Abstract
The development of HIV-1 vaccines is challenged by the lack of relevant models to accurately induce human B- and T-cell responses in lymphoid organs. In humanized mice reconstituted with human hematopoietic stem cells (hu-mice), human B cell-development and function are impaired and cells fail to efficiently transition from IgM B cells to IgG B cells. Here, we found that CD40-targeted vaccination combined with CpG-B adjuvant overcomes the usual defect of human B-cell switch and maturation in hu-mice. We further dissected hu-B cell responses directed against the HIV-1 Env protein elicited by targeting Env gp140 clade C to the CD40 receptor of antigen-presenting cells. The anti-CD40.Env gp140 vaccine was injected with CpG-B in a homologous prime/boost regimen or as a boost of a NYVAC-KC pox vector encoding Env gp140 clade C. Both regimens elicited Env-specific IgG-switched memory hu-B cells at a greater magnitude in hu-mice primed with NYVAC-KC. Single-cell RNA-seq analysis showed gp140-specific hu-B cells to express polyclonal IgG1 and IgG3 isotypes and a broad Ig VH/VL repertoire, with predominant VH3 family gene usage. These cells exhibited a higher rate of somatic hypermutation than the non-specific IgG+ hu-B-cell counterpart. Both vaccine regimens induced splenic GC-like structures containing hu-B and hu-Tfh-like cells expressing PD-1 and BCL-6. We confirmed in this model that circulating ICOS+ memory hu-Tfh cells correlated with the magnitude of gp140-specific B-cell responses. Finally, the NYVAC-KC heterologous prime led to a more diverse clonal expansion of specific hu-B cells. Thus, this study shows that CD40-targeted vaccination induces human IgG production in hu-mice and provides insights for the development of a CD40-targeting vaccine to prevent HIV-1 infection in humans.
Highlights
Challenges in the development of HIV-1 vaccines include more accurately directing protective immune responses
One finding of our study is that CD40-targeted vaccination combined with CpG-B adjuvant overcomes the usual defect of human B-cell switch and maturation in hu-mouse models
We further reported that the HIV-1 envelope-specific IgG+ hu-B cells elicited in hu-mice by the anti-CD40.Env vaccine used more VH3 and VH4 family genes and displayed higher rates of somatic hypermutations than the non-specific IgG+ hu-B-cell counterpart
Summary
Challenges in the development of HIV-1 vaccines include more accurately directing protective immune responses. Research on preventive HIV-1 vaccines first explored the efficacy of B cell-based vaccines using a bivalent recombinant envelope (Env) gp120 protein as a unique immunogen in a homologous prime/boost vaccination regimen in healthy volunteers [1,2]. The RV144 Phase 3 vaccine trial evaluated priming with the Alvac-HIV vector combined with a protein boost using a bivalent recombinant gp120 protein in healthy volunteers [6]. Correlative results of the RV144 trial support the usefulness of HIV-1 Env proteins for the design of preventive vaccines that induce both B- and T-cell responses [6]. The rate of protection in the RV144 trial rapidly waned and underscores the need to improve the durability of such protective responses
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