T Cell Regulatory and Suppression Mechanisms in Malaria

我们在2023财年发表的工作包括： KC N，Church LWP，Riyahi P，Chakravarty S，Seder RA，Epstein Je，Lyke Ke，Mordmler B，Kremsner PG，Sissoko MS，Healy S，Duffy PE，Jongo SA，Nchama Vunn，阿不都拉·S，Mpina M，Sirima SB，Laurens MB，Steinhardt LC，Oneko M，Li M，Murshedkar T，Billingsley PF，Sim BKL，Richie TL，Hoffman。在接受PfSPZ疫苗免疫的青春期后女性中，抗PfCSP抗体水平高于男性，但并不能转化为增强保护效果。2022年免疫学前沿：OCT25.13：1006716。DOI：10.3389/fimmu.2022.1006716. 虽然先前的研究表明男性和女性感染疟疾和患病的风险存在差异，但对疫苗诱导的疟疾免疫的性别差异知之甚少。查明这些差异可以阐明疟疾生物学的重要方面，并有助于制定改进的疟疾疫苗接种方法。使用标准化的ELISA法，在德国、美国和五个非洲国家进行的11项临床试验中，对5个月至61岁的儿童接种PfSPZ疫苗前和接种后两周的主要子孢子表面蛋白PfCSP的抗体进行了检测，以确定疫苗引起的抗体反应在男性和女性之间的差异，以及这些差异是否与对自然传播的肺吸虫病(非洲)或控制的人类疟疾感染(德国、美国和非洲)的差异有关。 在大多数试验中，11岁的女性对PfCSP的抗体水平明显高于男性，而婴儿或儿童中没有迹象表明这种差异。尽管成年女性的抗体水平较高，但没有证据表明与男性相比，保护效果更好。在有足够数据的7个试验中，2个受保护的男性的抗体水平明显高于未保护的男性，在另外3个试验中，受保护的女性的抗体水平高于未受保护的女性。我们的结论是，PfSPZ疫苗在青春期后的女性中诱导了更高水平的抗体，但在男性和女性中表现出同等的保护作用。青春期后女性的抗体水平增加并不能显著改善保护效果。我们推测，虽然PfCSP(和PfSPZ)的抗体可能直接起到保护作用，但它们主要与其他潜在的保护性免疫机制有关，例如肝脏中的抗体依赖和抗体非依赖的细胞反应。 里奇·TL，丘奇·莱文，墨舍卡尔·T，比林斯利·PF，詹姆斯·ER，希利·SA，迪亚瓦·H，西索科·MS，萨加拉一世，库克·DM，莫德姆勒B，查克拉瓦蒂·S，卡普鲁·M，克里登韦斯A，沃恩·A，忽必林J，墨菲·S，容戈·S，坦纳·M，西里玛·S，劳伦斯·M，道本伯格·C，席尔瓦·J，莱克·柯，阿不都拉·S，迪科·A，卡普·S，西姆·巴克尔，克里姆斯纳·PG，达菲·PE，霍夫曼·SL。子孢子免疫：支持防治疟疾的创新转化科学。2023年。疫苗专家评论。在媒体上。电话：10.1080/14760584.2023.2245890 迫切需要一种高效的疟疾疫苗，特别是对恶性疟原虫，这是人类最致命的疟疾寄生虫。子孢子(SPZ)是由按蚊传播给人类的寄生虫期，是唯一一种对PF感染达到90%有效的疫苗免疫原。我们和PfSPZ财团的合作伙伴审查了PfSPZ疫苗在美国、欧洲、非洲和亚洲的30项临床试验，这些试验和PubMed搜索“子孢子”、“疟疾”和“疫苗”的第一手知识为基础。第一代(辐射减毒)PfSPZ疫苗安全、耐受性好，对同源受控人类疟疾感染(CHMI)有80%-100%的有效率。然而，在流行地区进行的试验对自然发生感染的保护效果较低，但效果显著；LMIV与马里和萨那里亚的科学家合作，在非洲展示了18-19个月的保护作用，但没有加强。未来的研究应该利用我们进行的试验的样本和数据，试图了解可能解释PfSPZ疫苗在非洲效果降低的免疫学机制。 在本报告所述期间，我们未公布的进展包括以下进展： 我们鉴定了KLRC1+Vd2 T细胞亚群和在PfSPZ疫苗接种过程中上调的与无菌免疫相关的基因。同时，使用SPZ全疫苗接种的小鼠模型，我们确定了在SPZ免疫的小鼠中发挥这一作用的相应的gdT细胞亚群，这些细胞是产生保护性CD8T细胞所必需的。

Our published work in FY2023 included: Kc N, Church LWP, Riyahi P, Chakravarty S, Seder RA, Epstein JE, Lyke KE, Mordmller B, Kremsner PG, Sissoko MS, Healy S, Duffy PE, Jongo SA, Nchama VUNN, Abdulla S, Mpina M, Sirima SB, Laurens MB, Steinhardt LC, Oneko M, Li M, Murshedkar T, Billingsley PF, Sim BKL, Richie TL, Hoffman SL. Increased levels of anti-PfCSP antibodies in post-pubertal females versus males immunized with PfSPZ Vaccine does not translate into increased protective efficacy. 2022. Frontiers in Immunology Oct 25.13:1006716. doi: 10.3389/fimmu.2022.1006716. While prior research has shown differences in the risk of malaria infection and sickness between males and females, little is known about sex differences in vaccine-induced immunity to malaria. Identifying such differences could elucidate important aspects of malaria biology and facilitate development of improved approaches to malaria vaccination. Using a standardized ELISA, IgG antibodies to the major sporozoite surface protein PfCSP were measured before and two weeks after administration of PfSPZ Vaccine to 5-month to 61-year-olds across 11 clinical trials conducted in Germany, the US and five African countries, to determine differences in vaccine elicited antibody response between males and females, and whether these differences were associated with differential protection against naturally transmitted Pf malaria (Africa) or controlled human