PDF(Pubmed)
Abstract：
Malaria transmission-blocking vaccines target mosquito-stage parasites and will support elimination programmes. Gamete vaccine Pfs230D1-EPA/Alhydrogel induced superior activity to zygote vaccine Pfs25-EPA/Alhydrogel in malaria-naive US adults. Here, we compared these vaccines in malaria-experienced Malians.
We did a pilot safety study then double-blind, block-randomised, comparator-controlled main-phase trial in malaria-intense Bancoumana, Mali. 18-50-year-old healthy non-pregnant, non-breastfeeding consenting adult residents were randomly assigned (1:1:1:1) to receive four doses at months 0, 1, 4·5, and 16·5 of either 47 μg Pfs25, 40 μg Pfs230D1 or comparator (Twinrix or Menactra)-all co-administered with normal saline for blinding-or 47 μg Pfs25 plus 40 μg Pfs230D1 co-administered. We documented safety and tolerability (primary endpoint in the as-treated populations) and immunogenicity (secondary endpoint in the as-treated populations: ELISA, standard-membrane-feeding assay, and mosquito direct skin feed assay). This trial is registered at ClinicalTrials.gov, NCT02334462.
Between March 19, and June 2, 2015, we screened 471 individuals. Of 225 enrolled for the pilot and main cohorts, we randomly assigned 25 participants to pilot safety cohort groups of five (20%) to receive a two-dose series of Pfs25-EPA/Alhydrogel (16 μg), Pfs230D1-EPA/Alhydrogel (15 μg) or comparator, followed by Pfs25-EPA/Alhydrogel (16 μg) plus Pfs230D1-EPA/Alhydrogel (15 μg) or comparator plus saline. For the main cohort, we enrolled 200 participants between May 11 and June 2, 2015, to receive a four-dose series of 47 μg Pfs25-EPA/Alhydrogel plus saline (n=50 [25%]; Pfs25), 40 μg Pfs230D1-EPA/Alhydrogel plus saline (n=49 [25%]; Pfs230D1), 47 μg Pfs25-EPA/Alhydrogel plus 40 μg Pfs230D1-EPA/Alhydrogel (n=50 [25%]; Pfs25 plus Pfs230D1), or comparator (Twinrix or Menactra) plus saline (n=51 [25%]). Vaccinations were well tolerated in the pilot safety and main phases. Most vaccinees became seropositive after two Pfs230D1 or three Pfs25 doses; peak titres increased with each dose thereafter (Pfs230D1 geometric mean: 77·8 [95% CI 56·9-106·3], 146·4 [108·3-198·0], and 410·2 [301·6-558·0]; Pfs25 geometric mean 177·7 [130·3-242·4] and 315·7 [209·9-474·6]). Functional activity (mean peak transmission-reducing activity) appeared for Pfs230D1 (74·5% [66·6-82·5]) and Pfs25 plus Pfs230D1 (68·6% [57·3-79·8]), after the third dose and after the fourth dose (88·9% [81·7-96·2] for Pfs230D1 and 85·0% [78·4-91·5] Pfs25 plus Pfs230D1) but not for Pfs25 (58·2% [49·1-67·3] after the third dose and 58·2% [48·5-67·9] after the fourth dose). Pfs230D1 transmission-reducing activity (73·7% [64·1-83·3]) persisted 10 weeks after the fourth dose. Transmission-reducing activity of 80% was estimated at 1659 ELISA units for Pfs25, 218 for Pfs230D1, and 223 for Pfs230D1 plus Pfs25. After 3850 direct skin feed assays, 35 participants (12 Pfs25, eight Pfs230D1, five Pfs25 plus Pfs230D1, and ten comparator) had transmitted parasites at least once. The proportion of positive assays in vaccine groups (Pfs25 33 [3%] of 982 [-0·013 to 0·014], Pfs230D1 22 [2%] of 954 [-0·005 to 0·027], and combination 11 [1%] of 940 [-0·024 to 0·002]) did not differ from that of the comparator (22 [2%] of 974), nor did Pfs230D1 and combination groups differ (-0·024 to 0·001).
