Phase 1 • Primary objective: to determine the safety and tolerability, including the attenuation phenotype of a novel late-arresting GAP, named GA2 parasite, administered by sequentially increasing numbers of mosquito bites.• Secondary objective: to…
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Source
Brief title
Condition
- Protozoal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints:
Phase 1:
• Number of volunteers with blood-stage parasitaemia after exposure to the GA2
parasite, as assessed by qPCR.
• Number and magnitude of adverse events (AEs) and serious adverse events
(SAEs).
Phase 2:
• Number of volunteers protected against CHMI after immunisation with the GA2
parasite.
• Number and magnitude of AEs and SAEs.
Secondary outcome
Secondary endpoints (Phase 1 and Phase 2):
• Kinetics of cellular and humoral immune response of volunteers exposed to the
GA2 and GA1 parasite.
Background summary
Malaria is one of the most common infectious diseases worldwide, affecting as
many as 228 million people and causing 405.000 deaths each year. Given the
rising resistance of both parasites against anti-malarial drugs and mosquitoes
against insecticides, the goal of defeating malaria is becoming more elusive
and an alternative to existing tools of eradications is urgently needed. One
promising possibility is the development of a vaccine against the disease.
Among the different approaches to vaccine development, attenuated sporozoite
(ASp) vaccines for Plasmodium falciparum (Pf) malaria stand out for their high
(>90%) protective efficacy in human trials. There are different types Pf ASp
vaccines, namely radiation attenuated sporozoites (RAS) and genetically
attenuated parasites (GAP).
The way RAS and GAP work is that they prime the immune system for recognition
of the wild-type (WT) parasite at a later time point. The parasites used for
vaccination interrupt development in the pre-erythrocytic liver stages (RAS and
GAP), allowing for recognition by the immune system while at the same time also
avoiding the debilitating symptoms of clinical malaria.
Recently, a new GAP, the GA2 parasite (Pf*mei2), lacking one gene and arresting
development during the late liver-stage, was created. The advantage of the GA2
parasite is that, by arresting development at a later stage than RAS and
previous GAPs, it may allow for prolonged antigenic exposure to the immune
system and thus have more powerful immunogenic properties. The hope is then
that the GA2 parasite will have good protective efficacy and be a suitable
vaccine candidate.
The GA2 phenotype closely resembles the *sporozoites under chemoprophylaxis
strategy*, whereby live sporozoites are administered under chloroquine or
mefloquine prophylaxis cover, which has previously shown to very efficiently
induce immunity in healthy malaria-naïve individuals.
The scope of this trial is to evaluate the safety and tolerability of GA2
parasite in humans and to test its preliminary protective efficacy against
controlled human malaria infection (CHMI). Moreover, immunological responses
elicited by the GA2 parasite will be compared to those elicited by one of its
predecessors, the GA1 parasite (Pf*b9*slarp).
Study objective
Phase 1
• Primary objective: to determine the safety and tolerability, including the
attenuation phenotype of a novel late-arresting GAP, named GA2 parasite,
administered by sequentially increasing numbers of mosquito bites.
• Secondary objective: to analyse the humoral and cellular immune response of
healthy volunteers exposed to the novel late-arresting GA2 parasite.
Phase 2
• Primary objective: to determine the safety, tolerability and the preliminary
protective efficacy of the novel late-arresting GA2 parasite against CHMI.
• Secondary objective: to analyse and compare the cellular and humoral immune
response of healthy volunteers exposed to the late-arresting GA2 or the
early-arresting GA1 parasite.
Study design
This will be a first-in-human, double-blind, randomized clinical trial of the
GA2 parasite in healthy, malaria-naïve male and female volunteers. Recruitment
and follow-up will take place at the LUMC, exposure to parasites by mosquito
bites will take place at RUMC.
Phase 1 will be an open label, dose escalation, safety trial in two cohorts of
volunteers to assess safety, tolerability and attenuation phenotype (lack of
breakthrough blood-stage infections) of the GA2 parasite.
21 volunteers will participate in Phase 1 in two different cohorts: six
individuals in the first cohort and 15 individuals the second cohort.
Volunteers in Cohort 1 and Cohort 2 will be exposed to 15 and 50 GA2-infected
mosquito bites respectively. End of follow-up in Phase 1 will be six months
after the last exposure to the GA2 parasite.
