Takala Shannon L, Coulibaly Drissa, Thera Mahamadou A, Dicko Alassane, Smith David L, Guindo Ando B, Kone Abdoulaye K, Traore Karim, Ouattara Amed, Djimde Abdoulaye A, Sehdev Paul S, Lyke Kirsten E, Diallo Dapa A, Doumbo Ogobara K, Plowe Christopher V
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
PLoS Med. 2007 Mar;4(3):e93. doi: 10.1371/journal.pmed.0040093.
Malaria vaccines based on the 19-kDa region of merozoite surface protein 1 (MSP-1(19)) derived from the 3D7 strain of Plasmodium falciparum are being tested in clinical trials in Africa. Knowledge of the distribution and natural dynamics of vaccine antigen polymorphisms in populations in which malaria vaccines will be tested will guide vaccine design and permit distinction between natural fluctuations in genetic diversity and vaccine-induced selection.
Using pyrosequencing, six single-nucleotide polymorphisms in the nucleotide sequence encoding MSP-1(19) were genotyped from 1,363 malaria infections experienced by 100 children who participated in a prospective cohort study in Mali from 1999 to 2001. The frequencies of 14 MSP-1(19) haplotypes were compared over the course of the malaria transmission season for all three years, in three age groups, and in consecutive infections within individuals. While the frequency of individual MSP-1(19) haplotypes fluctuated, haplotypes corresponding to FVO and FUP strains of P. falciparum (MSP-1(19) haplotypes QKSNGL and EKSNGL, respectively) were most prevalent during three consecutive years and in all age groups with overall prevalences of 46% (95% confidence interval [CI] 44%-49%) and 36% (95% CI 34%-39%), respectively. The 3D7 haplotype had a lower overall prevalence of 16% (95% CI 14%-18%). Multiplicity of infection based on MSP-1(19) was higher at the beginning of the transmission season and in the oldest individuals (aged > or =11 y). Three MSP-1(19) haplotypes had a reduced frequency in symptomatic infections compared to asymptomatic infections. Analyses of the dynamics of MSP-1(19) polymorphisms in consecutive infections implicate three polymorphisms (at positions 1691, 1700, and 1701) as being particularly important in determining allele specificity of anti-MSP-1(19) immunity.
Parasites with MSP-1(19) haplotypes different from that of the leading vaccine strain were consistently the most prevalent at a vaccine trial site. If immunity elicited by an MSP-1-based vaccine is allele-specific, a vaccine based on either the FVO or FUP strain might have better initial efficacy at this site. This study, to our knowledge the largest of its kind to date, provides molecular information needed to interpret population responses to MSP-1-based vaccines and suggests that certain MSP-1(19) polymorphisms may be relevant to cross-protective immunity.
基于恶性疟原虫3D7株裂殖子表面蛋白1（MSP-1(19)）19-kDa区域的疟疾疫苗正在非洲进行临床试验。了解疟疾疫苗试验人群中疫苗抗原多态性的分布和自然动态，将为疫苗设计提供指导，并有助于区分遗传多样性的自然波动和疫苗诱导的选择。
采用焦磷酸测序法，对1999年至2001年在马里参加前瞻性队列研究的100名儿童经历的1363次疟疾感染中编码MSP-1(19)的核苷酸序列中的6个单核苷酸多态性进行基因分型。在三年的疟疾传播季节中，比较了三个年龄组以及个体内连续感染中14种MSP-1(19)单倍型的频率。虽然单个MSP-1(19)单倍型的频率有所波动，但与恶性疟原虫FVO和FUP株相对应的单倍型（分别为MSP-1(19)单倍型QKSNGL和EKSNGL）在连续三年中以及所有年龄组中最为普遍，总体患病率分别为46%（95%置信区间[CI] 44%-49%）和36%（95% CI 34%-39%）。3D7单倍型的总体患病率较低，为16%（95% CI 14%-18%）。基于MSP-1(19)的感染多样性在传播季节开始时以及年龄最大的个体（年龄≥11岁）中较高。与无症状感染相比，三种MSP-1(19)单倍型在有症状感染中的频率降低。对连续感染中MSP-1(19)多态性动态的分析表明，三个多态性位点（第1691、1700和1701位）在确定抗MSP-1(19)免疫的等位基因特异性方面尤为重要。
在一个疫苗试验地点，具有与主要疫苗株不同的MSP-1(19)单倍型的寄生虫始终是最普遍的。如果基于MSP-1的疫苗引发的免疫是等位基因特异性的，那么基于FVO或FUP株的疫苗在该地点可能具有更好的初始疗效。据我们所知，本研究是迄今为止同类研究中规模最大的，提供了解释人群对基于MSP-1的疫苗反应所需的分子信息，并表明某些MSP-1(19)多态性可能与交叉保护性免疫相关。
