Preclinical proof of concept of a tetravalent lentiviral T-cell vaccine against dengue viruses

Dengue virus (DENV) is responsible for approximately 100 million cases of dengue fever annually, including severe forms such as hemorrhagic dengue and dengue shock syndrome. Despite intensive vaccine research and development spanning several decades, a universally accepted and approved vaccine against dengue fever has not yet been developed. The major challenge associated with the development of such a vaccine is that it should induce simultaneous and equal protection against the four DENV serotypes, because past infection with one serotype may greatly increase the severity of secondary infection with a distinct serotype, a phenomenon known as antibody-dependent enhancement (ADE). Using a lentiviral vector platform that is particularly suitable for the induction of cellular immune responses, we designed a tetravalent T-cell vaccine candidate against DENV (“LV-DEN”). This vaccine candidate has a strong CD8+ T-cell immunogenicity against the targeted non-structural DENV proteins, without inducing antibody response against surface antigens. Evaluation of its protective potential in the preclinical flavivirus infection model, i.e., mice knockout for the receptor to the type I IFN, demonstrated its significant protective effect against four distinct DENV serotypes, based on reduced weight loss, viremia, and viral loads in peripheral organs of the challenged mice. These results provide proof of concept for the use of lentiviral vectors for the development of efficient polyvalent T-cell vaccine candidates against all DENV serotypes

Lentiviral vector induces high-quality memory T cells via dendritic cells transduction

Ku et al. report a lentiviral (LV) vector system in which expression of vaccine antigens is driven by β2-microglobulin (β2m) promoter. Conducting comparative studies in mice and rats, they find that LV-based vaccine outperforms the ‘gold-standard’ Ad5 by inducing a polyfunctional and long-lived immune response

Impact d’une prise de benzodiazépine et d’une tâche distractive sur la conduite automobile simulée et réelle

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Lorazepam impairs highway driving performance more than heavy alcohol consumption

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T-cell immunity induced and reshaped by an anti-HPV immuno-oncotherapeutic lentiviral vector

International audienceWerecently developed animmuno-oncotherapy against human papillomavirus (HPV)-induced tumorsbased on a lentiviral vector encoding the Early E6 and E7 oncoproteins of HPV16 and HPV18genotypes, namely “Lenti-HPV-07”. The robust and long-lasting anti-tumor efficacy of Lenti-HPV-07is dependent on CD8+ T-cell induction and remodeling of the tumor microenvironment. Here, we firstestablished that anti-vector immunity induced by Lenti-HPV-07 prime has no impact on the efficacy ofahomologous boost to amplify anti-HPV T-cell immunity. To longitudinally monitor the evolution of theT-cell repertoire generated after the prime, homologous or heterologous boost with Lenti-HPV-07, wetracked T-cell clonotypes by deep sequencing of T-Cell Receptor (TCR) variable β and α chainmRNA,applied to whole peripheral blood cells (PBL) and a T cell population specific of an immunodominantE7HPV16 epitope. We observed a hyper-expansion of clonotypes post prime, accompanied byincreased frequencies of HPV-07-specific T cells. Additionally, there was a notable diversification ofclonotypes post boost in whole PBL, but not in the E7HPV16-specific T cells. We then demonstratedthat the effector functions of such Lenti-HPV-07-induced T cells synergize with anti-checkpointinhibitory treatments by systemic administration of anti-TIM3 or anti-NKG2A monoclonal antibodies.While Lenti-HPV-07 is about to enter a Phase I/IIa clinical trial, these results will help better elucidate itsmode of action in immunotherapy against established HPV-mediated malignancies

Cannabis smoking impairs driving performance on the simulator and real driving: a randomized, double-blind, placebo-controlled, crossover trial

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A lentiviral vector encoding fusion of light invariant chain and mycobacterial antigens induces protective CD4+ T cell immunity

International audienceLentiviral vectors (LVs) are highly efficient at inducing CD8+ T cell responses. However, LV-encoded antigens are processed inside the cytosol of antigen-presenting cells, which does not directly communicate with the endosomal major histocompatibility complex class II (MHC-II) presentation pathway. LVs are thus poor at inducing CD4+ T cell response. To overcome this limitation, we devised a strategy whereby LV-encoded antigens are extended at their N-terminal end with the MHC-II-associated light invariant chain (li), which contains an endosome-targeting signal sequence. When evaluated with an LV-encoded polyantigen composed of CD4+ T cell targets from Mycobacterium tuberculosis, intranasal vaccination in mice triggers pulmonary polyfunctional CD4+ and CD8+ T cell responses. Adjuvantation of these LVs extends the mucosal immunity to Th17 and Tc17 responses. A systemic prime and an intranasal boost with one of these LV induces protection against M. tuberculosis. This strategy improves the protective power of LVs against infections and cancers, where CD4+ T cell immunity plays an important role

