VACUNAS FELIPE GARCÍA HOSPITAL CLINIC. BARCELONA RESUMEN 17TH CROI.

Presentación del tema: "VACUNAS FELIPE GARCÍA HOSPITAL CLINIC. BARCELONA RESUMEN 17TH CROI."— Transcripción de la presentación:

1 VACUNAS FELIPE GARCÍA HOSPITAL CLINIC. BARCELONA RESUMEN 17TH CROI

2 TEST & TREAT TEST & TREAT PROFILAXIS PREEXPOSICION (PreP) PROFILAXIS PREEXPOSICION (PreP) PROFILAXIS POSTEXPOSICION (PEP) PROFILAXIS POSTEXPOSICION (PEP) MICROBICIDAS MICROBICIDAS VACUNAS VACUNAS

3 TEST & TREAT TEST & TREAT PROFILAXIS PREEXPOSICION (PreP) PROFILAXIS PREEXPOSICION (PreP) PROFILAXIS POSTEXPOSICION (PEP) PROFILAXIS POSTEXPOSICION (PEP) MICROBICIDAS MICROBICIDAS VACUNAS VACUNAS

4 TEST & TREAT 33 Decreases in Community Viral Load Are Associated with a Reduction in New HIV Diagnoses in San Francisco 88LB an association between expanded HAART coverage, decreased community plasma HIV-1-viral load, and decreased new HIV diagnoses

5 TEST & TREAT TEST & TREAT PROFILAXIS PREEXPOSICION (PreP) PROFILAXIS PREEXPOSICION (PreP) PROFILAXIS POSTEXPOSICION (PEP) PROFILAXIS POSTEXPOSICION (PEP) MICROBICIDAS MICROBICIDAS VACUNAS VACUNAS

6 PREP Antirretrovirales Modelos animales 83 Efficacy of Intermittent Prophylaxis with Tenofovir and Emtricitabine against Rectal SHIV Transmission in Macaques – Grupo I: 2 h y +26 h HR 4.1 Grupo II: -2 h y +24 horas HR 4 – Grupo III: -22 h y +2 h HR 16.7 Grupo IV: -3 d y +2 h HR 15.4 – Grupo V: -7 d y +2 h HR 9.3 Grupo VI: -3 d HR 0.5 950 SHIV-specific T Cell Responses During Successful PrEP and Following Infection During PrEP -Robust SHIV-specific T cell responses following successful PrEP and repeated rectal SHIV exposures. -These T cell responses did not prevent infections in all animals during subsequent virus exposures in all animals during subsequent virus exposures -Intermittent detection and changes in epitope specificity suggest that memory T cells were not efficiently induced during repeated virus exposures. This might explain the inability of the T-cells to completely protect from subsequent infection.

7 PREP Humanos 85 MVC 300mg BID for 8 days PK1PK2 BP SE * SE:BP * GMR RT* RT:B P RatioBPSE SE:B P GMRRT* RT:B P Ratio C 12h (ng/mL or ng/g) 21 (7 to 52) 2411,370 6049 (23 to 102) 38 (19 to 75) 0.7 (0.5 to 1) 448991 AUC 12h (ng*hr/m L or ng*hr/g) 1,766 (527 to 3,199) 91 3 0.6 14,31 8 91,953 (1,417 to 4,687) 1196 (655 to 2,577) 0.6 (0.5 to 0.8) 58,74 4 28 MVC AUCs in semen: 56% (1 doses) and 62% (8 days) lower than BP MVC AUC in RT: 9-fold (1 doses) and 28-fold (8 days) blood plasma.

8 TEST & TREAT TEST & TREAT PROFILAXIS PREEXPOSICION (PreP) PROFILAXIS PREEXPOSICION (PreP) PROFILAXIS POSTEXPOSICION (PEP) PROFILAXIS POSTEXPOSICION (PEP) MICROBICIDAS MICROBICIDAS VACUNAS VACUNAS

