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BackgroundMalaria vaccines based on the 19-kDa region of merozoite surface protein 1 (MSP-119) 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.Methods and FindingsUsing pyrosequencing, six single-nucleotide polymorphisms in the nucleotide sequence encoding MSP-119 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-119 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-119 haplotypes fluctuated, haplotypes corresponding to FVO and FUP strains of P. falciparum (MSP-119 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-119 was higher at the beginning of the transmission season and in the oldest individuals (aged ≥11 y). Three MSP-119 haplotypes had a reduced frequency in symptomatic infections compared to asymptomatic infections. Analyses of the dynamics of MSP-119 polymorphisms in consecutive infections implicate three polymorphisms (at positions 1691, 1700, and 1701) as being particularly important in determining allele specificity of anti-MSP-119 immunity.ConclusionsParasites with MSP-119 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-119 polymorphisms may be relevant to cross-protective immunity.

In this setting of low antifolate resistance, TS was highly effective in preventing falciparum malaria infection and disease and did not appear to select for SP-resistant parasites.

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Reports describing the behavior of micropapillary serous carcinomas (MPSCs) of the ovary have focused on those that are noninvasive. There are only very limited data on the behavior of those that are invasive. To further characterize the behavior of MPSCs, invasive versus noninvasive primary tumors were distinguished based on the presence or absence of destructive infiltrative growth. To qualify for inclusion, invasive MPSCs, like the noninvasive tumors, were required to display a micropapillary architecture and low-grade nuclei. A total of 135 cases of MPSC were identified: 96 noninvasive and 39 invasive. On follow-up, survival for 10 patients with stage I noninvasive and invasive MPSCs was 100%, and survival for women with stage II and III noninvasive and invasive MPSCs with noninvasive implants was 80%. In contrast, the 5-year and 10-year survival for patients with stage II and III noninvasive MPSCs with invasive implants was 85% and 55%, respectively. The 5-year and 10-year survival for women with invasive MPSCs and invasive implants was 55% and 45%, respectively. The median time from diagnosis to death for women with noninvasive and invasive MPSCs with invasive implants was 60 months (range 33-240 months). The indolent behavior of these low-grade carcinomas distinguishes them from conventional serous carcinomas, which are high-grade aggressive neoplasms. Five of six patients with small (<5 mm) MPSCs in whom follow-up was available presented with high stage disease. Of these five women, three are alive and well and two are alive with disease (one with invasive and one with noninvasive implants). Nearly three fourths of noninvasive MPSCs were associated with atypical proliferative serous tumors, adenofibromas, or both, and 62% of invasive MPSCs were associated with noninvasive MPSCs, atypical proliferative serous tumors, and adenofibromas, alone or in combination. In addition to the frequent mixtures of these tumor components, transitions between them were common. These data in conjunction with recent molecular genetic studies strongly suggest that MPSCs (low-grade carcinomas) arise from atypical proliferative serous tumors unlike conventional serous carcinomas (high-grade carcinomas), which appear to develop de novo. The findings provide further support for the hypothesis that there are distinct pathways of carcinogenesis for low-grade and high-grade serous carcinoma of the ovary.