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