Phase 2 will be a double-blind, randomized trial aimed at assessing the
preliminary protective efficacy of the GA2 parasite.
30 volunteers will participate in Phase 2 and will be randomly allocated to
either of three groups: 15 volunteers in Group 1 will be exposed to bites of
GA2-infected mosquitoes, 10 volunteers in Cohort Group 2 will be exposed to
bites of GA1-infected mosquitoes and five volunteers in Group 3 will be exposed
to uninfected mosquitoes and serve as infectivity controls. Immunization by
exposure to mosquito bites will be repeated three times at intervals of 28
days. Three weeks after the last immunization, all volunteers will undergo CHMI
by five bites of mosquitoes infected with WT PfNF54 sporozoites. As soon as
blood stage parasitaemia is detected by qPCR (equal to or more than 100
parasites per ml) or 28 days after CHMI at the latest, volunteers will be
treated with a curative regimen of antimalarials (atovaquone/proguanil or,
alternatively, artemether/lumefantrine), dosed according to local hospital
guidelines. End of follow-up in Phase 2 will be six months after CHMI.
Intervention
Phase 1: six volunteers will be allocated to Cohort 1 and will be exposed to 15
bites of GA2-infected mosquitoes. If this dose is safe and there are no
breakthrough blood-stage infections, 15 volunteers will be allocated to Cohort
2 and will be exposed to 50 bites of GA2-infected mosquitoes. If this dose is
safe and there are no more than five (30%) breakthrough blood-stage infections,
the trial will proceed to the next phase.
Phase 2: 30 volunteers will be allocated to three groups in a double-blind
randomized fashion. Group 1 will consist of 15 volunteers who will be exposed
to 50 GA2 infected mosquitoes, Group 2 will consist of 10 volunteers who will
be exposed to 50 GA1 by 50 mosquito bitess and Group 3 will consist of five
volunteers who will be exposed to 50 uninfected mosquito bites. Exposure to
either intervention will be repeated three times at 28-day intervals. Three
weeks after the last exposure, all volunteers will undergo CHMI with five (WT)
PfNF54-infected mosquitoes.
Recruitment and follow-up of all volunteers will take place at the Leiden
University Medical Centre (LUMC). Exposure to mosquitoes in Phase 1 and 2 for
the purpose of immunisation and the CHMI will take place at Radboud University
Medical Centre (RUMC). All exposed volunteers will be followed closely for
possible breakthrough blood infections by testing for the presence of
parasitaemia by qPCR. As soon as a breakthrough blood-stage infection develops
or at the latest at 28 days after exposure to the GA2 parasite in Phase 1 or 28
after CHMI in Phase 2, all volunteers will be treated with a curative regimen
of atovaquone/proguanil or, alternatively, artemether/lumefantrine. Six months
after the inoculation, a final visit will take place to assess immune
responses.
Study burden and risks
Benefits: There are no direct benefits for volunteers. Volunteers will still be
advised to take regular malaria chemoprophylaxis when travelling to malaria
endemic areas in the future.
Risks: Risks for volunteers in both studies are related to:
• Potential breakthrough blood-stage infection after exposure to the GA2
parasite;
• Systemic AEs related to exposure to the GA2 and GA1 parasites;
• Local AEs related to mosquito bites;
• Potential blood-stage infection after CHMI;
• Side effects of antimalarial treatment.
Burden:
Volunteers will have to visit the trial centre on 26 occasions for Phase 1 and
on 37 occasions for Phase 2. In Phase 1, the maximum cumulative amount of blood
collected will be 500 ml for each volunteer. In Phase 2, the maximum amount of
blood collected will be 500 ml in four months with an additional 75 ml six
months after CHMI per volunteer. In addition, physical examinations will be
performed when clinically indicated and volunteers will be asked to complete a
diary of AEs on a daily basis.
Burden for volunteers is related to the frequent visits, frequent venapuncture,
itching after mosquito bites and potential symptoms after immunisation or CHMI.
Albinusdreef 2
Leiden 2333 ZA
NL
Albinusdreef 2
Leiden 2333 ZA
NL
Listed location countries
Age
Inclusion criteria
1. Subject is aged >= 18 and <= 35 years and in good health.
2. Subject has adequate understanding of the procedures of the study and agrees
to abide strictly thereby.
