Viral vector-based vaccines: AAV vector-based vaccines
SOCAIL MEDIA
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.
| 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 |
1) 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).
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).
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].
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.
| 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 | √ | √ | √ | |||||
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.
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].
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.
| Disease | Vaccine component | Status | Clinical trials |
| HIV | AAV2 | Phase I | NCT00482027 |
| HIV | AAV2 | Phase II | NCT00888446 |
| HIV | AAV8 | Phase I | NCT03374202 |
| HIV | AAV1 | Phase I | NCT01937455 |
| Stage IV gastric cancer | AAV-DC-CTL | Phase I | NCT01637805 |
| Stage IV gastric cancer | AAV-DC-CTL | Phase I | NCT02496273 |
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].
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.com/i/aav-packaging.
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