Next Article in Journal
Evidence for the Involvement of the Master Transcription Factor NF-κB in Cancer Initiation and Progression
Next Article in Special Issue
Comment on Khanal et al. The Repertoire of Adenovirus in Human Disease: The Innocuous to the Deadly. Biomedicines 2018, 6, 30
Previous Article in Journal
GABA Levels in Left and Right Sensorimotor Cortex Correlate across Individuals
Previous Article in Special Issue
Oncolytic Adenoviruses in Gastrointestinal Cancers
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomedicines
Volume 6
Issue 3
10.3390/biomedicines6030081
biomedicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Progress in Adenoviral Capsid-Display Vaccines

by
Marija Vujadinovic
* and
Jort Vellinga
Janssen Infectious Diseases and Vaccines, Pharmaceutical Companies of Johnson and Johnson, 2301 CA Leiden, The Netherlands
*
Author to whom correspondence should be addressed.
Biomedicines 2018, 6(3), 81; https://doi.org/10.3390/biomedicines6030081
Submission received: 29 June 2018 / Revised: 20 July 2018 / Accepted: 23 July 2018 / Published: 26 July 2018
(This article belongs to the Special Issue Adenoviruses: From Virus to Medicine)
Browse Figures
Versions Notes

Abstract

:
Adenoviral vectored vaccines against infectious diseases are currently in clinical trials due to their capacity to induce potent antigen-specific B- and T-cell immune responses. Heterologous prime-boost vaccination with adenoviral vector and, for example, adjuvanted protein-based vaccines can further enhance antigen-specific immune responses. Although leading to potent immune responses, these heterologous prime-boost regimens may be complex and impact manufacturing costs limiting efficient implementation. Typically, adenoviral vectors are engineered to genetically encode a transgene in the E1 region and utilize the host cell machinery to express the encoded antigen and thereby induce immune responses. Similarly, adenoviral vectors can be engineered to display foreign immunogenic peptides on the capsid-surface by insertion of antigens in capsid proteins hexon, fiber and protein IX. The ability to use adenoviral vectors as antigen-display particles, with or without using the genetic vaccine function, greatly increases the versatility of the adenoviral vector for vaccine development. This review describes the application of adenoviral capsid antigen-display vaccine vectors by focusing on their distinct advantages and possible limitations in vaccine development.

Graphical Abstract

1. Introduction

The hallmark of vaccine-mediated protection against infectious diseases is the induction of B- and T-cell immune responses [1]. Recombinant replication-incompetent adenoviral human (AdV) vaccine vectors are generally engineered to genetically encode a transgene in the E1 region and utilize the host cell machinery to express the transgene and to induce antigen-specific T-cell and B-cell responses [2,3,4,5,6]. AdVs broad application as vaccine vectors is greatly facilitated due to several valuable attributes: (i) They contain a well characterized ~36 kbp in size genome which can easily be engineered; (ii) they can be grown to high titers in a number of available complementing cell lines such as HEK293 [7], 911 [8] or PER.C6 cells [9,10], and (iii) they have a broad cell tropism which enables them to efficiently transduce a wide range of dividing and non-dividing cells [11]. Importantly, in the clinical evaluations, AdV vaccines have been shown to induce potent T-cell and B-cell responses against pathogens, for instance HIV and Ebola, with a good safety profile [12,13,14,15]. By contrast, protein-based vaccines such as virus-like particles (VLP), typically in combination with an adjuvant, are usually highly effective at inducing mainly B-cell responses [16,17,18,19,20]. For some complex pathogens, effective vaccine-mediated protection requires potent multifaceted B- and T-cell immune responses [21,22]. This can be achieved using a prime-boost vaccination approach with, for example, an AdV prime and adjuvanted recombinant protein boost, containing the same antigens [23,24,25,26].
While the AdV prime-protein boost offers the advantages of well-known vaccine platforms, it is limited by increased cost of goods and potentially complex vaccine regimens. Combining the benefits of AdV and protein vaccination in a single vaccine formulation could be an attractive alternative.
AdV vector capsid proteins can be engineered to display antigens on the capsid surface—referred to as capsid-antigen display vectors herein—thus offering the potential to combine genetic and protein-based vaccination in a single AdV vector. The AdV capsid consists of seven structural proteins; three major capsid proteins hexon, fiber and penton; and four minor ‘cement’ proteins protein IIIa (pIIIa), VI, VIII and protein IX (pIX) [27,28,29,30,31] (Figure 1), some of which have been modified to display heterologous peptide sequences for different purposes.
Hexon, as a major capsid component, is a target for host immune responses against AdV [32], resulting in anti-vector immunity which may hamper with AdV vector efficacy [33,34,35,36]. To circumvent anti-vector immunity, hexon surface-exposed hypervariable regions (HVRs) can be replaced by alternative hexon sequences [32,37,38,39,40]. A human AdV5 (HAdV5) vector containing HAdV48 HVRs has been tested in phase I as an HIV vaccine [41]. Fiber and penton base are important for viral cell entry by binding to cellular receptor(s) (e.g., coxsackievirus and adenovirus receptor (CAR)) [42,43], and can be modified to alter AdV vector tropism to a specific cell type by replacing the native receptor binding motif by an alternative receptor motif sequence for gene therapy purposes [44,45,46]. Protein IX functions as a ‘cement’ protein and contributes to overall capsid stability [47,48]. Its surface-exposed C-terminus can accommodate fusion of peptides and proteins, for instance to alter the tropism or by generating viruses that express reporter proteins on the outer capsid surface for use in AdV trafficking studies [49,50,51,52]. Even though pIIIa allows small heterologous peptide/epitope fusions to its N-terminus, its tolerance for modification seems to be very low ([53,54], and M. Vujadinavic et al. [55].
In this review, we focus on studies describing capsid-antigen display AdV vectors with antigen peptide insertions in AdV hexon, fiber, penton and pIX (Figure 2 and Table 1), with the aim to establish their value as vaccine vectors by highlighting their distinct advantages and possible limitations. Such knowledge can contribute to the successful future application of AdV vectors as an antigen display platform. The availability of multiple modification sites in the AdV capsid allows the selection of the optimal AdV antigen-display strategy. These AdV capsid-display vectors induce antigen-specific immune responses without an adjuvant in animal models. Next to the VLP-like antigen-display, AdV capsid-display vectors can be engineered to genetically encode antigens allowing the benefits of AdV-based genetic and protein vaccination to be combined within one vaccine vehicle.

