Malaria (mal aria) - Sabin Dic 09_40... · 2014. 12. 7. · Vaccine appro... Ashley J. Birkett ,...

Malaria(“mal aria”)

Vaccinology 2014Dr. Jan Wilhelm

Introducción

• Parásito unicelular Plasmodium

• 5 especies de Plasmodium que infectan humanos:•Plasmodium falciparum•Plasmodium vivax•Plasmodium ovale•Plasmodium malariae•Plasmodium knowlesi

• Transmitido por mosquito Anopheles hembra

http://www.who.int/malaria

Introducción

• 3.5 mil millones de personas en riesgo

• > 200 millones de casos anuales

• > 650. 000 muertes anuales

• > 80% de casos y > 90% muertes en Africasubsahariana

• Más severa en < 5 años y embarazadas

• 2000 a 2010 ↓ incidencia de malaria en 17% y Ɨ en26%

http://www.who.int/malaria/world malaria report 2011/en/

http://www.who.int/malaria/world

Introducción

•1950s OMS (DDT; cloroquina) → Resistencia

•1960s y 1970s vacunas de parásitos atenuados

• 2006 Malaria Vaccine Technology Roadmap, WHO GVRF• Foco en P. falciparum en niños en Africa• Vacuna contra enfermedad severa• Eficacia >50% y protección > 1 año• Áreas de priorización

http://www.malariavaccineroadmap. net/pdfs/Malaria Vaccine TRM Final.pdf; 2006.

• 2007 Malaria Forum (Gates Foundation, OMS, RBM Partnership)• Erradicación

Roberts L, Enserink M. Malaria. Did they really say. . .eradication?Science. 2007;318(5856):1544–5.

Introducción

•2008 malERA initiativehttp://www.ploscollections.org/malera2011

Alonso PL, et al. PLoS Med2011;8(1):e1000406.

The malERA Consultative Group on Vaccines. A research agenda for malaria

eradication: vaccines. PLoS Med 2011;8(1):e1000398.

• 2012 Foro científico de la OMS: Nueva “hoja de ruta”• > espectro geográfico• > espectro de edad• > nº de especies• Vacunas que reduzcan la transmisión

http://www.who.int/vaccineresearch/diseases/malaria/roadmapupdate

jul12/en/index.html

Vacuna contra enfermedad clínica

1- Vacunas contra antígenos etapa Pre-eritrocito

2- Vacunas contra antígenos etapa Hematógena Asexual

Vacuna contra la transmisión

≠ metas , ≠ población objetivo, ≠ perfiles, ≠ procesos de aprobación, ≠ estrategias de implementación

Schwartz L, et al. Malar J 2012;11:p11.

Fig. 1 Association between malaria lifecycle stage targeted, clinical outcome and anticipated goal/impact. Vaccine approaches that

target only sexual, sporogonic and/or mosquito antigens are expected to have a role in control and elimination. Vaccine appro...

Ashley J. Birkett , Vasee S. Moorthy , Christian Loucq , Chetan E. Chitnis , David C. Kaslow

Malaria vaccine R&D in the Decade of Vaccines: Breakthroughs, challenges and opportunities

Vaccine, Volume 31, Supplement 2, 2013, B233 - B243

http://dx.doi.org/10.1016/j.vaccine.2013.02.040


1- Vacunas contra antígenos etapa Pre-eritrocito

Estudios controlados de infección con esporozoitos en voluntarios vacunados han demostrado protección

¿Biomarcadores?¿Grado de protección? ¿Volumen de muestras?

Altos niveles de LT CD8(+) se asociarían a protección

Roestenberg M, et al. N Engl J Med 2009;361(5):468–77.

Kester KE, et al. J Infect Dis 2009;200(3):337–46.

Epstein JE, et al. J Infect Dis 2007;196(1):145–54.