3. Subject is able to communicate well with the investigator, is available to
attend all study visits.
4. Furthermore, the subject will remain within the Netherlands from day -1 till
day +28 after each parasite exposure. After exposure to parasites, subjects
have to be reachable by phone (24/7) from day -1 until day 35.
5. Subject agrees that his/her general practitioner (GP) will be informed about
participation in the study.
6. Subject agrees to refrain from blood donation to Sanquin or for other
purposes throughout the study period and for a defined period thereafter
according to Sanquin guidelines (three years minimum, depending on serology).
7. Non-pregnant, non-lactating, fertile (i.e., have a uterus and are neither
surgically sterilized nor post-menopausal) female subjects agree to use
adequate contraception and to not breastfeed for the duration of study.
8. Subject agrees to refrain from intensive physical exercise (disproportionate
to the subjects* usual daily activity or exercise routine) for twenty-one days
following each immunization and during the malaria challenge period.
9. Subject signs informed consent.
Exclusion criteria
1. Any history, or evidence at screening, of clinically significant symptoms,
physical signs or abnormal laboratory values suggestive of systemic conditions,
such as cardiovascular, pulmonary, renal, hepatic, neurological,
dermatological, endocrine, malignant, haematological, infectious,
immune-deficient, psychiatric or other disorders, which could compromise the
health of the volunteer during the study or interfere with the interpretation
of the study results. These include, but are not limited to, any of the
following:
a. Body weight <50 kg or Body Mass Index (BMI) <18.0 or >30.0 kg/m2 at
screening.
b. A heightened risk of cardiovascular disease, defined as:
i. An estimated ten-year risk of fatal cardiovascular disease of >=5% at
screening, as determined by the Systematic Coronary Risk Evaluation (SCORE).
ii. History, or evidence at screening, of clinically significant arrhythmia*s,
prolonged QT-interval or other clinically relevant ECG abnormalities; or
iii. A positive family history of cardiac events in first- or second-degree
relatives (according to the system used in medical genetics) <50 years old.
c. Functional asplenia, sickle cell trait/disease, thalassemia trait/disease or
G6PD deficiency.
d. History of epilepsy in the period of five years prior to study onset, even
if no longer on medication.
e. Positive HIV, HBV or HCV screening tests.
f. Chronic use of i) immunosuppressive drugs, ii) antibiotics, iii) or other
drugs that might have an influence on the immune system (excluding inhaled and
topical corticosteroids and incidental use of oral anti-histamines), within
three months prior to study onset or expected use of such during the study
period.
g. History of malignancy of any organ system (other than localized basal cell
carcinoma of the skin), treated or untreated, within the past five years.
h. Any history of treatment for severe psychiatric disease by a psychiatrist in
the past year.
i. History of drug or alcohol abuse interfering with normal social function in
the period of one year prior to study onset, positive urine toxicology test for
cocaine or amphetamines at screening or prior to exposure to parasites or
positive urine toxicology test for cannabis prior to exposure to parasites.
2. For female subjects: breastfeeding, or positive urine pregnancy test at
screening or prior to immunization or prior to CHMI.
3. Any history of malaria, positive serology for Pf, or previous participation
in any malaria (vaccine) study or CHMI.
4. Known hypersensitivity to or contra-indications (including co-medication)
for use of atovaquone/proguanil or artemether/lumefantrine, or history of
severe (allergic) reactions to mosquito bites.
5. Receipt of any vaccinations in the three months prior to the start of the
study or plans to receive any other vaccinations during the study period or up
to eight weeks thereafter. Exceptions are made for influenza vaccination and,
if it becomes available during the study period, for vaccination against the
novel coronavirus SARS-COV2.
6. Participation in any other clinical study in the 30 days prior to the start
of the study or during the study period.
7. Being an employee or student of the department of Parasitology, Medical
Microbiology or Infectious Diseases of the LUMC or RUMC.
8. Any other condition or situation that would, in the opinion of the
investigator, place the subject at an unacceptable risk of injury or render the
subject unable to meet the requirements of the protocol or would compromise the
integrity of the data.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-005646-41-NL |
| ClinicalTrials.gov | NCT04577066 |
| CCMO | NL75577.000.21 |