<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03813108</url>
  </required_header>
  <id_info>
    <org_study_id>CPS135</org_study_id>
    <nct_id>NCT03813108</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of NF135 CPS Immunization</brief_title>
  <acronym>CPS135</acronym>
  <official_title>Safety and Protective Efficacy of Chemoprophylaxis and Sporozoite Immunization With Plasmodium Falciparum NF135 Against Homologous and Heterologous Challenge Infection in Healthy Volunteers in the Netherlands</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Radboud University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The PATH Malaria Vaccine Initiative (MVI)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Radboud University Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an open label, randomized, controlled clinical trial. The primary aim of this project&#xD;
      is to determine the safety and tolerability of NF135.C10 sporozoite immunization under&#xD;
      chemoprophylaxis against homologous and heterologous challenge infection.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A total of 49 healthy volunteers will be allocated to receive either three immunizations with&#xD;
      15 NF135.C10 infected Anopheles mosquitoes (n=30), 3 immunizations with 5 NF135.C10 infected&#xD;
      mosquitoes (n=10) or no immunizations (n=6). Immunizations in cohort A (n=20) will be&#xD;
      performed under mefloquine prophylaxis, spaced 4 weeks apart. In cohort B, volunteers will&#xD;
      not take mefloquine prophylaxis, instead all volunteers will be treated presumptively on day&#xD;
      7 after each immunization with a curative regimen of artemether/lumefantrine, regardless of&#xD;
      parasitaemia or symptoms.&#xD;
&#xD;
      Nineteen weeks after the last immunization, all volunteers plus naïve controls will be&#xD;
      challenged either by the bites of 5 NF135.C10 (n=36) or 5 NF54 (n=13) infected mosquitoes.&#xD;
      After challenge infection, volunteers will be followed up on an out-patient basis once daily&#xD;
      for qPCR and safety lab measurements from day 6 until day 21 post challenge. All volunteers&#xD;
      will be treated with a curative regimen of atovaquone/proguanil, either at the time of&#xD;
      detection of blood stage parasitemia, or 28 days after challenge infection.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Subject withdrawals after temporal suspension of the trial (for personal, logistic reasons). At&#xD;
    time of reinitiation the number of enrolled subjects did not meet the predefined threshold for&#xD;
    continuation of the trial.&#xD;
  </why_stopped>
  <start_date type="Actual">April 1, 2019</start_date>
  <completion_date type="Actual">February 1, 2021</completion_date>
  <primary_completion_date type="Actual">February 1, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Frequency of Adverse Events After NF135.C10 CPS Immunization</measure>
    <time_frame>Cohort A: Inclusion until 35 days after challenge infection (35 weeks) Cohort B: Inclusion - premature end of study (22 weeks)</time_frame>
    <description>The number of adverse events will be recorded by the trial clinicians for all participants.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Magnitude of Adverse Events After NF135.C10 CPS Immunization</measure>
    <time_frame>Cohort A: Inclusion until 35 days after challenge infection (35 weeks) Cohort B: Inclusion - premature end of study (22 weeks)</time_frame>
    <description>The severity of adverse events will be recorded (mild/moderate/severe) for each adverse event</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to Parasitemia</measure>
    <time_frame>Day 1 - 28 after malaria challenge infection (28 days)</time_frame>
    <description>The effectiveness of CPS-immunization with NF135 sporozoites to protect against malaria challenge infection with homologous N135.C10 or heterologous NF54 sporozoites will be determined by the time to parasitemia in immunized versus non-immunized volunteers after the challenge infection.</description>
  </secondary_outcome>
  <number_of_arms>7</number_of_arms>
  <enrollment type="Actual">43</enrollment>
  <condition>Malaria,Falciparum</condition>
  <condition>Controlled Human Malaria Infection</condition>
  <condition>Immunization; Infection</condition>
  <arm_group>
    <arm_group_label>1: NF135 CPS-immunization challenged by NF135</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>10 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2: Low dose NF135 CPS-immunization challenged by NF135</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>10 volunteers will receive three immunizations with 5 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>3: NF135 CPS-immunization (A/L) challenged by NF135</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>10 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes and are presumptively treated with artemether/lumefantrine starting on day 7 after each immunization. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>4: NF135 CPS-immunization (A/L) challenged by NF54</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>10 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes and are presumptively treated with artemether/lumefantrine starting on day 7 after each immunization. Volunteers will be challenged by the bites of 5 NF54 infected Anopheles mosquitoes 19 weeks after the last immunization.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>5: Control group challenged by NF135.C10 Cohort A</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>6: Control group challenged by NF54 Cohort B</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF54 infected Anopheles mosquitoes 19 weeks after the last immunization.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>7: Control group challenged by NF135 Cohort B</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>CPS-immunization</intervention_name>
    <description>Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.</description>
    <arm_group_label>1: NF135 CPS-immunization challenged by NF135</arm_group_label>
    <arm_group_label>2: Low dose NF135 CPS-immunization challenged by NF135</arm_group_label>
    <other_name>Plasmodium falciparum NF135.C10 sporozoites</other_name>
    <other_name>Mefloquine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>malaria challenge infection, P. falciparum NF135.C10</intervention_name>
    <description>Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.</description>
    <arm_group_label>1: NF135 CPS-immunization challenged by NF135</arm_group_label>
