Inactivated Eyedrop Influenza Vaccine Adjuvanted with Poly(I:C) Is Safe and Effective for Inducing Protective Systemic and Mucosal Immunity

Abstract

The eye route has been evaluated as an efficient vaccine delivery routes. However, in order to induce sufficient antibody production with inactivated vaccine, testing of the safety and efficacy of the use of inactivated antigen plus adjuvant is needed. Here, we assessed various types of adjuvants in eyedrop as an anti-influenza serum and mucosal Ab production-enhancer in BALB/c mice. Among the adjuvants, poly (I:C) showed as much enhancement in antigen-specific serum IgG and mucosal IgA antibody production as cholera toxin (CT) after vaccinations with trivalent hemagglutinin-subunits or split H1N1 vaccine antigen in mice. Vaccination with split H1N1 eyedrop vaccine antigen plus poly(I:C) showed a similar or slightly lower efficacy in inducing antibody production than intranasal vaccination; the eyedrop vaccine-induced immunity was enough to protect mice from lethal homologous influenza A/California/04/09 (H1N1) virus challenge. Additionally, ocular inoculation with poly(I:C) plus vaccine antigen generated no signs of inflammation within 24 hours: no increases in the mRNA expression levels of inflammatory cytokines nor in the infiltration of mononuclear cells to administration sites. In contrast, CT administration induced increased expression of IL-6 cytokine mRNA and mononuclear cell infiltration in the conjunctiva within 24 hours of vaccination. Moreover, inoculated visualizing materials by eyedrop did not contaminate the surface of the olfactory bulb in mice; meanwhile, intranasally administered materials defiled the surface of the brain. On the basis of these findings, we propose that the use of eyedrop inactivated influenza vaccine plus poly(I:C) is a safe and effective mucosal vaccine strategy for inducing protective anti-influenza immunity.

Mucosal and Systemic Immune Responses to Influenza H7N9 Antigen HA1–2 Co-Delivered Intranasally with Flagellin or Polyethyleneimine in Mice and Chickens

“…The advantage of subunit vaccines is that they provide a safe and specific stimulus for the induction of immunity (3). The administration of antigen to mucosal surfaces is possibly the best method of inducing mucosal immune responses at distant as well as local sites (4), and efforts are on the way to develop mucosal vaccines for influenza (5, 6). A main obstacle to mucosal subunit vaccines has been the lack of an appropriate adjuvant; the only one licensed for human use (aluminum) is unsuitable for mucosal applications (3).…”

Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems

“…Perhaps because both routes use cervical lymph nodes as inductive sites, sublingual immunization generally induces IgA responses with similar mucosal tropisms than intranasal immunization. The ocular route has also investigated for delivery of experimental vaccines (54, 55). This route of immunization was found to induce SIgA in the tears, but also in the airways and in the genito-urinary tract (54).…”

“…The ocular route has also investigated for delivery of experimental vaccines (54, 55). This route of immunization was found to induce SIgA in the tears, but also in the airways and in the genito-urinary tract (54). The nature of homing receptors imprinted in the Tear-Duct-Associated Lymphoid Tissues (TALT) has not been studies in detail.…”

Intranasal Immunization Using Mannatide as a Novel Adjuvant for an Inactivated Influenza Vaccine and Its Adjuvant Effect Compared with MF59

“…Currently, the major route of vaccination is muscular injection, which mainly induces serum IgG antibodies without inducing IgA secretion in the mucosal surfaces of the respiratory tract. Mucosal vaccination is an attractive strategy for the prevention of infection because this route evokes both systemic and local mucosal immunity to induce IgG and secretory IgA (SIgA) production [5–7]. Therefore, mucosal vaccines and their adjuvants have recently become a focus of vaccine research.…”

“…Furthermore, this vaccination route has additional advantages; for instance, intranasal vaccination is painless, has higher acceptance for recipients, is safer, and is easily administered, which facilitates mass immunization campaigns [5, 8–11]. However, immunostimulatory adjuvants are essential for intranasal vaccines because the poor efficiency of antigen uptake across the nasal mucosa is a key issue [12].…”