TB, Malaria, VIH ( y en 20 minutos!) Vaccinology 2015 Dr. Jan Wilhelm

Transcripción

1 TB, Malaria, VIH ( y en 20 minutos!) Vaccinology 2015 Dr. Jan Wilhelm

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3 Objetivos específicos de la presentación 1- Generalidades VIH, TBC y Malaria 2- Introducción a Biología de Sistemas 3- Estado actual de vacunas contra VIH, TBC y Malaria

4 Introducción Qué tienen en común un virus, un parásito y una bacteria?!

5 Introducción Qué tienen en común un virus, un parásito y una bacteria? Las 3 son un desafío para la humanidad!

6 Introducción: SIDA > 25 millones de 33 millones viviendo con VIH 2.6 millones de casos nuevos / año 1.8 millones de /año

7 Introducción: Malaria 225 millones de casos nuevos /año 1 millón de /año

8 Introducción: Tuberculosis 1/3 población mundial infectada con MTB 9.6 millones de casos nuevos/año 1.7 millones de /año Emergencia de MDR TB

9 Introducción Vacunas no estaban incluidas en objetivos ONU para el 2015! (TB si para el 2035 ) Nuevos avances tecnológicos aportan esperanza: Nuevos esquemas inmunización Nuevos adyuvantes Nuevos métodos de presentación de antígenos Nuevas formas de enfrentar el problema Biología de sistemas Identificación de marcadores de protección adecuados Innovación clínica y regulatoria

10 Introducción Vacunas no estaban incluidas en objetivos ONU para el 2015! Nuevos avances tecnológicos aportan esperanza: Nuevos esquemas inmunización Nuevos adyuvantes Nuevos métodos de presentación de antígenos Nuevas formas de enfrentar el problema Biología de sistemas Identificación de marcadores de protección Innovación clínica y regulatoria

11 Biología de Sistemas Recoger e integrar datos biológicos a diferentes niveles Visualizar propiedades no demostrables o predecibles Ejemplo: Respuesta a vacuna? Factores Genéticos Factores Moleculares Factores Ambientales + Interacción de ellos

12 Biología de Sistemas Análisis computacional Representaciones gráficas Modelos Vacuna nueva Respuesta protectora Ej: Vacuna YF-17D

15 Vaccinología Estructural Diseño de antigenos (en base a una estructura) Nuevos antígenos Inducen respuesta immune protectora óptima Estabilización de antígenos Exposición de epítopes conservados Diseño de moleculas con múltiples epitopes inmunodominantes

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18 VIH Vacunas de subunidades de la envoltura del VIH (Estudio clínicos fase I y II, 1990s) Nabs in vitro solo neutralizan cepas vaccinales Vacunas de mezclas de subunidades recombinantes Resultados negativos (Diversidad antigénica e inhabilidad para neutralizar cepas salvajes)

19 VIH Inmunidad mediada por células T Estudio Step: Adenovirus 5 (MRKAd5 HIV-1) Gag/Pol/Nef o placebo.

20 VIH Estudio RV144: Canary pox B HIVGag + Pro + E gp120 (ALVAC-HIV), luego booster con gp120 AIDS VAX B/E. 31% prevención

21 VIH No Ac solos No LT solos Combinación Protección marginal Biología de Sistemas? Identificar marcadores de inmunogenicidad! CD41 específicos CD81 específicos Carga viral

22 VIH Perfiles de expresión de ARN en sangre de monos rhesus pre y post vacuna adenovirus 5 Análisis de la expresión de ARN en PBMCs y ganglios linfáticos Marcadores de la magnitud de la respuesta específica en CD41, CD81 y CV

23 Genes asociados a respuesta CD4 y a CV Rappuoli, Rino; Aderem, Alan Nature. 473(7348): , May 26, DOI: /nature10124 Figure 1 Signatures that predict T-helper-cell responses after vaccination and viral load after infection. We propose that networks have stronger predictive power than do individual molecules. The network represents innate immune signatures, measured days after primary vaccination, which predict enhanced SIV Gag-specific CD4+ T-cell responses, and reduced SIV load after challenge, measured months later. In this network, the circles or 'nodes' represent genes expressed in the PBMCs of macaques 6 days after vaccination. The lines between the nodes ('edges') represent associations between them. The edges indicate which combination of genes is predictive of Gag-specific CD4+ T cells (blue edges) or SIV load (red edges). 3

24 VIH Subgrupo ensayo STEP 2 años: < CV si HLA B27, B57 o B58 (> respuesta protectora CD81) > Títulos de Ac < transcripción de vías antivirales e inflamasoma

25 VIH Controladores versus Progresores? Variantes genéticas protectoras de HLA Diferencias funcionales en CD8 específicos para VIH