    <arm_group_label>2: Low dose NF135 CPS-immunization challenged by NF135</arm_group_label>
    <arm_group_label>3: NF135 CPS-immunization (A/L) challenged by NF135</arm_group_label>
    <arm_group_label>5: Control group challenged by NF135.C10 Cohort A</arm_group_label>
    <arm_group_label>7: Control group challenged by NF135 Cohort B</arm_group_label>
    <other_name>Plasmodium falciparum NF135.C10 sporozoites</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>malaria challenge infection, P. falciparum NF54</intervention_name>
    <description>Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 sporozoites.</description>
    <arm_group_label>4: NF135 CPS-immunization (A/L) challenged by NF54</arm_group_label>
    <arm_group_label>6: Control group challenged by NF54 Cohort B</arm_group_label>
    <other_name>Plasmodium falciparum NF54 sporozoites</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>CPS-immunization (A/L)</intervention_name>
    <description>Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes and receive presumptive treatment with artemether/lumefantrine initiated on day 7 after each immunization.</description>
    <arm_group_label>3: NF135 CPS-immunization (A/L) challenged by NF135</arm_group_label>
    <arm_group_label>4: NF135 CPS-immunization (A/L) challenged by NF54</arm_group_label>
    <other_name>Plasmodium falciparum NF135.C10 sporozoites</other_name>
    <other_name>Artemether/lumefantrine (A/L)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atovaquone / Proguanil Oral Tablet [Malarone]</intervention_name>
    <description>All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
    <arm_group_label>1: NF135 CPS-immunization challenged by NF135</arm_group_label>
    <arm_group_label>2: Low dose NF135 CPS-immunization challenged by NF135</arm_group_label>
    <arm_group_label>3: NF135 CPS-immunization (A/L) challenged by NF135</arm_group_label>
    <arm_group_label>4: NF135 CPS-immunization (A/L) challenged by NF54</arm_group_label>
    <arm_group_label>5: Control group challenged by NF135.C10 Cohort A</arm_group_label>
    <arm_group_label>6: Control group challenged by NF54 Cohort B</arm_group_label>
    <arm_group_label>7: Control group challenged by NF135 Cohort B</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Subject is aged ≥ 18 and ≤ 35 years and in good health.&#xD;
&#xD;
          2. Subject has adequate understanding of the procedures of the study and agrees to abide&#xD;
             strictly thereby.&#xD;
&#xD;
          3. Subject is able to communicate well with the investigator and is available to attend&#xD;
             all study visits.&#xD;
&#xD;
          4. The subject will remain within the Netherlands during the challenge period, not travel&#xD;
             to a malaria-endemic area during the study period, and is reachable (24/7) by mobile&#xD;
             telephone throughout the entire study period.&#xD;
&#xD;
          5. Subject agrees to inform his/her general practitioner about participation in the study&#xD;
             and to sign a request to release by the General Practitioner (GP), and medical&#xD;
             specialist when necessary, any relevant medical information concerning possible&#xD;
             contra- indications for participation in the study.&#xD;
&#xD;
          6. The subject agrees to refrain from blood donation throughout the study period and for&#xD;
             a defined period thereafter according to current guidelines.&#xD;
&#xD;
          7. For female subjects: subject agrees to use adequate contraception and not to&#xD;
             breastfeed for the duration of study. Acceptable forms of contraception include:&#xD;
             established use of oral, injected or implanted hormonal contraceptives; intrauterine&#xD;
             device or intrauterine system; barrier methods (condoms or diaphragm with additional&#xD;
             spermicide); male partner's sterilisation (with appropriate post-vasectomy&#xD;
             documentation of absence of sperm in the ejaculate); true abstinence when this is in&#xD;
             line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g.,&#xD;
             calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not&#xD;
             acceptable methods of contraception.&#xD;
&#xD;
          8. Subject agrees to refrain from intensive physical exercise (disproportionate to the&#xD;
             subjects usual daily activity or exercise routine) during the malaria challenge&#xD;
             period.&#xD;
&#xD;
          9. Subject agrees to avoid additional triggers that may cause elevations in liver enzymes&#xD;
             including alcohol from baseline up to 1 week post treatment.&#xD;
&#xD;
         10. Subject has signed informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any history, or evidence at screening, of clinically significant symptoms, physical&#xD;
             signs or abnormal laboratory values suggestive of systemic conditions, such as&#xD;
             cardiovascular, pulmonary, renal, hepatic, neurological, dermatological, endocrine,&#xD;
             malignant, haematological, infectious, immunodeficient, psychiatric and other&#xD;
             disorders, which could compromise the health of the volunteer during the study or&#xD;
             interfere with the interpretation of the study results. These include, but are not&#xD;
             limited to, any of the following.&#xD;
&#xD;
             1.1 Body weight &lt;50 kg or Body Mass Index (BMI) &lt;18 or &gt;30 kg/m2 at screening. 1.2 A&#xD;
             heightened risk of cardiovascular disease, as determined by: an estimated ten year&#xD;
             risk of fatal cardiovascular disease of ≥5% at screening, as determined by the&#xD;
             Systematic Coronary Risk Evaluation (SCORE); history, or evidence at screening, of&#xD;
             clinically significant arrhythmia's, prolonged QT-interval or other clinically&#xD;
             relevant ECG abnormalities; or a positive family history of cardiovascular events&#xD;
             (including ischemia and myocarditis) in 1st or 2nd degree relatives &lt;50 years old.&#xD;
&#xD;
             1.3 A medical history of functional asplenia, sickle cell trait/disease, thalassaemia&#xD;
             trait/disease or G6PD deficiency.&#xD;
&#xD;
             1.4 History of epilepsy in the period of five years prior to study onset, even if no&#xD;
             longer on medication.&#xD;
&#xD;
             1.5 Screening tests positive for Human Immunodeficiency Virus (HIV), or active&#xD;
             Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV).&#xD;
