IL-12 plus CTB in intranasal DNA-MVA schemes improved magnitude and quality

ANA MARÍA RODRIGUEZ; CYNTHIA MAETO; JULIANA FALIVENE; MARIA PIA HOLGADO; M.MAGDALENA GHERARDI

Boston, MA

Conferencia; Aids Vaccine Conference 2012; 2012

BACKGROUND: Mucosal tissues are the major route of HIV transmission.Therefore, designing immunization regimes aimed to induce mucosal immuneresponse is needed. The aim of this study was to analyze the activity of IL-12 aloneor in combination with the cholera toxin B subunit (CTB), applied in DNA-prime/MVA-boost intranasal immunizations. METHODS: Balb/c mice were intranasally immunized with DNA expressingHIV-1 EnvB plus DNAIL-12 alone or in combination with CTB (10ug, applied at primeand booster doses). Groups receiving CTB, complete cholera toxin (CT) or non-adjuvants (control) were included. All groups received MVAEnvB as boost dose.Immune responses were evaluated 14, 30 or 53 days after immunization. RESULTS: IL-12 plus CTB generated the highest response, showing asynergistic effect for both adjuvants, measure by IFN-g and IL-2 ELISPOT, in spleen(7-fold increment), in regional (cervical) lymph nodes (LN), genital LN (iliac, GLN) and,more importantly, in genital tract mucosa (GT). At memory phase, we found that in theIL-12+CTB group IFN-ã and IL-2 secreting cells were two to three-fold higher in bothsystemic (p=0.001) and mucosal compartments (GLNs and GT).IL-12+CTB improved several quality features of the response: i) Higher levelsof T-cell polyfunctionality in spleen and GT. ii) % of specific proliferating cells wasincreased at 10, 30 and 53 days. iii) Enhanced in vivo citotoxicity: median 53% vs16.4% for control group. iv) Higher T-cell avidity in spleen cells (p=0.01). v) T-cellresponses with a superior breadth: cross-reactivity against different Env subtypes wassuperior. CONCLUSIONS: We demonstrated that IL-12 plus CTB generated a cooperativeadjuvant effect on the cellular immune response against Env applied in DNA-MVAintranasal immunizations. The improvement observed was not only in magnitude, butalso in the breadth and quality of the responses induced. These results are importantdue to the need to develop mucosal vaccine strategies against HIV.