2. Hexon Antigen Display

Hexon is an attractive choice for the generation of AdV antigen-display vectors because of the high number of surface-exposed antigen insertion sites (Figure 2B and Table 1). There are 720 hexon monomer proteins per capsid, which consist of a relatively conserved base and a top section containing HVR1–7 [28,29,82,83]. The size of each HVR loop differs per AdV type e.g., human adenovirus 5 (HAdV5) HVR1 44 amino acids (aa) [84]. HVRs are exposed on the outer capsid surface, however, their relative surface exposure can vary [84]. For instance, in HAdV5 the largest HVR1, HVR5 and HVR7 are located on top, while HVR2, HVR3, HVR4 and HVR6 are positioned lower towards the base [84]. Nonetheless, all HVRs contain AdV-specific epitopes and are at target for host antibody responses [32,84]. Consequently, pre-existing specific anti-AdV antibodies can neutralize the AdV vector and reduce vaccine immunogenicity [33,34,35,36]. To circumvent anti-vector immunity for gene delivery purposes, single (e.g., HVR1), or all (i.e., HVR1–7) HVRs, or the complete hexon have been replaced with their counterparts from alternative less-prevalent AdV [32,37,38,39,40,85]. Similar modifications have been made for the generation of antigen-display vectors by replacing some or all HVR sequences, or by inserting a target-specific epitope in the hexon HVR loop to display mostly linear epitopes on the outer capsid surface.
Successful epitope-display and antigen-specific immune responses in mice have been demonstrated for HAdV5 expressing the target epitope on HVR1 [56,57,58,59,62,63] (Aotus nancymaae [58]), HVR5 [63,69,70] and HVR2 [70]. In particular, antigen-display via HVR1 is highly versatile. HVR1 was shown to accommodate linear epitope from different pathogens (e.g., HIV gp120) in a size range of 8 to 30 amino acids (aa) resulting in potent antigen-specific immune responses [56,57,58,59,62,63]. However, the display of a 10aa-HIV gp120-epitope alone in HVR1 [59] or HVR5 [86] was unsuccessful. Surrounding this epitope with ‘spacer’-sequences (~15 aa) resulted in antigen display, suggesting that additional spacing or peptide engineering may rescue epitope presentation. The latter observations demonstrate the importance of epitope design (e.g., size of the epitope and presence of additional spacers) in combination with the appropriate HVR for successful epitope display to induce potent immune responses. HVR1 and HVR5 appear to display similar sized epitopes (~30 aa) inducing comparable antigen-specific immune responses [63]. HVR5 can display linear epitopes from different pathogens (e.g., Anthrax) [63,69,70] in the size range of 12 to 66 aa with potent antigen-specific immune responses in mice. In contrast, HVR2 has not been extensively utilized for epitope display. Similar sized epitope display via HVR2 or HVR5 demonstrate HVR2 to be less permissive for larger peptide insertions, with the induction of lower antigen-specific immune responses compared to HVR5 [70].
To generate AdV display vectors presenting more than one antigen per capsid or more copies of the same epitope from a single AdV vector, multiple hexon HVRs can be modified. Antigen-specific immune responses were detected with display via HVR1 (HIV, 7 aa) combined with His-epitope in HVR5, but not HVR2 [61], supporting previous results of poor immunogenicity against epitopes displayed via HVR2 [70]. The suboptimal antigen display via HVR2 may be due to poor accessibility of the epitope, since HVR2 is located away from the top relative to HVR1 and HVR5 [84]. Comparable immune responses against both antigens displayed via HVR1 and HVR5 [61] illustrate the potential of displaying different epitopes from a single AdV vector to generate a multivalent vaccine.
To combine the benefits of genetic and protein-based vaccination, hexon-display vectors can be engineered to genetically encode an antigen resulting in a (multivalent) display-expression. HAdV5 hexon display-expression vectors encoding and displaying antigens from pathogens such as Pseudomonas aeruginosa outer membrane protein F (OprF) epitope (HVR5, 14 aa) [68,71,72,87], elicited potent (protective) immune responses against the displayed epitope and the encoded transgene in mice. Epitope display via HVRs may be a means to reduce or interfere with anti-vector immunity in the host and enhance transgene-specific immune responses with display-expression vectors [68,86,87]. For example, HAdV5 HVR1 malaria circumsporozoite (CS) display vectors were largely unaffected by anti-HAdV5 neutralizing antibodies in vitro, supporting the notion that the majority of anti-HAdV5 antibodies after immunization are directed against HVR1 [86,87].
To fully evade anti-vector immunity, replacement of all HVRs is necessary [32]. As a result, use of HAdV5-based hexon-antigen display vectors remains restricted [88,89]. Vectors derived from rare AdV types such as HAdV26 [90] and chimpanzee AdV type 3 (CAdV3) [91] are less likely to be limited by pre-existing immunity in the human population. Due to variations in the HVR loop aa sizes and possibly surface-exposure among AdV types (e.g., HAdV5 HVR1 has 30 aa vs. HAdV48 HVR1 which has 8 aa), it is important to determine whether alternative AdV types can be successfully used to display antigens via different HVRs. Epitope display via hexon using alternative AdV types was demonstrated with HAdV3 [64,65], and simian adenovirus 25 (SAdV25) [66,67] vectors, with both vectors inducing potent immune responses in mice. For the HAdV3 vector, a 15 aa enterovirus epitope was successfully displayed via HVR1, HVR2 and HVR7, whereas display via HVR4 and HVR5 was unsuccessful [64,65]. Overall, these results suggest that alternative AdV types can be successfully used to display antigens via different HVRs to a similar extent as HAdV5 vectors.
3. pIX-Display Vectors
The most important advantage of pIX-display vectors is that unlike hexon, pIX tolerates fusion of larger peptides to its C-terminus (Figure 2C and Table 1). Protein IX minor capsid protein acts as a capsid stabilizing element in the AdV capsid [47,92]. It is believed to have additional functions as a transcriptional activator [93] and suppressor of the host-cell anti-viral response, thereby contributing to optimal virus production [94]. AdV vectors lacking pIX can be generated without deleterious effects on viral replication [95], albeit at a cost of reduced thermostability [96] and impaired packaging of full-length genomes [97]. There are 240 protein IX copies per capsid, arranged to protrude from the hexon cavities to expose the C-terminus tail to the outer surface [98,99] (Figure 1). Protein IX has proven suitable for the display of linear and globular functional proteins, for example, a polylysine motif or an eGFP protein, on the outer capsid surface [49,50,51]. This trait has been exploited for cell-specific AdV vector re-targeting and purification by fusion of specific ligands [51,100,101,102], or as a tool for AdV tracking in vitro and in vivo by fusion of functional reporter proteins [49,50,103]. Even though the pIX C-terminus is accessible on the outer capsid surface [104] it is embedded within the hexon cavity [98]. To increase the accessibility of the fusion peptide on the outer capsid surface, an alpha helical spacer can be added to lift the heterologous peptide fused to the pIX C-terminus out of the hexon grove [100].
In a HAdV5 vector, pIX was shown to display different antigens in a size range of 15 kDa to ~70 kDa (e.g., Yersinia pestis antigens) [73,74,76], inducing potent antigen-specific immune responses. Display of Yersinia pestis antigens via pIX elicited antigen-specific humoral responses and provided protection against lethal challenge in mice [73]. In addition, expression of pIX and the fused antigen in vivo is observed [105], which may contribute to potent immune responses against the pIX-fused antigen [74,76].
The potential of alternative AdV types for the generation of pIX-display vectors was confirmed by HAdV35 [77,78] and HAdV48 vectors [75], which induced potent antigen-specific immune responses in mice. HAdV35 displaying a ~15 kDa malaria CS antigen and encoding a CS transgene in E1 elicited higher immune responses than the transgene-only vector or CS protein alone. This effect could not be achieved by mixing the CS protein with the vector, suggesting that the antigen needs to be displayed on the outer capsid surface for induction of enhanced antigen-specific humoral responses [77]. HAdV35 vectors displaying HPV protein L2 epitope-repeats via pIX (e.g., HPV type 6, 31, 33, 16 (93 aa)) elicited L2-specific immune responses against the HVP types included and not included in the vaccine, demonstrating the potential of using pIX to display multiple linear epitopes in a repetitive confirmation from a single AdV vector to generate a multivalent AdV display vaccine [78]. In some instances, alternative AdV vectors were shown be more potent at inducing antigen-specific immune responses. For example, HAdV48 displaying 16 aa and 24 aa Trypanosoma cruzi epitopes outperformed the HAdV5 display vector by inducing higher B- and T-cell responses in mice [75]. This difference may be explained by a difference in pIX-antigen capsid incorporation efficiency between HAdV5 and HAdV48, resulting in the observed variation in potency. Previous studies in non-human primates also indicated that HAdV48 and HAdV5 induce differential innate responses which might result in differences in adaptive immune responses to the vector and the antigen [5].

4. Fiber- and Penton-Display Vectors

Fiber and penton proteins are appealing targets for epitope insertion because fiber trimers and penton pentamers are highly exposed on the 12 AdV icosahedral capsid vertices [106] (Figure 2D,E and Table 1). Fiber and penton are pivotal for cell entry [106,107]. Fiber initiates the interaction with the primary cellular receptor followed by secondary receptor interaction by penton, resulting in cell entry [42,108]. Modifications to these proteins may impact their binding efficiency to cellular receptors and consequently cell entry, which can be detrimental to vector potency and/or production in producer cell lines. Fiber consists of three distinct domains: (i) a C-terminal knob domain which binds to the primary receptor, (ii) the central shaft region consisting of flexible β-sheets, (iii) and a highly conserved N-terminal tail which interacts with the penton base [106,109]. Penton binding with secondary integrin receptors is mediated by the highly conserved Arg-Gly-Asp (RGD) motif which is embedded in the most variable region of the otherwise highly conserved penton base [106,110,111,112].
Successful full fiber substitutions, knob and shaft and shaft-only substitutions with counterpart alternative AdV fiber domains have been demonstrated, mainly for AdV vector retargeting in gene therapy [113,114,115,116,117], although the potential of AdV vector retargeting for vaccination purposes has been demonstrated. Chimera HAdV5 containing a HAdV35 species B fiber showed efficient transduction of antigen-presenting dendritic cells, suggesting potential for targeting specific cells in vivo [118,119]. In AdV-based HIV vaccine development, HAdV fiber chimera vectors induced potent (protective) immune responses in mice and monkeys [120,121,122]. Less invasive fiber modifications for AdV vector retargeting have been demonstrated. Several different receptor ligand peptides up to 55 aa in length were inserted into the surface-exposed fiber knob HI-, DE-, FG-, CD-loops and the C-terminus [81,123,124,125,126,127]. Similarly, to facilitate AdV binding to an alternative receptor penton base, modifications were achieved with replacement of the RGD motif for a different receptor binding motif [128,129].
Few studies demonstrate the potential of epitope-display via fiber [60,79,80,81] and only one via penton [79] (Figure 2D,E and Table 1). HAdV5 vectors displaying an influenza epitope via either the hexon HVR5, fiber HI-loop, penton RGD loop, or pIX, all induced antigen-specific immune responses in mice [79]. However, when mice were immunized with either the same AdV particle number or the same epitope copy number, influenza-specific humoral and cellular responses were highest with the fiber-display vector [79]. This observation is interesting considering that the fiber is the least abundant protein (36 copies vs. 60 of penton, 720 of hexon, and 240 of pIX) in the AdV capsid, suggesting that epitope accessibility and presentation is more important than the number of epitopes displayed per AdV capsid. HAdV5 vectors displaying a 14 aa P. aeruginosa OprF epitope via fiber HI-loop, FG-loop, CD-loop, DE-loop, C-terminus and hexon HVR5 induced potent immune responses in mice [81]. In contrast to immunization with HAdV5 OprF transgene vector, the fiber FG-loop display vector induced protection against P. aeruginosa even in the presence of high anti-HAdV5 pre-existing immunity [81], clearly demonstrating the benefits of AdV fiber-antigen display vectors.

