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| Status |
Public on Jun 01, 2024 |
| Title |
Immunological assessment of multiple clinical-stage adjuvants to induce durable immune responses to the R21 malaria vaccine |
| Organism |
Macaca mulatta |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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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| Overall design |
The study involved six groups of 6 - 10 male Rhesus macaques per group. All groups received four doses of 5 g R21 antigen with an adjuvant, as shown in Fig. 1A. The first two groups were immunized with R21 plus 30 or 10 g 3M-052 formulated in 0.5 mg Aluminum hydroxide subcutaneously at weeks 0, 4, 8 and 62. The third group was immunized with R21 plus 30 g 3M-052 formulated in 0.5 mg Aluminum hydroxide via the intramuscular route at the same time points (weeks 0, 4, 8, and 62) as a route comparison with group 1. Groups 4 and 5 were administered with R21 plus GLA-LSQ (25 g + 10 g QS-21) and 50 g Matrix-M via intramuscular route, respectively. The R21/MM group was immunized at weeks 0, 4, 8, and 62, comparable with groups 1, 2, and 3. The R21/GLA-LSQ group was immunized at weeks 0, 4, 8 and 72. Group 6 was immunized with 30 g 3M-052 using a longer interval between immunizations (weeks 0, 8, 24, and 72) to be consistent with our previous studies using HIV antigens (16-18). In summary, the study was designed to compare multiple parameters. Groups 1 and 2 served for dose comparison; groups 3, 4, and 5 for adjuvant comparison; and groups 3 and 6 for a comparison of interval between vaccinations. The animals were subjected to longitudinal sampling of blood and bone marrow for the analysis of immunogenicity and durability of immune responses
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| Contributor(s) |
Arunachalam PS, Kazmin D, Pulendran B |
| Citation(s) |
39083589 |
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| Submission date |
Dec 10, 2023 |
| Last update date |
Sep 05, 2024 |
| Contact name |
Dmitri A Kazmin |
| E-mail(s) |
dkazmin@stanford.edu
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| Organization name |
Stanford University
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| Department |
Institute for Immunity, Transplantation and Infection
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| Lab |
Bali Pulendran
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| Street address |
240 Pasteur Dr
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| City |
Palo Alto |
| State/province |
CA |
| ZIP/Postal code |
94304 |
| Country |
USA |
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| Platforms (1) |
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| Samples (256)
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| Relations |
| BioProject |
PRJNA1050767 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE249806_R21.counts.txt.gz |
7.5 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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