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Abstract：
BACKGROUND: In 2021 and 2023, the World Health Organization approved RTS,S/AS01 and R21/Matrix M malaria vaccines, respectively, for routine immunization of children in African countries with moderate to high transmission. These vaccines are made of Plasmodium falciparum circumsporozoite protein (PfCSP), but polymorphisms in the gene raise concerns regarding strain-specific responses and the long-term efficacy of these vaccines. This study assessed the Pfcsp genetic diversity, population structure and signatures of selection among parasites from areas of different malaria transmission intensities in Mainland Tanzania, to generate baseline data before the introduction of the malaria vaccines in the country.
METHODS: The analysis involved 589 whole genome sequences generated by and as part of the MalariaGEN Community Project. The samples were collected between 2013 and January 2015 from five regions of Mainland Tanzania: Morogoro and Tanga (Muheza) (moderate transmission areas), and Kagera (Muleba), Lindi (Nachingwea), and Kigoma (Ujiji) (high transmission areas). Wright\'s inbreeding coefficient (Fws), Wright\'s fixation index (FST), principal component analysis, nucleotide diversity, and Tajima\'s D were used to assess within-host parasite diversity, population structure and natural selection.
RESULTS: Based on Fws (< 0.95), there was high polyclonality (ranging from 69.23% in Nachingwea to 56.9% in Muheza). No population structure was detected in the Pfcsp gene in the five regions (mean FST = 0.0068). The average nucleotide diversity (π), nucleotide differentiation (K) and haplotype diversity (Hd) in the five regions were 4.19, 0.973 and 0.0035, respectively. The C-terminal region of Pfcsp showed high nucleotide diversity at Th2R and Th3R regions. Positive values for the Tajima\'s D were observed in the Th2R and Th3R regions consistent with balancing selection. The Pfcsp C-terminal sequences revealed 50 different haplotypes (H_1 to H_50), with only 2% of sequences matching the 3D7 strain haplotype (H_50). Conversely, with the NF54 strain, the Pfcsp C-terminal sequences revealed 49 different haplotypes (H_1 to H_49), with only 0.4% of the sequences matching the NF54 strain (Hap_49).
CONCLUSIONS: The findings demonstrate high diversity of the Pfcsp gene with limited population differentiation. The Pfcsp gene showed positive Tajima\'s D values, consistent with balancing selection for variants within Th2R and Th3R regions. The study observed differences between the intended haplotypes incorporated into the design of RTS,S and R21 vaccines and those present in natural parasite populations. Therefore, additional research is warranted, incorporating other regions and more recent data to comprehensively assess trends in genetic diversity within this important gene. Such insights will inform the choice of alleles to be included in the future vaccines.
METHODS: The analysis involved 589 whole genome sequences generated by and as part of the MalariaGEN Community Project. The samples were collected between 2013 and January 2015 from five regions of Mainland Tanzania: Morogoro and Tanga (Muheza) (moderate transmission areas), and Kagera (Muleba), Lindi (Nachingwea), and Kigoma (Ujiji) (high transmission areas). Wright\'s inbreeding coefficient (Fws), Wright\'s fixation index (FST), principal component analysis, nucleotide diversity, and Tajima\'s D were used to assess within-host parasite diversity, population structure and natural selection.
RESULTS: Based on Fws (< 0.95), there was high polyclonality (ranging from 69.23% in Nachingwea to 56.9% in Muheza). No population structure was detected in the Pfcsp gene in the five regions (mean FST = 0.0068). The average nucleotide diversity (π), nucleotide differentiation (K) and haplotype diversity (Hd) in the five regions were 4.19, 0.973 and 0.0035, respectively. The C-terminal region of Pfcsp showed high nucleotide diversity at Th2R and Th3R regions. Positive values for the Tajima\'s D were observed in the Th2R and Th3R regions consistent with balancing selection. The Pfcsp C-terminal sequences revealed 50 different haplotypes (H_1 to H_50), with only 2% of sequences matching the 3D7 strain haplotype (H_50). Conversely, with the NF54 strain, the Pfcsp C-terminal sequences revealed 49 different haplotypes (H_1 to H_49), with only 0.4% of the sequences matching the NF54 strain (Hap_49).
CONCLUSIONS: The findings demonstrate high diversity of the Pfcsp gene with limited population differentiation. The Pfcsp gene showed positive Tajima\'s D values, consistent with balancing selection for variants within Th2R and Th3R regions. The study observed differences between the intended haplotypes incorporated into the design of RTS,S and R21 vaccines and those present in natural parasite populations. Therefore, additional research is warranted, incorporating other regions and more recent data to comprehensively assess trends in genetic diversity within this important gene. Such insights will inform the choice of alleles to be included in the future vaccines.