5. Concluding Remarks

AdV capsid-display vaccine vectors can be generated by inserting antigens or epitopes into hexon, fiber, penton and pIX. The tolerance for epitope insertion varies per capsid protein and seems to depend on the specific region that is targeted (e.g., hexon HVR1 vs. HVR2) and antigen properties (e.g., epitope size, conformation and biophysical properties). Hexon, fiber and penton proteins typically allow the insertion of small and linear T-cell or B-cell epitopes, and such limits to antigen size and confirmation might limit their utility for vaccine development. In contrast, by allowing fusion of both linear and larger globular antigens to its C-terminus, pIX has the potential to induce broader or stronger antigen-specific immune responses. The studies described in this review indicate a wide range of successful pIX-antigen fusions in terms of peptide size (i.e., 15 to ~70 kDa). However, there might be some peptide characteristic other than size, such as charge, which can influence successful pIX-display (e.g., pIX-HA) [130,131]. The pIX-antigen display as well as the expression of pIX-antigen contributes to the potency of these vectors, a characteristic which distinguishes the pIX-display platform from conventional VLP platforms. Since AdV vectors can be generated without pIX, suboptimal pIX-antigen capsid incorporation (e.g., 240 copies vs. 100 copies per capsid) may pose as a risk for consistent AdV manufacturing and/or vector quality.
VLP particle-based epitope display has been explored in vaccine development using, for instance, adeno-associated virus (AAV) [132] or various other viruses [133,134,135,136]. AdV display-vectors have the potential to carry multiple antigens for instance in hexon (e.g., HVR1 and HVR5) or fiber (e.g., HI-loop and FG-loop), or epitope insertion in different capsid proteins (e.g., hexon and pIX). Insertion of multiple epitopes can be exploited to generate single AdV vectors displaying multiple epitopes, or greater numbers of the same epitope per capsid. In addition, AdV display vectors can be engineered to genetically encode an antigen to enhance antigen-specific humoral and cellular responses, combining the benefits of protein and AdV-based vaccines.
Several strategies exist to overcome the impact of pre-existing immunity to highly prevalent vectors (e.g., HAdV5) on immunogenicity. For example, alternative AdV vectors (e.g., HAdV26 or ChAdV3) [90,91] with lower prevalence in human populations are available for genetic vaccination and/or capsid-display. Secondly, epitope insertions in the AdV capsid may reduce anti-AdV vector immunity [68,86,87]. Due to the spectrum of anti-AdV immune responses (e.g., anti-fiber and anti-hexon) in humans [137,138], it remains to be determined whether epitope display may indeed be sufficient to evade anti-AdV immunity in the clinic.
One possible limitation of antigen-display on the AdV capsid may be that the neutralizing antibodies raised against the displayed epitope (e.g., HVR1-CS display) can neutralize the AdV capsid-display vector encoding a transgene, resulting in reduced (T-cell) immune responses against the encoded transgene after second administration [87]. The AdV capsid-display studies so far focus on homologous prime-boost regimens; to test the full potential of the platform it might be interesting to explore heterologous prime-boost regimens as well. However, in most homologous prime-boost regimens, AdV antigen-display vectors show potent (protective) antigen-specific immune responses against many different pathogens. The repetitive epitopes displayed on the AdV capsid enhances the induction of humoral immunity due to B-cell receptor crosslinking [139,140], which might be an advantage over genetic AdV vectors for the generation of antigen-specific nAb responses. Furthermore, the difference in responses of capsid-modified and genetic vectors might be attributed to differential processing of the antigen in hosts cell.
To date, available publications offer little insight into the possible effects of the modification on the capsid protein’s additional biological function (e.g., AdV particle hexon-mediated transport to nucleus [141]), or critical AdV capsid-display particle characteristics such as viral titers yields, genetic stability in producer cell lines, particle stability, or appropriate formulation buffers. Yet, successful advancement of AdV capsid-display vectors depends highly on a potent vector generated at high yields in producer cell lines. Nonetheless, pre-clinical evaluations of the AdV capsid-display vectors describe potent (protective) antigen-specific immune responses against a range of complex infectious diseases, mostly without the addition of an adjuvant. Considering that the AdV capsid-display vectors are based on a well-established recombinant AdV vector platform, easily engineered and producible at high yields in producer cell lines, their suitability for commercial application is encouraging [10,142].

Author Contributions

Conceptualization: M.V. and J.V. Writing—Original Draft Preparation: M.V. Writing—Review & Editing: M.V. and J.V. Visualization: M.V. Supervision: J.V. Project Administration: J.V.

Funding

This research received no external funding.

Acknowledgments

We thank Kerstin Wunderlich, Rinke Bos, Taco Uil and Jerome Custers for their invaluable input and critical review of the manuscript.

Conflicts of Interest

The authors are employees of Johnson and Johnson.

