Nanocell COVID-19 vaccine triggers a novel immune response pathway producing high-affinity antibodies which neutralize all variants of concern

• Published in: Frontiers in immunology Vol. 13; p. 1038562
• Main Authors: Gao, Steven Y, Amaro-Mugridge, Nancy B, Madrid-Weiss, Jocelyn, Petkovic, Nikolina, Vanegas, Natasha, Visvanathan, Kumar, Williams, Bryan R G, MacDiarmid, Jennifer A, Brahmbhatt, Himanshu
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 27.01.2023
• Subjects: Animals; Antigen Presentation; COVID-19; COVID-19 Vaccines; Humans; Immunology; iNKT activation; Leukocytes, Mononuclear; memory B cell; memory T cell; Mice; nanocell vaccine; SARS-CoV-2; variants of concern; COVID-19; iNKT activation; memory T cell; nanocell vaccine; variants of concern; memory B cell
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.1038562

Most current anti-viral vaccines elicit a humoral and cellular immune response the pathway of phagocytic cell mediated viral antigen presentation to B and T cell surface receptors. However, this pathway results in reduced ability to neutralize S-protein Receptor Binding Domains (RBDs) from several Variants of Concern (VOC) and the rapid waning of memory B cell response requiring vaccine reformulation to cover dominant VOC S-proteins and multiple boosters. Here we show for the first time in mice and humans, that a bacterially derived, non-living, nanocell (EDV; EnGeneIC Dream Vector) packaged with plasmid expressed SARS-CoV-2 S-protein and α-galactosyl ceramide adjuvant (EDV-COVID-αGC), stimulates an alternate pathway due to dendritic cells (DC) displaying both S-polypeptides and αGC thereby recruiting and activating iNKT cells with release of IFNγ. This triggers DC activation/maturation, activation of follicular helper T cells (T ), cognate help to B cells with secretion of a cytokine milieu promoting B cell maturation, somatic hypermutation in germinal centers to result in high affinity antibodies. Surrogate virus neutralization tests show 90-100% neutralization of ancestral and early VOC in mice and human trial volunteers. EDV-COVID-αGC as a third dose booster neutralized Omicron BA. 4/5. Serum and PBMC analyses reveal long lasting S-specific memory B and T cells. In contrast, control EDVs lacking αGC, did not engage the iNKT/DC pathway resulting in antibody responses unable to neutralize all VOCs and had a reduced B cell memory. The vaccine is lyophilized, stored and transported at room temperature with a shelf-life of over a year.