Safety, Tolerability and Efficacy of PfSPZ Vaccine Administered by Direct 1 Venous Inoculation (DVI) to Healthy Children and Infants 5 Months through 9 Years of Age Living in an Area of High Malaria Transmission in Western Kenya: Age de-escalation and Dose Escalation and a Double Blind, Randomized Placebo-Controlled Trial for Safety and Efficacy.

 

Malaria morbidity and mortality have been reduced substantially as malaria control interventions have been scaled up across Africa, including in Kenya. Nonetheless, malaria continues to cause considerable morbidity and mortality, especially in children under 5 years of age living in sub Saharan Africa.  As we aim for a reduction in malaria burden, and towards malaria elimination, it has become clear that new tools to fight malaria are urgently needed. A highly efficacious vaccine would be an important addition to complement current malaria control measures and to contribute to elimination efforts. Among the different vaccine approaches used to prevent malaria infection, whole Plasmodium falciparum sporozoite (PfSPZ) vaccines have shown consistent, high-level protection in a number of clinical trials.

The candidate malaria vaccine, PfSPZ Vaccine, consists of aseptic, purified, cryopreserved, radiation-attenuated Plasmodium falciparum (Pf) sporozoites, which when given by direct venous inoculation (DVI) to malaria naïve volunteers in the United States was safe, well tolerated and showed dose-dependent, high level protection against controlled human malaria infection.  The Kenya Medical Research Institute and the U.S. Centers for Disease Control and Prevention, in collaboration with National Institute of Health (NIH) and Sanaria, propose to conduct a study to measure safety, immunogenicity and efficacy of this novel candidate malaria vaccine when given to infants from 5 to 12 months inclusive.  The study will be conducted in Siaya County in western Kenya. Initially, in Part 1 of the trial, 156 children will be recruited into an age de-escalation and dose escalation study to document safety of the vaccine in three age groups (children aged 5–9 years, children aged 13 – 59 months, and infants aged 5–12 months) and at the following dosages of sporozoites versus placebo: 1.35 x 10⁵, 2.7 x 10⁵, 4.5 x 10⁵, 9.0 x 10⁵ and 1.8 x 10⁶PfSPZ Vaccine (only the higher three doses in children aged 5–9 years), given by direct venous inoculation (DVI). Children will receive one vaccination at each PfSPZ dose, except for the two highest doses, for which they will receive 2 PfSPZ doses by DVI with the second dose administered 8 weeks after the first.  Part 1, age de-escalation and dose escalation, will begin with administration of 4.5 x 10⁵ PfSPZ in 12 children aged 5-9 years (8 vaccine, 4 placebo), provided to a limited number of participants each day (for example, approximately 3 participants each day on days 1–4).  The PfSPZ Vaccine dose will only be increased to the next level when safety has been assessed in participants of the first group, and earliest at 14 days after the first injection. When the first two dosages (4.5 x 10⁵, 9.0 x 10⁵ PfSPZ) are well tolerated by children aged 5-9 years,  the lowest dose (1.35 x 10⁵) will be administered to children age 13-59 months, with doses doubling every two weeks, after assessment of safety signals, until the final dose of 1.8 x 10⁶ PfSPZ is reached. Concurrent with the 1.35 x 10⁵ PfSPZ dose in 13-59 months old, the highest dose (1.8 x 10⁶ PfSPZ) will be administered to the 5-9 year olds. Progression to the next age category, infants, will proceed similarly: the lowest dose will be administered to infants aged 5–12 months after the two lowest doses (1.35 x 10⁵, 2.7 x 10⁵) have shown to be safe in children aged 13-59 months-olds, and doses will be doubled every two weeks, after assessment of safety signals, until the dose of 1.8 x 10⁶ PfSPZ is reached. Overall vaccine doses will only be increased if they are assessed as well tolerated and the safety data are acceptable for further evaluation of the vaccine at a higher dose, applicable to all the age groups. The vaccine at all but the highest dose (1.8 x 10⁶ PfSPZ) has been tested in US adults and has been shown to be well tolerated with no serious safety signals.The vaccine has also been tested in African adults at the two lowest doses(1.35 x 10⁵  and 2.7 x 10⁵ PfSPZ) and was well tolerated.  The two highest doses ( 9.0 x 10⁵and 1.8 x 10⁶PfSPZ) will be tested in adults in Tanzania and Germany, in teenagers (11-17 years old) and 6-10 year old children in Tanzania prior to being administered to children in the trial described here.Based on the critical importance of dose in mediating protection with this vaccine, the 3 highest dosages found to be well tolerated will be used for the Part 2 of the trial, which will measure safety and efficacy of the PfSPZ vaccine. Each dose, likely to be 4.5 x 10⁵, 9.0 x 10⁵ and 1.8 x 10⁶ PfSPZ, will be administered by DVI 3 times at 8 week intervals to  3 study arms  of 104 infants each.  The rationale for the amount of PfSPZ Vaccine (4.5 x 10⁵ , 9.0 x 10⁵  or 1.8 x 10⁶ PfSPZ), number of doses and intervals between doses (  8 weeks) is based on both safety and efficacy data from ongoing studies in US and African adults for conferring durable immunity and protection, and will be further informed by safety data from the the preceding dose escalation part of the trial. Another group of 104 infants will receive 3  doses of normal saline (NS) by direct venous injection as placebo. The main objectives of this study are to measure the safety, tolerability and immunogenicity of PfSPZ Vaccine in infants (measured in Part 1 and Part 2 of this trial) and to determine whether PfSPZ Vaccine administered by DVI to infants provides high-level protection (point estimate >60%) against Pf infection during 6 months following the last vaccine dose when compared to a placebo group (Part 2 of the trial).  A secondary objective will be to measure safety tolerability, immunogenicity and efficacy during 12 months follow-up.These endpoints will be assessed during scheduled clinic visits as well as monthly home visits and unscheduled sick visits.

