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Abstract：
Diverse vaccination outcomes and protection levels among different populations pose a serious challenge to the development of an effective malaria vaccine. Co-infections are among many factors associated with immune dysfunction and sub-optimal vaccination outcomes. Chronic, asymptomatic viral infections can contribute to the modulation of vaccine efficacy through various mechanisms. Human Pegivirus-1 (HPgV-1) persists in immune cells thereby potentially modulating immune responses. We investigated whether Pegivirus infection influences vaccine-induced responses and protection in African volunteers undergoing whole P. falciparum sporozoites-based malaria vaccination and controlled human malaria infections (CHMI).
HPgV-1 prevalence was quantified by RT-qPCR in plasma samples of 96 individuals before, post vaccination with PfSPZ Vaccine and after CHMI in cohorts from Tanzania and Equatorial Guinea. The impact of HPgV-1 infection was evaluated on (1) systemic cytokine and chemokine levels measured by Luminex, (2) PfCSP-specific antibody titers quantified by ELISA, (3) asexual blood-stage parasitemia pre-patent periods and parasite multiplication rates, (4) HPgV-1 RNA levels upon asexual blood-stage parasitemia induced by CHMI.
The prevalence of HPgV-1 was 29.2% (28/96) and sequence analysis of the 5\' UTR and E2 regions revealed the predominance of genotypes 1, 2 and 5. HPgV-1 infection was associated with elevated systemic levels of IL-2 and IL-17A. Comparable vaccine-induced anti-PfCSP antibody titers, asexual blood-stage multiplication rates and pre-patent periods were observed in HPgV-1 positive and negative individuals. However, a tendency for higher protection levels was detected in the HPgV-1 positive group (62.5%) compared to the negative one (51.6%) following CHMI. HPgV-1 viremia levels were not significantly altered after CHMI.
HPgV-1 infection did not alter PfSPZ Vaccine elicited levels of PfCSP-specific antibody responses and parasite multiplication rates. Ongoing HPgV-1 infection appears to improve to some degree protection against CHMI in PfSPZ-vaccinated individuals. This is likely through modulation of immune system activation and systemic cytokines as higher levels of IL-2 and IL17A were observed in HPgV-1 infected individuals. CHMI is safe and well tolerated in HPgV-1 infected individuals. Identification of cell types and mechanisms of both silent and productive infection in individuals will help to unravel the biology of this widely present but largely under-researched virus.
HPgV-1 prevalence was quantified by RT-qPCR in plasma samples of 96 individuals before, post vaccination with PfSPZ Vaccine and after CHMI in cohorts from Tanzania and Equatorial Guinea. The impact of HPgV-1 infection was evaluated on (1) systemic cytokine and chemokine levels measured by Luminex, (2) PfCSP-specific antibody titers quantified by ELISA, (3) asexual blood-stage parasitemia pre-patent periods and parasite multiplication rates, (4) HPgV-1 RNA levels upon asexual blood-stage parasitemia induced by CHMI.
The prevalence of HPgV-1 was 29.2% (28/96) and sequence analysis of the 5\' UTR and E2 regions revealed the predominance of genotypes 1, 2 and 5. HPgV-1 infection was associated with elevated systemic levels of IL-2 and IL-17A. Comparable vaccine-induced anti-PfCSP antibody titers, asexual blood-stage multiplication rates and pre-patent periods were observed in HPgV-1 positive and negative individuals. However, a tendency for higher protection levels was detected in the HPgV-1 positive group (62.5%) compared to the negative one (51.6%) following CHMI. HPgV-1 viremia levels were not significantly altered after CHMI.
HPgV-1 infection did not alter PfSPZ Vaccine elicited levels of PfCSP-specific antibody responses and parasite multiplication rates. Ongoing HPgV-1 infection appears to improve to some degree protection against CHMI in PfSPZ-vaccinated individuals. This is likely through modulation of immune system activation and systemic cytokines as higher levels of IL-2 and IL17A were observed in HPgV-1 infected individuals. CHMI is safe and well tolerated in HPgV-1 infected individuals. Identification of cell types and mechanisms of both silent and productive infection in individuals will help to unravel the biology of this widely present but largely under-researched virus.
摘要：
不同人群的不同疫苗接种结果和保护水平对开发有效的疟疾疫苗构成了严峻挑战。共感染是与免疫功能障碍和次优疫苗接种结果相关的许多因素之一。慢性,无症状的病毒感染可以通过各种机制调节疫苗的效力。人PEgivirus-1(HPgV-1)在免疫细胞中持续存在,从而潜在地调节免疫应答。我们调查了接受基于完整恶性疟原虫子孢子的疟疾疫苗接种和控制人类疟疾感染（CHMI）的非洲志愿者中，Pegivirus感染是否会影响疫苗诱导的反应和保护。
通过RT-qPCR对之前96名个体的血浆样品中的HPgV-1患病率进行定量,在坦桑尼亚和赤道几内亚的队列中接种PfSPZ疫苗后和CHMI后。评估了HPgV-1感染对（1）Luminex测量的全身细胞因子和趋化因子水平的影响，（2）通过ELISA定量的PfCSP特异性抗体滴度，(3)无性血期寄生虫血症专利前期和寄生虫繁殖率,(4)CHMI诱导的无性血液期寄生虫血症时的HPgV-1RNA水平。
HPgV-1的患病率为29.2％（28/96），5'UTR和E2区域的序列分析显示基因型1、2和5占优势。HPgV-1感染与IL-2和IL-17A的全身水平升高有关。可比较的疫苗诱导的抗PfCSP抗体滴度，在HPgV-1阳性和阴性个体中观察到无性血液阶段的增殖率和专利前期。然而,与CHMI后的阴性组(51.6%)相比,HPgV-1阳性组(62.5%)有更高保护水平的趋势.CHMI后HPgV-1病毒血症水平无明显变化。
HPgV-1感染没有改变PfSPZ疫苗引起的PfCSP特异性抗体反应和寄生虫增殖率的水平。正在进行的HPgV-1感染似乎在一定程度上改善了接种PfSPZ的个体对CHMI的保护。这可能是通过调节免疫系统活化和全身细胞因子,因为在HPgV-1感染的个体中观察到更高水平的IL-2和IL17A。CHMI在HPgV-1感染个体中是安全且耐受性良好的。鉴定个体中沉默和生产性感染的细胞类型和机制将有助于解开这种广泛存在但大部分研究不足的病毒的生物学。
通过RT-qPCR对之前96名个体的血浆样品中的HPgV-1患病率进行定量,
HPgV-1的患病率为29.2％（28/96），5'UTR和E2区域的序列分析显示基因型1、2和5占优势。
HPgV-1感染没有改变PfSPZ疫苗引起的PfCSP特异性抗体反应和寄生虫增殖率的水平。
