背景:为了提高恶性疟原虫疟疾疫苗RTS的疗效,S/AS02,我们在2001年进行了一项健康的研究,初治疟疾的成年人服用RTS,S/AS02与FMP1(重组裂殖子表面蛋白-1,C末端42kD片段)组合。
方法:一项双盲I/IIa期研究将N=60名受试者1:1:1:1随机分为四组之一,N=15/组,为了评估安全性,免疫原性,三角肌内半剂量RTS的疗效,S/AS02和FMP1/AS02在对侧给药(RTS,S+FMP1-separate)或相同(RTS,S+FMP1-相同)站点,或单独的FMP1/AS02(单独的FMP1),或RTS,单独使用S/AS02(RTS,S-单独)在0-上,1-,3个月的时间表。接受三剂疫苗和非免疫对照(N=11)的受试者通过受控人疟疾感染(CHMI)用同源恶性疟原虫3D7子孢子感染。
结果:所有疫苗接种组的受试者大多经历了轻度或中度的局部和一般不良事件,这些不良事件在8天内消失。当FMP1和RTS时,抗环子孢子抗体水平较低,S在同一部位共同给药(35.0µg/mL:95%CI20.3-63),与单独的臂(57.4µg/mL:95%CI32.3-102)或RTS,S单独(62.0μg/mL:95%CI:37.8-101.8)。RTS,在接受RTS的组中,S特异性淋巴增生反应和离体ELISpotCSP特异性干扰素-γ(IFN-γ)反应无法区分,S/AS02。在接受FMP1/AS02的组中,针对FMP1的抗体没有差异。在CHMI之后,用RTS免疫的组,含S方案对寄生虫血症有~30%的无菌保护作用,以及寄生虫血症时间的等效延迟。单独的FMP1/AS02组未显示无菌免疫或寄生虫血症延迟。
结论:RTS的共同管理,S和FMP1/AS02降低了抗RTS,S抗体,但不影响耐受性,细胞免疫,或在严格的CHMI模型中的功效。FMP1/AS02组的子孢子攻击模型中缺乏功效或通畅延迟并不排除FMP1/AS02在地方性人群中的功效。然而,在疟疾流行的肯尼亚儿童中进行的FMP1/AS02的IIb期试验未证明对自然感染有效.
结果:gov标识符:NCT01556945。
BACKGROUND: To improve the efficacy of Plasmodium falciparum malaria vaccine RTS,S/AS02, we conducted a
study in 2001 in healthy, malaria-naïve adults administered RTS,S/AS02 in combination with FMP1, a recombinant merozoite surface-protein-1, C-terminal 42kD fragment.
METHODS: A double-blind Phase I/IIa
study randomized N = 60 subjects 1:1:1:1 to one of four groups, N = 15/group, to evaluate safety, immunogenicity, and efficacy of intra-deltoid half-doses of RTS,S/AS02 and FMP1/AS02 administered in the contralateral (RTS,S + FMP1-separate) or same (RTS,S + FMP1-same) sites, or FMP1/AS02 alone (FMP1-alone), or RTS,S/AS02 alone (RTS,S-alone) on a 0-, 1-, 3-month schedule. Subjects receiving three doses of vaccine and non-immunized controls (N = 11) were infected with homologous P. falciparum 3D7 sporozoites by Controlled Human Malaria Infection (CHMI).
RESULTS: Subjects in all vaccination groups experienced mostly mild or moderate local and general adverse events that resolved within eight days. Anti-circumsporozoite antibody levels were lower when FMP1 and RTS,S were co-administered at the same site (35.0 µg/mL: 95 % CI 20.3-63), versus separate arms (57.4 µg/mL: 95 % CI 32.3-102) or RTS,S alone (62.0 µg/mL: 95 % CI: 37.8-101.8). RTS,S-specific lymphoproliferative responses and ex vivo ELISpot CSP-specific interferon-gamma (IFN-γ) responses were indistinguishable among groups receiving RTS,S/AS02. There was no difference in antibody to FMP1 among groups receiving FMP1/AS02. After CHMI, groups immunized with a RTS,S-containing regimen had ∼ 30 % sterile protection against parasitemia, and equivalent delays in time-to-parasitemia. The FMP1/AS02 alone group showed no sterile immunity or delay in parasitemia.
CONCLUSIONS: Co-administration of RTS,S and FMP1/AS02 reduced anti-RTS,S antibody, but did not affect tolerability, cellular immunity, or efficacy in a stringent CHMI model. Absence of efficacy or delay of patency in the sporozoite challenge model in the FMP1/AS02 group did not rule out efficacy of FMP1/AS02 in an endemic population. However, a Phase IIb
trial of FMP1/AS02 in children in malaria-endemic Kenya did not demonstrate efficacy against natural infection.
RESULTS: gov identifier: NCT01556945.