PDF(Pubmed)
Abstract：
Detailed analyses of genetic diversity, antigenic variability, protein localization and immunological responses are vital for the prioritization of novel malaria vaccine candidates. Comprehensive approaches to determine the most appropriate antigen variants needed to provide broad protection are challenging and consequently rarely undertaken.
Here, we characterized PF3D7_1136200, which we named Asparagine-Rich Merozoite Antigen (ARMA) based on the analysis of its sequence, localization and immunogenicity. We analyzed IgG and IgM responses against the common variants of ARMA in independent prospective cohort studies in Burkina Faso (N = 228), Kenya (N = 252) and Mali (N = 195) using a custom microarray, Div-KILCHIP.
We found a marked population structure between parasites from Africa and Asia. African isolates shared 34 common haplotypes, including a dominant pair although the overall selection pressure was directional (Tajima\'s D = -2.57; Fu and Li\'s F = -9.69; P < 0.02). ARMA was localized to the merozoite surface, IgG antibodies induced Fc-mediated degranulation of natural killer cells and strongly inhibited parasite growth in vitro. We found profound serological diversity, but IgG and IgM responses were highly correlated and a hierarchical clustering analysis identified only three major serogroups. Protective IgG and IgM antibodies appeared to target both cross-reactive and distinct epitopes across variants. However, combinations of IgG and IgM antibodies against selected variants were associated with complete protection against clinical episodes of malaria.
Our systematic strategy exploits genomic data to deduce the handful of antigen variants with the strongest potential to induce broad protection and may be broadly applicable to other complex pathogens for which effective vaccines remain elusive.
Here, we characterized PF3D7_1136200, which we named Asparagine-Rich Merozoite Antigen (ARMA) based on the analysis of its sequence, localization and immunogenicity. We analyzed IgG and IgM responses against the common variants of ARMA in independent prospective cohort studies in Burkina Faso (N = 228), Kenya (N = 252) and Mali (N = 195) using a custom microarray, Div-KILCHIP.
We found a marked population structure between parasites from Africa and Asia. African isolates shared 34 common haplotypes, including a dominant pair although the overall selection pressure was directional (Tajima\'s D = -2.57; Fu and Li\'s F = -9.69; P < 0.02). ARMA was localized to the merozoite surface, IgG antibodies induced Fc-mediated degranulation of natural killer cells and strongly inhibited parasite growth in vitro. We found profound serological diversity, but IgG and IgM responses were highly correlated and a hierarchical clustering analysis identified only three major serogroups. Protective IgG and IgM antibodies appeared to target both cross-reactive and distinct epitopes across variants. However, combinations of IgG and IgM antibodies against selected variants were associated with complete protection against clinical episodes of malaria.
Our systematic strategy exploits genomic data to deduce the handful of antigen variants with the strongest potential to induce broad protection and may be broadly applicable to other complex pathogens for which effective vaccines remain elusive.
摘要：
■遗传多样性的详细分析，抗原变异性，蛋白质定位和免疫反应对于新型疟疾疫苗候选物的优先排序至关重要。确定提供广泛保护所需的最合适的抗原变体的综合方法具有挑战性，因此很少进行。
■这里，我们对PF3D7_1136200进行了表征，根据对其序列的分析，我们将其命名为富含天冬酰胺的孢子抗原（ARMA），定位和免疫原性。我们在布基纳法索（N=228）的独立前瞻性队列研究中分析了针对ARMA常见变体的IgG和IgM反应，肯尼亚（N=252）和马里（N=195）使用定制微阵列，Div-KILCHIP.
■我们在非洲和亚洲的寄生虫之间发现了明显的种群结构。非洲分离株共有34种常见单倍型，包括优势对，尽管总体选择压力是方向性的（Tajima\sD=-2.57；Fu和Li\sF=-9.69；P<0.02）。ARMA位于裂殖子表面，IgG抗体诱导Fc介导的自然杀伤细胞脱颗粒，并在体外强烈抑制寄生虫的生长。我们发现了深刻的血清学多样性，但IgG和IgM应答高度相关,分层聚类分析仅鉴定出三种主要血清群.保护性IgG和IgM抗体似乎靶向跨变体的交叉反应性表位和不同表位。然而,针对选定变异体的IgG和IgM抗体组合与针对疟疾临床发作的完全保护相关.
我们的系统策略利用基因组数据来推断少数抗原变体，这些抗原变体具有最强的诱导广泛保护的潜力，并且可能广泛适用于有效疫苗仍然难以捉摸的其他复杂病原体。
■这里，我们对PF3D7_1136200进行了表征，根据对其序列的分析，我们将其命名为富含天冬酰胺的孢子抗原（ARMA），定位和免疫原性。我们在布基纳法索（N=228）的独立前瞻性队列研究中分析了针对ARMA常见变体的IgG和IgM反应，肯尼亚（N=252）和马里（N=195）使用定制微阵列，Div-KILCHIP.
■我们在非洲和亚洲的寄生虫之间发现了明显的种群结构。非洲分离株共有34种常见单倍型，包括优势对，尽管总体选择压力是方向性的（Tajima\sD=-2.57；Fu和Li\sF=-9.69；P<0.02）。ARMA位于裂殖子表面，IgG抗体诱导Fc介导的自然杀伤细胞脱颗粒，并在体外强烈抑制寄生虫的生长。我们发现了深刻的血清学多样性，但IgG和IgM应答高度相关,分层聚类分析仅鉴定出三种主要血清群.保护性IgG和IgM抗体似乎靶向跨变体的交叉反应性表位和不同表位。然而,针对选定变异体的IgG和IgM抗体组合与针对疟疾临床发作的完全保护相关.
我们的系统策略利用基因组数据来推断少数抗原变体，这些抗原变体具有最强的诱导广泛保护的潜力，并且可能广泛适用于有效疫苗仍然难以捉摸的其他复杂病原体。
