PfSPZ Vaccine: Dose Optimization With Heterologous Challenge in Healthy Malaria-Naïve Adults

NCT02601716 | Completed Phase 2 DMC

• 2 other identifiers: NMRC.2015.0009CVD Malaria 26000
• Study Type: interventional
• Target: 92
• Locations: 1 country
• Sites: 2

Brief Summary

This is an open-label evaluation of the safety, tolerability, immunogenicity and efficacy of PfSPZ Vaccine administered by direct venous inoculation (DVI) in healthy, malaria-naïve adult subjects.

Conditions

Malaria

Keywords

Plasmodium falciparum; PfSPZ Vaccine; Sporozoites; Controlled Human Malaria Infection

Outcome Measures

Primary Outcomes (3)

• Incidence and type of Adverse Events

  Incidence and type of adverse events (including breakthrough infections), vital signs, clinical laboratory assessments, physical examination findings post first immunization onwards.

  52 weeks

• Efficacy

  Evidence of vaccine-mediated protection against CHMI at 28 and 40 weeks in Groups 1 and 2 by preventing blood stage infection for 28 days (as detected by qPCR) following CHMI. Evidence of vaccine-mediated protection against CHMI at 40 and 66 weeks in Groups 3 and 4 by preventing blood stage infection for 28 days (as detected by blood smear analysis) following CHMI.

  28 days post-CHMI

• Immunological response

  Antibody responses by PfCSP ELISA two weeks after the second, third and booster immunizations (Groups 2-4) or after the fourth, fifth and booster immunizations (Group 1) (serum dilution at which the optical density is 1.0 referred to as the OD 1.0) Positive predictive values for anti-PfCSP antibody responses at or above a threshold for predicting sterile protection following CHMI (threshold = OD 1.0 of 2,000)

  2 weeks post-immunization and 28 days post-CHMI

Secondary Outcomes (1)

• Immunological outcomes

  Day of immunization till 28 days post-CHMI

Study Arms (6)

Group 1

EXPERIMENTAL

Group 1 subjects (n=15) will receive 4 doses of PfSPZ Vaccine (4.5 x 10\^5 PfSPZ/dose) every 2 days, followed by a single, boosting dose (same dose as before) given 16 weeks later, for a total PfSPZ dose = 22.5 x 10\^5. PfSPZ Vaccine administered by DVI. Protective efficacy assessed by heterologous CHMI (7G8) Pf parasites at 28 and 40 weeks after the first immunization, along with 8 infectivity controls. Subjects may proceed to CHMI if they have received at least 2 of 4 priming immunizations and the boost scheduled for Group 1. Participants not protected after the first CHMI will be invited to receive a booster vaccination (4.5 x 10\^5 PfSPZ) 21 days prior to the second CHMI. Subjects may participate in the second CHMI whether or not they were protected in the 1st CHMI, to serve as controls for the effect of the 1st CHMI on immunity. Subjects will be followed for 56 days beyond the final CHMI (post-immunization week 40).

Biological: PfSPZ Vaccine; Biological: CHMI (7G8)

Group 2

EXPERIMENTAL

Subjects (n=15) will receive 3 doses of PfSPZ Vaccine (9.0 x 10\^5 PfSPZ/dose) every 8 weeks, total PfSPZ dose = 27 x 10\^5. PfSPZ Vaccine administered by DVI. Protective efficacy assessed by heterologous CHMI (7G8) Pf parasites at 28 and 40 weeks after first immunization, along with 8 infectivity controls. Subjects may proceed to CHMI if they have received at least 2 of 3 immunizations scheduled for Group 2. Participants not protected after the first CHMI will be invited to receive a booster vaccination (9.0 x 10\^5 PfSPZ) 21 days prior to the second CHMI. Subjects may participate in the second CHMI whether or not they were protected in the 1st CHMI, to serve as controls for the effect of the 1st CHMI on immunity. Subjects will be followed for 56 days beyond the final CHMI (post-immunization week 40).