&#xD;
             1.6 Chronic use of i) immunosuppressive drugs, ii) antibiotics or antimalarials, iii)&#xD;
             or other immune modifying drugs within three months prior to study onset (inhaled and&#xD;
             topical corticosteroids and oral anti-histamines exempted) or expected use of such&#xD;
             during the study period.&#xD;
&#xD;
             1.7 History of malignancy of any organ system (other than localized basal cell&#xD;
             carcinoma of the skin), treated or untreated, within the past 5 years.&#xD;
&#xD;
             1.8 Any history severe psychiatric disease diagnosed by a psychiatrist. 1.9 History of&#xD;
             drug or alcohol abuse interfering with normal social function in the period of one&#xD;
             year prior to study onset, positive urine toxicology test for cocaine or amphetamines&#xD;
             at screening or inclusion, or positive urine toxicology test for cannabis at&#xD;
             inclusion.&#xD;
&#xD;
          2. For female subjects: positive urine pregnancy test at screening or at inclusion.&#xD;
&#xD;
          3. Any history of malaria, positive serology for P. falciparum, or previous participation&#xD;
             in any malaria (vaccine) study.&#xD;
&#xD;
          4. Known hypersensitivity to or contra-indications (including co-medication) for use of&#xD;
             Mefloquine, Malarone or artemether-lumefantrine, or history of severe (allergic)&#xD;
             reactions to mosquito bites.&#xD;
&#xD;
          5. Receipt of any vaccinations in the 3 months prior to the start of the study or plans&#xD;
             to receive any other vaccinations during the study period or up to 90 days thereafter.&#xD;
&#xD;
          6. Participation in any other clinical study in the 30 days prior to the start of the&#xD;
             study or during the study period.&#xD;
&#xD;
          7. Being an employee or student of the department of Medical Microbiology of the&#xD;
             Radboudumc or the department of Internal Medicine.&#xD;
&#xD;
          8. Any other condition or situation that would, in the opinion of the investigator, place&#xD;
             the subject at an unacceptable risk of injury or render the subject unable to meet the&#xD;
             requirements of the protocol.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Matthew BB McCall, MD PhD DTMH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Radboud University Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Radboud university medical centre</name>
      <address>
        <city>Nijmegen</city>
        <state>Gelderland</state>
        <zip>6525 GA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <results_reference>
    <citation>van der Boor SC, Alkema M, van Gemert GJ, Teelen K, van de Vegte-Bolmer M, Walk J, van Crevel R, de Mast Q, Ockenhouse CF, Sauerwein RW, McCall MBB. Whole sporozoite immunization with Plasmodium falciparum strain NF135 in a randomized trial. BMC Med. 2023 Apr 7;21(1):137. doi: 10.1186/s12916-023-02788-9.</citation>
    <PMID>37024868</PMID>
  </results_reference>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>January 17, 2019</study_first_submitted>
  <study_first_submitted_qc>January 22, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 23, 2019</study_first_posted>
  <results_first_submitted>October 28, 2021</results_first_submitted>
  <results_first_submitted_qc>February 22, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">May 11, 2022</results_first_posted>
  <last_update_submitted>May 25, 2023</last_update_submitted>
  <last_update_submitted_qc>May 25, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 26, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Radboud University Medical Center</investigator_affiliation>
    <investigator_full_name>Matthew McCall</investigator_full_name>
    <investigator_title>dr. MBB McCall</investigator_title>
  </responsible_party>
  <keyword>Mosquito bites</keyword>
  <keyword>Sporozoite</keyword>
  <keyword>Immunization</keyword>
  <keyword>Malaria</keyword>
  <keyword>Falciparum</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>Malaria</mesh_term>
    <mesh_term>Malaria, Falciparum</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lumefantrine</mesh_term>
    <mesh_term>Artemether</mesh_term>
    <mesh_term>Mefloquine</mesh_term>
    <mesh_term>Atovaquone</mesh_term>
    <mesh_term>Proguanil</mesh_term>
    <mesh_term>Atovaquone, proguanil drug combination</mesh_term>
    <mesh_term>Artemether, Lumefantrine Drug Combination</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>November 3, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/08/NCT03813108/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>1: NF135 CPS-immunization Challenged by NF135</title>
          <description>10 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
        <group group_id="P2">
          <title>2: Low Dose NF135 CPS-immunization Challenged by NF135</title>
          <description>10 volunteers will receive three immunizations with 5 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
        <group group_id="P3">
          <title>3: NF135 CPS-immunization (A/L) Cohort B</title>
          <description>20 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes and are presumptively treated with artemether/lumefantrine starting on day 7 after each immunization. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes.&#xD;
malaria challenge infection, P. falciparum NF135.C10: 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites. 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 sporozoites.&#xD;
CPS-immunization (A/L): Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes and receive presumptive treatment with artemether/lumefantrine initiated on day 7 after each immunization.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
        <group group_id="P4">
          <title>5: Control Group Challenged by NF135.C10 Cohort A</title>
          <description>Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
        <group group_id="P5">
          <title>6: Control Group Challenged by NF54 Cohort B</title>
          <description>Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF54 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
malaria challenge infection, P. falciparum NF54: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
        <group group_id="P6">
          <title>7: Control Group Challenged by NF135 Cohort B</title>
          <description>Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="10"/>