Pfs230D1 but not Pfs25 vaccine induces durable serum functional activity in Malian adults. Direct skin feed assays detect parasite transmission to mosquitoes but increased event rates are needed to assess vaccine effectiveness.
Intramural Research Program of the National Institute of Allergy and Infectious Diseases and US National Institutes of Health.
We did a pilot safety study then double-blind, block-randomised, comparator-controlled main-phase trial in malaria-intense Bancoumana, Mali. 18-50-year-old healthy non-pregnant, non-breastfeeding consenting adult residents were randomly assigned (1:1:1:1) to receive four doses at months 0, 1, 4·5, and 16·5 of either 47 μg Pfs25, 40 μg Pfs230D1 or comparator (Twinrix or Menactra)-all co-administered with normal saline for blinding-or 47 μg Pfs25 plus 40 μg Pfs230D1 co-administered. We documented safety and tolerability (primary endpoint in the as-treated populations) and immunogenicity (secondary endpoint in the as-treated populations: ELISA, standard-membrane-feeding assay, and mosquito direct skin feed assay). This trial is registered at ClinicalTrials.gov, NCT02334462.
Between March 19, and June 2, 2015, we screened 471 individuals. Of 225 enrolled for the pilot and main cohorts, we randomly assigned 25 participants to pilot safety cohort groups of five (20%) to receive a two-dose series of Pfs25-EPA/Alhydrogel (16 μg), Pfs230D1-EPA/Alhydrogel (15 μg) or comparator, followed by Pfs25-EPA/Alhydrogel (16 μg) plus Pfs230D1-EPA/Alhydrogel (15 μg) or comparator plus saline. For the main cohort, we enrolled 200 participants between May 11 and June 2, 2015, to receive a four-dose series of 47 μg Pfs25-EPA/Alhydrogel plus saline (n=50 [25%]; Pfs25), 40 μg Pfs230D1-EPA/Alhydrogel plus saline (n=49 [25%]; Pfs230D1), 47 μg Pfs25-EPA/Alhydrogel plus 40 μg Pfs230D1-EPA/Alhydrogel (n=50 [25%]; Pfs25 plus Pfs230D1), or comparator (Twinrix or Menactra) plus saline (n=51 [25%]). Vaccinations were well tolerated in the pilot safety and main phases. Most vaccinees became seropositive after two Pfs230D1 or three Pfs25 doses; peak titres increased with each dose thereafter (Pfs230D1 geometric mean: 77·8 [95% CI 56·9-106·3], 146·4 [108·3-198·0], and 410·2 [301·6-558·0]; Pfs25 geometric mean 177·7 [130·3-242·4] and 315·7 [209·9-474·6]). Functional activity (mean peak transmission-reducing activity) appeared for Pfs230D1 (74·5% [66·6-82·5]) and Pfs25 plus Pfs230D1 (68·6% [57·3-79·8]), after the third dose and after the fourth dose (88·9% [81·7-96·2] for Pfs230D1 and 85·0% [78·4-91·5] Pfs25 plus Pfs230D1) but not for Pfs25 (58·2% [49·1-67·3] after the third dose and 58·2% [48·5-67·9] after the fourth dose). Pfs230D1 transmission-reducing activity (73·7% [64·1-83·3]) persisted 10 weeks after the fourth dose. Transmission-reducing activity of 80% was estimated at 1659 ELISA units for Pfs25, 218 for Pfs230D1, and 223 for Pfs230D1 plus Pfs25. After 3850 direct skin feed assays, 35 participants (12 Pfs25, eight Pfs230D1, five Pfs25 plus Pfs230D1, and ten comparator) had transmitted parasites at least once. The proportion of positive assays in vaccine groups (Pfs25 33 [3%] of 982 [-0·013 to 0·014], Pfs230D1 22 [2%] of 954 [-0·005 to 0·027], and combination 11 [1%] of 940 [-0·024 to 0·002]) did not differ from that of the comparator (22 [2%] of 974), nor did Pfs230D1 and combination groups differ (-0·024 to 0·001).
Pfs230D1 but not Pfs25 vaccine induces durable serum functional activity in Malian adults. Direct skin feed assays detect parasite transmission to mosquitoes but increased event rates are needed to assess vaccine effectiveness.