摘要：
背景：在2021年和2023年，世界卫生组织批准了RTS，S/AS01和R21/MatrixM疟疾疫苗，分别,用于非洲国家中度到高度传播儿童的常规免疫接种。这些疫苗由恶性疟原虫环子孢子蛋白（PfCSP）制成，但该基因的多态性引起了人们对毒株特异性反应和这些疫苗长期疗效的担忧.这项研究评估了Pfcsp的遗传多样性，来自坦桑尼亚大陆不同疟疾传播强度地区的寄生虫的种群结构和选择特征，在该国引入疟疾疫苗之前生成基线数据。
方法：分析涉及589个由MalariaGEN社区项目产生的全基因组序列。样本是在2013年至2015年1月期间从坦桑尼亚大陆的五个地区收集的：Morogoro和Tanga（Muheza）（中度传播区），和Kagera（Muleba），Lindi(Nachingwea),和基戈马（Ujiji）（高传播区）。赖特近亲繁殖系数(Fws)，赖特的固定指数（FST），主成分分析，核苷酸多样性，和田岛的D被用来评估宿主内寄生虫的多样性，种群结构和自然选择。
结果：基于Fws（<0.95），多克隆性高（从Nachingwea的69.23％到Muheza的56.9％）。在五个区域的Pfcsp基因中未检测到种群结构（平均FST=0.0068）。平均核苷酸多样性(π)，五个区域的核苷酸分化（K）和单倍型多样性（Hd）分别为4.19、0.973和0.0035。Pfcsp的C端区域在Th2R和Th3R区域显示出高度的核苷酸多样性。在Th2R和Th3R区域观察到Tajima'sD的正值，与平衡选择一致。PfcspC端序列揭示了50种不同的单倍型（H_1至H_50），只有2％的序列匹配3D7菌株单倍型（H_50）。相反，NF54菌株，PfcspC端序列揭示了49种不同的单倍型(H_1至H_49)，只有0.4%的序列匹配NF54菌株(Hap_49)。
结论：研究结果表明Pfcsp基因具有高度多样性，种群分化有限。Pfcsp基因显示田岛的D值呈阳性，与Th2R和Th3R区域内变体的平衡选择一致。该研究观察到纳入RTS设计的预期单倍型之间的差异，S和R21疫苗以及存在于天然寄生虫种群中的疫苗。因此,额外的研究是必要的，纳入其他地区和最新数据，以全面评估这一重要基因的遗传多样性趋势。这些见解将为将来的疫苗中包括的等位基因的选择提供信息。
方法：分析涉及589个由MalariaGEN社区项目产生的全基因组序列。样本是在2013年至2015年1月期间从坦桑尼亚大陆的五个地区收集的：Morogoro和Tanga（Muheza）（中度传播区），和Kagera（Muleba），Lindi(Nachingwea),和基戈马（Ujiji）（高传播区）。赖特近亲繁殖系数(Fws)，赖特的固定指数（FST），主成分分析，核苷酸多样性，和田岛的D被用来评估宿主内寄生虫的多样性，种群结构和自然选择。
结果：基于Fws（<0.95），多克隆性高（从Nachingwea的69.23％到Muheza的56.9％）。在五个区域的Pfcsp基因中未检测到种群结构（平均FST=0.0068）。平均核苷酸多样性(π)，五个区域的核苷酸分化（K）和单倍型多样性（Hd）分别为4.19、0.973和0.0035。Pfcsp的C端区域在Th2R和Th3R区域显示出高度的核苷酸多样性。在Th2R和Th3R区域观察到Tajima'sD的正值，与平衡选择一致。PfcspC端序列揭示了50种不同的单倍型（H_1至H_50），只有2％的序列匹配3D7菌株单倍型（H_50）。相反，NF54菌株，PfcspC端序列揭示了49种不同的单倍型(H_1至H_49)，只有0.4%的序列匹配NF54菌株(Hap_49)。
结论：研究结果表明Pfcsp基因具有高度多样性，种群分化有限。Pfcsp基因显示田岛的D值呈阳性，与Th2R和Th3R区域内变体的平衡选择一致。该研究观察到纳入RTS设计的预期单倍型之间的差异，S和R21疫苗以及存在于天然寄生虫种群中的疫苗。因此,额外的研究是必要的，纳入其他地区和最新数据，以全面评估这一重要基因的遗传多样性趋势。这些见解将为将来的疫苗中包括的等位基因的选择提供信息。
