Vaccines prevent hundreds of millions of illnesses and save millions of lives every year. Various types of licensed vaccines (live attenuated and inactivated pathogens, adjuvanted protein subunits) provide some level of protection against a variety of dangerous illnesses. However, there are multiple pathogens for which no effective vaccines are available. Protective immunity against many pathogens can be achieved through long- lived and high-affinity antibody responses, which are driven by T follicular helper (Tfh) cells. Tfh cells are required for the formation and maintenance of germinal centers (GC), where B cell affinity maturation, class switch, and development of long-lived plasma and memory B cells occur. Thus, the magnitude or quality of antibody responses induced by a vaccine is shaped by its ability to induce Tfh cells. The identification of vaccine platforms or adjuvants that induce potent Tfh cell responses and broadly protective and durable antibody responses is a critical need in vaccinology. We have identified a potent vaccine adjuvant, lipid nanoparticles (LNPs), which induce strong Tfh cell differentiation and durable antibody responses after a single immunization when combined with protein subunits, inactivated virus or antigen-encoding mRNA. Importantly, our preliminary studies demonstrated the superiority of LNP's adjuvant activity over the FDA-approved vaccine adjuvant, MF59, in comparative studies. This proposal will aim to extend our preliminary findings, examine LNP's adjuvanticity in non-human primate immunization studies and investigate the mechanisms of action of LNPs. In 3 specific aims we will: 1.) Determine LNP's adjuvanticity in multiple vaccine platforms in mice. 2.) Assess the potency of LNP-adjuvanted Zika vaccines in non-human primates. 3.) Uncover LNP-induced immune mechanisms that regulate the biology of Tfh cells. This proposal aims to demonstrate that LNPs can be used as adjuvants in various conventional (inactivated pathogen and protein subunits) and unconventional (mRNA, DNA) vaccine types to induce strong Tfh cell and durable neutralizing antibody responses. This finding could have a significant impact on vaccine development as no licensed vaccines or adjuvants have been shown to potently activate Tfh cells that are critical for durable protective antibody responses against many pathogens. We believe that the data generated in this proposal will be capable of moving this vaccine adjuvant towards clinical trials.

Public Health Relevance

We aim to develop lipid nanoparticle (LNP)-adjuvanted vaccines that have the ability to develop strong T follicular helper (Tfh) cell responses and durable neutralizing antibody responses in small and large animals. LNPs can be combined with currently licensed vaccine formats such as inactivated pathogen and protein subunit vaccines and significantly increase their effectiveness. Additionally, we will perform experiments that investigate the cellular and molecular mechanisms of potent Tfh cell activation by LNP-based vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Vaccines Against Microbial Diseases Study Section (VMD)
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Lapham, Cheryl K
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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