Vacunas contra antígenos etapa Pre-eritrocito

IMRAS: Immunization via mosquito bite with radiation-attenuated sporozoites

Requiere aprox. 1000 picaduras de mosquitos

ITV: Infection-treatment vaccination

Requiere aprox. 45 picaduras de mosquitos

RTS,S/AS01: Circumsporozoite protein o CSP

50% protección (95% CI, 32.9–67.1%) Ideal para evaluar biomarcadores

Roestenberg M, et al. N Engl J Med 2009;361(5):468–77.

Kester KE, et al. J Infect Dis 2009;200(3):337–46.

Epstein JE, et al. J Infect Dis 2007;196(1):145–54.

En evaluación sporozoitos criopreservados inyectablesRoestenberg M, et al. Am J Trop Med Hyg 2013;88(1):5–13.


2- Vacunas contra antígenos etapa Hematógena Asexual

• Importante mecanismo de inmunidad natural

• No existen biomarcadores de protección disponibles

• Estudios Fase 2 en curso ¿Vaccinología Reversa?

A.J. Birkett et al. / Vaccine 31S (2013) B233– B243

Vacuna contra enfermedad

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): e1001685.

doi:10.1371/journal.pmed.1001685

http://www.plosmedicine.org/article/ info:doi/10.1371/journal.pmed.1001685

http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001685

Figure 2. CONSORT diagram of children aged 5–17 mo at enrollment and followed until 18 mo post-vaccination.






Figure 3. CONSORT diagram of infants aged 6–12 wk at enrollment followed until 18 mo post-vaccination.






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).






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).






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).






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).





Table 1. Vaccine efficacy against all episodes of clinical and severe malaria in children aged 5–17 mo at enrollment.





Table 2. Vaccine efficacy against all episodes of clinical and severe malaria in infants aged 6–12 wk at enrollment.





Vacuna contra la transmisión (VIMT)

• Contribuir a eliminación/erradicación (malERA)

• Conceptos:

• Dirigidas a etapas SSM que inhiban el desarrollo del parásito en el vector

• Vacunas pre-eritrocito (PE) altamente eficaces que reduzcan la densidadparasitaria

• Vacunas etapa hematógena (BS) altamente eficaces que inhiban la invasiónde GR

• Reducción en la transmisión por reducción prevalencia estadios sexuales


Fig. 1 Association between malaria lifecycle stage targeted, clinical outcome and anticipated goal/impact. Vaccine approaches that

target only sexual, sporogonic and/or mosquito antigens are expected to have a role in control and elimination. Vaccine appro...

Ashley J. Birkett , Vasee S. Moorthy , Christian Loucq , Chetan E. Chitnis , David C. Kaslow

Malaria vaccine R&D in the Decade of Vaccines: Breakthroughs, challenges and opportunities

Vaccine, Volume 31, Supplement 2, 2013, B233 - B243


Vacuna contra la transmisión (VIMT)

• Objetivo:

• Reducir la tasa de replicación efectiva (R0) del parásito a < 1

• Fórmula de Ross- MacDonald

• Vacunas reducirían “c” ó % de picaduras en humanos infectados que infecten mosquitos

PE/BS-VIMT conferirían protección individual directa

SSM-VIMT entregarían un beneficio retardado (↓ transmisión)

Combinación SSM-VIMTs con PE/BS-VIMT ó medicamentos


Fig. 1 Diagram of two potential clinical/regulatory pathways for an SSM-VIMT. In one potential pathway (the Phase 3 CRT-based

pathway), regulatory approval is based upon a CRT demonstrating vaccine efficacy against incidence of infection. The accelerated

pathway for regulatory approval is based on an analytically and biologically, but not clinically, validated surrogate of efficacy, and

depends on the success of the work described under Assays and Correlates. ..

Julia K. Nunes , Colleen Woods , Terrell Carter , Theresa Raphael , Merribeth J. Morin , Diadier Diallo , Didier ...

Development of a transmission-blocking malaria vaccine: Progress, challenges, and the path forward

Vaccine, Volume 32, Issue 43, 2014, 5531 - 5539


http://www.who.int/malaria

Malaria (mal aria) - Sabin Dic 09_40... · 2014. 12. 7. · Vaccine appro... Ashley J. Birkett ,...

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