Human immunodeficiency virus (HIV) primarily enters the host and initiates infection through mucosal tissues. Therefore, a vaccination strategy that can elicit cellular and humoral immune responses in mucosal tissues is urgently needed. However, there is currently no approved adjuvant that can achieve robust levels of both T-cell and antibody responses in mucosal tissues. Therefore, there is a critical need for an alternative, effective, and safe strategy for mucosal vaccination. Our long-range goal is to develop vaccine delivery systems that can elicit protective immunity against HIV-1. Our objective here is to engineer nanoparticles for mucosal delivery of HIV-1 antigens and investigate their impact on elicitation of systemic and mucosal immune responses. To that end, we have developed a new nanoparticle (NP) system that can elicit strong cytotoxic CD8+ T lymphocyte (CTL) responses with subunit protein antigens. We show that these new vaccine NPs promote antigen delivery to antigen-presenting cells in vivo, generate CTLs that disseminate to mucosal tissues, including cervicovaginal and gastrointestinal tracts, and protect animals against viral infection. We also show that NPs induce significantly higher antibody titers, lasting > 400 days in mice with greater avidity, durability, and breadth, compared with conventional adjuvants on the market (e.g. alum or Montanide). Based on these preliminary data, we propose to develop a new NP-based strategy for mucosal immunization against HIV-1. We will test our central hypothesis that NPs incorporated with T and B-cell HIV-1 immunogens will elicit concerted cellular and humoral immune responses in mucosal tissues. At the completion of the proposed studies, we will have identified a new vaccination technology that can induce mucosal T and B cell responses against HIV-1. These studies will accelerate HIV-1 vaccine development and advance our understanding of the impact of vaccine delivery systems on mucosal immunity.

Public Health Relevance

The outcomes of the proposed research are expected to have an important positive impact on public health by identifying a new vaccination strategy that can promote cellular and humoral immune responses against HIV-1.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI127070-01A1
Application #
9271737
Study Section
HIV/AIDS Vaccines Study Study Section (VACC)
Program Officer
Boggiano, Cesar Augusto
Project Start
2016-09-26
Project End
2021-08-31
Budget Start
2016-09-26
Budget End
2017-08-31
Support Year
1
Fiscal Year
2016
Total Cost
$94,093
Indirect Cost
$33,388
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Kuai, Rui; Yuan, Wenmin; Son, Sejin et al. (2018) Elimination of established tumors with nanodisc-based combination chemoimmunotherapy. Sci Adv 4:eaao1736
Park, Hyun-Ji; Kuai, Rui; Jeon, Eun Je et al. (2018) High-density lipoprotein-mimicking nanodiscs carrying peptide for enhanced therapeutic angiogenesis in diabetic hindlimb ischemia. Biomaterials 161:69-80
Ochyl, Lukasz J; Bazzill, Joseph D; Park, Charles et al. (2018) PEGylated tumor cell membrane vesicles as a new vaccine platform for cancer immunotherapy. Biomaterials 182:157-166
Kuai, Rui; Sun, Xiaoqi; Yuan, Wenmin et al. (2018) Dual TLR agonist nanodiscs as a strong adjuvant system for vaccines and immunotherapy. J Control Release 282:131-139
Aikins, Marisa E; Bazzill, Joseph; Moon, James J (2017) Vaccine nanoparticles for protection against HIV infection. Nanomedicine (Lond) 12:673-682
Fan, Yuchen; Moon, James J (2017) Particulate delivery systems for vaccination against bioterrorism agents and emerging infectious pathogens. Wiley Interdiscip Rev Nanomed Nanobiotechnol 9:
Nam, Jutaek; Son, Sejin; Moon, James J (2017) Adjuvant-Loaded Spiky Gold Nanoparticles for Activation of Innate Immune Cells. Cell Mol Bioeng 10:341-355
Gao, Jie; Ochyl, Lukasz J; Yang, Ellen et al. (2017) Cationic liposomes promote antigen cross-presentation in dendritic cells by alkalizing the lysosomal pH and limiting the degradation of antigens. Int J Nanomedicine 12:1251-1264
Kuai, Rui; Subramanian, Chitra; White, Peter T et al. (2017) Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma. Int J Nanomedicine 12:6581-6594
Bailey, Brittany A; Desai, Kashappa-Goud H; Ochyl, Lukasz J et al. (2017) Self-encapsulating Poly(lactic-co-glycolic acid) (PLGA) Microspheres for Intranasal Vaccine Delivery. Mol Pharm 14:3228-3237

Showing the most recent 10 out of 14 publications