Clinical Trial of the PfSPZ Vaccine

A Phase 1/2a Trial of the PfSPZ Vaccine Administered Subcutaneously or Intradermally to Malaria-Naïve Adult Volunteers

The purpose of this study is to determine the safety and tolerability of a non-replicating, metabolically active Plasmodium falciparum sporozoite (PfSPZ) vaccine in malaria-naïve healthy volunteers following multiple-dose subcutaneous (SC) or intradermal (ID) administration.

In addition, the investigators wish to evaluate PfSPZ vaccine-mediated protection against P. falciparum challenge in the following 4 groups (see below) and compare protective efficacy of the PfSPZ vaccine when given by SC v ID administration in all these groups:

• Group 1: 4 doses of 7,500 PfSPZ/immunization,
• Group 2: 4 doses of 30,000 PfSPZ/immunization,
• Group 3: 4 doses of 135,000 PfSPZ/immunization
• Group 4: 4 or 6 doses of 135,000 PfSPZ/immunization.

If > 80% protective efficacy is not achieved in Groups 1, 2, or 3, volunteers in Group 4 will receive a fifth and sixth dose.

Study Overview

• Status: Completed
• Conditions: Plasmodium Falciparum
• Intervention / Treatment: Biological: Plasmodium falciparum Sporozoite (strain NF-54; Anopheles stephensi mosquitoes) Vaccine, Live, Inactivated (gamma irradiation)

Detailed Description

The first clinical trial of the Pf SPZ vaccine is a Phase 1 trial in non-immune healthy adult volunteers. Sanaria is the Sponsor and PATH MVI is funding the trial. The study will be conducted as a collaborative effort between Sanaria, PATH MVI, the NMRC Malaria Program (U.S. Military Malaria Vaccine Program), and the Center for Vaccine Development at the University of Maryland at Baltimore (CVD-UMB). The study will take place at the NMRC Malaria Program Clinical Trials Center on the campus of the National Naval Medical Center in Bethesda, MD and at the CVD and/or General Clinical Research Center, UMB. The study is designed to evaluate the safety, tolerability, immunogenicity and protective efficacy of successively higher doses of the vaccine administered by the subcutaneous (SC) or intradermal (ID) route.

There will be 4 groups of volunteers with each group comprised of a subset of volunteers who receive the vaccine by the SC route and a subset who receive the vaccine by the ID route.

Groups 1-3: The first 3 groups will receive 3 ascending doses of vaccine administered as 4 SC or ID injections separated by 4 week intervals (7,500 PfSPZ/dose, 30,000 PfSPZ/dose, and 135,000 PfSPZ/dose respectively). Each of these groups will be challenged a minimum of 3 weeks after the final dose by exposure to A. stephensi mosquitoes infected with P. falciparum sporozoites. All 3 groups will be followed for safety until 48 weeks after the first immunization.

Group 4: Group 4 will start a minimum of 3 weeks after the first immunization of Group 3. If there is > 80% efficacy in one or more of the subsets of Groups 1, 2, or 3 (SC or ID), Group 4 volunteers will receive 4 immunizations (just like Group 3) but will not have experimental challenge; they will simply be followed for safety for 12 months after the first immunization. The FDA has requested that we follow a group of volunteers receiving the highest dose (135 PfSPZ/immunization) without challenge at 3 weeks. However, if there is NOT > 80% efficacy in one of more subsets of Groups 1, 2, or 3, after a 6 month observation period, Group 4 volunteers will receive two additional monthly immunizations (Immunizations #5 and #6) followed by challenge at approximately 3 weeks after the sixth immunization. All volunteers in Group 4 will be followed for safety until 52 weeks after the first immunization.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • The Center for Vaccine Development, University of Maryland (CVD/UMB)
    • Bethesda, Maryland, United States, 20889-5607
      • Naval Medical Research Center (NMRC) Clinical Trials Center, on the campus of the National Naval Medical Center (NNMC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Healthy adults (male or non-pregnant female) 18-50 years of age, inclusive.
2. Able and willing to participate for the duration of the study.
3. Able and willing to provide written (not proxy) informed consent.
4. Women of childbearing potential must agree to use effective means of birth control through the duration of the study.
5. Willing to refrain from blood donation (except as required in this study) for 3 years following P. falciparum challenge.
6. Agree not to travel to a malaria endemic region during the entire course of the trial.

