Abstract
Development of vaccines able to induce mucosal immunity in the genital and gastrointestinal tracts is a major challenge to counter sexually transmitted pathogens such as HIV-1 and HSV-2. Herein, we showed that intradermal (ID) immunisation with sub-unit vaccine antigens (i.e., HIV-1 gp140 and HSV-2 gD) delivered with Poly(I:C) or CpG1668 as adjuvant induces long-lasting virus-specific immunoglobulin (Ig)-G and IgA antibodies in the vagina and feces. Poly(I:C)-supplemented sub-unit viral vaccines caused minimal skin reactogenicity at variance to those containing CpG1668, promoted a delayed-type hypersensitivity (DTH) to the vaccine and protected mice from genital and neurological symptoms after a lethal vaginal HSV-2 challenge. Interestingly, Poly(I:C12U) (Ampligen), a Poly(I:C) structural analogue that binds to TLR3 but not MDA-5, promoted robust mucosal and systemic IgG antibodies, a weak skin DTH to the vaccine but not IgA responses and failed to confer protection against HSV-2 infection. Moreover, Poly(I:C) was far superior to Poly(I:C12U) at inducing prompt and robust upregulation of IFNß transcripts in lymph nodes draining the injection site. These data illustrate that ID vaccination with glycoproteins and Poly(I:C) as adjuvant promotes long-lasting mucosal immunity and protection from genital HSV-2 infection, with an acceptable skin reactogenicity profile. The ID route thus appears to be an unexpected inductive site for mucosal immunity and anti-viral protection suitable for sub-unit vaccines. This works further highlights that TLR3/MDA5 agonists such as Poly(I:C) may be valuable adjuvants for ID vaccination against sexually transmitted diseases.
Highlights
Mucosal immune responses are deemed critical for the prevention of sexually transmitted diseases, such as those induced by human immunodeficiency virus-1 (HIV-1) and herpes simplex virus type 2 (HSV-2)
We show that long-lasting HIV-1 gp140-specific IgG and IgA Ab responses in the vagina can be induced by ID, but not subcutaneous (s.c.), immunisation with trimeric HIV-1 gp[140] in the presence of the TLR3 agonist Poly(I:C), with minimal skin reactogenicity
The site of antigen delivery and the nature of the revealed that all mice of phosphate-buffered saline (PBS) and glycoprotein D (gD) alone-vaccinated groups adjuvant both critically condition induction of mucosal IgA Ab exhibited severe genital lesions and neurological responses, and combining Poly(I:C) with ID immunisation appears symptoms starting from uncoordinated body movements and highly efficient in this respect
Summary
Mucosal immune responses are deemed critical for the prevention of sexually transmitted diseases, such as those induced by human immunodeficiency virus-1 (HIV-1) and herpes simplex virus type 2 (HSV-2). These data indicate that ID immunisation with gp[140] plus Poly(I:C) efficiently generates gp140-specific Ab-producing cells in the genital and gastrointestinal mucosae, which likely contribute to the specific IgG and IgA Ab responses detected in the vaginal fluids and fecal extracts.
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