                <participants group_id="P3" count="20"/>
                <participants group_id="P4" count="3"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="3"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="20"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>No subjects for groups 6 and 7 were enrolled as the trial was prematurely ended before the challenge infection; control groups were therefore not needed.</population>
      <group_list>
        <group group_id="B1">
          <title>1: NF135 CPS-immunization Challenged by NF135</title>
          <description>10 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
        <group group_id="B2">
          <title>2: Low Dose NF135 CPS-immunization Challenged by NF135</title>
          <description>10 volunteers will receive three immunizations with 5 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
        <group group_id="B3">
          <title>3: NF135 CPS-immunization (A/L) Challenged by NF135 Cohorst B</title>
          <description>20 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes and are presumptively treated with artemether/lumefantrine starting on day 7 after each immunization. 10 volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes. 10 volunteers will be challenged by the bites of 5 NF54 infected Anopheles mosquitoes.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
CPS-immunization (A/L): Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes and receive presumptive treatment with artemether/lumefantrine initiated on day 7 after each immunization.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
        <group group_id="B4">
          <title>5: Control Group Challenged by NF135.C10 Cohort A</title>
          <description>Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
        <group group_id="B5">
          <title>6: Control Group Challenged by NF54 Cohort B</title>
          <description>Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF54 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
malaria challenge infection, P. falciparum NF54: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
        <group group_id="B6">
          <title>7: Control Group Challenged by NF135 Cohort B</title>
          <description>Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
        <group group_id="B7">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="10"/>
            <count group_id="B2" value="10"/>
            <count group_id="B3" value="20"/>
            <count group_id="B4" value="3"/>
            <count group_id="B5" value="0"/>
            <count group_id="B6" value="0"/>
            <count group_id="B7" value="43"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                    <measurement group_id="B7" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="20"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                    <measurement group_id="B7" value="43"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                    <measurement group_id="B7" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="24" lower_limit="20" upper_limit="29"/>
                    <measurement group_id="B2" value="23.5" lower_limit="21" upper_limit="27"/>
                    <measurement group_id="B3" value="23.0" lower_limit="18" upper_limit="30"/>
                    <measurement group_id="B4" value="21" lower_limit="20" upper_limit="24"/>
                    <measurement group_id="B7" value="23" lower_limit="18" upper_limit="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B7" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B7" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Race</title>
              <category_list>
                <category>
                  <title>Caucasian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="15"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B7" value="33"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B7" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B7" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Netherlands</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="20"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B7" value="43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body Mass Index (kg/m^2)</title>
          <units>kg/m^2</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="23.2" lower_limit="19.4" upper_limit="29.3"/>
                    <measurement group_id="B2" value="23.7" lower_limit="19.8" upper_limit="29.7"/>
                    <measurement group_id="B3" value="23.4" lower_limit="18.4" upper_limit="29.9"/>
                    <measurement group_id="B4" value="22" lower_limit="21.9" upper_limit="23.2"/>
                    <measurement group_id="B7" value="23.2" lower_limit="18.4" upper_limit="29.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Hemoglobin (mmol/L)</title>
          <units>mmol/L</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9.3" lower_limit="6.7" upper_limit="10.8"/>
                    <measurement group_id="B2" value="9.0" lower_limit="7.6" upper_limit="10.1"/>
                    <measurement group_id="B3" value="9.0" lower_limit="7.1" upper_limit="9.6"/>
                    <measurement group_id="B4" value="8.3" lower_limit="8.2" upper_limit="8.9"/>
                    <measurement group_id="B7" value="9.0" lower_limit="6.7" upper_limit="10.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Frequency of Adverse Events After NF135.C10 CPS Immunization</title>
        <description>The number of adverse events will be recorded by the trial clinicians for all participants.</description>
        <time_frame>Cohort A: Inclusion until 35 days after challenge infection (35 weeks) Cohort B: Inclusion - premature end of study (22 weeks)</time_frame>
        <population>The Control Group Challenged by NF135.C10 Cohort A, was not included in this analysis as it served only as infection control. As subjects in cohort B did not complete their immunizations they were not yet randomized for infection when the trial ended prematurely. Cohort is therefore analyzed as one group that received 1 immunization with 15 NF135.C10 infected mosquitoes under presumptive A/L treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>1: NF135 CPS-immunization Challenged by NF135</title>
            <description>10 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
          </group>
          <group group_id="O2">
            <title>2: Low Dose NF135 CPS-immunization Challenged by NF135</title>
            <description>10 volunteers will receive three immunizations with 5 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
