Biology subjects

Jakubowski, A.

Publications and source records attributed to Jakubowski, A..

4 recordsLinked to original sources

bioRxiv2024

Amphiphile-engineered DNA adjuvants stimulate strong type I IFN production in lymph nodes via cytosolic danger-sensing to induce potent cellular and humoral immunity in mice and non-human primates

Adjuvants are immuno-activators capable of shaping the magnitude and quality of antigen-specific immune responses induced by subunit immunization. Presently, there is an acute need for effective adjuvants that safely induce durable and balanced humoral and cellular responses; the latter being indispensable for protection against intracellular pathogens and cancer. Here, we iteratively optimized a novel class of Amphiphile (AMP)-modified, immunostimulatory DNA-adjuvants designed for targeted delivery to lymph nodes and enhanced stimulation of cytosolic danger-sensing pathways to generate strong adaptive immunity. AMP-DNA adjuvants induced potent IFN-I-driven inflammatory environments in mouse and NHP lymph nodes that were dependent on TBK1 signaling, leading to significantly enhanced cytokine secretion by polyfunctional CD8+ and CD4+ T cells in multiple tissues, and strongly elevated TH1-associated and neutralizing antibody responses, without toxicity. These results demonstrate that AMP-engineering enables lymph node-targeted DNA-adjuvants to uniquely activate cytosolic immune-signaling to generate robust adaptive responses crucial for vaccine efficacy.

immunology↗

bioRxiv2022

Programming the lymph node immune response with Amphiphile-CpG induces potent cellular and humoral immunity following COVID-19 subunit vaccination in mice and non-human primates

Despite the success of currently authorized vaccines for the reduction of severe COVID-19 disease risk, rapidly emerging viral variants continue to drive pandemic waves of infection, resulting in numerous global public health challenges. Progress will depend on future advances in prophylactic vaccine activity, including advancement of candidates capable of generating more potent induction of cross-reactive T cells and durable cross-reactive antibody responses. Here we evaluated an Amphiphile (AMP) adjuvant, AMP-CpG, admixed with SARS-CoV-2 Spike receptor binding domain (RBD) immunogen, as a lymph node-targeted protein subunit vaccine (ELI-005) in mice and non-human primates (NHPs). AMP-mediated targeting of CpG DNA to draining lymph nodes resulted in comprehensive local immune activation characterized by extensive transcriptional reprogramming, inflammatory proteomic milieu, and activation of innate immune cells as key orchestrators of antigen-directed adaptive immunity. Prime-boost immunization with AMP-CpG in mice induced potent and durable T cell responses in multiple anatomical sites critical for prophylactic efficacy and prevention of severe disease. Long-lived memory responses were rapidly expanded upon re-exposure to antigen. In parallel, RBD-specific antibodies were long-lived, and exhibited cross-reactive recognition of variant RBD. AMP-CpG-adjuvanted prime-boost immunization in NHPs was safe and well tolerated, while promoting multi-cytokine-producing circulating T cell responses cross-reactive across variants of concern (VOC). Expansion of RBD-specific germinal center (GC) B cells in lymph nodes correlated to rapid seroconversion with variant-specific neutralizing antibody responses exceeding those measured in convalescent human plasma. These results demonstrate the promise of lymph-node adjuvant-targeting to coordinate innate immunity and generate robust adaptive responses critical for vaccine efficacy.

immunology↗

bioRxiv2022

Lymph node-targeted vaccine boosting of TCR-T cell therapy enhances anti-tumor 1 function and eradicates solid tumors

While T cell receptor (TCR)-modified T cell therapies have shown promise against solid tumors, overall therapeutic benefits in clinical practice have been modest due in part to suboptimal T cell persistence and activation in vivo, alongside the possibility of tumor antigen escape. In this study, we demonstrate an approach to enhance the in vivo persistence and activation of TCR-T cells through combination with Amphiphile (AMP)-vaccination including cognate TCR-T peptides. AMP-modification improves lymph node targeting of conjugated tumor immunogens and adjuvants, thereby coordinating a robust T cell-priming endogenous immune response. Vaccine combination with TCR-T cell therapy provided simultaneous in vivo invigoration of adoptively transferred TCR-T cells and in situ priming of the endogenous anti-tumor T cell repertoire. The resulting induction of an adoptive and endogenous anti-tumor effect led to durable responses in established murine solid tumors refractory to TCR-T cell monotherapy. Protection against recurrence was associated with antigen spreading to additional tumor-associated antigens not targeted by vaccination. Enhanced anti-tumor efficacy was further correlated with pro-inflammatory lymph node transcriptional reprogramming and increased antigen presenting cell maturation, resulting in TCR-T cell expansion and functional enhancement in lymph nodes and solid tumor parenchyma without lymphodepletion. In vitro evaluation of AMP-peptides with matched human TCR-T cells targeting NY-ESO-1, mutant KRAS, and HPV16 E7 illustrated the clinical potential of AMP-vaccination to enhance human TCR-T cell proliferation, activation, and anti-tumor activity. Taken together, these studies provide rationale and evidence to support clinical evaluation of the combination of AMP-vaccination with TCR-T cell therapies to augment anti-tumor activity. SummaryAMP-vaccination targets the lymph nodes to enhance TCR-T cell therapy resulting in solid tumor eradication and durable protection against recurrence.

immunology↗

bioRxiv2020

A Lymph Node Targeted Amphiphile Vaccine Induces Potent Cellular and Humoral Immunity to SARS-CoV-2

The SARS-CoV-2 pandemic has led to public health, economic, and social consequences that mandate urgent development of effective vaccines to contain or eradicate infection. To that end, we evaluated a novel amphiphile (AMP) vaccine adjuvant, AMP-CpG, composed of diacyl lipid-modified CpG, admixed with the SARS-CoV-2 Spike-2 receptor binding domain protein as a candidate vaccine (ELI-005) in mice. AMP immunogens are efficiently delivered to lymph nodes, where innate and adaptive immune responses are generated. Compared to alum, AMP immunization induced >25-fold higher antigen-specific T cells which produced multiple Th1 cytokines and trafficked into lung parenchyma and respiratory secretions. Antibody responses favored Th1 isotypes (IgG2bc, IgG3) and potently neutralized Spike-2-ACE2 receptor binding, with titers 265-fold higher than the natural immune response from convalescent COVID-19 patients; responses were maintained despite 10-fold dose-reduction in Spike antigen. Both cellular and humoral immune responses were preserved in aged mice. These advantages merit clinical translation to SARS-CoV-2 and other protein subunit vaccines.

immunology↗