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Viral vector-based vaccines

Viral vector-based vaccines are vaccines that can deliver specific antigen gene to target cells based on the infection ability of viruses, produce antigens via the nutrition substances in host cells, and then provoke immune responses with the newly synthesized antigens. Compared with the traditional vaccines, viral vector vaccines have a great number of advantages: ①highly efficient in gene transduction; ② mediate specific gene delivery to target cells; ③induce of both humoral and cell-mediated immune responses; ④ better efficacy and safety;⑤ just need low administration dose; ⑥ easy to be applied into large-scale manufacturing; ⑦ possessing widespread potential target diseases, ranging from infectious diseases to cancers. As well, some drawbacks also have been discovered: ① several kinds of vectors mediate gene integration into host genome, which may lead to cancer; ② some hosts may be exposed to antigens prior to the vaccine administration, which may result in the production of neutralizing antibodies (pre-existing immunity) and thus reduce the vaccine efficacy [1].

To date, numerous kinds of viral vectors have been introduced to produce vaccines, such as adeno-associated virus (AAV) vectors (Fig. 2A), adenoviral vectors (Fig. 2B) and lentiviral vectors (Fig. 2C) [2]. Different kinds of viral vectors have their advantages and drawbacks, which are summarized in Table 1.

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Figure 2. Schematics of viral structure and antigens that may stimulate host immune system [2]. (A) AAV viral vector-based vaccines. (B) Adenoviral vector-based vaccines. (C) Lentiviral vector-based vaccines. dsDNA: double-stranded DNA; TLR: toll-like receptor; cGAS: cyclic GMP-AMP synthase; IFN: interferon; APCs: antigen presenting cells; CTL: cytotoxic T lymphocyte; dsRNA: double-stranded RNA; MDA5: melanoma differentiation-associated protein 5; pDC: plasmacytoid dendritic cell; ssRNA: single-stranded RNA.

Table 1. Comparison between Lentivirus, Adenovirus and Adeno-associated virus (AAV) vectors.
Viral vectors Lentivirus Adenovirus AAV
Genome ss RNA ds DNA ss DNA
Integration Yes No No
Packaging Capacity 4kb 5.5kb 2kb
Time to peak expression 72h 36h-72h Cell: 7 days;
Animals: 2 weeks
Sustainable time Stable expression Transient expression > 6 months
Cell Type Most Dividing/Non-Dividing Cells Most Dividing/Non-Dividing Cells Most Dividing/Non-Dividing Cells
Titer 10^8 TU/ml 10^11 PFU/ml 10^12 vg/ml
Animal experiment Low efficiency Lowest efficiency Most suitable
Immune Response Medium High mild

AAV vector-based vaccines

Adeno-associated virus (AAV) is a small single strand DNA virus, member of human parvovirus [3, 4], approximately 25nm in diameter and encapsidates a single-stranded DNA genome of 4.7 kilobases (Fig. 3A). The genome consists of two large open reading frames (ORFs) flanked by 145bp inverted terminal repeats (ITR), which are the only cis-acting elements required for AAV genome replication and AAV packaging. The left ORF encodes four replication proteins, Rep40, Rep52, Rep68, and Rep78, in charge of site-specific integration, as well as regulation of AAV capsid formation initiation within the AAV genome, while the right ORF encodes the viral structural proteins, VP1, VP2, and VP3, which interact together to assemble into icosahedral virion shells comprising 60 subunits each (Fig. 3B).

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Figure 3. AAV genome map. (A) The capsid structure of AAV. (B) The positions of the three promoters (p5, p19, p40) as well as the seven protein coding regions of the AAV have been highlighted.

