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Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection.

ABSTRACT: HIV-1 infection occurs primarily through mucosal transmission. Application of biologically relevant mucosal models can advance understanding of the functional properties of antibodies that mediate HIV protection, thereby guiding antibody-based vaccine development. Here, we employed a human ex vivo vaginal HIV-1 infection model and a rhesus macaque in vivo intrarectal SHIV challenge model to probe the protective capacity of monoclonal broadly-neutralizing (bnAb) and non-neutralizing Abs (nnAbs) that were functionally modified by isotype switching. For human vaginal explants, we developed a replication-competent, secreted NanoLuc reporter virus system and showed that CD4 binding site bnAbs b12 IgG1 and CH31 IgG1 and IgA2 isoforms potently blocked HIV-1_JR-CSF and HIV-1_Bal26 infection. However, IgG1 and IgA nnAbs, either alone or together, did not inhibit infection despite the presence of FcR-expressing effector cells in the tissue. In macaques, the CH31 IgG1 and IgA2 isoforms infused before high-dose SHIV challenge were completely to partially protective, respectively, while nnAbs (CH54 IgG1 and CH38 mIgA2) were non-protective. Importantly, in both mucosal models IgG1 isotype bnAbs were more protective than the IgA2 isotypes, attributable in part to greater neutralization activity of the IgG1 variants. These findings underscore the importance of potent bnAb induction as a primary goal of HIV-1 vaccine development.

SUBMITTER: Astronomo RD

PROVIDER: S-EPMC5161443 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection.

Astronomo Rena D RD Santra Sampa S Ballweber-Fleming Lamar L Westerberg Katharine G KG Mach Linh L Hensley-McBain Tiffany T Sutherland Laura L Mildenberg Benjamin B Morton Georgeanna G Yates Nicole L NL Mize Gregory J GJ Pollara Justin J Hladik Florian F Ochsenbauer Christina C Denny Thomas N TN Warrier Ranjit R Rerks-Ngarm Supachai S Pitisuttithum Punnee P Nitayapan Sorachai S Kaewkungwal Jaranit J Ferrari Guido G Shaw George M GM Xia Shi-Mao SM Liao Hua-Xin HX Montefiori David C DC Tomaras Georgia D GD Haynes Barton F BF McElrath Juliana M JM

EBioMedicine 20161121

HIV-1 infection occurs primarily through mucosal transmission. Application of biologically relevant mucosal models can advance understanding of the functional properties of antibodies that mediate HIV protection, thereby guiding antibody-based vaccine development. Here, we employed a human ex vivo vaginal HIV-1 infection model and a rhesus macaque in vivo intrarectal SHIV challenge model to probe the protective capacity of monoclonal broadly-neutralizing (bnAb) and non-neutralizing Abs (nnAbs) t ...[more]

PMID: 27919754

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Project description:IntroductionA Proteosome-adjuvanted trivalent inactivated influenza vaccine (P-TIV) administered intra-nasally was shown to be safe, well tolerated and immunogenic in both systemic and mucosal compartments, and effective at preventing illness associated with evidence of influenza infection.MethodsIn two separate studies using the human viral challenge model, subjects were selected to be immunologically naive to A/Panama/2007/1999 (H3N2) virus and then dosed via nasal spray with one of three regimens of P-TIV or placebo. One or two doses, 15 ?g or 30 ?g, were given either once only or twice 14 days apart (1 x 30 ?g, 2 x 30 ?g, 2 x 15 ?g) and subjects were challenged with A/Panama/2007/1999 (H3N2) virus. Immune responses to the vaccine antigens were measured by haemagglutination inhibition assay (HAI) and nasal wash secretory IgA (sIgA) antibodies.ResultsVaccine reactogenicity was mild, predictable and generally consistent with earlier Phase I studies with this vaccine. Seroconversion to A/Panama/2007/1999 (H3N2), following vaccination but prior to challenge, occurred in 57% to 77% of subjects in active dosing groups and 2% of placebo subjects. The greatest relative rise in sIgA, following vaccination but prior to challenge, was observed in groups that received 2 doses.ConclusionIntranasal vaccination significantly protected against influenza (as defined by influenza symptoms combined with A/Panama seroconversion) following challenge with A/Panama/2007/1999 (H3N2). When data were pooled from both studies, efficacy ranged from 58% to 82% in active dosing groups for any influenza symptoms with seroconversion, 67% to 85% for systemic or lower respiratory illness and seroconversion, and 65% to 100% for febrile illness and seroconversion. The two dose regimen was found to be superior to the single dose regimen. In this study, protection against illness associated with evidence of influenza infection (evidence determined by seroconversion) following challenge with virus, significantly correlated with pre-challenge HAI titres (p = 0.0003) and mucosal sIgA (p?0.0001) individually, and HAI (p = 0.028) and sIgA (p = 0.0014) together. HAI and sIgA levels were inversely related to rates of illness.Trial registrationClinicalTrials.gov NCT02522754.

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Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection.

Publications

Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection.

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