References

  1. Siegrist, C. Vaccine immunology. In Vaccines. Saunders Elsevier, 5th ed.; Plotkin, S., Orenstein, W., Offit, P., Eds.; Saunders/Elsevier: Philadelphia, PA, USA, 2008; pp. 17–36. [Google Scholar]
  2. Rodriguez, A.; Mintardjo, R.; Tax, D.; Gillissen, G.; Custers, J.; Pau, M.G.; Klap, J.; Santra, S.; Balachandran, H.; Letvin, N.L.; et al. Evaluation of a prime-boost vaccine schedule with distinct adenovirus vectors against malaria in rhesus monkeys. Vaccine 2009, 27, 6226–6233. [Google Scholar] [CrossRef] [PubMed]
  3. Capone, S.; Meola, A.; Ercole, B.B.; Vitelli, A.; Pezzanera, M.; Ruggeri, L.; Davies, M.E.; Tafi, R.; Santini, C.; Luzzago, A.; et al. A novel adenovirus type 6 (Ad6)-based hepatitis C virus vector that overcomes preexisting anti-ad5 immunity and induces potent and broad cellular immune responses in rhesus macaques. J. Virol. 2006, 80, 1688–1699. [Google Scholar] [CrossRef] [PubMed]
  4. Folgori, A.; Capone, S.; Ruggeri, L.; Meola, A.; Sporeno, E.; Ercole, B.B.; Pezzanera, M.; Tafi, R.; Arcuri, M.; Fattori, E.; et al. A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees. Nat. Med. 2006, 12, 190–197. [Google Scholar] [CrossRef] [PubMed]
  5. Teigler, J.E.; Iampietro, M.J.; Barouch, D.H. Vaccination with adenovirus serotypes 35, 26, and 48 elicits higher levels of innate cytokine responses than adenovirus serotype 5 in rhesus monkeys. J. Virol. 2012, 86, 9590–9598. [Google Scholar] [CrossRef] [PubMed]
  6. Zahn, R.; Gillisen, G.; Roos, A.; Koning, M.; van der Helm, E.; Spek, D.; Weijtens, M.; Pau, M.G.; Radosevic, K.; Weverling, G.J.; et al. Ad35 and ad26 vaccine vectors induce potent and cross-reactive antibody and T-cell responses to multiple filovirus species. PLoS ONE 2012, 7, e44115. [Google Scholar] [CrossRef] [PubMed]
  7. Graham, F.L.; Smiley, J.; Russell, W.C.; Nairn, R. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J. Gen. Virol. 1977, 36, 59–74. [Google Scholar] [CrossRef] [PubMed]
  8. Fallaux, F.J.; Kranenburg, O.; Cramer, S.J.; Houweling, A.; van Ormondt, H.; Hoeben, R.C.; van der Eb, A.J. Characterization of 911: A new helper cell line for the titration and propagation of early region 1-deleted adenoviral vectors. Hum. Gene Ther. 1996, 7, 215–222. [Google Scholar] [CrossRef] [PubMed]
  9. Fallaux, F.J.; Bout, A.; van der Velde, I.; van den Wollenberg, D.J.; Hehir, K.M.; Keegan, J.; Auger, C.; Cramer, S.J.; van Ormondt, H.; van der Eb, A.J.; et al. New helper cells and matched early region 1-deleted adenovirus vectors prevent generation of replication-competent adenoviruses. Hum. Gene Ther. 1998, 9, 1909–1917. [Google Scholar] [CrossRef] [PubMed]
  10. Vellinga, J.; Smith, J.P.; Lipiec, A.; Majhen, D.; Lemckert, A.; van Ooij, M.; Ives, P.; Yallop, C.; Custers, J.; Havenga, M. Challenges in manufacturing adenoviral vectors for global vaccine product deployment. Hum. Gene Ther. 2014, 25, 318–327. [Google Scholar] [CrossRef] [PubMed]
  11. Havenga, M.J.; Lemckert, A.A.; Ophorst, O.J.; van Meijer, M.; Germeraad, W.T.; Grimbergen, J.; van den Doel, M.A.; Vogels, R.; van Deutekom, J.; Janson, A.A.; et al. Exploiting the natural diversity in adenovirus tropism for therapy and prevention of disease. J. Virol. 2002, 76, 4612–4620. [Google Scholar] [CrossRef] [PubMed]
  12. Baden, L.R.; Walsh, S.R.; Seaman, M.S.; Tucker, R.P.; Krause, K.H.; Patel, A.; Johnson, J.A.; Kleinjan, J.; Yanosick, K.E.; Perry, J.; et al. First-in-Human Evaluation of the Safety and Immunogenicity of a Recombinant Adenovirus Serotype 26 HIV-1 Env Vaccine (IPCAVD 001). J. Infect. Dis. 2013, 207, 240–247. [Google Scholar] [CrossRef] [PubMed]
  13. O’Hara, G.A.; Duncan, C.J.; Ewer, K.J.; Collins, K.A.; Elias, S.C.; Halstead, F.D.; Goodman, A.L.; Edwards, N.J.; Reyes-Sandoval, A.; Bird, P.; et al. Clinical assessment of a recombinant simian adenovirus ChAd63: A potent new vaccine vector. J. Infect. Dis. 2012, 205, 772–781. [Google Scholar] [CrossRef] [PubMed]
  14. Ouedraogo, A.; Tiono, A.B.; Kargougou, D.; Yaro, J.B.; Ouedraogo, E.; Kabore, Y.; Kangoye, D.; Bougouma, E.C.; Gansane, A.; Henri, N.; et al. A phase 1b randomized, controlled, double-blinded dosage-escalation trial to evaluate the safety, reactogenicity and immunogenicity of an adenovirus type 35 based circumsporozoite malaria vaccine in Burkinabe healthy adults 18 to 45 years of age. PLoS ONE 2013, 8, e78679. [Google Scholar] [CrossRef] [PubMed]
  15. De Santis, O.; Audran, R.; Pothin, E.; Warpelin-Decrausaz, L.; Vallotton, L.; Wuerzner, G.; Cochet, C.; Estoppey, D.; Steiner-Monard, V.; Lonchampt, S.; et al. Safety and immunogenicity of a chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: A randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study. Lancet Infect. Dis. 2016, 16, 311–320. [Google Scholar] [CrossRef]
  16. White, M.T.; Bejon, P.; Olotu, A.; Griffin, J.T.; Riley, E.M.; Kester, K.E.; Ockenhouse, C.F.; Ghani, A.C. The relationship between RTS,S vaccine-induced antibodies, CD4(+) T cell responses and protection against Plasmodium falciparum infection. PLoS ONE 2013, 8, e61395. [Google Scholar] [CrossRef] [PubMed]
  17. Chaudhury, S.; Ockenhouse, C.F.; Regules, J.A.; Dutta, S.; Wallqvist, A.; Jongert, E.; Waters, N.C.; Lemiale, F.; Bergmann-Leitner, E. The biological function of antibodies induced by the RTS,S/AS01 malaria vaccine candidate is determined by their fine specificity. Malar. J. 2016, 15, 301. [Google Scholar] [CrossRef] [PubMed]
  18. Handisurya, A.; Schellenbacher, C.; Haitel, A.; Senger, T.; Kirnbauer, R. Human papillomavirus vaccination induces neutralising antibodies in oral mucosal fluids. Br. J. Cancer 2016, 114, 409–416. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Bruce, M.G.; Bruden, D.; Hurlburt, D.; Zanis, C.; Thompson, G.; Rea, L.; Toomey, M.; Townshend-Bulson, L.; Rudolph, K.; Bulkow, L.; et al. Antibody Levels and Protection After Hepatitis B Vaccine: Results of a 30-Year Follow-up Study and Response to a Booster Dose. J. Infect. Dis. 2016, 214, 16–22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Palladini, A.; Thrane, S.; Janitzek, C.M.; Pihl, J.; Clemmensen, S.B.; de Jongh, W.A.; Clausen, T.M.; Nicoletti, G.; Landuzzi, L.; Penichet, M.L.; et al. Virus-like particle display of HER2 induces potent anti-cancer responses. Oncoimmunology 2018, 7, e1408749. [Google Scholar] [CrossRef] [PubMed]
  21. Barouch, D.H.; Liu, J.; Peter, L.; Abbink, P.; Iampietro, M.J.; Cheung, A.; Alter, G.; Chung, A.; Dugast, A.S.; Frahm, N.; et al. Characterization of humoral and cellular immune responses elicited by a recombinant adenovirus serotype 26 HIV-1 Env vaccine in healthy adults (IPCAVD 001). J. Infect. Dis. 2013, 207, 248–256. [Google Scholar] [CrossRef] [PubMed]
  22. Lu, S. Heterologous prime-boost vaccination. Curr. Opin. Immunol. 2009, 21, 346–351. [Google Scholar] [CrossRef] [PubMed]
  23. Barouch, D.H.; Alter, G.; Broge, T.; Linde, C.; Ackerman, M.E.; Brown, E.P.; Borducchi, E.N.; Smith, K.M.; Nkolola, J.P.; Liu, J.; et al. Protective efficacy of adenovirus/protein vaccines against SIV challenges in rhesus monkeys. Science 2015, 349, 320–324. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Stewart, V.A.; McGrath, S.M.; Dubois, P.M.; Pau, M.G.; Mettens, P.; Shott, J.; Cobb, M.; Burge, J.R.; Larson, D.; Ware, L.A.; et al. Priming with an adenovirus 35-circumsporozoite protein (CS) vaccine followed by RTS,S/AS01B boosting significantly improves immunogenicity to Plasmodium falciparum CS compared to that with either malaria vaccine alone. Infect. Immun. 2007, 75, 2283–2290. [Google Scholar] [CrossRef] [PubMed]
  25. Chmielewska, A.M.; Naddeo, M.; Capone, S.; Ammendola, V.; Hu, K.; Meredith, L.; Verhoye, L.; Rychlowska, M.; Rappuoli, R.; Ulmer, J.B.; et al. Combined adenovirus vector and hepatitis C virus envelope protein prime-boost regimen elicits T cell and neutralizing antibody immune responses. J. Virol. 2014, 88, 5502–5510. [Google Scholar] [CrossRef] [PubMed]
  26. Keele, B.F.; Li, W.; Borducchi, E.N.; Nkolola, J.P.; Abbink, P.; Chen, B.; Seaman, M.S.; Barouch, D.H. Adenovirus prime, Env protein boost vaccine protects against neutralization-resistant SIVsmE660 variants in rhesus monkeys. Nat. Commun. 2017, 8, 15740. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Reddy, V.S.; Natchiar, S.K.; Stewart, P.L.; Nemerow, G.R. Crystal structure of human adenovirus at 3.5 A resolution. Science 2010, 329, 1071–1075. [Google Scholar] [CrossRef] [PubMed]
  28. Reddy, V.S.; Natchiar, S.K.; Gritton, L.; Mullen, T.M.; Stewart, P.L.; Nemerow, G.R. Crystallization and preliminary X-ray diffraction analysis of human adenovirus. Virology 2010, 402, 209–214. [Google Scholar] [CrossRef] [PubMed]
  29. Liu, H.; Jin, L.; Koh, S.B.; Atanasov, I.; Schein, S.; Wu, L.; Zhou, Z.H. Atomic structure of human adenovirus by cryo-EM reveals interactions among protein networks. Science 2010, 329, 1038–1043. [Google Scholar] [CrossRef] [PubMed]
