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Peripheral blood transcriptomics following immunization with TLR-adjuvanted nanoparticle vaccine in rhesus macaques

ABSTRACT: Transmission-blocking vaccines (TBVs) aim to disrupt malaria parasite development by targeting antigens expressed in the mosquito midgut and are considered an integral element of malaria eradication efforts. Here, we used non-human primates to demonstrate that immune responses to Pfs25, the leading TBV candidate, can be improved using unconjugated Pfs25 encapsulated in PLGA-based synthetic vaccine particles (SVP[Pfs25]) delivered subcutaneously, compared to the multimeric form, Pfs25-EPA administered intramuscularly. Pfs25-EPA given with the toll-like receptor (TLR)-based adjuvant GLA-LSQ induced robust Ab responses, but SVP[Pfs25] adjuvanted with GLA-LSQ or SVPs containing CpG or R848 increased Ab titers, Pfs25-specific plasmablasts, circulating memory B cells, and plasma cells in the bone marrow. Animals receiving R848 or CpG showed particularly strong type I IFN polarized innate activation, which correlated with increased Ab half-life. Only SVP[Pfs25] induced detectable Pfs25-specific CD4 Th1 and Tfh cells, correlating with improved Ab avidity. Collectively, multiple aspects of the responses elicited to Pfs25 indicate that the nanoparticle technology combined with TLR agonists is a promising platform for TBVs.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE102909 | GEO | 2017/08/23

SECONDARY ACCESSION(S): PRJNA399253

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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Peripheral blood transcriptomics following immunization with TLR-adjuvanted nanoparticle vaccine in rhesus macaques

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