Principle

Principle of AAV entry into cells

AAV transduces cells through several stages: ① viral binding to cell surface receptor/coreceptor, ② endocytosis of the virus, ③ intracellular trafficking of the virus through the endosomal compartment, ④ endosomal escape of the virus, ⑤ intracellular trafficking of the virus to the nucleus and nuclear import, ⑥ virion uncoating, ⑦ viral genome conversion from a single-stranded to a double-stranded genome capable of expressing an encoded gene [5-7]. Since AAV has no ability to encode polymerases, AAV is dependent upon cellular polymerase activity to replicate its own genome [8]. The presence of a helper virus such as adenovirus is indispensable for wild-type AAV to facilitate gene expression and replication (Fig. 4A). Without helper virus, expression of Rep68/Rep78 would be restricted owing to Ying Yang 1 (YY1) repression of the P5 promoter, leading to inhibition of AAV genome replication and gene expression, and initiation of AAV chromosome integration (Fig. 4B) [9]. AAV establishes latency by undergoing specifically integration into a genome site, termed as the adeno-associated virus integration site 1 (AAVS1), a 4kb region on chromosome 19 (q13.4).

Picture loading failed. Figure 4. AAV life cycle. (A) AAV can amplify itself with the help of helper virus. (B) AAV establishes latency by undergoing specifically integration into AAVS1 without helper virus.


Immune responses induced by AAV-based vaccine

During the entry of AAV into host cells, AAV virions may uncoat and release their genomes into the endosome, and be recognized by toll like receptor 9 (TLR9) of plasmacytoid dendritic cell (pDC) to provoke innate immune response and produce Interferon (IFN) α/β [10]. This process is dependent on MyD88 signaling, but not the form of transgene or capsid serotype [10]. Besides TLR9, TLR2 dependent cytokine expression was also observed in Kupffer cells [11]. Moreover, some AAV virions are degraded and processed into peptides within proteasomes, and then presented by MHC I of antigen presenting cells (APCs), such as conventional dendritic cells (cDCs), which can be targeted by capsid-specific CD8+ T cells to lyse virally infected cells [12]. In addition to IFNα/β, CD40-CD40L co-stimulation by CD4+ T helper cells, is required for cross-priming of CD8+ T cells against AAV capsid [13]. CD4+ T helper cells is also indispensable to generate memory responses and stimulate B cells to produce antibody against AAV capsid, which is dependent on MyD88 signaling [14].

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Figure 5. Schematic principle of AAV-induced immune responses [15]. IFNAR-1: interferon alpha/beta receptor 1; cDC: conventional dendritic cell; pDC: plasmacytoid dendritic cell; IFN: interferon; TLR: toll-like receptor; MyD88: myeloid differentiation primary response protein (88); MHC: major histocompatibility complex; moDC: monocyte-derived dendritic cell; CD: cluster of differentiation.


Application

AAV serotypes

Over the past decades, numerous AAV serotypes have been identified with variable tropism. To date, 12 AAV serotypes and over 100 AAV variants have been isolated from adenovirus stocks or from human/nonhuman primate tissues. Among them, AAV2, AAV3, AAV5, AAV6 were discovered in human cells, while AAV1, AAV4, AAV7, AAV8, AAV9, AAV10 (AAVrh10), AAV11, AAV12 in nonhuman primate samples [16]. Different serotypes have different tissue tropism, which are summarized in Table 2.

Table 2. AAV serotypes and their respective Tropism.
AAV Serotype Tissue tropism
CNS Retina Lung Liver Pancreas Kidney Heart Muscle
AAV1
AAV2
AAV3
AAV4
AAV5
AAV6
AAV7
AAV8
AAV9
AAV-DJ
AAV-DJ/8
AAV-Rh10
AAV-retro
AAV-PHP.B
AAV8-PHP.eB
AAV-PHP.S

Recombinant AAV

Though wild-type AAV is not associated with human disease, it is naturally defective and requiring helper adenovirus or herpes simplex virus (HSV) coinfection for AAV replication, so recombinant AAV (rAAV) has been developed for gene therapy or vaccines by replacing the viral genome with gene of interest (GOI) to reduce the risk. Traditionally, rAAV vectors used in clinical trials were prepared with a plasmid containing the therapeutic gene flanked by AAV-inverted terminal repeats (ITRs), co-transfected with AAV packaging plasmid pAAV-RC (AAV replication and AAV capsid) and pHelper (AAV helper plasmid) (Fig. 6). The adenovirus helper factors, such as E1A, E1B, E2A, E4 ORF6 and VA RNAs, would be provided by the third helper plasmid. Due to the deletion of Rep and Cap coding regions between the ITRs, rAAV vectors cannot integrate into the genome of host cells, just persist in an episomal form, which significantly reduced their tumorigenicity.

Picture loading failed. Figure 6. The three plasmids co-transfection system of recombinant AAV. pAAV-GOI: an AAV ITR-containing plasmid carrying the gene of interest (GOI); pAAV-RC: an AAV serotype plasmid that carries Rep and Capsid genes; pHelper: an AAV helper plasmid that provides the helper genes isolated from adenovirus.

AAV-based gene therapy

To date, more than 244 clinical trials have been carried out using AAV vectors for gene delivery [17], and promising gene therapy outcomes have been achieved from Phase 1, Phase 2 and Phase 3 trials for a great number of diseases, including lipoprotein lipase deficiency (LPLD) [18], spinal muscular atrophy (SMA) [19], retinal dystrophy [20, 21], cystic fibrosis [22, 23], Duchenne Muscular Dystrophy [24], Hemophilia [25], congestive heart failure [26], Parkinson's disease [27] and Rheumatoid Arthritis [28, 29].

AAV-based vaccine development

But, as a viral vector used for vaccine production, AAV only induces mild immune responses, which is not enough for vaccine to provoke the immune system in host. Several animal studies show that AAV vector-based vaccines can be used to defense HIV-1 [30-32], influenza [33], and papillomavirus [34] and have great potentials in clinical applications. However, AAV vector-based vaccines are rarely applied in clinical trials. Some of the examples are listed in the following Table 3. There are two reasons: ① AAV vectors only cause mild humoral and cellular immunity; ② infectious vaccines transduce a large population of people ranging from children and adolescents, and more safety risks need to be considered. Therefore, compared to the gene therapy with AAV vectors, there is a long way for the clinical applications of AAV vector-based vaccines.

Table 3 - Examples of AAV vector-based vaccines
Disease Vaccine component Status Clinical trials
HIVAAV2Phase INCT00482027
HIVAAV2Phase IINCT00888446
HIVAAV8Phase INCT03374202
HIVAAV1Phase INCT01937455
Stage IV gastric cancerAAV-DC-CTLPhase INCT01637805
Stage IV gastric cancerAAV-DC-CTLPhase INCT02496273

Advantages and disadvantage

AAV viral vector has been developed into a very attractive candidate for gene delivery due to various advantages: ① superior biosafety rating of recombinant AAV after removing most AAV genome elements; ② stable physical properties; ③ broad range of infectivity, AAV has the ability to infect both dividing and quiescent cells in vivo; ④ mediate long term and stable gene expression.

However, there are also some drawbacks for AAV to be used as vaccine vector: ① limited cloning capacity (less than 4.7kb) of the vector, which restricts its use in gene delivery of large genes [35]; ② only inducing mild immunity, restraining the vaccine development; ③ pre-existing immunity and neutralizing antibodies (NAB) against AAV vectors may attenuate the effect of AAV-based gene therapy or vaccines [36].

Optimization strategies

To improve the efficacy of AAV vector for vaccine development, several strategies are adopted: ① assemble and recombine proteins between different viruses, which can produce hybrid rAAVs, such as transcapsidation, which is a process involving the packaging of the ITR from one AAV serotype into the capsid of another serotype, which may determine the tissue tropism of hybrids. ② Recombine, redesign, or introduce random mutations into the capsid protein of AAV by different methods to artificially increase the variance of AAV serotypes, and then screen the appropriate AAV serotypes, including rational design AAV capsid [37], AAV directed evolution [38], point mutation [39], peptide display [40], and DNA shuffling [41]. ③ In combination with other kinds of vaccines.

GeneMedi holds the expertise at AAV production, you can find more information and protocols about AAV on this website: https://www.genemedi.net/i/aav-packaging.


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