Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA, 92037, USA.
Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA, 92037, USA.
Nat Commun. 2023 Nov 4;14(1):7107. doi: 10.1038/s41467-023-42923-x.
Adjuvants and antigen delivery kinetics can profoundly influence B cell responses and should be critically considered in rational vaccine design, particularly for difficult neutralizing antibody targets such as human immunodeficiency virus (HIV). Antigen kinetics can change depending on the delivery method. To promote extended immunogen bioavailability and to present antigen in a multivalent form, native-HIV Env trimers are modified with short phosphoserine peptide linkers that promote tight binding to aluminum hydroxide (pSer:alum). Here we explore the use of a combined adjuvant approach that incorporates pSer:alum-mediated antigen delivery with potent adjuvants (SMNP, 3M-052) in an extensive head-to-head comparison study with conventional alum to assess germinal center (GC) and humoral immune responses. Priming with pSer:alum plus SMNP induces additive effects that enhance the magnitude and persistence of GCs, which correlate with better GC-T cell help. Autologous HIV-neutralizing antibody titers are improved in SMNP-immunized animals after two immunizations. Over 9 months after priming immunization of pSer:alum with either SMNP or 3M-052, robust Env-specific bone marrow plasma cells (BM B) are observed. Furthermore, pSer-modification of Env trimer reduce targeting towards immunodominant non-neutralizing epitopes. The study shows that a combined adjuvant approach can augment humoral immunity by modulating immunodominance and shows promise for clinical translation.
佐剂和抗原传递动力学可以深刻影响 B 细胞反应,在合理的疫苗设计中应予以严格考虑,尤其是针对难以中和的抗体靶点,如人类免疫缺陷病毒(HIV)。抗原动力学取决于传递方法。为了提高免疫原的生物利用度并以多价形式呈现抗原,天然 HIV Env 三聚体用短磷酸丝氨酸肽接头进行修饰,以促进与氢氧化铝(pSer:alum)的紧密结合。在此,我们探索了一种联合佐剂方法,该方法将 pSer:alum 介导的抗原传递与有效佐剂(SMNP、3M-052)结合使用,在与传统铝佐剂的广泛头对头比较研究中评估生发中心(GC)和体液免疫反应。用 pSer:alum 和 SMNP 进行初免可产生累加效应,增强 GC 的数量和持久性,这与更好的 GC-T 细胞辅助相关。在两次免疫接种后,用 SMNP 免疫的动物中,HIV 中和抗体滴度得到提高。在用 SMNP 或 3M-052 对 pSer:alum 进行初始免疫接种后 9 个月以上,可观察到强烈的 Env 特异性骨髓浆细胞(BM B)。此外,Env 三聚体的 pSer 修饰减少了针对免疫显性非中和表位的靶向性。该研究表明,联合佐剂方法可以通过调节免疫显性来增强体液免疫,并显示出临床转化的前景。
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