochem. Parasitol. 1989, 32:15-24.

Miettinen-Baumann A, Strych W, McBride J, Heidrich HG, et al. (1988) A 46,000 dalton Plasmodium falciparum merozoite surface glycoprotein not related to the 185,000-195,000 dalton schizont precursor molecule: isolation and characterization. Parasitol. Res. 1988, 74:317-323.

Druilhe P, Bouharoun-Tayoun H. (2002) Antibody-dependent cellular inhibition assay. Methods Mol Med 72: 529-34.

Miles A, McClellan H, Rausch K, et al. (2005) Montanide ISA720 vaccines: quality control of emulsions, stability of formulated antigens, and comparative immunogenicity of vaccine formulations. Vaccine 23: 2530-39.

Sturchler D, Berger R, Rudin C, et al. (1995) Safety, immunogenicity, and pilot efficacy of Plasmodium falciparum sporozoite and asexual blood-stage combination vaccine in Swiss adults. Am J Trop Med Hyg 53: 423-31.

Saul A, Lawrence G, Smillie A, et al. (1999) Human phase I vaccine trials of 3 recombinant asexual stage malaria antigens with Montanide ISA720 adjuvant. Vaccine 17: 3145-59.

Lawrence G, Cheng QQ, Reed C, et al. (2000) Effect of vaccination with 3 recombinant asexual-stage malaria antigens on initial growth rates of Plasmodium falciparum in non-immune volunteers. Vaccine 18: 1925-31.

Cheng Q, Lawrence G, Reed C, et al. (1997) Measurement of Plasmodium falciparum growth rates in vivo: a test of malaria vaccines. Am J Trop Med Hyg 57: 495-500.

Genton B, Al-Yaman F, Anders R, et al. (2000) Safety and immunogenicity of a three-component blood-stage malaria vaccine in adults living in an endemic area of Papua New Guinea. Vaccine 18: 2504-11.

Genton B, Betuela I, Felger I, Al-Yaman F, et al. (2002) A recombinant blood-stage malaria vaccine reduces Plasmodium falciparum density and exerts selective pressure on parasite populations in a phase 1-2b trial in Papua New Guinea. J Infect Dis 185: 820-7. 

Genton B, Al-Yaman F, Betuela I, et al. (2003) Safety and immunogenicity of a three-component blood-stage malaria vaccine (MSP1, MSP2, RESA) against Plasmodium falciparum in Papua New Guinean children. Vaccine 22: 30-41.
Lopez JA, Weilenman C, Audran R, et al. (2001) A synthetic malaria vaccine elicits a potent CD8+ and CD4+ T lymphocyte immune response in humans. Implication for vaccination strategies. Eur J Immunol 31: 1989-98.

Saul A, Lawrence G, Allworth A, et al. (2005) A human phase 1 vaccine clinical trial of the Plasmodium falciparum malaria vaccine candidate apical membrane antigen 1 in Montanide ISA720 adjuvant. Vaccine 23: 3076-83.

Hermsen CC, Verhage DF, Telgt DS, et al. (2007) Glutamate-rich protein (GLURP) induces antibodies that inhibit in vitro growth of Plasmodium falciparum in a phase 1 malaria vaccine trial. Vaccine 25: 2930-40.

Audran R, Cachat M, Lurati F, et al. (2005) Phase I malaria vaccine trial with a long synthetic peptide derived from the merozoite surface protein 3 antigen. Infect Immun 73: 8017-26.

Oliveira GA, Wetzel K, Calvo-Calle JM, et al. (2005) Safety and enhanced immunogenicity of a hepatitis B core particle Plasmodium falciparum malaria vaccine formulated in adjuvant Montanide ISA 720 in a phase I trial. Infect Immun 73: 3587-97

Walther M, Dunachie S, Keating S, et al. (2005) Safety, immunogenicity and efficacy of a pre-erythrocytic malaria candidate vaccine, ICC-1132 formulated in Seppic ISA 720. Vaccine 23: 857-64.
Toledo H, Baly A, Castro O, et al. (2001) A phase I clinical trial of a multi-epitope polypeptide TAB9 combined with Montanide ISA720 adjuvant in non-HIV-1 infected human volunteers. Vaccine 19: 4328-36.

Engers H, Kieny MP, Malhotra P, Pink JR. (2003) Third meeting on Novel Adjuvants Currently in or Close to Clinical Testing World Health Organization--Organisation Mondiale de la Sante, Fondation Merieux, Annecy, France, 7-9 January 2002. Vaccine 21:3503-24.

Cody CL, Baraff LJ, Cherry JD, Marcy SM & Manclark CR. (1981) Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatrics 68:650-660. 

Persson KEM, Lee CT, Marsh K and Beeson JG. (2006) The development and optimization of high throughput methods to measure Plasmodium falciparum growth inhibitory antibodies. J. Clin. Microbiol. 44:1665-73)

Holm S. A simple sequentially rejective multiple test procedure. (1979) Scandinavian Journal of Statistics, 6:65–70.
Patterson H and Thompson R. (1971) Recovery of inter-block information when block sizes are unequal. Biometrika, 58:545–54.

Public notes

Contacts

Principal investigator

Name

Address

Country

Phone

Fax

Contact person for public queries

Name

Dr Suzanne Elliott

Address

Q-Pharm Pty Ltd
QIMR
Clive Berghofer Cancer Research Centre
Level D
300 Herston Rd
Herston QLD 4006

Country

Australia

Phone

61 7 3845 3636

Fax

61 7 3845 3637

s.elliott@qpharm.com.au

Contact person for scientific queries

Name

Dr Suzanne Elliott

Address

Q-Pharm Pty Ltd
QIMR
Clive Berghofer Cancer Research Centre
Level D
300 Herston Rd
Herston QLD 4006

Country

Australia

Phone

61 7 3845 3636

Fax

61 7 3845 3637

s.elliott@qpharm.com.au

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Dimensions AI	Blood stage vaccines for Plasmodium falciparum	2010	https://doi.org/10.4161/hv.6.8.11446
Embase	Human Immunization with a Polymorphic Malaria Vaccine Candidate Induced Antibodies to Conserved Epitopes That Promote Functional Antibodies to Multiple Parasite Strains.	2018	https://dx.doi.org/10.1093/infdis/jiy170

N.B. These documents automatically identified may not have been verified by the study sponsor.

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