Abstract
Vaccinations are extremely effective at combating infectious diseases. Many conserved antigen (Ag) targets, however, are poorly immunogenic. Protein subunit vaccines frequently elicit only humoral immune responses and fail to confer protection against serious intracellular pathogens. These barriers to vaccine development are often overcome by the use of appropriate adjuvants. Heat-labile enterotoxins (HLT) produced by enterotoxigenic strains of Escherichia coli are potent adjuvants when administered by mucosal or systemic routes. The efficacy of the type II HLT, however, has not been well-defined when administered by the intradermal (ID) route. Using a murine ID immunization model, the adjuvant properties of LT-IIb and LT-IIc, two type II HLTs, were compared with those of LT-I, a prototypical type I HLT. While all three HLT adjuvants enhanced Ag-specific humoral responses to similar levels, LT-IIb and LT-IIc, in contrast to LT-I, induced a more vigorous Ag-specific CD8+ T cell response and proffered faster clearance of Listeria monocytogenes in a challenge model. Additionally, LT-IIb and LT-IIc induced distinct differences in the profiles of the Ag-specific CD8+ T cell responses. While LT-IIc stimulated a robust and rapid primary CD8+ T cell response, LT-IIb exhibited slower CD8+ T cell expansion and contraction kinetics with the formation of higher percentages of effector memory cells. In comparison to LT-I and LT-IIc, LT-IIb evoked better long-term protection after immunization. Furthermore, LT-IIb and LT-IIc enhanced the total number of dendritic cells (DC) in the draining lymph node (DLN) and expression of costimulatory molecules CD80, CD86, and CD40 on DCs. In contrast to LT-I, LT-IIb and LT-IIc induced less edema, cellular infiltrates, and general inflammation at the site of ID injection. Thus, LT-IIb and LT-IIc are attractive comprehensive ID adjuvants with unique characteristic that enhance humoral and cellular immunity to a co-administered protein Ag.
Highlights
Vaccination remains one of the most efficient and cost-effective methods of combating infectious diseases [1,2,3]
To enhance immune reactions to poor immunogens and to provide comprehensive immune responses against complex infectious diseases, adjuvants are routinely required in vaccination
MO), a model Ag, was used at 50 mg in the presence or absence of Heat-labile enterotoxins (HLT) adjuvants diluted to a final volume of 20–30 ml using phosphate buffered saline (PBS)
Summary
Vaccination remains one of the most efficient and cost-effective methods of combating infectious diseases [1,2,3]. To enhance immune reactions to poor immunogens and to provide comprehensive immune responses (i.e., humoral and cellular components) against complex infectious diseases, adjuvants are routinely required in vaccination. Vaccines are administered by either the intramuscular (IM) or subcutaneous (SC) route These sites, lack dense populations of Ag presenting cells (APC) and, require higher concentrations of Ag to raise significant immune responses. Only approximately half the normal IM dose was required to induce a protective response when individuals were vaccinated with the first FDAapproved ID influenza vaccine (Fluzone Intradermal, Sanofi Pasteur) This Agsparing effect was evident even when the ID vaccine was used in poor responder populations (e.g., the elderly) [6]
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