          </group>
          <group group_id="O3">
            <title>3: NF135 CPS-immunization (A/L) Cohort B</title>
            <description>20 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes and are presumptively treated with artemether/lumefantrine starting on day 7 after each immunization. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes.&#xD;
malaria challenge infection, P. falciparum NF135.C10: 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites. 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 sporozoites.&#xD;
CPS-immunization (A/L): Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes and receive presumptive treatment with artemether/lumefantrine initiated on day 7 after each immunization.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
          </group>
        </group_list>
        <measure>
          <title>Frequency of Adverse Events After NF135.C10 CPS Immunization</title>
          <description>The number of adverse events will be recorded by the trial clinicians for all participants.</description>
          <population>The Control Group Challenged by NF135.C10 Cohort A, was not included in this analysis as it served only as infection control. As subjects in cohort B did not complete their immunizations they were not yet randomized for infection when the trial ended prematurely. Cohort is therefore analyzed as one group that received 1 immunization with 15 NF135.C10 infected mosquitoes under presumptive A/L treatment.</population>
          <units>Adverse events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="139"/>
                    <measurement group_id="O2" value="173"/>
                    <measurement group_id="O3" value="172"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Magnitude of Adverse Events After NF135.C10 CPS Immunization</title>
        <description>The severity of adverse events will be recorded (mild/moderate/severe) for each adverse event</description>
        <time_frame>Cohort A: Inclusion until 35 days after challenge infection (35 weeks) Cohort B: Inclusion - premature end of study (22 weeks)</time_frame>
        <population>The Control Group Challenged by NF135.C10 Cohort A, was not included in this analysis as it served only as infection control. As subjects in cohort B did not complete their immunizations they were not yet randomized for infection when the trial ended prematurely. Cohort is therefore analyzed as one group that received 1 immunization with 15 NF135.C10 infected mosquitoes under presumptive A/L treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>1: NF135 CPS-immunization Challenged by NF135</title>
            <description>10 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
          </group>
          <group group_id="O2">
            <title>2: Low Dose NF135 CPS-immunization Challenged by NF135</title>
            <description>10 volunteers will receive three immunizations with 5 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
          </group>
          <group group_id="O3">
            <title>3: NF135 CPS-immunization (A/L) Cohort B</title>
            <description>20 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes and are presumptively treated with artemether/lumefantrine starting on day 7 after each immunization. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes.&#xD;
malaria challenge infection, P. falciparum NF135.C10: 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites. 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 sporozoites.&#xD;
CPS-immunization (A/L): Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes and receive presumptive treatment with artemether/lumefantrine initiated on day 7 after each immunization.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
          </group>
        </group_list>
        <measure>
          <title>Magnitude of Adverse Events After NF135.C10 CPS Immunization</title>
          <description>The severity of adverse events will be recorded (mild/moderate/severe) for each adverse event</description>
          <population>The Control Group Challenged by NF135.C10 Cohort A, was not included in this analysis as it served only as infection control. As subjects in cohort B did not complete their immunizations they were not yet randomized for infection when the trial ended prematurely. Cohort is therefore analyzed as one group that received 1 immunization with 15 NF135.C10 infected mosquitoes under presumptive A/L treatment.</population>
          <units>Adverse events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Mild adverse events (grade 1)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="108"/>
                    <measurement group_id="O2" value="128"/>
                    <measurement group_id="O3" value="121"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Moderate adverse events (grade 2)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20"/>
                    <measurement group_id="O2" value="35"/>
                    <measurement group_id="O3" value="31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Severe adverse events (grade 3)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                    <measurement group_id="O2" value="10"/>
                    <measurement group_id="O3" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Serious adverse events (grade 4)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Parasitemia</title>
        <description>The effectiveness of CPS-immunization with NF135 sporozoites to protect against malaria challenge infection with homologous N135.C10 or heterologous NF54 sporozoites will be determined by the time to parasitemia in immunized versus non-immunized volunteers after the challenge infection.</description>
        <time_frame>Day 1 - 28 after malaria challenge infection (28 days)</time_frame>
        <population>The trial was prematurely ended before the challenge infection in cohort B. Only arms that received challenge infection are included in this analysis. In arm 1, 2 subjects withdrew from the trial before challenge infection and 3 subjects were sterily protected and not included in the analysis. In arm 2, 1 subject withdrew from the trial before challenge infection and 2 subjects were sterily protected and not included in this analysis</population>
        <group_list>
          <group group_id="O1">
            <title>1: NF135 CPS-immunization Challenged by NF135</title>
            <description>10 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
          </group>
          <group group_id="O2">