  30. Vellinga, J.; van der Heijdt, S.; Hoeben, R.C. The adenovirus capsid: Major progress in minor proteins. J. Gen. Virol. 2005, 86 Pt 6, 1581–1588. [Google Scholar] [CrossRef] [PubMed]
  31. Dai, X.; Wu, L.; Sun, R.; Zhou, Z.H. Atomic Structures of Minor Proteins VI and VII in the Human Adenovirus. J. Virol. 2017. [Google Scholar] [CrossRef] [PubMed]
  32. Bradley, R.R.; Maxfield, L.F.; Lynch, D.M.; Iampietro, M.J.; Borducchi, E.N.; Barouch, D.H. Adenovirus serotype 5-specific neutralizing antibodies target multiple hexon hypervariable regions. J. Virol. 2012, 86, 1267–1272. [Google Scholar] [CrossRef] [PubMed]
  33. Ahi, Y.S.; Bangari, D.S.; Mittal, S.K. Adenoviral vector immunity: Its implications and circumvention strategies. Curr. Gene Ther. 2011, 11, 307–320. [Google Scholar] [CrossRef] [PubMed]
  34. Yang, Y.; Li, Q.; Ertl, H.C.; Wilson, J.M. Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses. J. Virol. 1995, 69, 2004–2015. [Google Scholar] [PubMed]
  35. Ledgerwood, J.E.; Costner, P.; Desai, N.; Holman, L.; Enama, M.E.; Yamshchikov, G.; Mulangu, S.; Hu, Z.; Andrews, C.A.; Sheets, R.A.; et al. A replication defective recombinant Ad5 vaccine expressing Ebola virus GP is safe and immunogenic in healthy adults. Vaccine 2010, 29, 304–313. [Google Scholar] [CrossRef] [PubMed]
  36. Fausther-Bovendo, H.; Kobinger, G.P. Pre-existing immunity against Ad vectors: Humoral, cellular, and innate response, what’s important? Hum. Vaccines Immunother. 2014, 10, 2875–2884. [Google Scholar] [CrossRef] [PubMed]
  37. Gall, J.G.; Crystal, R.G.; Falck-Pedersen, E. Construction and characterization of hexon-chimeric adenoviruses: Specification of adenovirus serotype. J. Virol. 1998, 72, 10260–10264. [Google Scholar] [PubMed]
  38. Roy, S.; Shirley, P.S.; McClelland, A.; Kaleko, M. Circumvention of immunity to the adenovirus major coat protein hexon. J. Virol. 1998, 72, 6875–6879. [Google Scholar] [PubMed]
  39. Wu, H.; Han, T.; Belousova, N.; Krasnykh, V.; Kashentseva, E.; Dmitriev, I.; Kataram, M.; Mahasreshti, P.J.; Curiel, T.D. Identification of sites in adenovirus hexon for foreign peptide incorporation. J. Virol. 2005, 79, 3382–3390. [Google Scholar] [CrossRef] [PubMed]
  40. Roberts, D.M.; Nanda, A.; Havenga, M.J.; Abbink, P.; Lynch, D.M.; Ewald, B.A.; Liu, J.; Thorner, A.R.; Swanson, P.E.; Gorgone, D.A.; et al. Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity. Nature 2006, 441, 239–243. [Google Scholar] [CrossRef] [PubMed]
  41. Baden, L.R.; Walsh, S.R.; Seaman, M.S.; Johnson, J.A.; Tucker, R.P.; Kleinjan, J.A.; Gothing, J.A.; Engelson, B.A.; Carey, B.R.; Oza, A.; et al. First-in-human evaluation of a hexon chimeric adenovirus vector expressing HIV-1 Env (IPCAVD 002). J. Infect. Dis. 2014, 210, 1052–1061. [Google Scholar] [CrossRef] [PubMed]
  42. Arnberg, N. Adenovirus receptors: Implications for targeting of viral vectors. Trends Pharmacol. Sci. 2012, 33, 442–448. [Google Scholar] [CrossRef] [PubMed]
  43. Wickham, T.J.; Mathias, P.; Cheresh, D.A.; Nemerow, G.R. Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment. Cell 1993, 73, 309–319. [Google Scholar] [CrossRef]
  44. Nicol, C.G.; Graham, D.; Miller, W.H.; White, S.J.; Smith, T.A.; Nicklin, S.A.; Stevenson, S.C.; Baker, A.H. Effect of adenovirus serotype 5 fiber and penton modifications on in vivo tropism in rats. Mol. Ther. 2004, 10, 344–354. [Google Scholar] [CrossRef] [PubMed]
  45. Beatty, M.S.; Curiel, D.T. Chapter two—Adenovirus strategies for tissue-specific targeting. Adv. Cancer Res. 2012, 115, 39–67. [Google Scholar] [PubMed]
  46. Hogg, R.T.; Thorpe, P.; Gerard, R.D. Retargeting adenoviral vectors to improve gene transfer into tumors. Cancer Gene Ther. 2011, 18, 275–287. [Google Scholar] [CrossRef] [PubMed]
  47. Furcinitti, P.S.; van Oostrum, J.; Burnett, R.M. Adenovirus polypeptide IX revealed as capsid cement by difference images from electron microscopy and crystallography. EMBO J. 1989, 8, 3563–3570. [Google Scholar] [PubMed]
  48. Van Oostrum, J.; Burnett, R.M. Molecular composition of the adenovirus type 2 virion. J. Virol. 1985, 56, 439–448. [Google Scholar] [PubMed]
  49. Meulenbroek, R.A.; Sargent, K.L.; Lunde, J.; Jasmin, B.J.; Parks, R.J. Use of adenovirus protein IX (pIX) to display large polypeptides on the virion—Generation of fluorescent virus through the incorporation of pIX-GFP. Mol. Ther. 2004, 9, 617–624. [Google Scholar] [CrossRef] [PubMed]
  50. Matthews, Q.L.; Sibley, D.A.; Wu, H.; Li, J.; Stoff-Khalili, M.A.; Waehler, R.; Mathis, J.M.; Curiel, D.T. Genetic incorporation of a herpes simplex virus type 1 thymidine kinase and firefly luciferase fusion into the adenovirus protein IX for functional display on the virion. Mol. Imaging 2006, 5, 510–519. [Google Scholar] [CrossRef] [PubMed]
  51. Dmitriev, I.P.; Kashentseva, E.A.; Curiel, D.T. Engineering of adenovirus vectors containing heterologous peptide sequences in the C terminus of capsid protein IX. J. Virol. 2002, 76, 6893–6899. [Google Scholar] [CrossRef] [PubMed]
  52. Vellinga, J.; de Vrij, J.; Myhre, S.; Uil, T.; Martineau, P.; Lindholm, L.; Hoeben, R.C. Efficient incorporation of a functional hyper-stable single-chain antibody fragment protein-IX fusion in the adenovirus capsid. Gene Ther. 2007, 14, 664–670. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Martin, C.S.; Glasgow, J.N.; Borovjagin, A.; Beatty, M.S.; Kashentseva, E.A.; Curiel, D.T.; Marabini, R.; Dmitriev, I.P. Localization of the N-terminus of minor coat protein IIIa in the adenovirus capsid. J. Mol. Biol. 2008, 383, 923–934. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Curiel, D.T. Capsid-Modified Recombinant Adenovirus and Methods of Use. Patent US20030175244A1, 18 September 2003. [Google Scholar]
  55. Vujadinovic, M.; Vellinga, J.; Janssen Infectious Diseases and Vaccines, Pharmaceutical Companies of Johnson and Johnson, 2301 CA Leiden, The Netherlands. Personal Communication, 2015.
  56. Crompton, J.; Toogood, C.I.; Wallis, N.; Hay, R.T. Expression of a foreign epitope on the surface of the adenovirus hexon. J. Gen. Virol. 1994, 75 Pt 1, 133–139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Palma, C.; Overstreet, M.G.; Guedon, J.M.; Hoiczyk, E.; Ward, C.; Karen, K.A.; Zavala, F.; Ketner, G. Adenovirus particles that display the Plasmodium falciparum circumsporozoite protein NANP repeat induce sporozoite-neutralizing antibodies in mice. Vaccine 2011, 29, 1683–1689. [Google Scholar] [CrossRef] [PubMed]
  58. Karen, K.A.; Deal, C.; Adams, R.J.; Nielsen, C.; Ward, C.; Espinosa, D.A.; Xie, J.; Zavala, F.; Ketner, G. A replicating adenovirus capsid display recombinant elicits antibodies against Plasmodium falciparum sporozoites in Aotus nancymaae monkeys. Infect. Immun. 2015, 83, 268–275. [Google Scholar] [CrossRef] [PubMed]
  59. Gu, L.; Krendelchtchikova, V.; Krendelchtchikov, A.; Oster, R.A.; Fujihashi, K.; Matthews, Q.L. A recombinant adenovirus-based vector elicits a specific humoral immune response against the V3 loop of HIV-1 gp120 in mice through the “Antigen Capsid-Incorporation” strategy. Virol. J. 2014, 11, 112. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Gu, L.; Krendelchtchikova, V.; Krendelchtchikov, A.; Farrow, A.L.; Derdeyn, C.A.; Matthews, Q.L. Adenoviral vectors elicit humoral immunity against variable loop 2 of clade C HIV-1 gp120 via “Antigen Capsid-Incorporation” strategy. Virology 2016, 487, 75–84. [Google Scholar] [CrossRef] [PubMed]
  61. Gu, L.; Li, Z.C.; Krendelchtchikov, A.; Krendelchtchikova, V.; Wu, H.; Matthews, Q.L. Using multivalent adenoviral vectors for HIV vaccination. PLoS ONE 2013, 8, e60347. [Google Scholar] [CrossRef] [PubMed]
  62. Farrow, A.L.; Rachakonda, G.; Gu, L.; Krendelchtchikova, V.; Nde, P.N.; Pratap, S.; Lima, M.F.; Villalta, F.; Matthews, Q.L. Immunization with Hexon modified adenoviral vectors integrated with gp83 epitope provides protection against Trypanosoma cruzi infection. PLoS Negl. Trop. Dis. 2014, 8, e3089. [Google Scholar] [CrossRef] [PubMed]
  63. Wu, W.H.; Alkutkar, T.; Karanam, B.; Roden, R.B.; Ketner, G.; Ibeanu, O.A. Capsid display of a conserved human papillomavirus L2 peptide in the adenovirus 5 hexon protein: A candidate prophylactic hpv vaccine approach. Virol. J. 2015, 12, 140. [Google Scholar] [CrossRef] [PubMed]
  64. Tian, X.; Su, X.; Li, X.; Li, H.; Li, T.; Zhou, Z.; Zhong, T.; Zhou, R. Protection against enterovirus 71 with neutralizing epitope incorporation within adenovirus type 3 hexon. PLoS ONE 2012, 7, e41381. [Google Scholar] [CrossRef]
  65. Xue, C.; Tian, X.; Li, X.; Zhou, Z.; Su, X.; Zhou, R. Construction and characterization of a recombinant human adenovirus type 3 vector containing two foreign neutralizing epitopes in hexon. Virus Res. 2014, 183, 67–74. [Google Scholar] [CrossRef] [PubMed]
