Abstract
The generation of effective levels of antigen-specific immunity at the mucosal sites of pathogen entry is a key goal for vaccinologists. We explored topical vaginal application as an approach to initiate local antigen-specific immunity, enhance previously existing systemic immunity or re-target responses to the mucosae. To deliver a protein vaccine formulation to the vaginal mucosal surface, we used a novel vaginal ring device comprising a silicone elastomer body into which three freeze-dried, rod-shaped, hydroxypropylmethylcellulose inserts were incorporated. Each rod contained recombinant HIV-1 CN54gp140 protein (167μg)±R848 (167μg) adjuvant. The inserts were loaded into cavities within each ring such that only the ends of the inserts were initially exposed.Sheep received a prime-boost vaccination regime comprising intramuscular injection of 100μg CN54gp140+200μg R848 followed by three successive ring applications of one week duration and separated by one month intervals. Other sheep received only the ring devices without intramuscular priming. Serum and vaginal mucosal fluids were sampled every two weeks and analysed by CN54gp140 ELISA and antigen-specific B cells were measured by flow cytometry at necropsy. Vaccine antigen-specific serum antibody responses were detected in both the intramuscularly-primed and vaginal mucosally-primed groups. Those animals that received only vaginal vaccinations had identical IgG but superior IgA responses. Analysis revealed that all animals exhibited mucosal antigen-specific IgG and IgA with the IgA responses 30-fold greater than systemic levels. Importantly, very high numbers of antigen-specific B cells were detected in local genital draining lymph nodes.We have elicited local genital antigen-specific immune responses after topical application of an adjuvanted antigen formulation within a novel vaginal ring vaccine release device. This regimen and delivery method elicited high levels of antigen-specific mucosal IgA and large numbers of local antigen-reactive B cells, both likely essential for effective mucosal protection.
Highlights
While it is relatively easy to elicit antigen-specific serum antibodies, it is much more difficult to establish meaningful levels of specific antibodies at mucosal surfaces, the major route of viral invasion
We first assessed the release kinetics of the CN54gp140 vaccine antigen from covered rod-type devices comprising a hydroxypropyl methylcellulose (HPMC) + CN54gp140 ± R848 freeze-dried insert contained within a silicone elastomer tube
The recombinant HIV Envelope (Env) protein was released into 2 mL of either PBS or a simulated vaginal fluid (SVF; pH 4.2) to model release within the vaginal vault
Summary
While it is relatively easy to elicit antigen-specific serum antibodies, it is much more difficult to establish meaningful levels of specific antibodies at mucosal surfaces, the major route of viral invasion. We sought to determine if mucosal vaccination using topical vaginal application could initiate local antigen-specific immunity, and/or enhance or re-target previously existing systemic immunity to the mucosae. Studies have shown that direct mucosal vaccination via the intranasal, sublingual or intravaginal routes can efficiently enhance immune responses at other mucosal surfaces. This observation is generally attributed to common mucosal linkage, but this distribution of mucosal associated responses has been found to be very weak or absent in larger animals, and man [4,5,6,7]. These mucosal-directed interventions elicited higher levels of both B and T cell vaccine specific immune responses [8,9]
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