9 PEP 956 Open Randomized Multicenter Clinical Trial Comparing Zidovudine/Lamivudine (ZDV/3TC) plus Lopinavir/r (LPV/r) or plus Atazanavir (ATV) Used as Postexposure Prophylaxis (PEP) for HIV Infection 956 Open Randomized Multicenter Clinical Trial Comparing Zidovudine/Lamivudine (ZDV/3TC) plus Lopinavir/r (LPV/r) or plus Atazanavir (ATV) Used as Postexposure Prophylaxis (PEP) for HIV Infection Adverse Events (AE) Lop/rAtzp People with AE (% arm) 50(49%)42(43%)0.3 Total AE (% of Total AE) 94(63%)56(37%) AE Gastrointestinal (% arm AE) 66(70%)23(41%)0.0004 AE Neuropsychiatric (% arm AE) 10(11%)9(16%)0.3 AE Hepatic (% arm AE) 1(1%)9(16%)0.0003 AE Systemic (% arm AE) 16(17%)13(23%)0.8 AE Dermatologic (% arm AE) 1(1%)0(0%)0.4 AE ENT (% arm AE) 0(0%)2(4%)0.06 Discontinued study result AE (% arm) 7(7%)10(10%)0.4 Median period before discontinued result AE (days) 4120.23 Severity AE* Grade I (% people with AE arm) 43(86%)34(81%)0.5 Grade II (% people with AE arm) 4(8%)7(17%)0.2 Grade III (% people with AE arm) 3(6%)1(2%)0.4 Grade IV (% people with AE arm) 0(0%)0(0%) Withdrawal Interval 22% 14% 19% Withdrawal Interval 21% 23% 14% 15%

10 TEST & TREAT TEST & TREAT PROFILAXIS PREEXPOSICION (PreP) PROFILAXIS PREEXPOSICION (PreP) PROFILAXIS POSTEXPOSICION (PEP) PROFILAXIS POSTEXPOSICION (PEP) MICROBICIDAS MICROBICIDAS VACUNAS VACUNAS

11 MICROBICIDAS 87LB PRO 2000 Objetivo: probar la eficacia en humanos en un ensayo Objetivo: probar la eficacia en humanos en un ensayo Fase III de PRO2000 (afecta a la unión inicial y fase de fusión del VIH) Resultados: Resultados: – Se randomizaron 9385 mujeres a 4 ramas: placebo vs PRO2000. – Incidencia 4.7 (82/1741) and 3.9 (67/1717)/100 person- years respectively; HR = 1.21, 95%CI 0.88 to 1.68 949 949 Tenofovir Gel Protects Macaques Against SHIV Exposures Three Days after Vaginal Application

12 TEST & TREAT TEST & TREAT PROFILAXIS PREEXPOSICION (PreP) PROFILAXIS PREEXPOSICION (PreP) PROFILAXIS POSTEXPOSICION (PEP) PROFILAXIS POSTEXPOSICION (PEP) MICROBICIDAS MICROBICIDAS VACUNAS VACUNAS

13 VACUNA FRENTE A VIH VACUNA TERAPEUTICA VACUNA TERAPEUTICA VACUNA PREVENTIVA VACUNA PREVENTIVA

14 VACUNAS HUMANOS HUMANOS – Ensayos vacunas terapéuticas 76 Factors Associated with Viral Rebound in HIV-Positive Subjects Receiving a Therapeutic HIV-1 gag Vaccine 76 Factors Associated with Viral Rebound in HIV-Positive Subjects Receiving a Therapeutic HIV-1 gag Vaccine 77 A Phase I Double-blind Placebo-controlled Randomized Study of a Therapeutic Vaccine Using Autologous DC Loaded with Autologous HIV-1 in Untreated Patients with Asymptomatic Chronic HIV Infection 77 A Phase I Double-blind Placebo-controlled Randomized Study of a Therapeutic Vaccine Using Autologous DC Loaded with Autologous HIV-1 in Untreated Patients with Asymptomatic Chronic HIV Infection 385 Increased HIV-specific Immunity in HIV-infected Individuals Vaccinated with a DNA Prime, rAd5 Boost Regimen 385 Increased HIV-specific Immunity in HIV-infected Individuals Vaccinated with a DNA Prime, rAd5 Boost Regimen – Ensayos en vacunas preventivas 74 RV 144 Update: Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thai Adults 74 RV 144 Update: Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thai Adults 75 Vaccine-induced Changes in Breakthrough HIV-1 Sequences from the Step Trial 75 Vaccine-induced Changes in Breakthrough HIV-1 Sequences from the Step Trial 78LB Optimal Priming of Poxvirus Vector-based HIV Vaccine Regimens Requires 3 DNA Injections: Results of the Randomized Multicentre EV03/ANRS Vac20 Phase I/II Trial 78LB Optimal Priming of Poxvirus Vector-based HIV Vaccine Regimens Requires 3 DNA Injections: Results of the Randomized Multicentre EV03/ANRS Vac20 Phase I/II Trial

