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Vaccines combining slow release and follicle targeting of antigens increase germinal center B cell clonal diversity and clonal expansion

ABSTRACT: Vaccines incorporating slow release, multivalent antigen display, and/or immunomodulation through adjuvants have important roles in shaping the humoral immune response. Here, we analyzed mechanisms of action of a clinically relevant combination adjuvant strategy, where phosphoserine (pSer)-tagged immunogens bound to aluminum hydroxide (alum) adjuvant (promoting prolonged antigen release to draining lymph nodes) are combined with a potent saponin nanoparticle adjuvant termed SMNP (which alters lymph flow and antigen entry into lymph nodes). When employed with a stabilized HIV Env trimer antigen in mice, this combined adjuvant approach promoted substantial enhancements in germinal center (GC) and antibody responses relative to either adjuvant alone. Using scRNA-seq and scBCR-seq, we found that the alum-pSer/SMNP combination augmented the clonal expansion and diversity of GC B cell repertoire, coincident with increased expression of positive selection markers and proportion of S-phase GC B cells. To gain insight into the source of these changes in the GC response, we analyzed antigen biodistribution and structural integrity in draining lymph nodes and found that the combination adjuvant approach, but not alum-pSer delivery or SMNP alone, promoted accumulation of intact antigen on follicular dendritic cells (FDCs), reflecting an integration of the effects by slowing antigen release and altering lymph node uptake. Ablating the Cr1/2 complex on FDCs significantly hampered antigen-specific GC response, corroborating enhanced FDC decoration as the key mechanism of improved vaccine response. These results demonstrate how adjuvants with complementary mechanisms of action impacting vaccine biodistribution and kinetics can synergize to enhance humoral immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE288450 | GEO | 2025/02/04

REPOSITORIES: GEO

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Project description:Authorization of the Matrix-M-adjuvanted R21 vaccine by three countries and its subsequent endorsement by the World Health Organization (WHO) for malaria prevention in children is a milestone in the fight against malaria. Yet, to meet the unprecedented demand for malarial vaccines, there is a pressing need for additional adjuvants that induce robust and durable vaccine-induced immunity. Here, we performed a comparative assessment of three clinically relevant adjuvants (an alum formulation of the TLR7/8 agonist 3M-052 (3M-052+Alum), the TLR4 agonist GLA-LSQ (GLA in liposome QS-21 formulation), and Matrix-M, the currently approved adjuvant for R21) for their capacity to induce durable immune responses to the R21 malaria vaccine in non-human primates. Immunization of macaques with R21 adjuvanted with 3M-052+Alum on a 0, 8, and 24-week schedule elicited anti-circumsporozoite antibody responses comparable in magnitude to the R21/Matrix-M vaccine and persisted up to 72 weeks with a half-life of 337 (264 – 459) days. A booster dose at 72 weeks induced an antigen-specific recall response, similar to the R21/Matrix-M vaccination. In contrast, R21/GLA-LSQ immunization induced a considerably lower and short-lived response. Consistent with the durability of serum antibody responses, Matrix-M and 3M-052+Alum induced long-lived plasma cells in the bone marrow and other tissues, including the spleen, but GLA-LSQ stimulated only short-lived plasmablasts. Finally, we show distinct innate immune signatures early after vaccination with these adjuvants. While 3M-052+Alum stimulated potent and persistent antiviral transcriptional and cytokine signatures after primary and booster immunizations, Matrix-M induced an enhanced expression of interferon- and Th2-related signatures more highly after the booster vaccination. Collectively, these findings provide a comparative database on the immune responses of three clinically relevant adjuvants with R21 and highlight the promise of 3M-052+Alum as an additional adjuvant for the R21 malaria vaccine.

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Vaccines combining slow release and follicle targeting of antigens increase germinal center B cell clonal diversity and clonal expansion

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