            <title>2: Low Dose NF135 CPS-immunization Challenged by NF135</title>
            <description>10 volunteers will receive three immunizations with 5 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
          </group>
          <group group_id="O3">
            <title>5: Control Group Challenged by NF135.C10 Cohort A</title>
            <description>Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Parasitemia</title>
          <description>The effectiveness of CPS-immunization with NF135 sporozoites to protect against malaria challenge infection with homologous N135.C10 or heterologous NF54 sporozoites will be determined by the time to parasitemia in immunized versus non-immunized volunteers after the challenge infection.</description>
          <population>The trial was prematurely ended before the challenge infection in cohort B. Only arms that received challenge infection are included in this analysis. In arm 1, 2 subjects withdrew from the trial before challenge infection and 3 subjects were sterily protected and not included in the analysis. In arm 2, 1 subject withdrew from the trial before challenge infection and 2 subjects were sterily protected and not included in this analysis</population>
          <units>days to parasitaemia</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="7"/>
                <count group_id="O3" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9" lower_limit="7" upper_limit="11"/>
                    <measurement group_id="O2" value="7" lower_limit="7" upper_limit="11"/>
                    <measurement group_id="O3" value="7" lower_limit="7" upper_limit="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Post-Hoc</type>
        <title>Break Through Infections</title>
        <description>Number of subjects that required rescue treatment with atovaquone/proguanil due to a positive thick smear in combination with symptoms following NF135.C10 immunizations despite mefloquine prophylaxis (Cohort A) or presumptive artemether/lumefantrine treatment (Cohort B).</description>
        <time_frame>From day 0 until 28 days after each immunization (28 days)</time_frame>
        <population>Only study groups that received NF135.C10 immunizations were included in this analysis. One subject in group 2: Low dose NF135 CPS-immunization challenged by NF135, withdrew consent after the first immunization, and thus did not receive immunization 2 and 3. The study was prematurely terminated, therefore subjects in group 3: NF135 CPS-immunization (A/L) Cohort B only received immunization 1.</population>
        <group_list>
          <group group_id="O1">
            <title>1: NF135 CPS-immunization Challenged by NF135</title>
            <description>10 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
          </group>
          <group group_id="O2">
            <title>2: Low Dose NF135 CPS-immunization Challenged by NF135</title>
            <description>10 volunteers will receive three immunizations with 5 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
          </group>
          <group group_id="O3">
            <title>3: NF135 CPS-immunization (A/L) Cohort B</title>
            <description>20 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes and are presumptively treated with artemether/lumefantrine starting on day 7 after each immunization. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes.&#xD;
malaria challenge infection, P. falciparum NF135.C10: 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites. 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 sporozoites.&#xD;
CPS-immunization (A/L): Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes and receive presumptive treatment with artemether/lumefantrine initiated on day 7 after each immunization.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
          </group>
        </group_list>
        <measure>
          <title>Break Through Infections</title>
          <description>Number of subjects that required rescue treatment with atovaquone/proguanil due to a positive thick smear in combination with symptoms following NF135.C10 immunizations despite mefloquine prophylaxis (Cohort A) or presumptive artemether/lumefantrine treatment (Cohort B).</description>
          <population>Only study groups that received NF135.C10 immunizations were included in this analysis. One subject in group 2: Low dose NF135 CPS-immunization challenged by NF135, withdrew consent after the first immunization, and thus did not receive immunization 2 and 3. The study was prematurely terminated, therefore subjects in group 3: NF135 CPS-immunization (A/L) Cohort B only received immunization 1.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Break through following immunization 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                    <count group_id="O2" value="10"/>
                    <count group_id="O3" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                    <measurement group_id="O2" value="10"/>
                    <measurement group_id="O3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Break through following immunization 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Break through following immunization 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Groups 1 and 2 (Cohort A ): Inclusion until 35 days after challenge infection (35 weeks) Group 3 (Cohort B): Inclusion until premature end of study (22 weeks) Group 5 (Cohort A): Inclusion until 35 days after challenge infection (5 weeks)</time_frame>
      <desc>As subjects in cohort B did not complete their immunizations, they were not yet randomized for infection when the trial ended prematurely. Cohort B is therefore analyzed as one group that received 1 immunization with 15 NF135.C10 infected mosquitoes under presumptive A/L treatment.</desc>
      <group_list>
        <group group_id="E1">
          <title>1: NF135 CPS-immunization Challenged by NF135</title>
          <description>10 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
        <group group_id="E2">
          <title>2: Low Dose NF135 CPS-immunization Challenged by NF135</title>
          <description>10 volunteers will receive three immunizations with 5 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
        <group group_id="E3">
          <title>3: NF135 CPS-immunization (A/L) Cohort B</title>
          <description>20 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes and are presumptively treated with artemether/lumefantrine starting on day 7 after each immunization. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes.&#xD;
