More about immunomodulatory vaccines

The AlloPrime® mechanism harnesses the immunological concepts of “heterologous immunity” and “cross-reactive” killer cells.  The term heterologous immunity refers to the immunity that can develop after exposure to one pathogen, which in turn, can induce and/or modify the immune response to an infection with an unrelated pathogen.   

AlloPrime® creates immunity against alloantigens and results in high titers of anti-allogeneic memory T-cells of the Th1 phenotype.  This pool of allo-specific memory Th1 immune cells are readily activated, in a non-specific manner, by inflammatory cytokines released by immune cells that encounter viral particles or viral infected cells. These non-specifically activated Th1 memory cells, in turn, release additional inflammatory cytokines, in particular interferon-gamma, which creates a feed-forward enhancement of interferon-gamma from additional non-specifically activated memory Th1 cells. The activated pool of memory Th1 cells in turn activates innate immune cells, such as Natural Killer (NK) cells, which contribute additional interferon-gamma and kill viral infected cells, releasing ‘danger signals’.  This high level of interferon-gamma released in this immune cascade creates an “anti-viral state” which protects uninfected cells from viral infection and suppresses viral replication within cells. The activated NK cells and cross-reactive allo-specific killer cells (CTL), in turn, eliminate viral infected cells releasing the internal contents of the virally-infected cells into the microenvironment.  This creates the conditions for in-situ vaccination.

The internal contents of the lysed viral infected cells include heat shock proteins (HSP), which chaperone viral epitopes, and endogenous ‘danger signals’.   The processing of the HSP in the presence of danger and interferon-gamma creates the conditions for in-situ vaccination.  In-situ vaccination occurs when dendritic cells (DC) engulf the  released HSP and process the chaperoned viral epitopes to present on MHC II and cross present on MHC I molecules. In the presence of danger and interferon-gamma, the DC mature to the IL-12+ DC1 phenotype and traffic to draining lymph nodes where they activate viral-specific Th1 and CTL cells. These viral-specific T-cells can completely clear viral infections (sterilizing immunity).  Once the body is sterilized from the viral threat, memory cells mature and provide protection to prevent re-infection from the same virus. These memory cells also increase the diversity of non-exhausted memory cells that can be non-specifically activated upon a subsequent unrelated viral infection (heterologous immunity).

US FDA has cleared a Phase I/II clinical study of AlloPrime® in 40 healthy adults over 65yo.. See ClinicalTrials.gov Identifier: NCT04441047