Integrase Defective Lentiviral Vectors (IDLV) as a Vaccine ... · Ab response NHP Prime-boost •...
Transcript of Integrase Defective Lentiviral Vectors (IDLV) as a Vaccine ... · Ab response NHP Prime-boost •...
Integrase Defective Lentiviral Vectors (IDLV) as a Vaccine Platform for Delivering Viral Antigens
Andrea Cara, PhD Istituto Superiore di Sanità - Rome, Italy
Italy-South Africa Collaborative Workshop on the occasion of the Italian Research Day in the world
Bilateral Workshop on Transmissible Diseases: HIV/AIDS, Tuberculosis and Malaria
April 5, 2019 – Pretoria
Integrase defective lentiviral vectors (IDLVs) are self-inactivated, non-replicating and non-integrating lentiviral-based vectors (HIV and SIV)
In the absence of integration IDLVs accumulate non-integrated circular forms (episomes)
Circular forms of IDLVs are transcriptionally active and long-lasting in non-dividing cells in the absence of integration
IDLV features
Vargas et al, Hum Gene Ther, 2004
Entry and reverse transcription
Transcription
SCHEMATIC REPRESENTATION OF INTEGRASE DEFECTIVE LENTIVIRAL VECTOR
Expression in muscle and dLN Yi-Yu (Rafael) Lin Duke University, Durham, NC, USA
Episomes in target cells
IDLV-induced immunity after a single intramuscular immunization
• Strong immunogenicity
HIV-Env (mice and NHPs), SIV-Gag, HIV-Gag, HPV-E7,
Influenza HA and NP, GFP, OVA, Luciferase,
• Comprehensive immune response
both cellular and humoral (mice and NHPs), both systemic
and mucosal
• Long-term immunity
up to 1 year (mice and NHPs)
• Efficacy
tumor eradication (HPV-E7) and protection from viral
challenge (Influenza) in mice
NEXT GENERATION IDLV AGAINST HIV
IDLV as a scaffold for delivering immunogens designed to induce nAbs: stabilized native like ENV trimers (SOSIP, UFO, etc.) HIV-1 Envelope is expressed as a transgene and displayed on the vector membrane, as a pseudotyped Envelope, improving the overall Ab response
NHP Prime-boost
• Priming intramuscularly of five cynomolgus macaques with IDLV-ENV.UFO and boost after 8 months
• Monthly sampling of plasma/serum/mucosal samples for Ab characterization • IDLV expressing Env on the membrane elicited durable Abs, boosted with a second injection
Persistence of anti-ENV Abs in IDLV-ENV.UFO immunized NHPs
Yoann Aldon and Robin Shattock Imperial College, London, UK
Alessandra Gallinaro ISS, Italy, EU
0 6 12 18 24 30 36 42 48 5410
100
1 000
10 000
100 000
Time (weeks)
An
ti-E
nv Ig
G (
ng
/mL
)
Mean (N=5)
IDLV IDLV
Sera from immunized monkeys were tested for the ability to neutralize the clade C Tier 1 virus MW965.26 and the consensus autologous Tier 2 virus Con-S.
Induction of neutralizing Abs in immunized NHPs
Prime
Boost 1
Boost 2
Boost 3
Celia LaBranche and David Montefiori Duke University, Durham, NC, USA
Values are indicated as the serum dilution at which relative luminescence units (RLUs) were reduced 50% compared to virus control wells.
Gabriella Scarlatti San Raffaele, Milan, Italy, EU
PRIME-BOOST STRATEGY to assess induction of Tier1, Tier2 autologous and heterologous neutralizing Abs
Platform suitable for vaccines against infectious diseases: Malaria, TB, HIV, Influenza*, EBOLA, ZIKA,
CHIKV, WN, JEV, Dengue etc.
NEXT…
*Gallinaro et al, Frontiers in Immunology, 2018
Donatella Negri Alessandra Gallinaro Martina Borghi Roberta Bona Zuleika Michelini Valeria Morante Andrea Canitano Silvia Baroncelli Serena Cecchetti Felicia Grasso Antonio Di Virgilio
Mary E. Klotman Barton Haynes and DHVI team Celia La Branche David Montefiori Maria Blasi Yi-Yu (Rafael) Lin Robin Shattock Yoann Aldon Gabriella Scarlatti Rogier Sanders
ACKNOWLEDGMENTS
This project receives funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 681137 RF-ISS-2009-1302984
RF-ISS-2009-1300961 PE-2011-02347035
R21 AI066940-01
R21 AI073926-01A2
1P01AI110485-01A1
SVEU/NIAID contract