Therapeutic vaccination to treat chronic infectious diseases

Figures & data

Figure 1: Positioning of therapeutic vaccines: at the interface between two worlds (Capgemini LifeSciences Team Analysis 2006, with permission).

Figure 2: Therapeutic vaccines are exploring a wide array of platforms

Table 1: Principal experimental approaches used to study the interplay between MVA and the host’s innate immune system

Experimental approaches	Innate immune response signature	References
• Peritoneal cells of immunized mice:        – RT-PCR        – ELISA	• Production of: -TNF ; IL-1β ; IL-6 ; IL-12p40 ; IFN-α • Production of Chemokines : -IP10/CXCL10 ; RANTES/CCL5 ; MCP-5/CCL12 ; MIP-2/CXCL2	(Delaloye J. et al., 2009)
• Immunization of wild type (WT) mice:        – ELISA on serum   • Infection of bone marrow- derived mDCs and pDCs (from WT and TLR KO mice)        – ELISA on culture supernatant	• Production of IFN-α Primarily triggered by non-TLR molecules.	(Waibler Z. et al., 2007)
• Infection of bone marrow- derived macrophages from TLR KO mice        – ELISA on culture supernatant	• Activation of TLR-2/ TLR-6/ MYD88 for the induction of IFN-β− independent chemokines ( ex MIP-2)	(Delaloye J. et al., 2009)
• Infection and Treatment with chloroquine of:        – THP-1 cells        – ELISA on culture supernatant   • Bone marrow- derived pDCs       – ELISA on culture supernatant	• Inhibition of type I interferon response suggesting the involvement of TLR-7	(Delaloye J. et al., 2009) (Waibler Z. et al., 2007)
• Infection of human whole blood cells:        – ELISA	-IL-8/CXCL8 ; MIP-1α/CXCL3 ; IP10 ; TNF; IL-1β ; IL-6	(Delaloye J. et al., 2009)
• Infection of:        – THP-1 macrophages   • Primary human macrophages:        – Luminex technology on culture supernatant        – RayBio human cytokine antibody array V.	• Production of: -IL-8 ; MIP-1α ; MIP-1β/CCL4 ; MCP-1/CCL2 ; RANTES ; IP10 ; IFN-β; IL-1rα   • Upregulation of: -GRO(CXCL1/CXCL2/CXCL3); Eotaxin 2 (CCL24)	(Delaloye J. et al., 2009) (Lehmann M.H. et al., 2009)
– Infection of THP-1 cells: mRNA analysis with multiprobe RPA	– Transient induction of: -CCL2; CCL3; CCL4; CXCL10	(Lehmann M.H. et al., 2009)
• Infection of human monocyte-derived DCs:        – Micro-array analysis	• Upregulation of:           -RIG-1; MDA-5; IL-12; IFN-α; IRF-7           Interferon-stimulated genes:           -FIT1; IFIT4; SCYB10	(Guerra S. et al., 2007)
• Infection of bone marrow- derived DCs	• Up regulation of CD40 on TLR-9 sensing,      Redundancy of TLR9	(Samuelsson C. et al., 2008)

Table 2  : Current MVA-based clinical trials in infectious diseases

Company	Product name	Product Description	Indication	Phase	Clinical trial number
Bavarian Nordic	MVA-mBN120B	MVA-HIV multiantigen vaccine (containing Gag, Pol, Tat, Vif, Vpu, Vpr, Rev and Nef proteins)	HIV-infected subjects	I	NCT00623259 (completed)
GeoVax	JS7/MVA62B	pGA2/JS7 (JS7)DNA and MVA62B prime/boost, vectors expressing Gag, Pol, and Env	HIV-1 infected adults on ART	I	NCT01378156
Okairos	AdCh3NSmut and MVA-NSmut	Chimp adenovirus and MVA encoding NS3, NS4, NS5a and NS5b prime/boost	HCV infected patients	I	NCT01296451
University Oxford	MVA85A	MVA encoding Ag85A	asymptomatic volunteers in South Africa who are infected with Mtb, HIV or both	I	NCT00480558 (completed)
University Oxford	MVA85A	MVA encoding Ag85A	healthy volunteers in the UK who are infected with HIV	I	NCT00395720 (completed)
AERAS / Oxford Consortium	MVA85A/AERAS-485	MVA encoding Ag85A	protective efficacy against TB disease in healthy, HIV-infected adults	II	NCT01151189
Bavarian Nordic	MVA-Nef	MVA encoding Nef protein	MVA-Nef HIV vaccine in HIV-1 infected patients with CD4 > 250/µ	II	NCT00189930 (completed)
Bavarian Nordic	MVA-mBN32	MVA-BN® expressing CTL and HTL epitopes of HIV-1	HIV-infected subjects	II	NCT00390078 (completed)
Mexican group	MVA-E2	MVA encoding E2 from BPV1	CIN1, 2 and 3	II	(no information since 2007)
Oxxon Therapeutics (acquired by Oxford BioMedica plc)	DNA-MVA HBV vaccine	Plasmid pSG2.HBs + MVA.HBs containing the same pre-S2 and S sequences	chronic HBV infection	IIa	ISRCTN67270384 (completed in 2004)
Transgene / Roche	TG4001	MVA encoding HPV16 E6 and E7 antigens and IL-2	CIN1, 2 and 3	II	NCT01022346
Transgene	TG4040	MVA encoding HCV NS3, NS4 and NS5B antigens	chronic HCV infection	II	NCT01055821
University Oxford	MVA85A	MVA encoding Ag85A	MVA85A in healthy volunteers in the UK who are latently infected with Mtb	II	NCT00456183 (completed)

Figure 3: Postulated Mechanisms of Action of TG4040. Following subcutaneous administration of TG4040, antigen presentation and priming of T-cells is foreseen to happen in lymphoid organs. Primed T-cells but also likely other cells from the innate immune system are expected to migrate to the liver and exert their effector functions, including cytolytic and/or non-cytolytic activities, and contribute to the control and/or clearance of infected hepatocytes

Figure 4: Clinical trials (target population and time lines) performed with the MVA85A. (With permission from McShane; 2011).