期刊
JOURNAL OF CONTROLLED RELEASE
卷 347, 期 -, 页码 476-488出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2022.05.023
关键词
COVID-19 protein subunit vaccine; SARS-CoV-2 spike protein; Combination adjuvant; Monophosphoryl lipid A; Intranasal versus intramuscular vaccination; Adaptive immune response
资金
- Health-National Cancer Institute (NIH/NCI) [P30CA138292]
- National Institutes of Health-National Institute of Allergy and Infectious Disease (NIH/NIAID) [U01-AI124270-02]
- Georgia Tech Foundation [T32-GM0843]
- National Science Foundation Graduate Research Fellowship
- NIH T32 Cellular and Tissue Engineering training fellowship (National Institutes of Health (NIH))
- Robert A. Milton Chaired Professorship
Molecular adjuvants targeting pattern recognition receptors (PRRs) on antigen-presenting cells (APCs) delivered on nanoparticles (NPs) along with a stabilized spike protein antigen could stimulate broad and efficient immune responses against SARS-CoV-2. Combination adjuvant-NPs simultaneously targeting TLR and RIG-I receptors differentially induced T cell proliferation and increased proinflammatory cytokine secretion by APCs in vitro. In vivo studies showed that the adjuvant-NPs enhanced immune responses, including the generation of memory T cells and antibody production.
Despite success in vaccinating populations against SARS-CoV-2, concerns about immunity duration, continued efficacy against emerging variants, protection from infection and transmission, and worldwide vaccine availability remain. Molecular adjuvants targeting pattern recognition receptors (PRRs) on antigen-presenting cells (APCs) could improve and broaden the efficacy and durability of vaccine responses. Native SARS-CoV-2 infection stimulates various PRRs, including toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors. We hypothesized that targeting PRRs using molecular adjuvants on nanoparticles (NPs) along with a stabilized spike protein antigen could stimulate broad and efficient immune responses. Adjuvants targeting TLR4 (MPLA), TLR7/8 (R848), TLR9 (CpG), and RIG-I (PUUC) delivered on degradable polymer NPs were combined with the S1 subunit of spike protein and assessed in vitro with isogeneic mixed lymphocyte reactions (isoMLRs). For in vivo studies, the adjuvant-NPs were combined with stabilized spike protein or spike-conjugated NPs and assessed using a two-dose intranasal or intramuscular vaccination model in mice. Combination adjuvant-NPs simultaneously targeting TLR and RIG-I receptors (MPLA+PUUC, CpG+PUUC, and R848+PUUC) differentially induced T cell proliferation and increased proinflammatory cytokine secretion by APCs in vitro. When delivered intranasally, MPLA+PUUC NPs enhanced CD4+CD44+ activated memory T cell responses against spike protein in the lungs while MPLA NPs increased anti-spike IgA in the bronchoalveolar (BAL) fluid and IgG in the blood. Following intramuscular delivery, PUUC NPs induced strong humoral immune responses, characterized by increases in anti-spike IgG in the blood and germinal center B cell populations (GL7+ and BCL6+ B cells) in the draining lymph nodes (dLNs). MPLA+PUUC NPs further boosted spike protein-neutralizing antibody titers and T follicular helper cell populations in the dLNs. These results suggest that protein subunit vaccines with particledelivered molecular adjuvants targeting TLR4 and RIG-I could lead to robust and unique route-specific adaptive immune responses against SARS-CoV-2.
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