Exclusion Criteria:

1. Any history of malaria infection, or travel to a malaria endemic region within 6 months prior to first immunization.
2. History of long term residence (>5 years) in area known to have significant transmission of P. falciparum.
3. Positive HIV, HBsAg or HCV serology. Positive sickle cell screening test.
4. Has evidence of increased cardiovascular disease risk (defined as > 10%, 5 year risk) as determined by the method of Gaziano (Gaziano 2008). Risk factors include sex, age (years), systolic blood pressure (mm Hg), smoking status, body mass index (BMI, kg/mm2), reported diabetes status, and blood pressure.
5. Current use of systemic immunosuppressant pharmacotherapy.
6. An abnormal EKG, defined as one showing pathologic Q waves and significant ST-T wave changes; left ventricular hypertrophy; any non-sinus rhythm excluding isolated premature atrial contractions; right or left bundle branch block; or advanced (secondary or tertiary) A-V heart block.
7. Current significant medical condition (cardiovascular, hepatic, renal, or hematological) or evidence of any other serious underlying medical condition identified by medical history, physical examination, or laboratory examination.
8. History of a splenectomy.
9. History of any other illness or condition which, in the investigator's judgment, may substantially increase the risk associated with the volunteer's participation in the protocol or compromise the scientific objectives. This may include psychiatric disorders (such as personality disorders, anxiety disorders, or schizophrenia) or behavioral tendencies (including active alcohol or drug abuse) discovered during the screening process that in the opinion of the investigator would make compliance with the protocol difficult.
10. Plan for surgery between enrollment and challenge.
11. Females who are pregnant or nursing, females who plan on becoming pregnant or plan to nurse during the study period.
12. Known allergy to any component of the vaccine formulation, history of anaphylactic response to mosquito bites, retinal or visual field changes, or known allergy to the anti-malarial chloroquine phosphate, which will be used to treat volunteers developing malaria after P. falciparum challenge.
13. Participation in any study involving another investigational vaccine or drug within 90 days prior to the screening visit, or plan to participate in another investigational vaccine/drug research during or within 1 month following participation in this study.
14. Personal beliefs that prohibit the receiving of vaccine product containing human serum albumin within the diluent.
15. Use or planned use of any drug with anti-malarial activity that would coincide with immunization or challenge.
16. History of psoriasis or porphyria, which may be exacerbated after treatment with chloroquine.
17. Anticipated use of medications known to cause drug reactions with chloroquine or atovaquone- proguanil (Malarone) such as cimetidine, metoclopramide, antacids, and kaolin.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; 4 doses of 7,500 PfSPZ/immunization.	Biological: Plasmodium falciparum Sporozoite (strain NF-54; Anopheles stephensi mosquitoes) Vaccine, Live, Inactivated (gamma irradiation); Group 1: 4 doses of 7,500 PfSPZ/immunization, Group 2: 4 doses of 30,000 PfSPZ/immunization, Group 3: 4 doses of 135,000 PfSPZ/immunization, and Group 4: 4 or 6 doses of 135,000 PfSPZ/immunization. If > 80% protective efficacy is not achieved in Groups 1, 2, or 3, volunteers in Group 4 will receive a fifth and sixth dose.
Experimental: Group 2; 4 doses of 30,000 PfSPZ/immunization	Biological: Plasmodium falciparum Sporozoite (strain NF-54; Anopheles stephensi mosquitoes) Vaccine, Live, Inactivated (gamma irradiation); Group 1: 4 doses of 7,500 PfSPZ/immunization, Group 2: 4 doses of 30,000 PfSPZ/immunization, Group 3: 4 doses of 135,000 PfSPZ/immunization, and Group 4: 4 or 6 doses of 135,000 PfSPZ/immunization. If > 80% protective efficacy is not achieved in Groups 1, 2, or 3, volunteers in Group 4 will receive a fifth and sixth dose.
Experimental: Group 3; 4 doses of 135,000 PfSPZ/immunization	Biological: Plasmodium falciparum Sporozoite (strain NF-54; Anopheles stephensi mosquitoes) Vaccine, Live, Inactivated (gamma irradiation); Group 1: 4 doses of 7,500 PfSPZ/immunization, Group 2: 4 doses of 30,000 PfSPZ/immunization, Group 3: 4 doses of 135,000 PfSPZ/immunization, and Group 4: 4 or 6 doses of 135,000 PfSPZ/immunization. If > 80% protective efficacy is not achieved in Groups 1, 2, or 3, volunteers in Group 4 will receive a fifth and sixth dose.
Experimental: Group 4; 4 or 6 doses of 135,000 PfSPZ/immunization.	Biological: Plasmodium falciparum Sporozoite (strain NF-54; Anopheles stephensi mosquitoes) Vaccine, Live, Inactivated (gamma irradiation); Group 1: 4 doses of 7,500 PfSPZ/immunization, Group 2: 4 doses of 30,000 PfSPZ/immunization, Group 3: 4 doses of 135,000 PfSPZ/immunization, and Group 4: 4 or 6 doses of 135,000 PfSPZ/immunization. If > 80% protective efficacy is not achieved in Groups 1, 2, or 3, volunteers in Group 4 will receive a fifth and sixth dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To determine the safety and tolerability of a non-replicating, metabolically active Plasmodium falciparum sporozoite (PfSPZ) vaccine in malaria-naïve healthy volunteers following multiple-dose subcutaneous (SC) or intradermal (ID) administration.	October 2010