Biological: PfSPZ Vaccine; Biological: CHMI (7G8)

Group 3

EXPERIMENTAL

Group 3 subjects (n=15) will receive 3 doses of PfSPZ Vaccine (18 x 10\^5 PfSPZ/dose) every 8 weeks for a total PfSPZ dose of 54 x 10\^5. PfSPZ Vaccine administered by DVI. Protective efficacy assessed by CHMI with heterologous (7G8, NF135.C10) Pf parasites at 40 and 66 weeks after the first immunization, along with 8 infectivity controls. Subjects may proceed to CHMI if they have received at least 2 of 3 immunizations scheduled for Group 3. All participants will be invited to receive a booster vaccination (18 x 10\^5 PfSPZ) 21 days prior to the second CHMI. Subjects may participate in the second CHMI whether or not they were protected in the 1st CHMI, to serve as controls for the effect of the 1st CHMI on immunity. Subjects will be followed for 56 days beyond the final CHMI (post-immunization week66).

Biological: PfSPZ Vaccine; Biological: CHMI (7G8); Biological: CHMI (NF135.C10)

Group 4

EXPERIMENTAL

Subjects (n=15) will receive a single, priming dose of PfSPZ Vaccine (27 x 10\^5 PfSPZ/dose), followed by 2 additional immunizations (9.0 x 10\^5 PfSPZ per dose) every 8 weeks, total PfSPZ dose = 45 x 10\^5. PfSPZ Vaccine administered by DVI. Protective efficacy assessed by CHMI with heterologous 7G8 and NF135.C10 Pf parasites at 40 and 66 weeks, respectively, along with 8 infectivity controls at each CHMI. Subjects may proceed to CHMI if they have received at least 2 of 3 immunizations scheduled for Group 4. All participants will be invited to receive a booster vaccination (9.0x10\^5 PfSPZ) 21 days prior to the second CHMI. Subjects will be followed for 56 days beyond the final CHMI at (post-immunization week 66).

Biological: PfSPZ Vaccine; Biological: CHMI (7G8); Biological: CHMI (NF135.C10)

Infectivity Controls, CHMI (7G8)

OTHER

Infectivity controls (n=24) will not receive any PfSPZ Vaccine. They will serve as infectivity controls for CHMI for all groups. 8 infectivity controls will undergo CHMI with each of two CHMIs (at 28 and 40) for Groups 1 and 2, and 8 infectivity controls will undergo CHMI with the 40 week CHMI for Groups 3 and 4. All CHMI will be conducted by exposure to the bites of 5 mosquitoes infected with heterologous (7G8) Pf parasites. Subjects will be followed for 56 days beyond the last CHMI at week 40 at the UMB site.

Biological: CHMI (7G8)

Infectivity Controls, CHMI (NF135.C10)

OTHER

Infectivity controls (n=8) will not receive any PfSPZ Vaccine. They will serve as infectivity controls for the second CHMI at week 66 for Groups 3 and 4. CHMI will be conducted by exposure to the bites of 3-5 mosquitoes infected with heterologous (NF135.C10) Pf parasites. Subjects will be followed for 56 days beyond the last CHMI at week 66 at the NMRC site.

Biological: CHMI (NF135.C10)

Interventions

PfSPZ Vaccine BIOLOGICAL

Aseptic, purified, cryopreserved, radiation-attenuated, Plasmodium falciparum (Pf) sporozoites

Group 1; Group 2; Group 3; Group 4

CHMI (7G8) BIOLOGICAL

CHMI is conducted by exposure to the bites of five mosquitoes infected with heterologous (7G8) Pf parasites.

Group 1; Group 2; Group 3; Group 4; Infectivity Controls, CHMI (7G8)

CHMI (NF135.C10) BIOLOGICAL

CHMI is conducted by exposure to the bites of three to five mosquitoes infected with heterologous (NF135.C10) Pf parasites.

