Fries L F, Gordon D M, Schneider I, Beier J C, Long G W, Gross M, Que J U, Cryz S J, Sadoff J C
Center for Immunization Research, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205.
Infect Immun. 1992 May;60(5):1834-9. doi: 10.1128/iai.60.5.1834-1839.1992.
Twenty-one malaria-naive volunteers were immunized with a vaccine consisting of a 22-kDa recombinant peptide (R32LR), derived from the repeat region of Plasmodium falciparum circumsporozoite (CS) protein, covalently coupled to detoxified Pseudomonas aeruginosa toxin A. Nineteen volunteers received a second dose of vaccine at 8 weeks, and eighteen received a third dose at 8 to 12 months. The vaccine was well tolerated, with only one volunteer developing local discomfort and induration at the site of injection which limited function for 48 h. The geometric mean anti-CS immunoglobulin G antibody concentration 2 weeks after the second dose of vaccine was 10.6 micrograms/ml (standard deviation = 3.0 micrograms/ml). Eleven volunteers (52%) developed anti-CS antibody levels of greater than 9.8 micrograms/ml, the level measured in the one volunteer protected against P. falciparum challenge after immunization with the alum-adjuvanted recombinant protein R32tet32 in a prior study. Three separate experimental challenges were conducted with 10 volunteers 2 to 4 weeks after the third dose of vaccine. The four best responders, on the basis of antibody levels (6 to 26 micrograms/ml), were challenged with two infected-mosquito bites, but only one of four immunized volunteers and one of three malaria-naive controls became parasitemic. In a second challenge study using five infected-mosquito bites as the challenge dose, three of three malaria-naive control volunteers and two of three immunized volunteers developed malaria. The third vaccine was apparently completely protected. In the third and last challenge, three of three controls and five of five vaccinees became infected. Sera obtained on the days of challenge inhibited sporozoite invasion of hepatocytes variably in vitro (range, 45 to 90% inhibition), but the degree of inhibition did not correlate with protection. Although antibody against the CS repeat region may protect some individuals against experimental challenge, this protection cannot be predicted from antibody levels by current in vitro assays. The functionality and fine specificity of anti-CS antibody are probably critical determinants.
21名未曾感染过疟疾的志愿者接种了一种疫苗，该疫苗由一种22 kDa重组肽（R32LR）组成，其来源于恶性疟原虫环子孢子（CS）蛋白的重复区域，与脱毒的铜绿假单胞菌毒素A共价偶联。19名志愿者在8周时接受了第二剂疫苗，18名志愿者在8至12个月时接受了第三剂疫苗。该疫苗耐受性良好，只有一名志愿者在注射部位出现局部不适和硬结，持续48小时影响功能。第二剂疫苗接种2周后，抗CS免疫球蛋白G抗体浓度的几何平均值为10.6微克/毫升（标准差 = 3.0微克/毫升）。11名志愿者（52%）产生的抗CS抗体水平高于9.8微克/毫升，这是之前一项研究中用明矾佐剂重组蛋白R32tet32免疫后对恶性疟原虫攻击具有保护作用的一名志愿者所测得的水平。在第三剂疫苗接种2至4周后，对10名志愿者进行了3次独立的实验性攻击。根据抗体水平（6至26微克/毫升），4名反应最佳者接受了两次感染蚊子叮咬的攻击，但4名免疫志愿者中只有1名以及3名未感染疟疾的对照者中有1名出现了寄生虫血症。在第二项攻击研究中，使用5次感染蚊子叮咬作为攻击剂量，3名未感染疟疾的对照志愿者中有3名以及3名免疫志愿者中有2名感染了疟疾。第三名接种疫苗者显然完全受到了保护。在第三次也是最后一次攻击中，3名对照者中有3名以及5名接种疫苗者中有5名被感染。在攻击当天获得的血清在体外对子孢子侵入肝细胞的抑制程度各不相同（范围为45%至90%抑制），但抑制程度与保护作用无关。尽管针对CS重复区域的抗体可能会保护一些个体免受实验性攻击，但目前的体外检测无法根据抗体水平预测这种保护作用。抗CS抗体的功能和精细特异性可能是关键决定因素。
