Viral vector-based vaccines: Lentiviral vector-based vaccines | GeneMedi

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Lentiviral vector-based vaccines

Lentivirus (lente-, Latin for "slow") is a genus of retroviruses, medium sized (80-100nm) and enveloped, slightly pleomorphic, spherical with an isometric nucleocapsid containing two copies of positive-sense ssRNA genome (Fig. 11A). Most lentiviral vectors are based on the Human Immunodeficiency Virus (HIV), which causes AIDS, a chronic and deadly diseases in human or other mammalian species [88]. Its DNA genome, transcribed from HIV-1 ssRNA, is approximately 9.7 kb and contains 9 open reading frames (ORFs), which are flanked by 5’ and 3’ long terminal repeats (LTRs), which are required for HIV-1 life cycle, such as reverse transcription, integration, and gene expression (Fig. 11B). Picture loading failed.

Figure 11. Schematic of the lentivirus genome and lentivirus-based vectors. (A) Capsid crystal structure. (B) The viral genome encodes structural, regulatory and accessory genes flanked by LTRs [89]. There are 9 ORFs in lentiviral genome: env and gag responsible for structural proteins; pol for reverse transcriptase and integrase; tat and rev for gene regulatory proteins; vif, vpr, vpu, and nef for viral accessory proteins.

HIV-1 virus enters host cells through binding to the CD4 receptor or a coreceptor (CCR5 or CXCR4) with gp120 protein, thereby anchoring itself onto host cell surface, allowing fusion between the cellular and viral membranes. After entry into the cell, the viral nucleoprotein together with the contents, i.e. the genomic ssRNA, is released into cytoplasm. Then, utilizing the cellular nucleotides as the building blocks, double-stranded DNA is generated from the virus genome ssRNA directed by the HIV-1 reverse transcriptase (RT) in a nucleoprotein complex termed the RTC. Together with other viral proteins, the newly synthesized DNA constitutes an integration-competent nucleoprotein complex, migrating into host cell nucleus and mediating integration of viral DNA into host chromatin. Integrated viral DNA, named as provirus, becomes part of host genome and serves as a transcription template for the synthesis of viral mRNA and genomic RNA. Following the synthesis of viral genomes and proteins, the viral components are assembled together to produce new virions, the virus particles then bud out of host cell and undergo a maturation step to generate infectious HIV-1 (Fig. 12) [90].

Figure 12. Schematic representation of lentivirus replication [90].

Compared to HIV-1 virus, lentiviral vectors elicit weaker IFNα responses from pDC. SsRNA molecules of lentiviral vector in endosomes can be sensed by TLR7, while the reverse-transcribed CpG DNA is sensed by TLR9. TLR7 and TLR9 both contribute to induction of T1 IFN [91, 92] and regulation by mTOR pathway [93]. In addition to innate immune responses, lentiviral vector efficiently transduces APCs, such as MFs and DCs, which significantly facilitates the immune responses against transgene antigen. It was reported that transgene antigen expression in pDCs mainly drives immune responses, while antigen expression in myeloid cells may not obviously provoke immune responses [94, 95]. Furthermore, cell-derived MHC I molecules also helps trigger T cellular immune responses.

Figure 13. Schematic principle of lentiviral vector-induced innate immune responses [15].

Since wild-type HIV-1-based lentivirus is associated with destruction of host immune system, especially CD4+ helper T lymphocytes, multiple generations of lentivirus vectors have been designed with enhanced safety features and as attractive vectors for gene therapy and vaccine production. To date, there have been several generations of HIV-1-based lentivirus vectors by deleting the HIV viral envelope and some of the regulatory genes not required during vector production [89]. The recombinant lentiviral vectors in GeneMedi are prepared based on three plasmids co-transfection system: vector plasmid pLV-CMV-MCS-T2A-PURO, envelope expressing plasmid pMD2G, and packaging plasmid pSPAX2 (Fig. 14). Once packaged into 293T, recombinant lentiviral vectors will be easily produced.
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Figure 14. The three plasmids co-transfection system of recombinant lentivirus. pLV-CMV-MCS-T2A-PURO: a lentivirus LTR-containing plasmid carrying multiple clone sites, which can be cloned into a transgene; pMD2G: envelope VSVG expressing plasmid; pSPAX2: packaging plasmid, containing sequences of gag, pol, tat, and rev. To date, more than 236 clinical trials have been carried out using lentivirus vectors for gene delivery [17]. For instance, lentiviral vector-based gene delivery into CD34+ HSCs has been used as an alternative in clinical trials and proved to be effective in treatment of several diseases [96], including β-thalassemia [97], X-linked adrenoleukodystrophy (ALD) [98], metachromatic leukodystrophy [99, 100], and Wiskott-Aldrich Syndrome [101].

In addition, as a viral vector used for vaccine production, lentiviral vectors can transduce antigen-presenting cells with high efficiency, such as dendritic cells [102], which provides some priority to lentiviral vector-based vaccines. Animal studies demonstrate that lentiviral vector-based vaccines can provoke both CD8+ T-cells and CD4+ T-cell responses and show great defense effects against melanoma by targeting NY-ESO-1 antigen [102, 103], or Melan-A/MART-1 antigen [104]. Besides, lentiviral vector-based HIV vaccines induce Gag-specific T-cell responses [105-107]. Some examples of LV vector-based vaccines are listed in the following Table 5. Although promising outcomes by lentiviral vector-based have been achieved in animal studies, the virulence of lentivirus still raises safety concerns. As the virulence of immunodeficiency virus is species-specific, feline immunodeficiency virus (FIV)-based vectors have been developed [108] to combat HIV-1 and the Herpes simplex virus (HSV) with great potential [109, 110].

Table 5 - Examples of LV vector-based vaccines

Leukemia	LV-mediated genetically engineered AML cells	Phase I	NCT00718250
ALL	LV-mediated IL-12 expression in AML cells	Phase I	NCT02483312
CD19+ B cell Leukemia and Lymphoma	ARTEMIS™	Early Phase 1	NCT03895944

Recombinant lentiviral vectors have a lot of advantages for vaccine development: ① mediating long-term and stable exogenous gene expression by integrating into the host genome; ② great packaging capacity; ③ highly efficient in transfection in both diving cells to non-dividing cells; ④ low pre-existing immunity. However, lentiviral-mediated gene integration into host genome, which might arouse the risk of tumorigenesis. Additionally, the virulence of lentiviral-derived backbone, i.e. HIV-1, also arouses serious safety concern.

To avoid the virulence of HIV-1, FIV-based viral vectors [108] were discovered and showed great potential for the prevention of HIV-1 and HSV [109, 110]. Moreover, integration-deficient LV vectors are being exploited for vaccine development [111, 112].

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