15 VACUNAS MODELOS ANIMALES MODELOS ANIMALES – Adyuvantes 79LB Preclinical Studies on DNA/MVA Vaccines: Co-expressed GM-CSF, a Strong Adjuvant for Prevention of Infection 79LB Preclinical Studies on DNA/MVA Vaccines: Co-expressed GM-CSF, a Strong Adjuvant for Prevention of Infection 381 Modulation of Vaccine Responses by RANTES Significantly Lowers Viral Replication following SIVmac251 Challenge 381 Modulation of Vaccine Responses by RANTES Significantly Lowers Viral Replication following SIVmac251 Challenge 382 IL-28B Adjuvant Increases Granzyme B Content and CD107a Expression in HIV-specific CD8+ T Cells after DNA Vaccination 382 IL-28B Adjuvant Increases Granzyme B Content and CD107a Expression in HIV-specific CD8+ T Cells after DNA Vaccination – Vectores 81 Lentiviral Vector-based Anti-HIV-1 Vaccine Induces Strong T Cell and Antibody Responses in Macaques, with and without DNA Priming 81 Lentiviral Vector-based Anti-HIV-1 Vaccine Induces Strong T Cell and Antibody Responses in Macaques, with and without DNA Priming – Activación y Marcadores surrogados 378 Control of Immune Activation prior to SIV Challenge Is Tightly Linked to the Protective CD8+ T Cell Immunity Induced by a Live, Attenuated AIDS Vaccine 378 Control of Immune Activation prior to SIV Challenge Is Tightly Linked to the Protective CD8+ T Cell Immunity Induced by a Live, Attenuated AIDS Vaccine 384 MVA-SIV Boosting of AdHu5-SIV Immunized Rhesus Macaques Induces Higher Levels of SIV-specific CD8+ T Cells but Results in Increased Virus Replication after SIVmac239 Challenge 384 MVA-SIV Boosting of AdHu5-SIV Immunized Rhesus Macaques Induces Higher Levels of SIV-specific CD8+ T Cells but Results in Increased Virus Replication after SIVmac239 Challenge ESTUDIOS NEUTRALIZACION ESTUDIOS NEUTRALIZACION 361 Identification of Sera with Broad and Potent Cross-Neutralizing Activity against HIV-1 in a Group of Patients with Undetectable Viral Loads 361 Identification of Sera with Broad and Potent Cross-Neutralizing Activity against HIV-1 in a Group of Patients with Undetectable Viral Loads 82 Broad HIV Neutralizing Antibodies Can Be Elicited by the GBV-C glycoprotein E2 and Neutralize HIV via a 2F5-like Mechanism 82 Broad HIV Neutralizing Antibodies Can Be Elicited by the GBV-C glycoprotein E2 and Neutralize HIV via a 2F5-like Mechanism

16 DC-SIGN VIH CÉLULAS DENDRÍTICAS E INFECCIÓN POR EL VIH - Facilitan la infección por el VIH I.P.

17 VACUNAS Ensayos vacunas terapéuticas 77 Vacuna de CD A modest decrease in VL was observed in vaccine recipients and was correlated with a moderate increase of HIV specific T cell responses.

18 VACUNAS 76 factors independently associated with lower ATI VL: included lower pre-antiretroviral therapy VL, decreased proportion of HLA-associated escape mutations in Gag, absence of unfavorable HLA class I alleles, vaccine arm. Ensayos vacunas terapéuticas 385 Increased HIV-specific Immunity in HIV-infected Individuals Vaccinated with a DNA Prime, rAd5 Boost Regimen

19 VACUNAS Ensayos en vacunas preventivas 74 RV 144 Update: Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thai Adults 75 breakthrough viruses from vaccinees diverged further from the Step vaccine sequence than viruses from placebo recipients at potentially immune reactive sites 78LB Optimal Priming of Poxvirus Vector-based HIV Vaccine Regimens Requires 3 DNA Injections: Results of the Randomized Multicentre EV03/ANRS Vac20 Phase I/II Trial

20 VACUNAS MODELOS ANIMALES Adyuvantes 79LB DNA/MVA Vaccines + GM-CSF (NA) + GM-CSF (NA) CONTROLSDNA/MVA DNA/MVA + GM-CSF INFECTIONS9/96/82/7 381 DNA+ IL12 or DNA+RANTES can modulate immune responses and significantly impact viral replication following viral challenge. - the magnitude, proliferative capacity, or polyfunctionality of the responses does not predict the outcome of viral challenge 382 Plasmid HIV gag/pol + IL-28B