malaria infection (Germany, the US and Africa). Females 11 years of age made significantly higher levels of antibodies to PfCSP than did males in most trials, while there was no indication of such differences in infants or children. Although adult females had higher levels of antibodies, there was no evidence of improved protection compared to males. In 2 of the 7 trials with sufficient data, protected males had significantly higher levels of antibodies than unprotected males, and in 3 other trials protected females had higher levels of antibodies than did unprotected females. We concluded PfSPZ Vaccine induced higher levels of antibodies in post-pubertal females but showed equivalent protection in males and females. Increased antibody levels in post-pubertal females did not contribute substantially to improved protection. We hypothesize that while antibodies to PfCSP (and PfSPZ) may potentially contribute directly to protection, they primarily correlate with other, potentially protective immune mechanisms, such as antibody dependent and antibody independent cellular responses in the liver. Richie TL, Church LWP, Murshedkar T, Billingsley PF, James ER, Healy SA, Diawara H, Sissoko MS, Sagara I, Cook DM, Mordmller B, Chakravarty S, Kapulu M, Kreidenweiss A, Vaughan A, Kublin J, Murphy S, Jongo S, Tanner M, Sirima S, Laurens M, Daubenberger C, Silva J, Lyke KE, Abdulla S, Dicko A, Kappe S, Sim BKL, Kremsner PG, Duffy PE, Hoffman SL. Sporozoite Immunization: Innovative Translational Science to Support the Fight Against Malaria. 2023. Expert Review of Vaccines. In press. doi:10.1080/14760584.2023.2245890 A highly effective malaria vaccine is urgently needed, especially for Plasmodium falciparum (Pf), the deadliest human malaria parasite. Sporozoites (SPZ), the parasite stage transmitted by Anopheles mosquitoes to humans, are the only vaccine immunogen achieving > 90% efficacy against Pf infection. We and our partners in the PfSPZ Consortium reviewed > 30 clinical trials of PfSPZ vaccines in the U.S.A., Europe, Africa, and Asia, based on first-hand knowledge of the trials and PubMed searches of 'sporozoites,' 'malaria,' and 'vaccines.' First generation (radiation-attenuated) PfSPZ vaccines are safe, well tolerated, 80-100% efficacious against homologous controlled human malaria infection (CHMI). However, trials in endemic areas have achieved lower albeit significant protection against naturally occurring infection; LMIV in collaboration with Mali and Sanaria scientists demonstrated 18-19 months protection without boosting in Africa. Future studies should seek to understand immunological mechanisms that may explain reduced efficacy of PfSPZ Vaccine in Africa, using samples and data from the trials we have conducted. Our unpublished progress during this reporting period includes the following advances: We identified a subset of KLRC1+ Vd2 T cell and genes that are upregulated during PfSPZ vaccinations and associate with sterile immunity. In parallel, using a mouse model of whole SPZ vaccination, we identified the corresponding subset of gd T cells that play this role in SPZ-immunized mice and that are required to generate protective CD8 T cells.