  66. Zhou, D.; Wu, T.L.; Emmer, K.L.; Kurupati, R.; Tuyishime, S.; Li, Y.; Giles-Davis, W.; Zhou, X.; Xiang, Z.; Liu, Q.; et al. Hexon-modified recombinant E1-deleted adenovirus vectors as dual specificity vaccine carriers for influenza virus. Mol. Ther. 2013, 21, 696–706. [Google Scholar] [CrossRef] [PubMed]
  67. Zhang, C.; Yang, Y.; Chi, Y.; Yin, J.; Yan, L.; Ku, Z.; Liu, Q.; Huang, Z.; Zhou, D. Hexon-modified recombinant E1-deleted adenoviral vectors as bivalent vaccine carriers for Coxsackievirus A16 and Enterovirus 71. Vaccine 2015, 33, 5087–5094. [Google Scholar] [CrossRef] [PubMed]
  68. Matthews, Q.L.; Fatima, A.; Tang, Y.; Perry, B.A.; Tsuruta, Y.; Komarova, S.; Timares, L.; Zhao, C.; Makarova, N.; Borovjagin, A.V.; et al. HIV antigen incorporation within adenovirus hexon hypervariable 2 for a novel HIV vaccine approach. PLoS ONE 2010, 5, e11815. [Google Scholar] [CrossRef] [PubMed]
  69. McConnell, M.J.; Danthinne, X.; Imperiale, M.J. Characterization of a permissive epitope insertion site in adenovirus hexon. J. Virol. 2006, 80, 5361–5370. [Google Scholar] [CrossRef] [PubMed]
  70. Matthews, Q.L.; Yang, P.; Wu, Q.; Belousova, N.; Rivera, A.A.; Stoff-Khalili, M.A.; Waehler, R.; Hsu, H.C.; Li, Z.; Li, J.; et al. Optimization of capsid-incorporated antigens for a novel adenovirus vaccine approach. Virol. J. 2008, 5, 98. [Google Scholar] [CrossRef] [PubMed]
  71. Worgall, S.; Krause, A.; Qiu, J.; Joh, J.; Hackett, N.R.; Crystal, R.G. Protective immunity to Pseudomonas aeruginosa induced with a capsid-modified adenovirus expressing P. aeruginosa OprF. J. Virol. 2007, 81, 13801–13808. [Google Scholar] [CrossRef] [PubMed]
  72. Worgall, S.; Krause, A.; Rivara, M.; Hee, K.K.; Vintayen, E.V.; Hackett, N.R.; Roelvink, P.W.; Bruder, J.T.; Wickham, T.J.; Kovesdi, I.; et al. Protection against P. aeruginosa with an adenovirus vector containing an OprF epitope in the capsid. J. Clin. Investig. 2005, 115, 1281–1289. [Google Scholar] [CrossRef] [PubMed]
  73. Boyer, J.L.; Sofer-Podesta, C.; Ang, J.; Hackett, N.R.; Chiuchiolo, M.J.; Senina, S.; Perlin, D.; Crystal, R.G. Protective immunity against a lethal respiratory Yersinia pestis challenge induced by V antigen or the F1 capsular antigen incorporated into adenovirus capsid. Hum. Gene Ther. 2010, 21, 891–901. [Google Scholar] [CrossRef] [PubMed]
  74. Johrden, L.; Tenbusch, M.; Lietz, R.; Bonsmann, M.S.; Niezold, T.; Wildner, O.; Bayer, W. Comparison of polystyrene nanoparticles and UV-inactivated antigen-displaying adenovirus for vaccine delivery in mice. Virol. J. 2013, 10, 108. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Farrow, A.L.; Peng, B.J.; Gu, L.; Krendelchtchikov, A.; Matthews, Q.L. A Novel Vaccine Approach for Chagas Disease Using Rare Adenovirus Serotype 48 Vectors. Viruses 2016, 8, 78. [Google Scholar] [CrossRef] [PubMed]
  76. Bayer, W.; Tenbusch, M.; Lietz, R.; Johrden, L.; Schimmer, S.; Uberla, K.; Dittmer, U.; Wildner, O. Vaccination with an adenoviral vector that encodes and displays a retroviral antigen induces improved neutralizing antibody and CD4+ T-cell responses and confers enhanced protection. J. Virol. 2010, 84, 1967–1976. [Google Scholar] [CrossRef] [PubMed]
  77. Salisch, N.C.; Vujadinovic, M.; van der Helm, E.; Spek, D.; Vorthoren, L.; Serroyen, J.; Kuipers, H.; Schuitemaker, H.; Zahn, R.; Custers, J.; et al. Antigen capsid-display on human adenovirus 35 via pIX fusion is a potent vaccine platform. PLoS ONE 2017, 12, e0174728. [Google Scholar] [CrossRef] [PubMed]
  78. Vujadinovic, M.; Khan, S.; Oosterhuis, K.; Uil, T.G.; Wunderlich, K.; Damman, S.; Boedhoe, S.; Verwilligen, A.; Knibbe, J.; Serroyen, J.; et al. Adenovirus based HPV L2 vaccine induces broad cross-reactive humoral immune responses. Vaccine 2018, 36, 4462–4470. [Google Scholar] [CrossRef] [PubMed]
  79. Krause, A.; Joh, J.H.; Hackett, N.R.; Roelvink, P.W.; Bruder, J.T.; Wickham, T.J.; Kovesdi, I.; Crystal, R.G.; Worgall, S. Epitopes expressed in different adenovirus capsid proteins induce different levels of epitope-specific immunity. J. Virol. 2006, 80, 5523–5530. [Google Scholar] [CrossRef] [PubMed]
  80. Lanzi, A.; Youssef, G.B.; Perricaudet, M.; Benihoud, K. Anti-adenovirus humoral responses influence on the efficacy of vaccines based on epitope display on adenovirus capsid. Vaccine 2011, 29, 1463–1471. [Google Scholar] [CrossRef] [PubMed]
  81. Sharma, A.; Krause, A.; Xu, Y.; Sung, B.; Wu, W.; Worgall, S. Adenovirus-based vaccine with epitopes incorporated in novel fiber sites to induce protective immunity against Pseudomonas aeruginosa. PLoS ONE 2013, 8, e56996. [Google Scholar] [CrossRef] [PubMed]
  82. Rux, J.J.; Kuser, P.R.; Burnett, R.M. Structural and phylogenetic analysis of adenovirus hexons by use of high-resolution X-ray crystallographic, molecular modeling, and sequence-based methods. J. Virol. 2003, 77, 9553–9566. [Google Scholar] [CrossRef] [PubMed]
  83. Crawford-Miksza, L.; Schnurr, D.P. Analysis of 15 adenovirus hexon proteins reveals the location and structure of seven hypervariable regions containing serotype-specific residues. J. Virol. 1996, 70, 1836–1844. [Google Scholar] [PubMed]
  84. Rux, J.J.; Burnett, R.M. Type-specific epitope locations revealed by X-ray crystallographic study of adenovirus type 5 hexon. Mol. Ther. 2000, 1, 18–30. [Google Scholar] [CrossRef] [PubMed]
  85. Youil, R.; Toner, T.J.; Su, Q.; Chen, M.; Tang, A.; Bett, A.J.; Casimiro, D. Hexon gene switch strategy for the generation of chimeric recombinant adenovirus. Hum. Gene Ther. 2002, 13, 311–320. [Google Scholar] [CrossRef] [PubMed]
  86. Abe, S.; Okuda, K.; Ura, T.; Kondo, A.; Yoshida, A.; Yoshizaki, S.; Mizuguchi, H.; Klinman, D.; Shimada, M. Adenovirus type 5 with modified hexons induces robust transgene-specific immune responses in mice with pre-existing immunity against adenovirus type 5. J. Gene Med. 2009, 11, 570–579. [Google Scholar] [CrossRef] [PubMed]
  87. Shiratsuchi, T.; Rai, U.; Krause, A.; Worgall, S.; Tsuji, M. Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice. J. Clin. Investig. 2010, 120, 3688–3701. [Google Scholar] [CrossRef] [PubMed]
  88. Gray, G.E.; Moodie, Z.; Metch, B.; Gilbert, P.B.; Bekker, L.G.; Churchyard, G.; Nchabeleng, M.; Mlisana, K.; Laher, F.; Roux, S.; et al. Recombinant adenovirus type 5 HIV gag/pol/nef vaccine in South Africa: Unblinded, long-term follow-up of the phase 2b HVTN 503/Phambili study. Lancet Infect. Dis. 2014, 14, 388–396. [Google Scholar] [CrossRef]
  89. Fitzgerald, D.W.; Janes, H.; Robertson, M.; Coombs, R.; Frank, I.; Gilbert, P.; Loufty, M.; Mehrotra, D.; Duerr, A.; Step Study Protocol Team. An Ad5-vectored HIV-1 vaccine elicits cell-mediated immunity but does not affect disease progression in HIV-1-infected male subjects: Results from a randomized placebo-controlled trial (the Step study). J. Infect. Dis. 2011, 203, 765–772. [Google Scholar] [CrossRef] [PubMed]
  90. Barouch, D.H.; Kik, S.V.; Weverling, G.J.; Dilan, R.; King, S.L.; Maxfield, L.F.; Clark, S.; Ng’ang’a, D.; Brandariz, K.L.; Abbink, P.; et al. International seroepidemiology of adenovirus serotypes 5, 26, 35, and 48 in pediatric and adult populations. Vaccine 2011, 29, 5203–5209. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  91. Ledgerwood, J.E.; DeZure, A.D.; Stanley, D.A.; Coates, E.E.; Novik, L.; Enama, M.E.; Berkowitz, N.M.; Hu, Z.; Joshi, G.; Ploquin, A.; et al. Chimpanzee Adenovirus Vector Ebola Vaccine. N. Engl. J. Med. 2017, 376, 928–938. [Google Scholar] [CrossRef] [PubMed]
  92. Vellinga, J.; van den Wollenberg, D.J.; van der Heijdt, S.; Rabelink, M.J.; Hoeben, R.C. The coiled-coil domain of the adenovirus type 5 protein IX is dispensable for capsid incorporation and thermostability. J. Virol. 2005, 79, 3206–3210. [Google Scholar] [CrossRef] [PubMed]
  93. Lutz, P.; Rosa-Calatrava, M.; Kedinger, C. The product of the adenovirus intermediate gene IX is a transcriptional activator. J. Virol. 1997, 71, 5102–5109. [Google Scholar] [PubMed]
  94. Rosa-Calatrava, M.; Puvion-Dutilleul, F.; Lutz, P.; Dreyer, D.; de The, H.; Chatton, B.; Kedinger, C. Adenovirus protein IX sequesters host-cell promyelocytic leukaemia protein and contributes to efficient viral proliferation. EMBO Rep. 2003, 4, 969–975. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Sargent, K.L.; Ng, P.; Evelegh, C.; Graham, F.L.; Parks, R.J. Development of a size-restricted pIX-deleted helper virus for amplification of helper-dependent adenovirus vectors. Gene Ther. 2004, 11, 504–511. [Google Scholar] [CrossRef] [PubMed]
  96. Colby, W.W.; Shenk, T. Adenovirus type 5 virions can be assembled in vivo in the absence of detectable polypeptide IX. J. Virol. 1981, 39, 977–980. [Google Scholar] [PubMed]
  97. Ghosh-Choudhury, G.; Haj-Ahmad, Y.; Graham, F.L. Protein IX, a minor component of the human adenovirus capsid, is essential for the packaging of full length genomes. EMBO J. 1987, 6, 1733–1739. [Google Scholar] [PubMed]
