Muir Roshell, Metcalf Talibah, Fourati Slim, Bartsch Yannic, Lugemwa Jacqueline Kyosiimire, Canderan Glenda, Alter Galit, Muyanja Enoch, Okech Brenda, Namatovu Teddy, Namara Irene, Namuniina Annemarie, Ssetaala Ali, Mpendo Juliet, Nanvubya Annet, Kitandwe Paul Kato, Bagaya Bernard S, Kiwanuka Noah, Nassuna Jacent, Biribawa Victoria Menya, Elliott Alison M, de Dood Claudia J, Senyonga William, Balungi Priscilla, Kaleebu Pontiano, Mayanja Yunia, Odongo Mathew, Fast Pat, Price Matt A, Corstjens Paul L A M, van Dam Govert J, Kamali Anatoli, Sekaly Rafick Pierre, Haddad Elias K
medRxiv. 2023 Feb 26:2023.02.24.23284435. doi: 10.1101/2023.02.24.23284435.
The impact of endemic infections on protective immunity is critical to inform vaccination strategies. In this study, we assessed the influence of infection on host responses in a Ugandan fishing cohort given a Hepatitis B (HepB) vaccine. Concentrations of schistosome-specific circulating anodic antigen (CAA) pre-vaccination showed a significant bimodal distribution associated with HepB titers, which were lower in individuals with high CAA. We established that participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination and higher regulatory T cells (Tregs) post-vaccination. Polarization towards higher frequencies of Tregs: cTfh cells can be mediated by changes in the cytokine environment favoring Treg differentiation. In fact, we observed higher levels of CCL17 and soluble IL-2R pre-vaccination (important for Treg recruitment and development), in individuals with high CAA that negatively associated with HepB titers. Additionally, alterations in pre-vaccination monocyte function correlated with HepB titers, and changes in innate-related cytokines/chemokine production were associated with increasing CAA concentration. We report, that by influencing the immune landscape, schistosomiasis has the potential to modulate immune responses to HepB vaccination. These findings highlight multiple -related immune associations that could explain abrogated vaccine responses in communities with endemic infections.
Schistosomiasis drives host immune responses for optimal pathogen survival, potentially altering host responses to vaccine-related antigen. Chronic schistosomiasis and co-infection with hepatotropic viruses are common in countries where schistosomiasis is endemic. We explored the impact of ( ) infection on Hepatitis B (HepB) vaccination of individuals from a fishing community in Uganda. We demonstrate that high schistosome-specific antigen (circulating anodic antigen, CAA) concentration pre-vaccination, is associated with lower HepB antibody titers post-vaccination. We show higher pre-vaccination levels of cellular and soluble factors in instances of high CAA that are negatively associated with HepB antibody titers post-vaccination, which coincided with lower frequencies of circulating T follicular helper cell populations (cTfh), proliferating antibody secreting cells (ASCs), and higher frequencies of regulatory T cells (Tregs). We also show that monocyte function is important in HepB vaccine responses, and that high CAA is associated with alterations in the early innate cytokine/chemokine microenvironment. Our findings suggest that in individuals with high CAA and likely high worm burden, schistosomiasis creates and sustains an environment that is polarized against optimal host immune responses to the vaccine, which puts many endemic communities at risk for infection against HepB and other diseases that are preventable by vaccines.
地方性感染对保护性免疫的影响对于制定疫苗接种策略至关重要。在本研究中，我们评估了感染对乌干达一个渔民队列接种乙型肝炎（HepB）疫苗后宿主反应的影响。接种疫苗前血吸虫特异性循环阳极抗原（CAA）的浓度呈现出与HepB滴度相关的显著双峰分布，CAA水平高的个体中HepB滴度较低。我们发现，CAA水平高的参与者在接种疫苗前后循环滤泡辅助性T细胞（cTfh）亚群的频率显著较低，接种疫苗后调节性T细胞（Tregs）的频率较高。向更高频率的Tregs：cTfh细胞极化可由有利于Treg分化的细胞因子环境变化介导。事实上，我们观察到接种疫苗前CAA水平高的个体中CCL17和可溶性IL-2R水平较高（对Treg募集和发育很重要），这与HepB滴度呈负相关。此外，接种疫苗前单核细胞功能的改变与HepB滴度相关，与先天相关细胞因子/趋化因子产生的变化与CAA浓度增加有关。我们报告，通过影响免疫格局，血吸虫病有可能调节对HepB疫苗的免疫反应。这些发现突出了多种与感染相关的免疫关联，这可以解释地方性感染社区中疫苗反应减弱的原因。
血吸虫病驱动宿主免疫反应以实现病原体的最佳生存，可能改变宿主对疫苗相关抗原的反应。在血吸虫病流行的国家，慢性血吸虫病和与嗜肝病毒的共同感染很常见。我们探讨了血吸虫感染对乌干达一个渔民社区个体接种乙型肝炎（HepB）疫苗的影响。我们证明，接种疫苗前高血吸虫特异性抗原（循环阳极抗原，CAA）浓度与接种疫苗后较低的HepB抗体滴度相关。我们显示，在CAA水平高的情况下，接种疫苗前细胞和可溶性因子水平较高，这与接种疫苗后HepB抗体滴度呈负相关，同时循环滤泡辅助性T细胞群体（cTfh）、增殖性抗体分泌细胞（ASCs）的频率较低，调节性T细胞（Tregs）的频率较高。我们还表明，单核细胞功能在HepB疫苗反应中很重要，高CAA与早期先天细胞因子/趋化因子微环境的改变有关。我们的研究结果表明，在CAA水平高且可能虫负荷高的个体中，血吸虫病创造并维持了一个不利于宿主对疫苗产生最佳免疫反应极化的环境，这使许多地方性社区面临感染HepB和其他可通过疫苗预防疾病的风险。
