Integrase Defective Lentiviral Vector as a Vaccine Platform for Delivering Influenza Antigens

Gallinaro, Alessandra; Borghi, Martina; Bona, Roberta; Grasso, Felicia; Calzoletti, Laura; Palladino, Laura; Cecchetti, Serena; Vescio, Maria Fenicia; Macchia, Daniele; Morante, Valeria; Canitano, Andrea; Temperton, Nigel; Castrucci, Maria Rita; Salvatore, Mirella; Michelini, Zuleika; Cara, Andrea; Negri, Donatella

doi:10.3389/fimmu.2018.00171

Cited by 33 publications

(25 citation statements)

References 65 publications

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“…Integrase-defective lentiviral vectors have been designed as a vaccine platform to deliver vaccination against influenza and malaria antigens. 324 , 325 Such lentiviral vectors are being continuously developed and optimized, and could enjoy a broader application in future gene therapies. In addition, the development of safer vectors via photo-switchable non-canonical amino acids to regulate transgene expression in a spatial and temporal manner, 326 also represent the next generation of lentiviral vectors.…”

Section: Introductionmentioning

confidence: 99%

Viral vector platforms within the gene therapy landscape

Bulcha

Wang

et al. 2021

Sig Transduct Target Ther

698

572

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Throughout its 40-year history, the field of gene therapy has been marked by many transitions. It has seen great strides in combating human disease, has given hope to patients and families with limited treatment options, but has also been subject to many setbacks. Treatment of patients with this class of investigational drugs has resulted in severe adverse effects and, even in rare cases, death. At the heart of this dichotomous field are the viral-based vectors, the delivery vehicles that have allowed researchers and clinicians to develop powerful drug platforms, and have radically changed the face of medicine. Within the past 5 years, the gene therapy field has seen a wave of drugs based on viral vectors that have gained regulatory approval that come in a variety of designs and purposes. These modalities range from vector-based cancer therapies, to treating monogenic diseases with life-altering outcomes. At present, the three key vector strategies are based on adenoviruses, adeno-associated viruses, and lentiviruses. They have led the way in preclinical and clinical successes in the past two decades. However, despite these successes, many challenges still limit these approaches from attaining their full potential. To review the viral vector-based gene therapy landscape, we focus on these three highly regarded vector platforms and describe mechanisms of action and their roles in treating human disease.

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Section: Introductionmentioning

confidence: 99%

Viral vector platforms within the gene therapy landscape

Bulcha

Wang

et al. 2021

Sig Transduct Target Ther

698

572

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“…We have shown, in both mice and macaque studies, that integrase defective lentiviral vectors (IDLV) provide prolonged antigen expression and can induce potent and durable antigenspecific immune responses [9][10][11][12][13] . We demonstrated that immunization with an SIV-based IDLV expressing an HIV-1 Env induces continued antibody affinity maturation up to three months postprime, which is further improved upon additional IDLV-Env immunizations 12 .…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity, safety, and efficacy of sequential immunizations with an SIV-based IDLV expressing CH505 Envs

et al. 2020

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A preventative HIV-1 vaccine is an essential intervention needed to halt the HIV-1 pandemic. Neutralizing antibodies protect against HIV-1 infection in animal models, and thus an approach toward a protective HIV-1 vaccine is to induce broadly cross-reactive neutralizing antibodies (bnAbs). One strategy to achieve this goal is to define envelope (Env) evolution that drives bnAb development in infection and to recreate those events by vaccination. In this study, we report the immunogenicity, safety, and efficacy in rhesus macaques of an SIV-based integrase defective lentiviral vector (IDLV) expressing sequential gp140 Env immunogens derived from the CH505 HIV-1-infected individual who made the CH103 and CH235 bnAb lineages. Immunization with IDLV expressing sequential CH505 Envs induced higher magnitude and more durable binding and neutralizing antibody responses compared to protein or DNA +/− protein immunizations using the same sequential envelopes. Compared to monkeys immunized with a vector expressing Envs alone, those immunized with the combination of IDLV expressing Env and CH505 Env protein demonstrated improved durability of antibody responses at six months after the last immunization as well as lower peak viremia and better virus control following autologous SHIV-CH505 challenge. There was no evidence of vector mobilization or recombination in the immunized and challenged monkeys. Although the tested vaccines failed to induce bnAbs and to mediate significant protection following SHIV-challenge, our results show that IDLV proved safe and successful at inducing higher titer and more durable immune responses compared to other vaccine platforms.

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“…In our previous studies, we found that vaccination with IDLV expressing the conserved IAV nucleoprotein (IDLV-NP) can induce broad protective immunity against challenge with several IAV subtypes [ 35 , 40 ]. However, IDLV-NP requires two immunizations to be effective, thereby making it not suitable for inducing rapid protection.…”

Section: Resultsmentioning

confidence: 99%

“…administration of IDLV expressing IAV NP (IDLV-NP) can induce broad protective immunity against challenge with several IAV subtypes. However, this approach requires two administrations over the course of a month to be effective [ 35 , 40 ], thereby making it not suitable for inducing rapid protection. In the experiments described above, IDLV-VN04-2 achieved rapid protection against IAV in mice, although the protection did not persist at 30 days post-administration.…”

Section: Discussionmentioning

confidence: 99%

Integrase-Defective Lentiviral Vectors for Delivery of Monoclonal Antibodies against Influenza

Michelini

Minkoff

Yang

et al. 2020

Viruses

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Delivering rapid protection against infectious agents to non-immune populations is a formidable public health challenge. Although passive immunotherapy is a fast and effective method of protection, large-scale production and administration of monoclonal antibodies (mAbs) is expensive and unpractical. Viral vector-mediated delivery of mAbs offers an attractive alternative to their direct injection. Integrase-defective lentiviral vectors (IDLV) are advantageous for this purpose due to the absence of pre-existing anti-vector immunity and the safety features of non-integration and non-replication. We engineered IDLV to produce the humanized mAb VN04-2 (IDLV-VN04-2), which is broadly neutralizing against H5 influenza A virus (IAV), and tested the vectors’ ability to produce antibodies and protect from IAV in vivo. We found that IDLV-transduced cells produced functional VN04-2 mAbs in a time- and dose-dependent fashion. These mAbs specifically bind the hemagglutinin (HA), but not the nucleoprotein (NP) of IAV. VN04-2 mAbs were detected in the serum of mice at different times after intranasal (i.n.) or intramuscular (i.m.) administration of IDLV-VN04-2. Administration of IDLV-VN04-2 by the i.n. route provided rapid protection against lethal IAV challenge, although the protection did not persist at later time points. Our data suggest that administration of mAb-expressing IDLV may represent an effective strategy for rapid protection against infectious diseases.

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Integrase Defective Lentiviral Vector as a Vaccine Platform for Delivering Influenza Antigens

Cited by 33 publications

References 65 publications

Viral vector platforms within the gene therapy landscape

Viral vector platforms within the gene therapy landscape

Immunogenicity, safety, and efficacy of sequential immunizations with an SIV-based IDLV expressing CH505 Envs

Integrase-Defective Lentiviral Vectors for Delivery of Monoclonal Antibodies against Influenza

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