Secondary Outcome Measures

Outcome Measure	Time Frame
To evaluate PfSPZ vaccine-mediated protection against P. falciparum challenge in the 4 groups.	October 2010
To compare protective efficacy of the PfSPZ vaccine when given by SC versus ID administration in all groups.	October 2010

Collaborators and Investigators

• Sponsor: Sanaria Inc.
• Collaborators: The PATH Malaria Vaccine Initiative (MVI)
• Investigators: Principal Investigator: Judith E Epstein, M.D., Naval Medical Research Center

Publications and helpful links

General Publications

• Epstein JE, Tewari K, Lyke KE, Sim BK, Billingsley PF, Laurens MB, Gunasekera A, Chakravarty S, James ER, Sedegah M, Richman A, Velmurugan S, Reyes S, Li M, Tucker K, Ahumada A, Ruben AJ, Li T, Stafford R, Eappen AG, Tamminga C, Bennett JW, Ockenhouse CF, Murphy JR, Komisar J, Thomas N, Loyevsky M, Birkett A, Plowe CV, Loucq C, Edelman R, Richie TL, Seder RA, Hoffman SL. Live attenuated malaria vaccine designed to protect through hepatic CD8(+) T cell immunity. Science. 2011 Oct 28;334(6055):475-80. doi: 10.1126/science.1211548. Epub 2011 Sep 8.

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Actual): July 1, 2010
• Study Completion (Actual): September 1, 2010

Study Registration Dates

• First Submitted: October 22, 2009
• First Submitted That Met QC Criteria: October 23, 2009
• First Posted (Estimate): October 26, 2009

Study Record Updates

• Last Update Posted (Estimate): September 10, 2014
• Last Update Submitted That Met QC Criteria: September 9, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: Plasmodium falciparum; Malaria Vaccine
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria
• Other Study ID Numbers: Sanaria.2008.001; NMRC.2008.0004; NNMC: 2008.0071; CVD-UMB Site: H-30076; Malaria CVD 18000; WRAIR DHSP: #1487; HRPO: A-14947; PATH MVI: #PfSPZ001