  98. Reddy, V.S.; Nemerow, G.R. Structures and organization of adenovirus cement proteins provide insights into the role of capsid maturation in virus entry and infection. Proc. Natl. Acad. Sci. USA 2014, 111, 11715–11720. [Google Scholar] [CrossRef] [PubMed]
  99. Akalu, A.; Liebermann, H.; Bauer, U.; Granzow, H.; Seidel, W. The subgenus-specific C-terminal region of protein IX is located on the surface of the adenovirus capsid. J. Virol. 1999, 73, 6182–6187. [Google Scholar] [PubMed]
  100. Vellinga, J.; Rabelink, M.J.; Cramer, S.J.; van den Wollenberg, D.J.; van der Meulen, H.; Leppard, K.N.; Fallaux, F.J.; Hoeben, R.C. Spacers increase the accessibility of peptide ligands linked to the carboxyl terminus of adenovirus minor capsid protein IX. J. Virol. 2004, 78, 3470–3479. [Google Scholar] [CrossRef] [PubMed]
  101. Campos, S.K.; Barry, M.A. Comparison of adenovirus fiber, protein IX, and hexon capsomeres as scaffolds for vector purification and cell targeting. Virology 2006, 349, 453–462. [Google Scholar] [CrossRef] [PubMed]
  102. Campos, S.K.; Parrott, M.B.; Barry, M.A. Avidin-based targeting and purification of a protein IX-modified, metabolically biotinylated adenoviral vector. Mol. Ther. 2004, 9, 942–954. [Google Scholar] [CrossRef] [PubMed]
  103. Le, L.P.; Everts, M.; Dmitriev, I.P.; Davydova, J.G.; Yamamoto, M.; Curiel, D.T. Fluorescently labeled adenovirus with pIX-EGFP for vector detection. Mol. Imaging 2004, 3, 105–116. [Google Scholar] [CrossRef] [PubMed]
  104. Bauer, U.; Flunker, G.; Bruss, K.; Kallwellis, K.; Liebermann, H.; Luettich, T.; Motz, M.; Seidel, W. Detection of antibodies against adenovirus protein IX, fiber, and hexon in human sera by immunoblot assay. J. Clin. Microbiol. 2005, 43, 4426–4433. [Google Scholar] [CrossRef] [PubMed]
  105. Nakai, M.; Komiya, K.; Murata, M.; Kimura, T.; Kanaoka, M.; Kanegae, Y.; Saito, I. Expression of pIX gene induced by transgene promoter: Possible cause of host immune response in first-generation adenoviral vectors. Hum. Gene Ther. 2007, 18, 925–936. [Google Scholar] [CrossRef] [PubMed]
  106. Cao, C.; Dong, X.; Wu, X.; Wen, B.; Ji, G.; Cheng, L.; Liu, H. Conserved fiber-penton base interaction revealed by nearly atomic resolution cryo-electron microscopy of the structure of adenovirus provides insight into receptor interaction. J. Virol. 2012, 86, 12322–12329. [Google Scholar] [CrossRef] [PubMed]
  107. Arnberg, N. Adenovirus receptors: Implications for tropism, treatment and targeting. Rev. Med. Virol. 2009, 19, 165–178. [Google Scholar] [CrossRef] [PubMed]
  108. Nicklin, S.A.; Wu, E.; Nemerow, G.R.; Baker, A.H. The influence of adenovirus fiber structure and function on vector development for gene therapy. Mol. Ther. 2005, 12, 384–393. [Google Scholar] [CrossRef] [PubMed]
  109. Law, L.K.; Davidson, B.L. What does it take to bind CAR? Mol. Ther. 2005, 12, 599–609. [Google Scholar] [CrossRef] [PubMed]
  110. Zubieta, C.; Schoehn, G.; Chroboczek, J.; Cusack, S. The structure of the human adenovirus 2 penton. Mol. Cell 2005, 17, 121–135. [Google Scholar] [CrossRef] [PubMed]
  111. Huang, S.; Kamata, T.; Takada, Y.; Ruggeri, Z.M.; Nemerow, G.R. Adenovirus interaction with distinct integrins mediates separate events in cell entry and gene delivery to hematopoietic cells. J. Virol. 1996, 70, 4502–4508. [Google Scholar] [PubMed]
  112. Roelvink, P.W.; Kovesdi, I.; Wickham, T.J. Comparative analysis of adenovirus fiber-cell interaction: Adenovirus type 2 (Ad2) and Ad9 utilize the same cellular fiber receptor but use different binding strategies for attachment. J. Virol. 1996, 70, 7614–7621. [Google Scholar] [PubMed]
  113. Michael, S.I.; Hong, J.S.; Curiel, D.T.; Engler, J.A. Addition of a short peptide ligand to the adenovirus fiber protein. Gene Ther. 1995, 2, 660–668. [Google Scholar] [PubMed]
  114. Krasnykh, V.N.; Mikheeva, G.V.; Douglas, J.T.; Curiel, D.T. Generation of recombinant adenovirus vectors with modified fibers for altering viral tropism. J. Virol. 1996, 70, 6839–6846. [Google Scholar] [PubMed]
  115. Gall, J.; Kass-Eisler, A.; Leinwand, L.; Falck-Pedersen, E. Adenovirus type 5 and 7 capsid chimera: Fiber replacement alters receptor tropism without affecting primary immune neutralization epitopes. J. Virol. 1996, 70, 2116–2123. [Google Scholar] [PubMed]
  116. Stevenson, S.C.; Rollence, M.; Marshall-Neff, J.; McClelland, A. Selective targeting of human cells by a chimeric adenovirus vector containing a modified fiber protein. J. Virol. 1997, 71, 4782–4790. [Google Scholar] [PubMed]
  117. Coughlan, L.; Alba, R.; Parker, A.L.; Bradshaw, A.C.; McNeish, I.A.; Nicklin, S.A.; Baker, A.H. Tropism-modification strategies for targeted gene delivery using adenoviral vectors. Viruses 2010, 2, 2290–2355. [Google Scholar] [CrossRef] [PubMed]
  118. Rea, D.; Havenga, M.J.; van den Assem, M.; Sutmuller, R.P.; Lemckert, A.; Hoeben, R.C.; Bout, A.; Melief, C.J.; Offringa, R. Highly efficient transduction of human monocyte-derived dendritic cells with subgroup B fiber-modified adenovirus vectors enhances transgene-encoded antigen presentation to cytotoxic T cells. J. Immunol. 2001, 166, 5236–5244. [Google Scholar] [CrossRef] [PubMed]
  119. Cheng, C.; Gall, J.G.; Kong, W.P.; Sheets, R.L.; Gomez, P.L.; King, C.R.; Nabel, G.J. Mechanism of ad5 vaccine immunity and toxicity: Fiber shaft targeting of dendritic cells. PLoS Pathog. 2007, 3, e25. [Google Scholar] [CrossRef] [PubMed]
  120. Someya, K.; Xin, K.Q.; Ami, Y.; Izumi, Y.; Mizuguchi, H.; Ohta, S.; Yamamoto, N.; Honda, M.; Okuda, K. Chimeric adenovirus type 5/35 vector encoding SIV gag and HIV env genes affords protective immunity against the simian/human immunodeficiency virus in monkeys. Virology 2007, 367, 390–397. [Google Scholar] [CrossRef] [PubMed]
  121. Nanda, A.; Lynch, D.M.; Goudsmit, J.; Lemckert, A.A.; Ewald, B.A.; Sumida, S.M.; Truitt, D.M.; Abbink, P.; Kishko, M.G.; Gorgone, D.A.; et al. Immunogenicity of recombinant fiber-chimeric adenovirus serotype 35 vector-based vaccines in mice and rhesus monkeys. J. Virol. 2005, 79, 14161–14168. [Google Scholar] [CrossRef] [PubMed]
  122. Xin, K.Q.; Sekimoto, Y.; Takahashi, T.; Mizuguchi, H.; Ichino, M.; Yoshida, A.; Okuda, K. Chimeric adenovirus 5/35 vector containing the clade C HIV gag gene induces a cross-reactive immune response against HIV. Vaccine 2007, 25, 3809–3815. [Google Scholar] [CrossRef] [PubMed]
  123. Kurachi, S.; Koizumi, N.; Sakurai, F.; Kawabata, K.; Sakurai, H.; Nakagawa, S.; Hayakawa, T.; Mizuguchi, H. Characterization of capsid-modified adenovirus vectors containing heterologous peptides in the fiber knob, protein IX, or hexon. Gene Ther. 2007, 14, 266–274. [Google Scholar] [CrossRef] [PubMed]
  124. Kurachi, S.; Tashiro, K.; Sakurai, F.; Sakurai, H.; Kawabata, K.; Yayama, K.; Okamoto, H.; Nakagawa, S.; Mizuguchi, H. Fiber-modified adenovirus vectors containing the TAT peptide derived from HIV-1 in the fiber knob have efficient gene transfer activity. Gene Ther. 2007, 14, 1160–1165. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Krasnykh, V.; Dmitriev, I.; Mikheeva, G.; Miller, C.R.; Belousova, N.; Curiel, D.T. Characterization of an adenovirus vector containing a heterologous peptide epitope in the HI loop of the fiber knob. J. Virol. 1998, 72, 1844–1852. [Google Scholar] [PubMed]
  126. Magnusson, M.K.; Henning, P.; Myhre, S.; Wikman, M.; Uil, T.G.; Friedman, M.; Andersson, K.M.; Hong, S.S.; Hoeben, R.C.; Habib, N.A.; et al. Adenovirus 5 vector genetically re-targeted by an Affibody molecule with specificity for tumor antigen HER2/neu. Cancer Gene Ther. 2007, 14, 468–479. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Uil, T.G.; Seki, T.; Dmitriev, I.; Kashentseva, E.; Douglas, J.T.; Rots, M.G.; Middeldorp, J.M.; Curiel, D.T. Generation of an adenoviral vector containing an addition of a heterologous ligand to the serotype 3 fiber knob. Cancer Gene Ther. 2003, 10, 121–124. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Wickham, T.J.; Carrion, M.E.; Kovesdi, I. Targeting of adenovirus penton base to new receptors through replacement of its RGD motif with other receptor-specific peptide motifs. Gene Ther. 1995, 2, 750–756. [Google Scholar] [PubMed]
  129. Einfeld, D.A.; Brough, D.E.; Roelvink, P.W.; Kovesdi, I.; Wickham, T.J. Construction of a pseudoreceptor that mediates transduction by adenoviruses expressing a ligand in fiber or penton base. J. Virol. 1999, 73, 9130–9136. [Google Scholar] [PubMed]
  130. Custers, J.H.H.V.; Vellinga, J.; Vujadinovic, M.; van der Helm, E. An Improved Adenovirus Based Malaria Vaccine Encoding and Displaying a Malaria Antigen. Patent WO/2017/125463, 27 July 2017. [Google Scholar]
  131. Vujadinovic, M.; Uil, T.G.; Oosterhuis, K.N.; Vellinga, J.N.; Custers, J. HPV VACCINES. Patent WO/2018/011196, 18 January 2018. [Google Scholar]
