The use of viral vectors in vaccine development

Abstract

Vaccines represent the single most cost-efficient and equitable way to combat and eradicate infectious diseases. While traditional licensed vaccines consist of either inactivated/attenuated versions of the entire pathogen or subunits of it, most novel experimental vaccines against emerging infectious diseases employ nucleic acids to produce the antigen of interest directly in vivo. These include DNA plasmid vaccines, mRNA vaccines, and recombinant viral vectors. The advantages of using nucleic acid vaccines include their ability to induce durable immune responses, high vaccine stability, and ease of large-scale manufacturing. In this review, we present an overview of pre-clinical and clinical data on recombinant viral vector vaccines and discuss the advantages and limitations of the different viral vector platforms.

Fig. 1. Schematic representation of the Adenovirus 5 linear genome and an Ad5 vector.

The adenovirus genome is characterized by inverted terminal repeats (ITR) and several early (E) and late (L) genes. The early genes are responsible for modifying host gene expression to allow for viral protein synthesis and replication. The late genes allow for viral packaging and release. Replication-competent adenoviral vectors contain an intact E1 region and the transgene of choice in the E3 region. Typically, replication-defective adenoviral vectors contain a partial or complete deletion of the E1 region and contain a transgene in either the E1 or E3 region. Deletion of the E4 region may also allow for the insertion of a larger foreign gene.

Fig. 2. Schematic representation of the AAV genome and an AAV vector.

AAVs are small (~25 nm), non-enveloped viruses and have a 4.8-kb, single-stranded, linear DNA (ssDNA) genome encoding four open reading frames: rep encodes the four genes required for genome replication (Rep78, Rep68, Rep52, and Rep40), cap encodes the structural proteins of the viral capsid (VP1, VP2, and VP3). When the viral vector is used in vaccinations, the transgene of choice is placed in the promoter at the p40 location.

Fig. 3. Schematic representation of the wildtype VSV and an rVSV vector.

The wild type virus is a negative-sense RNA virus that encodes the nucleoprotein (N), phosphoprotein (P), matrix (M), glycoprotein (G), and RNA-dependent RNA polymerase (L) proteins. When the viral vector is used in vaccinations, the G gene is replaced with the transgene of choice.

Fig. 4. A schematic overview of the lentiviral vector system.

The HIV-1 virion and genome are included in the top panel for reference. a Transfer Vector Plasmid: this plasmid combines the 5’ and 3’ long terminal repeats (LTRs), and psi component of the HIV-1 genome, along with a promoter, transgene, and the woodchuck hepatitis virus regulatory element (Wpre). The full deletion of the U3 (unique 3’ end) region in the 5’ LTR and partial deletion of the U3 region in the 3’ LTR renders the vector self-inactivating (SIN). b Envelope plasmid: this plasmid contains a promoter to drive the expression of the VSV-G envelope protein (env) used to pseudotype lentiviral vector particles. c Packaging plasmid: This plasmid contains a promoter to drive expression of the group specific antigen (gag), DNA polymerase (pol), rev, and trans-activator of transcription (tat) elements of the HIV-1/SIV genome.

Fig. 5. Schematic representation of a poxvirus genome flanked by one origin for DNA replication and one terminal loop.

The central region of the genome contains a conserved series of genes needed for viral replication. The two flanking regions code for several proteins that help determine virulence. When used as a viral vector in vaccinations, the D1–13 transcription units (indicated between the dotted lines) are replaced by the transgene of choice.