Intranasal (i.n.) vaccination is potentially the most direct method for conveying upper respiratory and mucosal immunity to respiratory pathogens. However, for unclear reasons, vaccines introduced into the nasal sinuses often have lower efficacy than vaccines administered by the more frequently used parenteral routes. We examined i.n. vaccination in a mouse immune-response model with a commonly used Haemophilus influenzae type B vaccine (Hibv) composed of the polyribosylribitol phosphate (PRP) capsule antigen conjugated to tetanus toxoid. Intranasal vaccination with Hibv using a Toll-like receptor 4 (TLR4) agonist as an adjuvant significantly increased the levels of IgA specific for the PRP capsule antigen in blood serum, saliva, and mucosal secretion specimens. In contrast, control mice vaccinated transdermally (t.d.) with Hibv did not produce significant levels of PRP-specific IgA in the blood serum and saliva, and anti-PRP IgG was increased only in serum. The i.n. and t.d. vaccinations resulted in equivalent bactericidal antibody responses in blood serum, suggesting that vaccine-derived IgG is protective against infection. Elevated levels of IgG specific for the tetanus toxoid carrier protein were measured in nasal sinuses and vaginal secretions in mice vaccinated by either the t.d. or i.n. route. Tissue culture studies confirmed that the nasopharynx-associated lymphoid tissue (NALT) was at least one of the sources of PRP-specific IgA and carrier-specific IgG within the nasal sinuses. We conclude that i.n. vaccination aided by a TLR4 agonist results in robust immune responses to both the carrier protein and bacterial polysaccharide components of the Hibv.
Haemophilus influenzae type b (Hib) vaccines (Hibv) are widely used in the pediatric population and require several intramuscular vaccination rounds of to achieve optimal efficacy. Children are significant reservoirs of Hib, with carriage rates ranging from 4.2% to 9% in the school-aged population (1, 2). Vaccination with the Hib vaccine significantly reduces Hib carriage in the pediatric population (3). Despite the widespread use and existence of the Hib vaccine, the annual burden of Hib infection continues to reach millions of cases worldwide and fatalities of several hundred thousand in children Յ5 years of age (4). Hib infection is spread by aerosolized droplets, with the nasal passages being the primary portal of entry, and can lead to meningitis, epiglottitis, pneumonia, cellulitis, and arthritis. The primary component of the Hib vaccine is polyribosylribitol phosphate (PRP), a ubiquitous polysaccharide of the bacterial outer wall that is delivered either with or without an aluminum-based adjuvant (5). Like all polysaccharides, the PRP moiety is poorly immunogenic (6), and conjugation to a protein carrier, such as tetanus toxoid (TT), is required to significantly increase vaccine immunogenicity (7). The internalization of PRP-protein conjugates by antigen-presenting cells (APC) followed by major histocompatibility complex (MHC) presentation (6, 8) is r...