Group 3; Group 4; Infectivity Controls, CHMI (NF135.C10)

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy adults (male or non-pregnant female) 18 - 50 years of age, inclusive.
• Able and willing to participate for the duration of the study.
• Able and willing to provide written (not proxy) informed consent.
• Physical examination and laboratory results without clinically significant findings and a body mass index (BMI) ≤35 for vaccine groups or BMI ≤40 for control groups.
• Women of childbearing potential must agree to use effective means of birth control (e.g. oral or implanted contraceptives, IUD, female condom, diaphragm with spermicide, cervical cap, abstinence, use of a condom by the sexual partner or sterile sexual partner) during the entire study. Women with a history of surgical or chemical sterilization (e.g. tubal ligation, hysterectomy, other) must provide written documentation of infertility from a health care provider.
• Willing to refrain from blood donation for 3 years following CHMI.
• Agree not to travel to a malaria endemic region during the entire course of the trial.

You may not qualify if:

• Any history of malaria infection, or travel to a malaria endemic region within 6 months prior to first immunization.
• History of long-term residence (\>5 years) in area known to have significant transmission of P. falciparum.
• Body weight equal to, or less than, 110 pounds.
• 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, systolic blood pressure (mm Hg), smoking status, body mass index (BMI, kg/mm2), and reported diabetes status.
• Positive HIV, HBsAg or HCV serology.
• Positive sickle cell screening test.
• An abnormal electrocardiogram, defined as one showing pathologic Q waves and significant ST-T wave changes; left ventricular hypertrophy; any non-sinus rhythm including isolated premature ventricular contractions, but excluding isolated premature atrial contractions; right or left bundle branch block; or advanced (secondary or tertiary) A-V heart block.
• Current use of systemic immunosuppressant pharmacotherapy.
• 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.
• History of a splenectomy.
• History of neurologic disorder (including seizures) or diagnosis of migraine headache.
• History of 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.
• Plan for surgery between enrollment and CHMI.
• Females who are pregnant or nursing, females who plan on becoming pregnant or plan to nurse during the study period.
• Known allergy to any component of the vaccine formulation, history of anaphylactic response to mosquito-bites, or any history of anaphylactic reaction, retinal or visual field changes, or known allergy to anti-malarials including chloroquine phosphate, atovaquone/proguanil (Malarone®), or artemether/lumefantrine (Coartem®).

Sponsors & Collaborators

• Sanaria Inc.: lead
• Naval Medical Research Center: collaborator
• University of Maryland: collaborator
• Walter Reed Army Institute of Research (WRAIR): collaborator
• Joint Warfighter Medical Research Program: collaborator

Study Sites (2)

University of Maryland-Baltimore, Center for Vaccine Development

Baltimore, Maryland, 21201, United States

Location

Naval Medical Research Center

Silver Spring, Maryland, 20910, United States

Location

Related Publications (6)

• Seder RA, Chang LJ, Enama ME, Zephir KL, Sarwar UN, Gordon IJ, Holman LA, James ER, Billingsley PF, Gunasekera A, Richman A, Chakravarty S, Manoj A, Velmurugan S, Li M, Ruben AJ, Li T, Eappen AG, Stafford RE, Plummer SH, Hendel CS, Novik L, Costner PJ, Mendoza FH, Saunders JG, Nason MC, Richardson JH, Murphy J, Davidson SA, Richie TL, Sedegah M, Sutamihardja A, Fahle GA, Lyke KE, Laurens MB, Roederer M, Tewari K, Epstein JE, Sim BK, Ledgerwood JE, Graham BS, Hoffman SL; VRC 312 Study Team. Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine. Science. 2013 Sep 20;341(6152):1359-65. doi: 10.1126/science.1241800. Epub 2013 Aug 8.

  PMID: 23929949 BACKGROUND

• 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.