21 VACUNAS MODELOS ANIMALES Vectores 81 Lentiviral Vector-based Anti-HIV-1 Vaccine Induces Strong T Cell and Antibody Responses in Macaques, with and without DNA Priming Activación y Marcadores surrogados 378 Control of Immune Activation prior to SIV Challenge Is Tightly Linked to the Protective CD8+ T Cell Immunity Induced by a Live, Attenuated AIDS Vaccine 384 MVA-SIV Boosting of AdHu5-SIV Immunized Rhesus Macaques Induces Higher Levels of SIV-specific CD8+ T Cells but Results in Increased Virus Replication after SIVmac239 Challenge

22 VACUNAS ESTUDIOS NEUTRALIZACION ESTUDIOS NEUTRALIZACION 361 Identification of Sera with Broad and Potent Cross-Neutralizing Activity against HIV-1 in a Group of Patients with Undetectable Viral Loads 361 Identification of Sera with Broad and Potent Cross-Neutralizing Activity against HIV-1 in a Group of Patients with Undetectable Viral Loads 82 GB virus C Anti-E2 antibodies neutralize HIV-1 and 2, as well as SIV by targeting Phospholipids within the retroviral lipid bilayer via a 2F5-like Mechanism 82 GB virus C Anti-E2 antibodies neutralize HIV-1 and 2, as well as SIV by targeting Phospholipids within the retroviral lipid bilayer via a 2F5-like Mechanism Number of viruses neutralized a Detectable viral loads ID 90 <1/20 0 ID 90 <1/200 0 0109202 1783 2150 311 420 500 610 Number of viruses neutralized a Undetectable viral loads ID 90 <1/20 0 ID 90 <1/200 0 0109188 12819 218 311 403 512 69210

23 RESUMEN TEST & TREAT TEST & TREAT – Tratamiento generalizado se asocia con disminución de la incidencia PROFILAXIS PREEXPOSICION (PreP) PROFILAXIS PREEXPOSICION (PreP) – iPreP con Truvada disminuye la infección siempre que se asocie con refuerzo post. – La exp repetida aumenta las respuestas específicas, pero no son eficaces – MVC con una dosis tiene niveles altos en mucosa rectal PROFILAXIS POSTEXPOSICION (PEP): PROFILAXIS POSTEXPOSICION (PEP): – La tasa de abandonos es muy alta, no existen diferencias en efectos adversos Atazanavir vs Lopinavir/r MICROBICIDAS: MICROBICIDAS: – PRO 2000 no funciona

24 RESUMEN VACUNAS HUMANOS HUMANOS – Ensayos vacunas terapéuticas La vacuna de CD en pacientes sin tto disminuyó 0.5 log la CV asociado con respuestas específicas La vacuna de CD en pacientes sin tto disminuyó 0.5 log la CV asociado con respuestas específicas DNA + Ad5 induce respuestas en pacientes infectados por VIH DNA + Ad5 induce respuestas en pacientes infectados por VIH Un HLA favorable puede influir la respuesta a las vacunas Un HLA favorable puede influir la respuesta a las vacunas – Ensayos en vacunas preventivas En el STEP las respuestas inducidas podrían haber protegido frente a los virus provocando un escape En el STEP las respuestas inducidas podrían haber protegido frente a los virus provocando un escape Los ensayos en fase I son necesarios para probar diversas estrategias como 3 dosis de DNA + 1 NYVAC es superior a 2/2 Los ensayos en fase I son necesarios para probar diversas estrategias como 3 dosis de DNA + 1 NYVAC es superior a 2/2

25 RESUMEN VACUNAS MODELOS ANIMALES MODELOS ANIMALES – Adyuvantes: adyuvantes del tipo de GM-CSF, RANTES o IL-28 utilizados dentro de la propia vacuna pueden mejorar la respuesta virológica e inmunológica – Vectores: los vectores lentivirales son prometedores – Activación y Marcadores surrogados: la presencia de respuesta específica no se relaciona con el control de la replicación viral, este control parece depender de la capacidad de las vacunas de inducir respuestas CD8 y disminuir activación en mucosas ESTUDIOS NEUTRALIZACION ESTUDIOS NEUTRALIZACION – Los pacientes en tratamiento presentan una mejor respuesta neutralizante – Ac frente a Hep GB son neutralizantes de forma parecida a otros aislados de pacientes infectados por VIH