A broad-spectrum pneumococcal vaccine induces mucosal immunity and protects against lethal Streptococcus pneumoniae challenge.

Pneumococcal disease is a major threat to public health globally, impacting individuals across all age groups, particularly infants and elderly individuals. The use of current vaccines has led to unintended consequences, including serotype replacement, leading to a need for a new approach to combat pneumococcal disease. A promising solution is the development of a broad-spectrum pneumococcal vaccine. In this study, we present the development of a broad-spectrum protein-based pneumococcal vaccine that contains three pneumococcal virulence factors: rlipo-PsaA (lipidated form), rPspAΔC (truncated form), and rPspCΔC (truncated form). Intranasal immunization with rlipo-PsaA, rPspAΔC, and rPspCΔC (LAAC) resulted in significantly higher IgG titres than those induced by administration of nonlipidated rPsaA, rPspAΔC, and rPspCΔC (AAC). Furthermore, LAAC immunization induced the production of higher IgA titres in vaginal washes, feces, and sera in mice, indicating that LAAC can induce systemic mucosal immunity. In addition, administration of LAAC also induced Th1/Th17-biased immune responses and promoted opsonic phagocytosis of Streptococcus pneumoniae strains of various serotypes, implying that the immunogenicity of LAAC immunization provides a protective effect against pneumococcal infection. Importantly, challenge data showed that the LAAC-immunized mice had a reduced bacterial load not only for several serotypes of the 13-valent conjugate pneumococcal vaccine (PCV13) but also for selected non-PCV13 serotypes. Consistently, LAAC immunization increased the survival rate of mice after bacterial challenge with both PCV13 and non-PCV13 serotypes. In conclusion, our protein-based pneumococcal vaccine provides protective effects against a broad spectrum of Streptococcus pneumoniae serotypes.

Recombinant lipidated FLIPr effectively enhances mucosal and systemic immune responses for various vaccine types.

Formyl peptide receptor-like 1 inhibitor protein (FLIPr) is an immune evasion protein produced by Staphylococcus aureus, and FLIPr is a potential vaccine candidate for reducing Staphylococcus aureus virulence and biofilm formation. We produced recombinant lipidated FLIPr (rLF) to increase the immunogenicity of FLIPr and showed that rLF alone elicited potent anti-FLIPr antibody responses to overcome the FLIPr-mediated inhibition of phagocytosis. In addition, rLF has potent immunostimulatory properties. We demonstrated that rLF is an effective adjuvant. When an antigen is formulated with rLF, it can induce long-lasting antigen-specific immune responses and enhance mucosal and systemic antibody responses as well as broad-spectrum T-cell responses in mice. These findings support further exploration of rLF in the clinic as an adjuvant for various vaccine types with extra benefits to abolish FLIPr-mediated immunosuppressive effects.

Intranasal Vaccination With Recombinant Antigen-FLIPr Fusion Protein Alone Induces Long-Lasting Systemic Antibody Responses and Broad T Cell Responses.

A simple formulation is urgently needed for mucosal vaccine development. We employed formyl peptide receptor-like 1 inhibitory protein (FLIPr), an FcγR antagonist secreted by Staphylococcus aureus, as a vector to target ovalbumin (OVA) to dendritic cells (DCs) via intranasal administration. Our results demonstrate that intranasal administration of recombinant OVA-FLIPr fusion protein (rOVA-FLIPr) alone efficiently delivers OVA to DCs in nasal lymphoid tissue. Subsequently, OVA-specific IgG and IgA antibodies in the circulatory system and IgA antibodies in mucosal tissue were detected. Importantly, activation of OVA-specific CD4+ and CD8+ T cells and induction of a broad-spectrum cytokine secretion profile were detected after intranasal administration of rOVA-FLIPr alone in immunocompetent C57BL/6 mice. Furthermore, we employed immunodeficient AG129 mice as a Zika virus infection model and demonstrated that intranasal administration of recombinant Zika virus envelope protein domain III-FLIPr fusion protein induced protective immune responses against the Zika virus. These results suggest that antigen-FLIPr fusion protein alone via intranasal administration can be applied to mucosal vaccine development.