26 Nature. 473(7348): , May 26, DOI: /nature10124 Figure 2 Identifying novel regulatory networks associated with protection against HIV using large-scale clinical trials. Two large-scale HIV vaccine trials have shown only modest, if any, efficacy overall. Follow-up analyses are being performed to determine whether specific subgroups of participants acquire protective responses from vaccination. In principle, appropriate data mining of these trials can inform future trials by suggesting correlates of immunity and target networks that will enable rational vaccine design. For example, identification of a subpopulation of those vaccinated that became infected but controlled viral loads (red) can be compared to the population who became infected but did not control viral loads (blue). In this case, one can do systems analysis on both the innate and adaptive response to the vaccine, as well as the genetics of the individuals. Blood is collected from all of the trial participants at various times after vaccination and stored until it is known who became infected and who controlled the virus after infection. Innate cells that were collected early after vaccination and adaptive immune cells that were collected later are analysed at the molecular level using a variety of high-throughput measurements including transcriptional state, transcription-factor binding, signalling pathways, genetic variation, and metabolite and protein levels. These measurements are computationally integrated into dynamic network models that can be interpreted using 4 visualization programs. These networks can be used as correlates of protection in subsequent vaccine trials and

27 Diseño de antígenos basado en estructura Moléculas gp120 más estables, epítopes conservados Nabs de amplio espectro Identificación de epítopes neutralizantes inmunodominantes de variantes de VIH sería la base para el desarrollo de nuevas proteinas de membrana que generen protección más amplia

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29 Tuberculosis Bacilo de Calmette Guerin (BCG), 100 años (1921), cepa de Mycobacterium bovis atenuada Eficacia controversial Previene enfermedad diseminada y muerte en niños No previene infección crónica o TBC pulmonar en adultos

30 M. Tuberculosis Establece infección crónica latente y reactiva frente a bajas en la vigilancia inmunológica 2 mil millones de personas con infección latente 10% progresarán a enfermedad

31 Estrategias a. Prevención de Infección (prime) b. Prevención de enfermedad (booster) c. Prevención de recurrencias (terapéutica)

32 16 vacunas actualmente en ensayos clínicos (proof-of concept o fase fase IIb) 1- Antígenos recombinantes (Mtb72F, Ag85B-ESAT-6 + AS02, Ag85-TB IC31, Ag85B-ESAT-6-Rv2660c) 2- ADN o Vectores Virales 3- Vacunas de subunidades como refuerzo BCG (para prevenir infección crónica o evitar reactivación)

33 Reingeniería de BCG! (BCG enchulada ) Cepa rbcg30 sobreexpresa antígeno 85B > respuesta CD41 Otra (con citolisina de Listeria monocytogenes ) dirigida a activar vía presentadora de antígenos clase I (> respuesta T CD81 ) rbcgdurec:hly ( gen de ureasa, acidificación de la vacuola y escape) > protección, < reacción Estudios clínicos fase I

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37 Vacuna contra enfermedad

38 Figure 1. Study sites and malaria endemicity. The RTS,S Clinical Trials Partnership (2014) (2014) Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites. PLoS Med 11(7): e doi: /journal.pmed info:doi/ /journal.pmed

39 Figure 2. CONSORT diagram of children aged 5 17 mo at enrollment and followed until 18 mo post-vaccination. The RTS,S Clinical Trials Partnership (2014) (2014) Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites. PLoS Med 11(7): e doi: /journal.pmed

40 Figure 3. CONSORT diagram of infants aged 6 12 wk at enrollment followed until 18 mo post-vaccination. The RTS,S Clinical Trials Partnership (2014) (2014) Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites. PLoS Med 11(7): e doi: /journal.pmed

41 Figure 4. Vaccine efficacy against all episodes of clinical malaria (primary case definition) during an 18-mo follow-up period after dose 3 in children 5 17 mo of age at enrollment, ordered by increasing malaria incidence at each study site (per-protocol population). The RTS,S Clinical Trials Partnership (2014) (2014) Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites. PLoS Med 11(7): e doi: /journal.pmed

42 Figure 5. Vaccine efficacy against all episodes of clinical malaria (primary case definition) during an 18-mo follow-up period after dose 3 in children 5 17 mo of age at enrollment, ordered by increasing malaria incidence at each study site (intention-to-treat population). The RTS,S Clinical Trials Partnership (2014) (2014) Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites. PLoS Med 11(7): e doi: /journal.pmed

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45 Figure 6. Number of cases of clinical malaria (secondary case definition) averted per 1,000 participants vaccinated during an 18-mo follow-up period (per-protocol population). The RTS,S Clinical Trials Partnership (2014) (2014) Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites. PLoS Med 11(7): e doi: /journal.pmed

46 Figure 7. Number of cases of severe malaria (secondary case definition) averted per 1,000 participants vaccinated during an 18-mo follow-up period (per-protocol population). The RTS,S Clinical Trials Partnership (2014) (2014) Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites. PLoS Med 11(7): e doi: /journal.pmed

47 Table 1. Vaccine efficacy against all episodes of clinical and severe malaria in children aged 5 17 mo at enrollment. The RTS,S Clinical Trials Partnership (2014) (2014) Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites. PLoS Med 11(7): e doi: /journal.pmed

48 Table 2. Vaccine efficacy against all episodes of clinical and severe malaria in infants aged 6 12 wk at enrollment. The RTS,S Clinical Trials Partnership (2014) (2014) Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites. PLoS Med 11(7): e doi: /journal.pmed

49 Mosquirix

50 Rappuoli, Rino; Aderem, Alan Nature. 473(7348): , May 26, DOI: /nature

51 Gracias