  132. Nieto, K.; Weghofer, M.; Sehr, P.; Ritter, M.; Sedlmeier, S.; Karanam, B.; Seitz, H.; Muller, M.; Kellner, M.; Horer, M.; et al. Development of AAVLP(HPV16/31L2) particles as broadly protective HPV vaccine candidate. PLoS ONE 2012, 7, e39741. [Google Scholar] [CrossRef] [PubMed]
  133. Skamel, C.; Ploss, M.; Bottcher, B.; Stehle, T.; Wallich, R.; Simon, M.M.; Nassal, M. Hepatitis B virus capsid-like particles can display the complete, dimeric outer surface protein C and stimulate production of protective antibody responses against Borrelia burgdorferi infection. J. Biol. Chem. 2006, 281, 17474–17481. [Google Scholar] [CrossRef] [PubMed]
  134. Schellenbacher, C.; Roden, R.; Kirnbauer, R. Chimeric L1-L2 virus-like particles as potential broad-spectrum human papillomavirus vaccines. J. Virol. 2009, 83, 10085–10095. [Google Scholar] [CrossRef] [PubMed]
  135. Moreno, N.; Mena, I.; Angulo, I.; Gomez, Y.; Crisci, E.; Montoya, M.; Caston, J.R.; Blanco, E.; Barcena, J. Rabbit hemorrhagic disease virus capsid, a versatile platform for foreign B-cell epitope display inducing protective humoral immune responses. Sci. Rep. 2016, 6, 31844. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Ye, X.; Ku, Z.; Liu, Q.; Wang, X.; Shi, J.; Zhang, Y.; Kong, L.; Cong, Y.; Huang, Z. Chimeric virus-like particle vaccines displaying conserved enterovirus 71 epitopes elicit protective neutralizing antibodies in mice through divergent mechanisms. J. Virol. 2014, 88, 72–81. [Google Scholar] [CrossRef] [PubMed]
  137. Gahery-Segard, H.; Farace, F.; Godfrin, D.; Gaston, J.; Lengagne, R.; Tursz, T.; Boulanger, P.; Guillet, J.G. Immune response to recombinant capsid proteins of adenovirus in humans: Antifiber and anti-penton base antibodies have a synergistic effect on neutralizing activity. J. Virol. 1998, 72, 2388–2397. [Google Scholar] [PubMed]
  138. Stallwood, Y.; Fisher, K.D.; Gallimore, P.H.; Mautner, V. Neutralisation of adenovirus infectivity by ascitic fluid from ovarian cancer patients. Gene Ther. 2000, 7, 637–643. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  139. Zabel, F.; Kundig, T.M.; Bachmann, M.F. Virus-induced humoral immunity: On how B cell responses are initiated. Curr. Opin. Virol. 2013, 3, 357–362. [Google Scholar] [CrossRef] [PubMed]
  140. Bachmann, M.F.; Zinkernagel, R.M. Neutralizing antiviral B cell responses. Annu. Rev. Immunol. 1997, 15, 235–270. [Google Scholar] [CrossRef] [PubMed]
  141. Scherer, J.; Vallee, R.B. Conformational changes in the adenovirus hexon subunit responsible for regulating cytoplasmic dynein recruitment. J. Virol. 2015, 89, 1013–1023. [Google Scholar] [CrossRef] [PubMed]
  142. Danthinne, X.; Imperiale, M.J. Production of first generation adenovirus vectors: A review. Gene Ther. 2000, 7, 1707–1714. [Google Scholar] [CrossRef] [PubMed]
Biomedicines 06 00081 g001 550
Figure 1. Adenoviral capsid. Schematic representation of an icosahedral AdV capsid organization with double-stranded DNA genome (black spiraling line). The outer capsid shell consists of three major capsid proteins hexon, fiber and penton base, and four minor capsid elements pIX, pIIIa and protein VI and VIII.
Figure 1. Adenoviral capsid. Schematic representation of an icosahedral AdV capsid organization with double-stranded DNA genome (black spiraling line). The outer capsid shell consists of three major capsid proteins hexon, fiber and penton base, and four minor capsid elements pIX, pIIIa and protein VI and VIII.
Biomedicines 06 00081 g001
Biomedicines 06 00081 g002 550
Figure 2. Schematic overview of capsid-display AdV vaccine vectors. (A) Replication-incompetent (ΔE1) AdV vectors encoding a transgene (green) in E1 (AdV.E1). (B) Hexon protein contains seven hyper variable regions (HVR1–7). The size in amino acids (aa) can vary per AdV type e.g., HAdV5 HVR1 44 aa (137–181), HVR2 6 aa (187–193), HVR3 7 aa (211–218), HVR4 13 aa (247–260), HVR5 15 aa (267–282), HVR6 11 aa (304–315) and HVR7 28 aa (421–449). Single epitope can be inserted in or substitute the native HVR sequence resulting in 720 copies per capsid. AdV. Hexon display vectors are generated (e.g., HVR1 orange) with or without a genetically encoded transgene in the E1 region (green). (C) pIX can display 240 copies of linear peptides or globular proteins (blue) by fusion of the antigen (blue) to the C-terminus (with or without a spacer, dotted line). AdV.pIX display vectors are generated with or without a genetically encoded transgene in E1 (green). (D) Epitopes can be inserted in fiber protein HI-, DE-, FG-, CD-, loops and C-terminus. For example, HI-loop (purple) AdV.Fiber display vectors contain 36 copies per capsid and can be generated with or without a genetically encoded transgene in E1 (green). (E) Penton Arg-Gly-Asp (RGD) loop (yellow) can be modified to present linear epitopes, resulting in 60 copies of epitopes per AdV capsid (AdV.Penton) with or without a without a genetically encoded transgene in E1 (green). Right and left Inverted terminal repeat (RITR-LITR).
Figure 2. Schematic overview of capsid-display AdV vaccine vectors. (A) Replication-incompetent (ΔE1) AdV vectors encoding a transgene (green) in E1 (AdV.E1). (B) Hexon protein contains seven hyper variable regions (HVR1–7). The size in amino acids (aa) can vary per AdV type e.g., HAdV5 HVR1 44 aa (137–181), HVR2 6 aa (187–193), HVR3 7 aa (211–218), HVR4 13 aa (247–260), HVR5 15 aa (267–282), HVR6 11 aa (304–315) and HVR7 28 aa (421–449). Single epitope can be inserted in or substitute the native HVR sequence resulting in 720 copies per capsid. AdV. Hexon display vectors are generated (e.g., HVR1 orange) with or without a genetically encoded transgene in the E1 region (green). (C) pIX can display 240 copies of linear peptides or globular proteins (blue) by fusion of the antigen (blue) to the C-terminus (with or without a spacer, dotted line). AdV.pIX display vectors are generated with or without a genetically encoded transgene in E1 (green). (D) Epitopes can be inserted in fiber protein HI-, DE-, FG-, CD-, loops and C-terminus. For example, HI-loop (purple) AdV.Fiber display vectors contain 36 copies per capsid and can be generated with or without a genetically encoded transgene in E1 (green). (E) Penton Arg-Gly-Asp (RGD) loop (yellow) can be modified to present linear epitopes, resulting in 60 copies of epitopes per AdV capsid (AdV.Penton) with or without a without a genetically encoded transgene in E1 (green). Right and left Inverted terminal repeat (RITR-LITR).
Biomedicines 06 00081 g002
Table
Table 1. AdV-display vectors.
Table 1. AdV-display vectors.
AdV LocationVectorDisease and Antigen/Epitope (Size aa)Other ModificationsReference
Transgene in E1Capsid
Hexon HVR1HAdV5Polio type 3 (8 aa)NoNo[56]
Malaria Circumsporozoite protein (CSP) (20, 24 aa) and (12 aa)NoNo[57,58,59]
HIVgp120 (10, 21, 24, 26 aa) and HIV gp41 and His6 (7, 6 aa)YesYes[60,61]
Chagas disease Trypanosoma cruzi gp83 (24 aa)NoNo[62]
Human papillomavirus (HPV) HPV16 L2 protein (29 aa)NoYes[63]
HAdV3Enterovirus VP1 SP70 (15 aa) and Enterovirus VP1 SP70 and SP55 (15 aa)YesYes[64,65]
SAdV25 (AdC68)Influenza A M2e and NP antigen (13 aa)YesYes[66]
Coxsackievirus and Enterovirus VP1 (6, 15 aa)YesYes[67]
Hexon HVR2HAdV5HIV gp41 and Gag protein (39 aa)YesNo[68]
Hexon HVR5HAdV5Anthrax Bacillus anthracis
Protective antigen (PA) (16, 36, 66,143, 245 aa (eGFP))		NoNo[69]
Model antigen RGD motif + His-linker (45, 55, 65, 75, 85, 95 aa)YesYes[70]
Pseudomonas aeruginosa outer membrane protein F (OprF) (14 aa)YesYes[71,72]
pIX C-terminusHAdV5Plague Yersinia pestis (15, 37 aa)YesNo[73]
Ovalbumin (Ova) (43 aa)NoYes[74]
HAdV5 and HAdV48Chagas-disease vaccine ASP2 and gp83 (26, 24 aa) YesNo[75]
HAdV5HIV gp120 (67 aa)NoYes[60]
Friend Murine Leukemia Virus gp70, Gag and Ova (22, 43, 60, 70, 92) HAdV5/HAdV5.F35YesYes [76]
HAdV35Malaria P. falciparum Circumsprozoite protein (CSP) (17, 20, 40 aa)YesNo[77]
Human papillomavirus (HPV) HPV6, 11, 16, 18, 31, 45, 52/58 L2 protein (93 aa)NoNo[78]
Fiber Knob-loopHAdV5Influenza A HA (9 aa)YesYes[79]
Ovalbumin (20, 22 aa)YesYes[80]
Pseudomonas aeruginosa (14 aa)YesYes[81]

Share and Cite

MDPI and ACS Style

Vujadinovic, M.; Vellinga, J. Progress in Adenoviral Capsid-Display Vaccines. Biomedicines 2018, 6, 81. https://doi.org/10.3390/biomedicines6030081

AMA Style

Vujadinovic M, Vellinga J. Progress in Adenoviral Capsid-Display Vaccines. Biomedicines. 2018; 6(3):81. https://doi.org/10.3390/biomedicines6030081

Chicago/Turabian Style

Vujadinovic, Marija, and Jort Vellinga. 2018. "Progress in Adenoviral Capsid-Display Vaccines" Biomedicines 6, no. 3: 81. https://doi.org/10.3390/biomedicines6030081

APA Style

Vujadinovic, M., & Vellinga, J. (2018). Progress in Adenoviral Capsid-Display Vaccines. Biomedicines, 6(3), 81. https://doi.org/10.3390/biomedicines6030081

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop