Clinical trial NCT03281291: Study to Assess the Vaccine Efficacy Against Malaria Infection, in Children Immunized With the Primary and Yearly Booster of the RTS,S/AS01E Vaccine, as Part of Their Participation in the Malaria-094 (204889/NCT03276962) Study.
Official title: Molecular Detection and Genotyping of Plasmodium Falciparum Parasites in Young African Children After Immunization With RTS,S/AS01E Malaria Vaccine. An Ancillary Study Protocol to GlaxoSmithKline Phase IIb RTS,S/AS01E Malaria Vaccine Trial (Study Number 204889) Entitled, "Efficacy, Safety and Immunogenicity Study of GSK Biologicals' Candidate Malaria Vaccine (SB257049) Evaluating Schedules With or Without Fractional Doses, Early Dose 4 and Yearly Doses, in Children 5-17 Months of Age.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Malaria
Keywords: malaria vaccine
infants
malaria
RTS,S/AS01
falciparum
genomics
efficacy
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-09-13
Enrollment: 1500
Sex: ALL
Minimum age (years): 5
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Community sample

Brief summary: The aim of this study was to evaluate the effectiveness of the RTS,S/AS01E malaria vaccine against both clinical and asymptomatic malaria infections by detecting Plasmodium falciparum (P. falciparum) parasites in blood samples collected from children who received the primary and yearly booster doses of the RTS,S/AS01E vaccine, as part of their participation in the Malaria-094 parent clinical study. The genomic analysis was conducted on parasites found in blood spot samples from children aged 5-17 months, who were vaccinated according to different dosage and schedule regimens as part of the Malaria-094 parent clinical study.

Detailed description: This genotyping study of malaria parasites, collected from serial blood samples following RTS,S/AS01E immunization, assessed vaccine efficacy using molecular genetic data. The study aimed to identify the first infections post-vaccination and distinguish new infections from existing ones through an amplicon sequencing-based strategy. This involved deep sequencing of small, highly variable regions of the parasite genome, enabling both: 1. Highly sensitive detection of parasitemia (similar to conventional polymerase chain reaction \[PCR\]-based detection), and 2. Identification of genetically distinct parasite populations within or between affected individuals.

Eligibility criteria: Inclusion Criteria:

* Participants' parent(s)/LAR(s) who, in the opinion of the investigator, complied with the requirements of the protocol (e.g. return for follow-up visits).
* Signed or thumb-printed and witnessed informed consent obtained from the parent(s)/LAR(s) of the participant prior to performance of any study specific procedure. Where parent(s)/LAR(s) were illiterate, the consent form was countersigned by an independent witness.
* A male or female between, and including, five and 17 months of age at the time of the first vaccination.
* Healthy participants as established by medical history and clinical examination before entering into the study.
* Previously received three documented doses of diphtheria, tetanus, pertussis, hepatitis B vaccine (DTPHepB), and at least three doses of oral polio vaccine.

Exclusion Criteria:

* Child in care.
* Use of a drug or vaccine that is not approved for that indication (by one of the following regulatory authorities: Food and Drug Administration \[FDA; USA\] or European Union member state or WHO \[with respect to prequalification\]) other than the study vaccines during the period starting 30 days before the first dose of study vaccines (Day -29 to Day 0), or planned use during the study period.
* Any medical condition that in the judgment of the investigator would have made the intramuscular injection unsafe.

Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine dose. For corticosteroids, this meant prednisone (0.5 mg/kg/day (for pediatric participants) or equivalent. Inhaled and topical steroids are allowed.

* Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting seven days before each dose and ending seven days after each dose of vaccine administration.
* Concurrently participating in another clinical study, at any time during the study period, in which the participant has been or was to be exposed to an investigational or a non-investigational vaccine/product (pharmaceutical product or device).
* Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).
* Family history of congenital or hereditary immunodeficiency.
* History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines.
* History of anaphylaxis post-vaccination.
* History of any, or documented, serious adverse reaction to rabies vaccination.
* Contraindication to rabies vaccination (Rabipur is contraindicated in participants with a history of a severe hypersensitivity to any of the ingredients in the vaccine. Note that the vaccine contains polygeline and residues of chicken proteins, and may contain traces of neomycin, chlortetracycline and amphotericin B).
* Major congenital defects.
* Serious chronic illness.
* Children with a past history of a neurological disorder or atypical febrile seizure (a febrile seizure is atypical if it meets one of the following criteria: not associated with fever; lasts \> 5 minutes; focal (not generalized); followed by transient or persistent neurological abnormality; occurs in a child \< 6 months of age).
* Acute disease and/or fever at the time of enrolment.
* Fever is defined as temperature ≥ 37.5°C/99.5°F for oral, axillary or tympanic route, or ≥ 38.0°C/100.4°F for rectal route.
* Participants with a minor illness (such as mild diarrhea, mild upper respiratory infection) without fever may have been enrolled at the discretion of the investigator.
* Administration of immunoglobulins and/or any blood products during the period starting three months before the first dose of study vaccine or planned administration during the study period.
* Moderate or severe malnutrition at screening defined as weight for age or weight for height Z-score \< -2.
* Hemoglobin concentration \< 8 g/dl at screening.
* Same sex twins (to avoid misidentification).
* Maternal death.
* Prior receipt of an investigational malaria vaccine.

Primary outcomes:
measure: Time From First Vaccination to the Detection of the First New Malaria Infection Through to the Month 20 Study Visit
timeFrame: Up to 20 months post Dose 1
measure: Time From First Vaccination to the Detection of the First New Malaria Infection From 14 Days Post-Dose 3 Through to 12 Months Post-Dose 3
timeFrame: From Month 2.5 to Month 14 for the R012-20 + R012-14-mD Pooled Group, the Fx012-14-mFxD Group and the Control Group, and from Month 7.5 to Month 19 for the Fx017-mFxD Group
measure: Time From First Vaccination to the Detection of the First New Malaria Infection Through to the Month 32 Study Visit
timeFrame: Up to 32 months post Dose 1
measure: Time From First Vaccination to the Detection of the First New Malaria Infection From 14 Days Post-Dose 3 Through to 24 Months Post-Dose 3
timeFrame: From Month 2.5 to Month 26 for the R012-20 Group, the R012-14-mD Group, the Fx012-14-mFxD Group and the Control Group, and from Month 7.5 to Month 31 for the Fx017-mFxD Group
measure: Number of Molecularly Confirmed New Malaria Infections Through to the Month 20 Study Visit
timeFrame: Up to 20 months post Dose 1
measure: Number of Molecularly Confirmed New Malaria Infections From 14 Days Post-Dose 3 Through to 12 Months Post-Dose 3
timeFrame: From Month 2.5 to Month 14 for the R012-20 + R012-14-mD Pooled Group, the Fx012-14-mFxD Group and the Control Group, and from Month 7.5 to Month 19 for the Fx017-mFxD Group
measure: Number of Molecularly Confirmed New Malaria Infections Through to the Month 32 Study Visit
timeFrame: Up to 32 months post Dose 1
measure: Number of Molecularly Confirmed New Malaria Infections From 14 Days Post-Dose 3 Through to 24 Months Post-Dose 3
timeFrame: From Month 2.5 to Month 26 for the R012-20 Group, the R012-14-mD Group, the Fx012-14-mFxD Group and the Control Group, and from Month 7.5 to Month 31 for the Fx017-mFxD Group
Secondary outcomes:
Other outcomes:
Locations:
city: Kumasi
country: Ghana
facility: GSK Investigational Site
city: Kisumu
country: Kenya
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Juraska M, Early AM, Li L, Schaffner SF, Lievens M, Khorgade A, Simpkins B, Hejazi NS, Benkeser D, Wang Q, Mercer LD, Adjei S, Agbenyega T, Anderson S, Ansong D, Bii DK, Buabeng PBY, English S, Fitzgerald N, Grimsby J, Kariuki SK, Otieno K, Roman F, Samuels AM, Westercamp N, Ockenhouse CF, Ofori-Anyinam O, Lee CK, MacInnis BL, Wirth DF, Gilbert PB, Neafsey DE. Genotypic analysis of RTS,S/AS01E malaria vaccine efficacy against parasite infection as a function of dosage regimen and baseline malaria infection status in children aged 5-17 months in Ghana and Kenya: a longitudinal phase 2b randomised controlled trial. Lancet Infect Dis. 2024 Sep;24(9):1025-1036. doi: 10.1016/S1473-3099(24)00179-8. Epub 2024 May 6.