malaria challenge infection, P. falciparum NF135.C10: 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites. 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 sporozoites.&#xD;
CPS-immunization (A/L): Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes and receive presumptive treatment with artemether/lumefantrine initiated on day 7 after each immunization.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
        <group group_id="E4">
          <title>5: Control Group Challenged by NF135.C10 Cohort A</title>
          <description>Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.&#xD;
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.&#xD;
Atovaquone / Proguanil Oral Tablet [Malarone]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Acute coronary syndrome</sub_title>
                <description>Chest pain, dynamic ECG and elevated cardiac biomarkers 10 days after NF135 immunization. MRI, Coronary CT-A, CAG and echocardiography: no evidence of myocarditis, Tako Tsubo or coronary occlusion/dissection. Inflammatory response most likely.</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="20" subjects_at_risk="20"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrosis</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" events="7" subjects_affected="4" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Vivid dreams</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Sadness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>restlessness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="19" subjects_affected="8" subjects_at_risk="10"/>
                <counts group_id="E2" events="16" subjects_affected="8" subjects_at_risk="10"/>
                <counts group_id="E3" events="39" subjects_affected="18" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="13" subjects_affected="9" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Sweats</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="7" subjects_affected="6" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="4" subjects_affected="3" subjects_at_risk="20"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="8" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E2" events="12" subjects_affected="5" subjects_at_risk="10"/>
                <counts group_id="E3" events="10" subjects_affected="7" subjects_at_risk="20"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="35" subjects_affected="10" subjects_at_risk="10"/>
                <counts group_id="E2" events="62" subjects_affected="10" subjects_at_risk="10"/>
                <counts group_id="E3" events="37" subjects_affected="18" subjects_at_risk="20"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" events="13" subjects_affected="7" subjects_at_risk="10"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="10"/>
                <counts group_id="E3" events="16" subjects_affected="12" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="11" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E2" events="20" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E3" events="13" subjects_affected="11" subjects_at_risk="20"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="20" subjects_affected="8" subjects_at_risk="10"/>
                <counts group_id="E2" events="17" subjects_affected="8" subjects_at_risk="10"/>
                <counts group_id="E3" events="10" subjects_affected="7" subjects_at_risk="20"/>
                <counts group_id="E4" events="3" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="6" subjects_affected="6" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="6" subjects_affected="5" subjects_at_risk="10"/>
                <counts group_id="E3" events="7" subjects_affected="7" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="4" subjects_affected="2" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="15" subjects_affected="10" subjects_at_risk="10"/>
                <counts group_id="E2" events="10" subjects_affected="7" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Erythema</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E2" events="3" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Swelling</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="3" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Canker sores</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Herpes simplex</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>- Early termination of cohort B; heterologous protection could not be assessed.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Matthew McCall, MD, PhD</name_or_title>
      <organization>Radboud university medical center</organization>
      <phone>+3124 3615363</phone>
      <email>Matthew.mccall@Radboudumc.nl</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03813108
org study id: CPS135
nct id: NCT03813108
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is an open label, randomized, controlled clinical trial. The primary aim of this project
      is to determine the safety and tolerability of NF135.C10 sporozoite immunization under
      chemoprophylaxis against homologous and heterologous challenge infection.
A total of 49 healthy volunteers will be allocated to receive either three immunizations with
      15 NF135.C10 infected Anopheles mosquitoes (n=30), 3 immunizations with 5 NF135.C10 infected
      mosquitoes (n=10) or no immunizations (n=6). Immunizations in cohort A (n=20) will be
      performed under mefloquine prophylaxis, spaced 4 weeks apart. In cohort B, volunteers will
      not take mefloquine prophylaxis, instead all volunteers will be treated presumptively on day
      7 after each immunization with a curative regimen of artemether/lumefantrine, regardless of
      parasitaemia or symptoms.

      Nineteen weeks after the last immunization, all volunteers plus naïve controls will be
      challenged either by the bites of 5 NF135.C10 (n=36) or 5 NF54 (n=13) infected mosquitoes.
      After challenge infection, volunteers will be followed up on an out-patient basis once daily
      for qPCR and safety lab measurements from day 6 until day 21 post challenge. All volunteers
      will be treated with a curative regimen of atovaquone/proguanil, either at the time of
      detection of blood stage parasitemia, or 28 days after challenge infection.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Frequency of Adverse Events After NF135.C10 CPS Immunization
time frame: Cohort A: Inclusion until 35 days after challenge infection (35 weeks) Cohort B: Inclusion - premature end of study (22 weeks)
description: The number of adverse events will be recorded by the trial clinicians for all participants.
