Evaluation of TLR Agonists as Potential Mucosal Adjuvants for HIV gp140 and Tetanus Toxoid in Mice

Abstract

In the present study we investigate the impact of a range of TLR ligands and chitosan as potential adjuvants for different routes of mucosal immunisation (sublingual (SL), intranasal (IN), intravaginal (IVag) and a parenteral route (subcutaneous (SC)) in the murine model. We assess their ability to enhance antibody responses to HIV-1 CN54gp140 (gp140) and Tetanus toxoid (TT) in systemic and vaginal compartments. A number of trends were observed by route of administration. For non-adjuvanted antigen, SC>SL>IN immunisation with respect to systemic IgG responses, where endpoint titres were greater for TT than for gp140. In general, co-administration with adjuvants increased specific IgG responses where IN = SC>SL, while in the vaginal compartment IN>SL>SC for specific IgA. In contrast, for systemic and mucosal IgA responses to antigen alone SL>IN = SC. A number of adjuvants increased specific systemic IgA responses where in general IN>SL>SC immunisation, while for mucosal responses IN = SL>SC. In contrast, direct intravaginal immunisation failed to induce any detectable systemic or mucosal responses to gp140 even in the presence of adjuvant. However, significant systemic IgG responses to TT were induced by intravaginal immunisation with or without adjuvant, and detectable mucosal responses IgG and IgA were observed when TT was administered with FSL-1 or Poly I∶C. Interestingly some TLRs displayed differential activity dependent upon the route of administration. MPLA (TLR4) suppressed systemic responses to SL immunisation while enhancing responses to IN or SC immunisation. CpG B enhanced SL and IN responses, while having little or no impact on SC immunisation. These data demonstrate important route, antigen and adjuvant effects that need to be considered in the design of mucosal vaccine strategies.

Mucosal Immunization of Lactating Female Rhesus Monkeys with a Transmitted/Founder HIV-1 Envelope Induces Strong Env-Specific IgA Antibody Responses in Breast Milk

“…The TLR 7/8 agonist R848 (500 g/animal) was used as the adjuvant for the intranasal (i.n.) boosts (43).…”

“…boost regimen is remarkable. A recent evaluation of systemic and vaginal antibody responses elicited in mice following administration of a clade C HIV Env alone or with different TLR agonists showed differences based on the route of administration and adjuvant used (43). Thus, both the use of a TLR 7/8 agonist (R848) as the adjuvant and the i.n.…”

Common Features of Mucosal and Peripheral Antibody Responses Elicited by Candidate HIV-1 Vaccines in Rhesus Monkeys

“…The RV144 clinical trial suggested that vaccine-elicited HIV-1 envelope (Env)-specific humoral immune responses may have contributed to the partial protection observed for vaccinees (2), but mucosal immune responses were not assessed in that trial. In contrast, previous studies have shown that immunization with peptide, DNA, protein, or attenuated bacterial or viral vector-based vaccines through parental or mucosal routes may elicit antigen-specific humoral immune responses at mucosal sites in mice, nonhuman primates, and humans (3)(4)(5)(6)(7). However, the characteristics, functionality, and epitope specificity of vaccine-elicited mucosal antibody responses have not been fully explored.…”

Intranasal administration of TLR agonists induces a discriminated local innate response along murine respiratory tract

“…This ability has prompted the use of TLR agonist for development of therapeutic and prophylactic approaches against different pathologies [5,6]. Among them, strategies involving intranasal delivery of TLR agonists have been proposed to improve local and systemic immune response to peptide vaccines, achieving protection in several experimental models of respiratory infections [7][8][9][10]. These studies have established the proof of concept that TLR ligands can be combined with the appropriate antigens and delivered by intranasal route as vaccination strategy.…”