Intramural Research Program of the National Institute of Allergy and Infectious Diseases and US National Institutes of Health.
摘要：
背景：疟疾传播阻断疫苗针对蚊子期寄生虫，并将支持消灭计划。配子疫苗Pfs230D1-EPA/Alhydrogel在未感染疟疾的美国成年人中诱导的活性优于合子疫苗Pfs25-EPA/Alhydel。这里,我们在有疟疾经验的马里人中比较了这些疫苗。
方法：我们进行了一项试点安全性研究，然后进行了双盲，块随机化，在疟疾强烈的Bancoumana中进行比较控制的主要阶段试验，马里。18-50岁健康未怀孕，非母乳喂养同意的成年居民被随机分配(1:1:1:1),分别在0、1、4·5和16·5个月接受4剂47μgPfs25,40μgPfs230D1或对照品(Twinrix或Menactra)-所有患者均与生理盐水联合致盲或47μgPfs25加40μgPfs230D1联合给药.我们记录了安全性和耐受性（治疗人群的主要终点）和免疫原性（治疗人群的次要终点：ELISA，标准膜饲喂试验，和蚊子直接皮肤饲料测定)。该试验在ClinicalTrials.gov注册，NCT02334462。
结果：在2015年3月19日至6月2日之间，我们筛选了471名个体。在225名飞行员和主要队列中，我们将25名参与者随机分配到五个（20％）的试验安全性队列组，以接受双剂量系列的Pfs25-EPA/Alhydrogel（16μg），Pfs230D1-EPA/Alhydrogel（15μg）或比较器，然后是Pfs25-EPA/Alhydrogel（16μg）加Pfs230D1-EPA/Alhydrogel（15μg）或比较剂加盐水。对于主要队列，我们在2015年5月11日至6月2日之间招募了200名参与者，接受了47μgPfs25-EPA/Alhydrogel加生理盐水的四剂量系列（n=50[25％];Pfs25），40μgPfs230D1-EPA/Alhydrogel加盐水（n=49[25％]；Pfs230D1），47μgPfs25-EPA/Alhydrogel加40μgPfs230D1-EPA/Alhydel(n=50[25%];Pfs25加Pfs230D1),或比较器（Twinrix或Menactra）加盐水（n=51[25％]）。在飞行员安全和主要阶段，疫苗的耐受性良好。大多数疫苗接种者在两次Pfs230D1或三次Pfs25剂量后变得血清阳性；此后每次剂量的峰值滴度增加（Pfs230D1几何平均值：77·8[95％CI56·9-106·3]，146·4[108·3-198·0]，和410·2[301·6-558·0]；Pfs25几何平均值177·7[130·3-242·4]和315·7[209·9-474·6]）。Pfs230D1（74·5％[66·6-82·5]）和Pfs25加上Pfs230D1（68·6％[57·3-79·8]）出现功能活性（平均峰值传输减少活性），在第三剂和第四剂之后（Pfs230D1和85·0%[78·4-91·5]Pfs25加Pfs230D1的88·9%[81·7-96·2]），而不是Pfs25（第三剂之后的58·2%[49·1-67·3]和第四剂之后的58·2%[48·5-67·9]）。Pfs230D1降低传播活性（73·7％[64·1-83·3]）在第四次剂量后持续10周。对于Pfs25，在1659个ELISA单位下，对于Pfs230D1，在218个ELISA单位下，对于Pfs230D1加Pfs25，在223个ELISA单位下，传播减少活性估计为80％。在3850次直接皮肤饲料试验后，35名参与者（12名Pfs25，8名Pfs230D1，5名Pfs25加上Pfs230D1和10名比较者）至少传播了一次寄生虫。疫苗组中阳性检测的比例(982[-0·013至0·014]的Pfs2533[3%]，954[-0·005至0·027]的Pfs230D122[2%]，940[-0·024至0·002]的组合11[1%]）与比较器的组合（974的22[2%]）没有区别，Pfs230D1和组合组也没有差异（-0·024至0·001）。