Malaria morbidity and mortality have been reduced substantially as malaria control interventions have been scaled up across Africa, including in Kenya. Nonetheless, malaria continues to cause considerable morbidity and mortality, especially in children under 5 years of age living in sub Saharan Africa.  As we aim for a reduction in malaria burden, and towards malaria elimination, it has become clear that new tools to fight malaria are urgently needed. A highly efficacious vaccine would be an important addition to complement current malaria control measures and to contribute to elimination efforts. Among the different vaccine approaches used to prevent malaria infection, whole Plasmodium falciparum sporozoite (PfSPZ) vaccines have shown consistent, high-level protection in a number of clinical trials. 

The candidate malaria vaccine, PfSPZ Vaccine, consists of aseptic, purified, cryopreserved, radiation-attenuated Plasmodium falciparum (Pf) sporozoites, which when given by direct venous inoculation (DVI) to malaria naïve volunteers in the United States was safe, well tolerated and showed dose-dependent, high level protection against controlled human malaria infection.  The Kenya Medical Research Institute and the U.S. Centers for Disease Control and Prevention, in collaboration with National Institute of Health (NIH) and Sanaria, propose to conduct a study to measure safety, immunogenicity and efficacy of this novel candidate malaria vaccine when given to infants from 5 to 12 months inclusive.  The study will be conducted in Siaya County in western Kenya. Initially, in Part 1 of the trial, 156 children will be recruited into an age de-escalation and dose escalation study to document safety of the vaccine in three age groups (children aged 5–9 years, children aged 13 – 59 months, and infants aged 5–12 months) and at the following dosages of sporozoites versus placebo: 1.35 x 105, 2.7 x 105, 4.5 x 105, 9.0 x 105 and 1.8 x 10⁶PfSPZ Vaccine (only the higher three doses in children aged 5–9 years), given by direct venous inoculation (DVI). Children will receive one vaccination at each PfSPZ dose, except for the two highest doses, for which they will receive 2 PfSPZ doses by DVI with the second dose administered 8 weeks after the first.  Part 1, age de-escalation and dose escalation, will begin with administration of 4.5 x 105 PfSPZ in 12 children aged 5-9 years (8 vaccine, 4 placebo), provided to a limited number of participants each day (for example, approximately 3 participants each day on days 1–4).  The PfSPZ Vaccine dose will only be increased to the next level when safety has been assessed in participants of the first group, and earliest at 14 days after the first injection. When the first two dosages (4.5 x 105, 9.0 x 105 PfSPZ) are well tolerated by children aged 5-9 years,  the lowest dose (1.35 x 105) will be administered to children age 13-59 months, with doses doubling every two weeks, after assessment of safety signals, until the final dose of 1.8 x 10⁶ PfSPZ is reached. Concurrent with the 1.35 x 105 PfSPZ dose in 13-59 months old, the highest dose (1.8 x 10⁶ PfSPZ) will be administered to the 5-9 year olds. Progression to the next age category, infants, will proceed similarly: the lowest dose will be administered to infants aged 5–12 months after the two lowest doses (1.35 x 105, 2.7 x 105) have shown to be safe in children aged 13-59 months-olds, and doses will be doubled every two weeks, after assessment of safety signals, until the dose of 1.8 x 10⁶ PfSPZ is reached. Overall vaccine doses will only be increased if they are assessed as well tolerated and the safety data are acceptable for further evaluation of the vaccine at a higher dose, applicable to all the age groups. The vaccine at all but the highest dose (1.8 x 10⁶ PfSPZ) has been tested in US adults and has been shown to be well tolerated with no serious safety signals.The vaccine has also been tested in African adults at the two lowest doses(1.35 x 105  and 2.7 x 105 PfSPZ) and was well tolerated.  The two highest doses ( 9.0 x 105and 1.8 x 10⁶PfSPZ) will be tested in adults in Tanzania and Germany, in teenagers (11-17 years old) and 6-10 year old children in Tanzania prior to being administered to children in the trial described here.Based on the critical importance of dose in mediating protection with this vaccine, the 3 highest dosages found to be well tolerated will be used for the Part 2 of the trial, which will measure safety and efficacy of the PfSPZ vaccine. Each dose, likely to be 4.5 x 105, 9.0 x 105 and 1.8 x 10⁶ PfSPZ, will be administered by DVI 3 times at 8 week intervals to  3 study arms  of 104 infants each.  The rationale for the amount of PfSPZ Vaccine (4.5 x 105 , 9.0 x 105  or 1.8 x 10⁶ PfSPZ), number of doses and intervals between doses (  8 weeks) is based on both safety and efficacy data from ongoing studies in US and African adults for conferring durable immunity and protection, and will be further informed by safety data from the the preceding dose escalation part of the trial. Another group of 104 infants will receive 3  doses of normal saline (NS) by direct venous injection as placebo. The main objectives of this study are to measure the safety, tolerability and immunogenicity of PfSPZ Vaccine in infants (measured in Part 1 and Part 2 of this trial) and to determine whether PfSPZ Vaccine administered by DVI to infants provides high-level protection (point estimate >60%) against Pf infection during 6 months following the last vaccine dose when compared to a placebo group (Part 2 of the trial).  A secondary objective will be to measure safety tolerability, immunogenicity and efficacy during 12 months follow-up.These endpoints will be assessed during scheduled clinic visits as well as monthly home visits and unscheduled sick visits.