Novel AAV-based genetic vaccines encoding truncated dengue virus envelope proteins elicit humoral immune responses in mice

Li, Xueling; Cao, Hong; Wang, Qiang; Di, Biao; Wang, Ming; Lu, Jianxi; Pan, Longfa; Li, Yang; Mei, Mantong; Pan, Xingfei; Li, Gang; Wang, Lili

doi:10.1016/j.micinf.2012.05.002

Cited by 22 publications

(30 citation statements)

References 33 publications

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“…Notably, a study using AAV2 vectors expressing several simian immunodeficiency virus (SIV) genes indicated that a single intra-muscular administration of the vector was able to elicit SIVspecific T cells and Ab, demonstrating its potential in a macaque NHP model (22). Thereafter, other AAV serotypes rapidly entered the field and out-performed AAV2 in terms of immune responses, as expected from their higher efficiency for gene transfer (13,(17)(18)(19)28). The use of various AAV serotypes also allowed varying the injection routes ( Table 1).…”

Section: Evaluation Of Different Aav Serotypes and Routes Of Immunizamentioning

confidence: 99%

AAV Vectors Vaccines Against Infectious Diseases

2014

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Since their discovery as a tool for gene transfer, vectors derived from the adeno-associated virus (AAV) have been used for gene therapy applications and attracted scientist to this field for their exceptional properties of efficiency of in vivo gene transfer and the level and duration of transgene expression. For many years, AAVs have been considered as low immunogenic vectors due to their ability to induce long-term expression of non-self-proteins in contrast to what has been observed with other viral vectors, such as adenovirus, for which strong immune responses against the same transgene products were documented. The perceived low immunogenicity likely explains why the use of AAV vectors for vaccination was not seriously considered before the early 2000s. Indeed, while analyses conducted using a variety of transgenes and animal species slowly changed the vision of immunological properties of AAVs, an increasing number of studies were also performed in the field of vaccination. Even if the comparison with other modes of vaccination was not systemically performed, the analyses conducted so far in the field of active immunotherapy strongly suggest that AAVs possess some interesting features to be used as tools to produce an efficient and sustained antibody response. In addition, recent studies also highlighted the potential of AAVs for passive immunotherapy. This review summarizes the main studies conducted to evaluate the potential of AAV vectors for vaccination against infectious agents and discusses their advantages and drawbacks. Altogether, the variety of studies conducted in this field contributes to the understanding of the immunological properties of this versatile virus and to the definition of its possible future applications.

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Section: Evaluation Of Different Aav Serotypes and Routes Of Immunizamentioning

confidence: 99%

AAV Vectors Vaccines Against Infectious Diseases

2014

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“…AAV4, a serotype that is one of the most structurally and serologically different from other human and non-human primate AAVs (Gao et al, 2004; Govindasamy et al, 2006) but shares high (~81%) sequence similarity with AAVrh32.33, was found to have a similar low antibody response (Calcedo et al, 2009). Thus AAVrh32.33 (and AAV4) are attractive for development as a gene delivery vectors with the potential to evade pre-existing host antibody responses against AAV capsids (Calcedo et al, 2009; Li et al, 2012; Mays and Wilson, 2009; Mays et al, 2009). AAVrh32.33 is also being evaluated as a genetic vaccine platform, specifically for human immunodeficiency virus type 1 (HIV-1) and type A influenza virus (Lin et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