measure: Magnitude of Adverse Events After NF135.C10 CPS Immunization
time frame: Cohort A: Inclusion until 35 days after challenge infection (35 weeks) Cohort B: Inclusion - premature end of study (22 weeks)
description: The severity of adverse events will be recorded (mild/moderate/severe) for each adverse event
measure: Time to Parasitemia
time frame: Day 1 - 28 after malaria challenge infection (28 days)
description: The effectiveness of CPS-immunization with NF135 sporozoites to protect against malaria challenge infection with homologous N135.C10 or heterologous NF54 sporozoites will be determined by the time to parasitemia in immunized versus non-immunized volunteers after the challenge infection.
arm group label: 1: NF135 CPS-immunization challenged by NF135
arm group type: Experimental
description: 10 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.
arm group label: 2: Low dose NF135 CPS-immunization challenged by NF135
arm group type: Experimental
description: 10 volunteers will receive three immunizations with 5 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.
arm group label: 3: NF135 CPS-immunization (A/L) challenged by NF135
arm group type: Experimental
description: 10 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes and are presumptively treated with artemether/lumefantrine starting on day 7 after each immunization. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes.
arm group label: 4: NF135 CPS-immunization (A/L) challenged by NF54
arm group type: Experimental
description: 10 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes and are presumptively treated with artemether/lumefantrine starting on day 7 after each immunization. Volunteers will be challenged by the bites of 5 NF54 infected Anopheles mosquitoes 19 weeks after the last immunization.
arm group label: 5: Control group challenged by NF135.C10 Cohort A
arm group type: Other
description: Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.
arm group label: 6: Control group challenged by NF54 Cohort B
arm group type: Other
description: Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF54 infected Anopheles mosquitoes 19 weeks after the last immunization.
arm group label: 7: Control group challenged by NF135 Cohort B
arm group type: Other
description: Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.
intervention type: Biological
intervention name: CPS-immunization
description: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.
arm group label: 1: NF135 CPS-immunization challenged by NF135
arm group label: 2: Low dose NF135 CPS-immunization challenged by NF135
other name: Plasmodium falciparum NF135.C10 sporozoites
other name: Mefloquine
intervention type: Biological
intervention name: malaria challenge infection, P. falciparum NF135.C10
description: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.
arm group label: 1: NF135 CPS-immunization challenged by NF135
arm group label: 2: Low dose NF135 CPS-immunization challenged by NF135
arm group label: 3: NF135 CPS-immunization (A/L) challenged by NF135
arm group label: 5: Control group challenged by NF135.C10 Cohort A
arm group label: 7: Control group challenged by NF135 Cohort B
other name: Plasmodium falciparum NF135.C10 sporozoites
intervention type: Biological
intervention name: malaria challenge infection, P. falciparum NF54
description: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 sporozoites.
arm group label: 4: NF135 CPS-immunization (A/L) challenged by NF54
arm group label: 6: Control group challenged by NF54 Cohort B
other name: Plasmodium falciparum NF54 sporozoites
intervention type: Biological
intervention name: CPS-immunization (A/L)
description: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes and receive presumptive treatment with artemether/lumefantrine initiated on day 7 after each immunization.
arm group label: 3: NF135 CPS-immunization (A/L) challenged by NF135
arm group label: 4: NF135 CPS-immunization (A/L) challenged by NF54
other name: Plasmodium falciparum NF135.C10 sporozoites
other name: Artemether/lumefantrine (A/L)
intervention type: Drug
intervention name: Atovaquone / Proguanil Oral Tablet [Malarone]
description: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.
arm group label: 1: NF135 CPS-immunization challenged by NF135
arm group label: 2: Low dose NF135 CPS-immunization challenged by NF135
arm group label: 3: NF135 CPS-immunization (A/L) challenged by NF135
arm group label: 4: NF135 CPS-immunization (A/L) challenged by NF54
arm group label: 5: Control group challenged by NF135.C10 Cohort A
arm group label: 6: Control group challenged by NF54 Cohort B
arm group label: 7: Control group challenged by NF135 Cohort B
criteria: 
gender: All
minimum age: 18 Years
maximum age: 35 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Matthew BB McCall, MD PhD DTMH
role: Principal Investigator
affiliation: Radboud University Medical Center
facility: 
country: Netherlands
citation: van der Boor SC, Alkema M, van Gemert GJ, Teelen K, van de Vegte-Bolmer M, Walk J, van Crevel R, de Mast Q, Ockenhouse CF, Sauerwein RW, McCall MBB. Whole sporozoite immunization with Plasmodium falciparum strain NF135 in a randomized trial. BMC Med. 2023 Apr 7;21(1):137. doi: 10.1186/s12916-023-02788-9.
PMID: 37024868
responsible party type: Principal Investigator
investigator affiliation: Radboud University Medical Center
investigator full name: Matthew McCall
investigator title: dr. MBB McCall
mesh term: Infections
mesh term: Communicable Diseases
mesh term: Malaria
mesh term: Malaria, Falciparum
mesh term: Lumefantrine
mesh term: Artemether
mesh term: Mefloquine
mesh term: Atovaquone
mesh term: Proguanil
mesh term: Atovaquone, proguanil drug combination
mesh term: Artemether, Lumefantrine Drug Combination
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: - Early termination of cohort B; heterologous protection could not be assessed.
point of contact: 