结论：Pfs230D1而不是Pfs25疫苗在马里成年人中诱导持久的血清功能活性。直接皮肤饲料测定可检测寄生虫向蚊子的传播，但需要增加事件发生率来评估疫苗的有效性。
背景：国家过敏和传染病研究所和美国国立卫生研究院的校内研究计划。
方法：我们进行了一项试点安全性研究，然后进行了双盲，块随机化，在疟疾强烈的Bancoumana中进行比较控制的主要阶段试验，马里。18-50岁健康未怀孕，非母乳喂养同意的成年居民被随机分配(1:1:1:1),分别在0、1、4·5和16·5个月接受4剂47μgPfs25,40μgPfs230D1或对照品(Twinrix或Menactra)-所有患者均与生理盐水联合致盲或47μgPfs25加40μgPfs230D1联合给药.我们记录了安全性和耐受性（治疗人群的主要终点）和免疫原性（治疗人群的次要终点：ELISA，标准膜饲喂试验，和蚊子直接皮肤饲料测定)。该试验在ClinicalTrials.gov注册，NCT02334462。
结果：在2015年3月19日至6月2日之间，我们筛选了471名个体。在225名飞行员和主要队列中，我们将25名参与者随机分配到五个（20％）的试验安全性队列组，以接受双剂量系列的Pfs25-EPA/Alhydrogel（16μg），Pfs230D1-EPA/Alhydrogel（15μg）或比较器，然后是Pfs25-EPA/Alhydrogel（16μg）加Pfs230D1-EPA/Alhydrogel（15μg）或比较剂加盐水。对于主要队列，我们在2015年5月11日至6月2日之间招募了200名参与者，接受了47μgPfs25-EPA/Alhydrogel加生理盐水的四剂量系列（n=50[25％];Pfs25），40μgPfs230D1-EPA/Alhydrogel加盐水（n=49[25％]；Pfs230D1），47μgPfs25-EPA/Alhydrogel加40μgPfs230D1-EPA/Alhydel(n=50[25%];Pfs25加Pfs230D1),或比较器（Twinrix或Menactra）加盐水（n=51[25％]）。在飞行员安全和主要阶段，疫苗的耐受性良好。大多数疫苗接种者在两次Pfs230D1或三次Pfs25剂量后变得血清阳性；此后每次剂量的峰值滴度增加（Pfs230D1几何平均值：77·8[95％CI56·9-106·3]，146·4[108·3-198·0]，和410·2[301·6-558·0]；Pfs25几何平均值177·7[130·3-242·4]和315·7[209·9-474·6]）。Pfs230D1（74·5％[66·6-82·5]）和Pfs25加上Pfs230D1（68·6％[57·3-79·8]）出现功能活性（平均峰值传输减少活性），在第三剂和第四剂之后（Pfs230D1和85·0%[78·4-91·5]Pfs25加Pfs230D1的88·9%[81·7-96·2]），而不是Pfs25（第三剂之后的58·2%[49·1-67·3]和第四剂之后的58·2%[48·5-67·9]）。Pfs230D1降低传播活性（73·7％[64·1-83·3]）在第四次剂量后持续10周。对于Pfs25，在1659个ELISA单位下，对于Pfs230D1，在218个ELISA单位下，对于Pfs230D1加Pfs25，在223个ELISA单位下，传播减少活性估计为80％。在3850次直接皮肤饲料试验后，35名参与者（12名Pfs25，8名Pfs230D1，5名Pfs25加上Pfs230D1和10名比较者）至少传播了一次寄生虫。疫苗组中阳性检测的比例(982[-0·013至0·014]的Pfs2533[3%]，954[-0·005至0·027]的Pfs230D122[2%]，940[-0·024至0·002]的组合11[1%]）与比较器的组合（974的22[2%]）没有区别，Pfs230D1和组合组也没有差异（-0·024至0·001）。
结论：Pfs230D1而不是Pfs25疫苗在马里成年人中诱导持久的血清功能活性。直接皮肤饲料测定可检测寄生虫向蚊子的传播，但需要增加事件发生率来评估疫苗的有效性。
背景：国家过敏和传染病研究所和美国国立卫生研究院的校内研究计划。