The structure of AAVrh32.33, a novel gene delivery vector

Mikals

Nam

Vliet

et al. 2014

Journal of Structural Biology

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The Adeno-Associated viruses (AAVs) are being developed as gene delivery vectors for therapeutic clinical applications. However, the host antibody immune response directed against their capsid, prevalent in ~40–70% of the general population, depending on serotype, negatively impacts efficacy. AAVrh32.33, a novel vector developed from rhesus macaques isolates, has significantly lower seroprevalence in human populations compared to AAV2 and AAV8, which are both in clinical use. To better understand the capsid determinants of this differential immune response to AAVrh32.33, its structure was determined by X-ray crystallography to 3.5 Å resolution. The capsid viral protein (VP) structure conserves the eight-stranded β-barrel core and αA helix reported for other parvoviruses and the distinct capsid surface topology of the AAVs: a depression at the icosahedral two-fold axis, three protrusions surrounding the three-fold axis, and a depression surround a cylindrical channel at the five-fold axis. A comparison to AAV2, AAV4, and AAV8, to which AAVrh32.33 shares ~61%, ~81%, and ~63% identity, respectively, identified differences in previously defined AAV VP structurally variable regions (VR-1 to VR-IX) which function as receptor attachment, transduction efficiency, and/or antigenic determinants. This structure thus provides a 3D platform for capsid engineering in ongoing efforts to develop AAVrh32.33, as well as other AAV serotypes, for tissue targeted gene-therapy applications with vectors that can evade pre-existing antibody responses against the capsid. These features are required for full clinical realization of the promising AAV gene delivery system.

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“…It was found to be much less seroprevalent than AAV2, AAV7, and AAV8 (13), decreasing the problem of preexisting neutralizing antibodies to the capsid and making it a potential candidate for gene transfer. However, unlike AAV8, AAVrh32.33 vectors induce strong T cell responses to transgene products, which, while a beneficial feature for use in vaccine development (28), are not desired in gene therapy applications. Ultimately, by mapping the domain responsible for augmenting cellular immunity to AAVrh32.33 transgenes or inducing tolerance 11 GCs of AAV2/8, AAV2/rh32.33, or LM14 (AAV2/rh32.33-8_VR.IV) expressing nLacZ.…”

Section: Discussionmentioning

confidence: 99%

Mapping the Structural Determinants Responsible for Enhanced T Cell Activation to the Immunogenic Adeno-Associated Virus Capsid from Isolate Rhesus 32.33

Mays

Wang

Tenney

et al. 2013

J Virol

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bAvoiding activation of immunity to vector-encoded proteins is critical to the safe and effective use of adeno-associated viral (AAV) vectors for gene therapy. While commonly used serotypes, such as AAV serotypes 1, 2, 7, 8, and 9, are often associated with minimal and/or dysfunctional CD8 ؉ T cell responses in mice, the threshold for immune activation appears to be lower in higher-order species. We have modeled this discrepancy within the mouse by identifying two capsid variants with differential immune activation profiles: AAV serotype 8 (AAV8) and a hybrid between natural rhesus isolates AAVrh32 and AAVrh33 (AAVrh32.33). Here, we aimed to characterize the structural determinants of the AAVrh32.33 capsid that augment cellular immunity to vector-encoded proteins or those of AAV8 that may induce tolerance. We hypothesized that the structural domain responsible for differential immune activation could be mapped to surface-exposed regions of the capsid, such as hypervariable regions (HVRs) I to IX of VP3. To test this, a series of hybrid AAV capsids was constructed by swapping domains between AAV8 and AAVrh32.33. By comparing their ability to generate transgene-specific T cells in vivo versus the stability of transgene expression in the muscle, we confirmed that the functional domain lies within the VP3 portion of the capsid. Our studies were able to exclude the regions of VP3 which are not sufficient for augmenting the cellular immune response, notably, HVRs I, II, and V. We have also identified HVR IV as a region of interest in conferring the efficiency and stability of muscle transduction to AAVrh32.33.

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Novel AAV-based genetic vaccines encoding truncated dengue virus envelope proteins elicit humoral immune responses in mice

Cited by 22 publications

References 33 publications

AAV Vectors Vaccines Against Infectious Diseases

AAV Vectors Vaccines Against Infectious Diseases

The structure of AAVrh32.33, a novel gene delivery vector

Mapping the Structural Determinants Responsible for Enhanced T Cell Activation to the Immunogenic Adeno-Associated Virus Capsid from Isolate Rhesus 32.33

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