Safety and immunogenicity of Pfs25H-EPA/Alhydrogel, a transmission-blocking vaccine against Plasmodium falciparum: a randomised, double-blind, comparator-controlled, dose-escalation study in healthy Malian adults.
Safety and immunogenicity of Pfs25H-EPA/Alhydrogel, a transmission-blocking vaccine against Plasmodium falciparum: a randomised, double-blind, comparator-controlled, dose-escalation study in healthy Malian adults.
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DOI：
10.1016/s1473-3099(18)30344-x
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发表时间：
2018-09
期刊：
影响因子：
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通讯作者：
Duffy PE
中科院分区：
文献类型：
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作者：
Sagara I;Healy SA;Assadou MH;Gabriel EE;Kone M;Sissoko K;Tembine I;Guindo MA;Doucoure M;Niaré K;Dolo A;Rausch KM;Narum DL;Jones DL;MacDonald NJ;Zhu D;Mohan R;Muratova O;Baber I;Coulibaly MB;Fay MP;Anderson C;Wu Y;Traore SF;Doumbo OK;Duffy PE
Pfs 25 H-EPA是一种蛋白质-蛋白质结合的恶性疟原虫传播阻断疫苗，在疟疾初治个体中是安全的并诱导功能性抗体。在第一次疟疾传播阻断疫苗田间试验中，我们评估了Pfs 25 H-EPA/Alhydrogel®在马里成年人中的安全性和功能性免疫原性。在剂量递增后，我们在马里的Bombardmana进行了一项双盲、随机、对照试验（ClinicalTrials.gov编号NCT 01867463）。100名18-45岁的健康成人通过区组随机分配（1：1）至47µg Pfs 25或对照疫苗组。主要结果是所有疫苗接种者的安全性和耐受性。计算样本量的传播阻断活性，通过标准膜喂养试验和3或4次疫苗接种后直接皮肤喂养进行测量。Pfs 25 H疫苗接种者报告了更多的征集性AE（137 vs 86，p= 0.022; Fisher精确）和相关AE（191 vs 126，p= 0.034），但Pfs 25 H组和对照组之间的其他AE没有差异（792 vs 683）。Pfs 25抗体滴度随每次给药增加，在第4次给药后达到峰值几何平均值422·3 EU（95%CI 290-615），然后相对于EPA滴度（59天）相对快速地下降（半衰期42天）（第600天/峰值的中值比率分别为0·18 vs 0·29，p=<0·001，配对Wilcoxon检验）。Pfs 25 H在第4次接种后的血清传播减少活性大于对照组（p<0.001，配对Wilcoxon检验），但在第3次接种后的血清传播减少活性则不大于对照组（p= 0.09），这与美国未接种疟疾疫苗者的结果相似。重复的直接皮肤喂食，其中蚊子直接喂食参与者，耐受性良好，但在第4次给药后Pfs 25 H和对照疫苗接种者之间没有差异（p=1，条件精确），分别产生5/41和4/38个体至少有一个阳性DSF。Pfs 25 H-EPA/Alhydrogel®耐受性良好，并且通过膜饲喂测定诱导显著的血清活性，但通过直接皮肤饲喂不能诱导显著的血清活性，因此不能提供实际的传递阻断活性。这种活性需要四个剂量，滴度迅速下降;应评估替代抗原或组合以提高活性。
Pfs25H-EPA, a protein-protein conjugate Plasmodium falciparum transmission-blocking vaccine, is safe and induces functional antibodies in malaria-naive individuals. In the first malaria transmission-blocking vaccine field trial, we assessed Pfs25H-EPA/Alhydrogel® safety and functional immunogenicity in Malian adults. After dose-escalation, we conducted a double-blind, randomised, comparator-controlled trial (ClinicalTrials.gov number NCT01867463) in Bancoumana, Mali. One hundred 18–45-year-old healthy adults were assigned (1:1) by block randomisation to 47µg Pfs25 or comparator vaccine. Primary outcome was safety and tolerability for all vaccinees. Sample size was calculated for transmission-blocking activity, measured by standard membrane-feeding assay and direct skin feeds after 3 or 4 vaccinations. Pfs25H vaccinees reported more solicited AEs (137 vs 86, p=0·022; Fishers exact) and related AEs (191 vs 126, p=0·034), but other AEs did not differ between Pfs25H and comparator groups (792 vs. 683). Pfs25 antibody titres increased with each dose to peak geometric mean 422·3 EU (95%CI 290–615) post-dose 4, then declined relatively rapidly (half-life 42 days) versus EPA titres (59 days) (median ratio day 600/peak 0·18 vs 0·29, respectively, p=<0·001, paired Wilcoxon’s test). Serum transmission-reducing activity was greater for Pfs25H than comparator post-dose 4 (p<0·001, paired Wilcoxon’s test) but not 3 (p=0·09), similar to that seen in malaria-naïve US vaccinees. Repeated direct skin feeds, wherein mosquitoes fed directly on participants, were well-tolerated but did not differ between Pfs25H and comparator vaccinees post-dose 4 (p=1, conditional exact), yielding 5/41 and 4/38 individuals (respectively) with at least one positive DSF. Pfs25H-EPA/Alhydrogel® was well-tolerated and induced significant serum activity by membrane feeding assay, but not by direct skin feed thus failing to provide actual transmission blocking activity. This activity required four doses and titres declined rapidly; alternative antigens or combinations should be assessed to improve activity.