  PMID: 21903775 BACKGROUND

• Ishizuka AS, Lyke KE, DeZure A, Berry AA, Richie TL, Mendoza FH, Enama ME, Gordon IJ, Chang LJ, Sarwar UN, Zephir KL, Holman LA, James ER, Billingsley PF, Gunasekera A, Chakravarty S, Manoj A, Li M, Ruben AJ, Li T, Eappen AG, Stafford RE, K C N, Murshedkar T, DeCederfelt H, Plummer SH, Hendel CS, Novik L, Costner PJ, Saunders JG, Laurens MB, Plowe CV, Flynn B, Whalen WR, Todd JP, Noor J, Rao S, Sierra-Davidson K, Lynn GM, Epstein JE, Kemp MA, Fahle GA, Mikolajczak SA, Fishbaugher M, Sack BK, Kappe SH, Davidson SA, Garver LS, Bjorkstrom NK, Nason MC, Graham BS, Roederer M, Sim BK, Hoffman SL, Ledgerwood JE, Seder RA. Protection against malaria at 1 year and immune correlates following PfSPZ vaccination. Nat Med. 2016 Jun;22(6):614-23. doi: 10.1038/nm.4110. Epub 2016 May 9.

  PMID: 27158907 BACKGROUND

• Lyke KE, Ishizuka AS, Berry AA, Chakravarty S, DeZure A, Enama ME, James ER, Billingsley PF, Gunasekera A, Manoj A, Li M, Ruben AJ, Li T, Eappen AG, Stafford RE, Kc N, Murshedkar T, Mendoza FH, Gordon IJ, Zephir KL, Holman LA, Plummer SH, Hendel CS, Novik L, Costner PJ, Saunders JG, Berkowitz NM, Flynn BJ, Nason MC, Garver LS, Laurens MB, Plowe CV, Richie TL, Graham BS, Roederer M, Sim BK, Ledgerwood JE, Hoffman SL, Seder RA. Attenuated PfSPZ Vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection. Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):2711-2716. doi: 10.1073/pnas.1615324114. Epub 2017 Feb 21.

  PMID: 28223498 BACKGROUND

• Epstein JE, Paolino KM, Richie TL, Sedegah M, Singer A, Ruben AJ, Chakravarty S, Stafford A, Ruck RC, Eappen AG, Li T, Billingsley PF, Manoj A, Silva JC, Moser K, Nielsen R, Tosh D, Cicatelli S, Ganeshan H, Case J, Padilla D, Davidson S, Garver L, Saverino E, Murshedkar T, Gunasekera A, Twomey PS, Reyes S, Moon JE, James ER, Kc N, Li M, Abot E, Belmonte A, Hauns K, Belmonte M, Huang J, Vasquez C, Remich S, Carrington M, Abebe Y, Tillman A, Hickey B, Regules J, Villasante E, Sim BKL, Hoffman SL. Protection against Plasmodium falciparum malaria by PfSPZ Vaccine. JCI Insight. 2017 Jan 12;2(1):e89154. doi: 10.1172/jci.insight.89154.

  PMID: 28097230 BACKGROUND

• Lyke KE, Singer A, Berry AA, Reyes S, Chakravarty S, James ER, Billingsley PF, Gunasekera A, Manoj A, Murshedkar T, Laurens MB, Church WP, Garver Baldwin LS, Sedegah M, Banania G, Ganeshan H, Guzman I, Reyes A, Wong M, Belmonte A, Ozemoya A, Belmonte M, Huang J, Villasante E, Sim BKL, Hoffman SL, Richie TL, Epstein JE; Warfighter II Study Team. Multidose Priming and Delayed Boosting Improve Plasmodium falciparum Sporozoite Vaccine Efficacy Against Heterologous P. falciparum Controlled Human Malaria Infection. Clin Infect Dis. 2021 Oct 5;73(7):e2424-e2435. doi: 10.1093/cid/ciaa1294.

  PMID: 32920641 DERIVED

MeSH Terms

Conditions

Malaria; Malaria, Falciparum

Interventions

1-acetyl-1,2,3,3a,8,8a-hexahydro-8a-hydroxy-5-methoxypyrrolo(2,3-b)indole

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Study Officials

• Alexandra Singer, MD

  Naval Medical Research Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 6, 2015
• First Posted: November 10, 2015
• Study Start: January 1, 2016
• Primary Completion: September 1, 2017
• Study Completion: November 1, 2017
• Last Updated: October 16, 2018

Record last verified: 2018-10

Locations

US (2)