Lyon Jeffrey A, Angov Evelina, Fay Michael P, Sullivan JoAnn S, Girourd Autumn S, Robinson Sally J, Bergmann-Leitner Elke S, Duncan Elizabeth H, Darko Christian A, Collins William E, Long Carole A, Barnwell John W
Division Malaria Vaccine Development, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
PLoS One. 2008 Jul 30;3(7):e2830. doi: 10.1371/journal.pone.0002830.
Vaccination with Plasmodium falciparum MSP1(42)/complete Freund's adjuvant (FA) followed by MSP1(42)/incomplete FA is the only known regimen that protects Aotus nancymaae monkeys against infection by erythrocytic stage malaria parasites. The role of adjuvant is not defined; however complete FA cannot be used in humans. In rodent models, immunity is strain-specific. We vaccinated Aotus monkeys with the FVO or 3D7 alleles of MSP1(42) expressed in Escherichia coli or with the FVO allele expressed in baculovirus (bv) combined with complete and incomplete FA, Montanide ISA-720 (ISA-720) or AS02A. Challenge with FVO strain P. falciparum showed that suppression of cumulative day 11 parasitemia was strain-specific and could be induced by E. coli expressed MSP1(42) in combination with FA or ISA-720 but not with AS02A. The coli42-FVO antigen induced a stronger protective effect than the bv42-FVO antigen, and FA induced a stronger protective effect than ISA-720. ELISA antibody (Ab) responses at day of challenge (DOC) were strain-specific and correlated inversely with c-day 11 parasitemia (r = -0.843). ELISA Ab levels at DOC meeting a titer of at least 115,000 ELISA Ab units identified the vaccinees not requiring treatment (noTx) with a true positive rate of 83.3% and false positive rate of 14.3 %. Correlation between functional growth inhibitory Ab levels (GIA) and cumulative day 11 parasitemia was weaker (r = -0.511), and was not as predictive for a response of noTx. The lowest false positive rate for GIA was 30% when requiring a true positive rate of 83.3%. These inhibition results along with those showing that antigen/FA combinations induced a stronger protective immunity than antigen/ISA-720 or antigen/AS02 combinations are consistent with protection as ascribed to MSP1-specific cytophilic antibodies. Development of an effective MSP1(42) vaccine against erythrocytic stage P. falciparum infection will depend not only on antigen quality, but also upon the selection of an optimal adjuvant component.
先用恶性疟原虫MSP1(42)/完全弗氏佐剂（FA）免疫，随后用MSP1(42)/不完全FA免疫，是目前已知的唯一能保护南希夜猴免受红细胞期疟原虫感染的方案。佐剂的作用尚不明确；然而，完全FA不能用于人类。在啮齿动物模型中，免疫具有品系特异性。我们用在大肠杆菌中表达的MSP1(42)的FVO或3D7等位基因，或用杆状病毒（bv）中表达的FVO等位基因与完全和不完全FA、Montanide ISA - 720（ISA - 720）或AS02A联合免疫夜猴。用FVO株恶性疟原虫攻击后发现，对第11天累积寄生虫血症的抑制具有品系特异性，并且可以由大肠杆菌表达的MSP1(42)与FA或ISA - 720联合诱导，但不能由AS02A诱导。大肠杆菌42 - FVO抗原诱导的保护作用比杆状病毒42 - FVO抗原更强，并且FA诱导的保护作用比ISA - 720更强。攻击日（DOC）的ELISA抗体（Ab）反应具有品系特异性，并且与第11天的累积寄生虫血症呈负相关（r = -0.843）。DOC时ELISA Ab水平达到至少115,000 ELISA Ab单位可识别出无需治疗（noTx）的疫苗接种者，真阳性率为83.3%，假阳性率为14.3%。功能性生长抑制Ab水平（GIA）与第11天累积寄生虫血症之间的相关性较弱（r = -0.511），并且对noTx反应的预测性不如前者。当要求真阳性率为83.3%时，GIA的最低假阳性率为30%。这些抑制结果以及那些表明抗原/FA组合比抗原/ISA - 720或抗原/AS02组合诱导更强的保护性免疫的结果，与归因于MSP1特异性亲细胞抗体的保护作用一致。开发一种有效的针对红细胞期恶性疟原虫感染的MSP1(42)疫苗不仅将取决于抗原质量，还将取决于最佳佐剂成分的选择。
