Preclinical Efficacy of a Trivalent Human FcγRI-Targeted Adjuvant-Free Subunit Mucosal Vaccine against Pulmonary Pneumococcal Infection.

Sudeep Kumar,Edmund J Gosselin,Raju Sunagar

doi:10.3390/vaccines8020193

Sudeep Kumar, Edmund J Gosselin + Show 1 more

Open Access

https://doi.org/10.3390/vaccines8020193

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Journal: Vaccines	Publication Date: Apr 23, 2020
Citations: 4	License type: CC BY 4.0

Affiliation: Albany Medical Center Hospital

Abstract

Lack of safe and effective mucosal adjuvants has severely hampered the development of mucosal subunit vaccines. In this regard, we have previously shown that immunogenicity of vaccine antigens can be improved by targeting the antigens to the antigen-presenting cells. Specifically, groups of mice immunized intranasally with a fusion protein (Bivalent-FP) containing a fragment of pneumococcal-surface-protein-A (PspA) as antigen and a single-chain bivalent antibody raised against the anti-human Fc-gamma-receptor-I (hFcγRI) elicited protective immunity to pulmonary Streptococcus pneumoniae infection. In order to further enhance the immunogenicity, an additional hFcγRI-binding moiety of the single chain antibody was incorporated. The modified vaccine (Trivalent-FP) induced significantly improved protection against lethal pulmonary S. pneumoniae challenge compared to Bivalent-FP. In addition, the modified vaccine exhibited over 85% protection with only two immunizations. Trivalent-FP also induced S. pneumoniae-specific systemic and mucosal antibodies. Moreover, Trivalent-FP also induced IL-17- and IL-22-producing CD4+ T cells. Furthermore, it was found that the hFcγRI facilitated uptake and presentation of Trivalent-FP. In addition, Trivalent-FP also induced IL-1α, MIP-1α, and TNF-α; modulated recruitment of dendritic cells and macrophages; and induced CD80/86 and MHC-II expression on antigen presenting cells.

Highlights

Mucosal surfaces are prone to infection by many pathogens, and adequate protection of mucosal surfaces require the presence of effective local immune response [1,2,3,4,5,6]
The wild type littermates generated by crossbreeding the human-FcγRI heterozygous males with C57BL/6 females, which are referred to here as WT, were utilized as controls
The involvement of human-FcγRI targeting was evident with immunization with Bivalent-FP, as the Tg mice showed 50% protection but the WT mice showed only 14% protection (Figure 1C)

Summary

Introduction

Mucosal surfaces are prone to infection by many pathogens, and adequate protection of mucosal surfaces require the presence of effective local immune response [1,2,3,4,5,6]. The mucosal vaccines such as typhoid, cholera, and flu vaccines are effective at eliciting mucosal immunity, these are based on live-attenuated or inactivated whole cell vaccine platforms. Due to potential reversion to pathogenic forms or incomplete inactivation, the live attenuated and whole cell-inactivated vaccines pose significant safety concerns [8]. The increased safety profile of subunit vaccines comes at a cost of reduced efficacy. Subunit vaccines require adjuvants and often times require multiple immunizations to evoke an adequate immune response [8]

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