Trial Outcomes & Findings for Study of Malaria Vaccine RTS,S/AS01E in Plasmodium Falciparum-infected and Uninfected Adults Pre-treated With Anti-malarial Therapy (NCT NCT04661579)

Participants were recruited from the villages in the Kombewa Health and Demographics Surveillance System (HDSS) consisting of half of Kisumu West and all of Seme sub-counties of Kisumu County, Kenya. Prior to enrollment participants were tested for the presence or absence of asymptomatic infection with Plasmodium falciparum (P. falciparum, the parasite that causes malaria) measured using a highly sensitive polymerase chain reaction (PCR) assay.

Participants were stratified by baseline P. falciparum parasitemia status and then block randomized. The first 105 participants who were positive for parasitemia at baseline were randomized in a 1:1:1 ratio with 35 participants assigned to each of Groups 1, 3 and 4. The next 258 participants with baseline parasitemia were randomized in a 1:1 ratio to Groups 1 and 4. Participants who were negative for parasitemia at baseline were randomized in a 1:1 ratio to Groups 2 and 5.

Study of Malaria Vaccine RTS,S/AS01E in Plasmodium Falciparum-infected and Uninfected Adults Pre-treated With Anti-malarial Therapy

Participants were actively monitored for malarial infection starting 2 weeks after the third vaccination. Blood samples were assayed using a highly sensitive polymerase chain reaction (PCR) (Plasmodium falciparum/ Pan-Plasmodium 18S ribosomal ribonucleic acid (rRNA) laboratory developed test \[LDT\]) that can detect sub-clinical parasitemia at the US Army Medical Research Directorate-Africa (USAMRD-A) / Kenya Medical Research Institute (KEMRI) laboratories in Kisumu, Kenya. A positive PCR result from blood samples collected during the ADI was recorded as a positive event for the presence of P. falciparum blood stage infection. The time to first malaria infection is expressed in terms of rate of first malaria infection, that is, the number of malaria infection events reported over the time period elapsed until the event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group.

Participants were actively monitored for malarial infection starting 2 weeks after the third vaccination. Blood samples were assayed using a highly sensitive PCR (Plasmodium falciparum/ Pan-Plasmodium 18S rRNA LDT) that can detect sub-clinical parasitemia. A positive PCR result from blood samples collected during the ADI phase was recorded as a positive event for the presence of P. falciparum blood stage infection. The time to first malaria infection is expressed in terms of rate of first malaria infection, that is, the number of malaria infection events reported over the time period elapsed until the event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group.

An adverse event is any untoward medical occurrence in a study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, or temporally associated with a study procedure. A serious adverse event is any adverse event that: * Resulted in death, * Was life-threatening, * Resulted in disability/incapacity, * Required hospitalization or prolongation of existing hospitalization, * Resulted in disability/incapacity. * Resulted in a congenital anomaly and / or birth defect.

Solicited AEs are pre-specified local and systemic AEs that occur relatively more frequently or are known to be associated with immunization, which are monitored actively as potential indicators of vaccine reactogenicity. Solicited local and general AEs were collected among RTS,S vaccinated groups in the first 50 participants enrolled in Groups 1 and 2 and all participants enrolled in Group 3 (Reactogenicity Cohort) for seven days (day of vaccination and six subsequent days) after each dose of vaccine. Local (injection site) adverse events are defined as: * Pain at injection site * Swelling at injection site Systemic adverse events are defined as: * Fever (temperature ≥ 37.5°C) * Headache * Gastrointestinal problems * Fatigue * Muscle ache

An adverse event is defined as any untoward medical occurrence in a study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, or temporally associated with a study procedure. Unsolicited AEs are any AEs reported spontaneously by the participant, observed by the study staff during study visits or those identified during review of medical records or source documents. Solicited AEs with an onset after the seven-day solicitation period were also considered unsolicited AEs.

The RTS,S antigen consists of sequences of both the P. falciparum circumsporozoite protein and hepatitis B surface antigen. Antibody levels against P. falciparum circumsporozoite (CS) protein central repeat region (NANP) were measured from blood samples of participants in Groups 1, 2 and 3 using standard enzyme-linked immunosorbent assays (ELISA) at Walter Reed Army Institute of Research (WRAIR), in Silver Spring, MD, United States.

Antibody levels against P. falciparum circumsporozoite (CS) protein central repeat region (NANP) measured by standard enzyme-linked immunosorbent assays (ELISA) for participants in Groups 1, 2 and 3. To measure antibody-antigen avidity (strength of binding) ELISA was performed with and without urea (to dissociate the antigen-antibody complex). The avidity index is calculated by dividing the serum titer obtained in the presence of the urea by the serum titer without urea.

The RTS,S vaccine antigen consists of sequences of both the P. falciparum circumsporozoite protein and hepatitis B surface antigen, hence anti-HBsAg antibodies were also measured. Anti-hepatitis B surface antigen antibodies were assessed at the International AIDS Vaccine Initiative Human Immunology Laboratory (IAVI-HIL) at Imperial College, London, UK, using a commercially available ELISA kit.