Full-Lung Prophylaxis against SARS-CoV-2 by One-Shot or Booster Intranasal Lentiviral Vaccination in Syrian Golden Hamsters

International audienceFollowing the breakthrough of numerous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in recent months and the incomplete efficiency of the currently available vaccines, development of more effective vaccines is desirable. Non-integrative, non-cytopathic and non-inflammatory lentiviral vectors elicit sterilizing prophylaxis against SARS-CoV-2 in preclinical animal models and are particularly suitable for mucosal vaccination, which is acknowledged as the most effective in reducing viral transmission. Here, we demonstrate that a single intranasal administration of a vaccinal lentiviral vector encoding a stabilized form of the original SARS-CoV-2 Spike glycoprotein induces full-lung protection of respiratory tracts and strongly reduces pulmonary inflammation in the susceptible Syrian golden hamster model against the prototype SARS-CoV-2. In addition, we show that a lentiviral vector encoding stabilized Spike of SARS-CoV-2 Beta variant (LV::SBeta-2P) prevents pathology and reduces infectious viral loads in lungs and nasal turbinates following inoculation with the SARS-CoV-2 Omicron variant. Importantly, an intranasal boost with LV::SBeta-2P improves cross-seroneutralization much better in LV::SBeta-2P-primed hamsters than in their counterparts primed with an LV-encoding Spike from the ancestral SARS-CoV-2. These results strongly suggest that an immune imprint with the original Spike sequence has a negative impact on cross-protection against new variants. Our results tackle the issue of vaccine effectiveness in people who have already been vaccinated and have vanished immunity and indicate the efficiency of LV-based intranasal vaccination, either as a single dose or as booster

Full-Lung Prophylaxis against SARS-CoV-2 by One-Shot or Booster Intranasal Lentiviral Vaccination in Syrian Golden Hamsters

International audienceFollowing the breakthrough of numerous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in recent months and the incomplete efficiency of the currently available vaccines, development of more effective vaccines is desirable. Non-integrative, non-cytopathic and non-inflammatory lentiviral vectors elicit sterilizing prophylaxis against SARS-CoV-2 in preclinical animal models and are particularly suitable for mucosal vaccination, which is acknowledged as the most effective in reducing viral transmission. Here, we demonstrate that a single intranasal administration of a vaccinal lentiviral vector encoding a stabilized form of the original SARS-CoV-2 Spike glycoprotein induces full-lung protection of respiratory tracts and strongly reduces pulmonary inflammation in the susceptible Syrian golden hamster model against the prototype SARS-CoV-2. In addition, we show that a lentiviral vector encoding stabilized Spike of SARS-CoV-2 Beta variant (LV::SBeta-2P) prevents pathology and reduces infectious viral loads in lungs and nasal turbinates following inoculation with the SARS-CoV-2 Omicron variant. Importantly, an intranasal boost with LV::SBeta-2P improves cross-seroneutralization much better in LV::SBeta-2P-primed hamsters than in their counterparts primed with an LV-encoding Spike from the ancestral SARS-CoV-2. These results strongly suggest that an immune imprint with the original Spike sequence has a negative impact on cross-protection against new variants. Our results tackle the issue of vaccine effectiveness in people who have already been vaccinated and have vanished immunity and indicate the efficiency of LV-based intranasal vaccination, either as a single dose or as booster

Full eradication of pre‐clinical human papilloma virus‐induced tumors by a lentiviral vaccine

Abstract Human papillomavirus (HPV) infections are the cause of all cervical and numerous oropharyngeal and anogenital cancers. The currently available HPV vaccines, which induce neutralizing antibodies, have no therapeutic effect on established tumors. Here, we developed an immuno‐oncotherapy against HPV‐induced tumors based on a non‐integrative lentiviral vector encoding detoxified forms of the Early E6 and E7 oncoproteins of HPV16 and 18 genotypes, namely, “Lenti‐HPV‐07”. A single intramuscular injection of Lenti‐HPV‐07 into mice bearing established HPV‐induced tumors resulted in complete tumor eradication in 100% of the animals and was also effective against lung metastases. This effect correlated with CD8+ T‐cell induction and profound remodeling of the tumor microenvironment. In the intra‐tumoral infiltrates of vaccinated mice, the presence of large amounts of activated effector, resident memory, and transcription factor T cell factor‐1 (TCF‐1)+ “stem‐like” CD8+ T cells was associated with full tumor eradication. The Lenti‐HPV‐07‐induced immunity was long‐lasting and prevented tumor growth after a late re‐challenge, mimicking tumor relapse. Lenti‐HPV‐07 therapy synergizes with an anti‐checkpoint inhibitory treatment and therefore shows promise as an immuno‐oncotherapy against established HPV‐mediated malignancies