Vaccine With Bacterium-like Particles Displaying HIV-1 Gp120 Trimer Elicits Specific Mucosal Responses And Neutralizing Antibodies In Rhesus Macaques

Background and Purpose HIV-1 is the primary pathogen causing AIDS which mainly transmitted through sex and an effective vaccine is the best way to prevent the spread of HIV-1.To fight the spread of HIV,an army of pre-clinical and clinical research have been performed since the first case reported in 1981.It is said that the most promising vaccine of RV144 was declared failed based on the repeat clinical study in Africa.The epoch for HIV-1 vaccine sophisticated design arrived,pre-clinical studies have shown that the induction of secretory IgA(s IgA)in mucosa and neutralizing antibodies(NAbs)in sera are essential for the design of vaccines that can effectively block the transmission of HIV-1 based on the optimization of vaccine and exploration of delivery systems.However,there is hardly any single HIV-1 vaccine that can simultaneously induce both mucosal responses and NAbs in serum via conventional immunization route.Previously,we found that gp120 trimer Protan-gp120AE-MTQ(PAM)bound to bacterium-like particles(BLPs)delivered via intranasal(IN)drip successfully induced Env-specific IgA at mucosal sites in mice.And it could also induce NAbs in guinea pigs via intramuscular(IM)injection.Here,we further evaluated the ability of this vaccine of BLP displaying PAM(BLP-PAM)to elicit HIV-1 specific mucosal and systemic immune responses by combination of IN and IM immunization strategies in rhesus macaques which revealed that the BLP delivery system can provide a promising platform for the vaccine design for the other pathogens such as influenza,SARS-Co V-2,etc.Methods(1)Immunogold labeled by goat-anti-human Ig G was used to visualize PAM binding to BLP by Transmission Electron microscopy(TEM).Enzyme-linked immunosorbent assays(ELISA)were performed for antigenicity analysis after the binding of PAM to BLP.(2)Enzyme-linked immunosorbent assays,Enzyme-linked Immunospot Assay and Flow Cyto Metry were used to measure mucosal and systemic responses after the intranasal drip and intramuscular immunizations including HIV-1 Env specific IgA and Ig G level in sera and mucosal tissues,memory B cell and T cell responses in rhesus macaques model.(3)Neutralization assays were performed to test the neutralization potency and breadth of sera for the the global panel of 12 tier 2,2 tier 1 HIV-1 pseudoviruses which and autologous pseudoviruse.Results(1)PAM effectively bound to BLPs while maintaining the antigenicity and epitope accessibility.(2)Intranasal immunization with BLP-PAM rapidly induced HIV-1 specific s IgA in multiple mucosal tissues in rhesus macaques.(3)Intramuscular immunization with BLP-PAM induced NAbs in sera and enhanced the Ig G level in mucosal tissues.(4)r Ad2-gp120 AE boost increased the nasal IgA and Ig G levels while enhancing the T cell response.Conclusions These results demonstrated that the BLP displaying HIV-1 gp120 trimer vaccine and the combined IN/IM strategy would help to block sexual transmission of HIV by increasing B cell immune responses in the mucosal tissues and blood.And the BLP delivery system also provides a promising platform for the vaccine design of other pathogens such as influenza,SARS-Co V-2,etc.