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. 2018 Jan 23;14(7):1679–1685. doi: 10.1080/21645515.2017.1419108

Development of novel vaccine vectors: Chimpanzee adenoviral vectors

Jingao Guo a,†, Moumita Mondal a,b,†, Dongming Zhou a,✉
PMCID: PMC6067905  PMID: 29300685

ABSTRACT

Adenoviral vector has been employed as one of the most efficient means against infectious diseases and cancer. It can be genetically modified and armed with foreign antigens to elicit specific antibody responses and T cell responses in hosts as well as engineered to induce apoptosis in cancer cells. The chimpanzee adenovirus-based vector is one kind of novel vaccine carriers whose unique features and non-reactivity to pre-existing human adenovirus neutralizing antibodies makes it an outstanding candidate for vaccine research and development. Here, we review the different strategies for constructing chimpanzee adenoviral vectors and their applications in recent clinical trials and also discuss the oncolytic virotherapy and immunotherapy based on chimpanzee adenoviral vectors.

KEYWORDS: Adenovirus, cancer, infectious disease, vaccine, vector, viral vector

Introduction

Adenoviruses (Ads) are non-enveloped, icosahedral, double-stranded DNA viruses that can broadly infect vertebrates including humans and non-human primates. 1 Adenovirus was first discovered in 1953.2 Most efforts have previously focused on human Ad serotype 5 (AdHu5)-based vectors, which have been extensively studied in laboratories and clinical trials over the past decades.3 It was demonstrated that the AdHu5 vector can elicit potent antigen-specific immune responses in both preclinical and clinical studies.3-5 Although the AdHu5 vector was shown to be very efficient, AdHu5 infection is endemic in humans. In America, 40–60% of humans carry detectable neutralizing antibodies (NAs) against AdHu5 wild-type virus.6 The high prevalence of AdHu5 NAs within the human population reduces the efficiency of gene transfer by the vector and impairs the vaccine potency.7 Among the population of healthy adults in China, seroprevalence rates of AdHu5 are as high as 74.2%8 and this percentage is even higher in Africa and other Asian countries.9 NAs against AdHu5 strongly impair the B- and T-cell responses to the transgene product of the vaccine candidates.6

To overcome this problem, Ads isolated from multiple different species are tested for their ability to serve as potential vaccine vectors. Among them, Ads derived from chimpanzees were advanced to clinical trials owing to their many advantageous features. First, chimpanzee adenoviruses (AdCs) can be cultured in human cell lines such as human embryonic kidney 293 cells (HEK293), which are commonly used for the production of clinical material.10 In addition, AdCs have a low seroprevalence in the human population as they rarely circulate in humans. The amino acid sequences of their hexon hypervariable regions, which contain the majority of the neutralization determinants, are distinguished from common human serotypes of Ad (AdHus).11 AdCs can avoid significant cross-neutralization in sera directed against AdHus. NAs against AdCs are rare in sera among human populations in Europe and the United States, with prevalence rates from 0 to 4%. In contrast, the prevalence is up to 20% in human sera from developing countries, like sub-Saharan Africa.12 This difference might be attributable to the differences in lifestyles and interaction levels with wild animals.9,12 However, this rate is still significantly less than that of AdHu5.

Importantly, some AdCs can induce T- and B-cell immune responses comparable to those of commonly used human Ad serotypes like AdHu5,6,13-15 even in the presence of NAs against them.16 AdC vectors are attractive candidates as vaccine carriers because of the potency and longevity of the induced adaptive immunity, which has proved in relevant animal models.17 Although AdCs have their own advantages compared with AdHus, not all of them can be developed as vaccine vectors. In previous studies, researchers have isolated a large collection of simian Ads and classified them into the existing species of human Ads according to their capsid hexon gene10 (Table 1). These simian Ads as vaccine vectors were screened for immunological potency by dose-response in mice. Similar to the human Ads, AdCs displayed a wide range of immunogenicity. Some of the AdC vectors were able to induce T-cell responses at very low doses (1 × 106 to 3 × 106 virus particles), thus ranking in the same category as the clinically validated AdHu5 and AdHu610. Therefore, the high level of immunological potency of these AdC vectors is not a species-specific phenomenon.18,19 Because of these strong points, AdC vectors could be considered as an ideal candidate for clinic use. In this review, we briefly summarize the construction of AdC-based vectors as well as their applications in lab studies and clinical trials against infectious diseases or cancers.

Table 1.

Classification of chimpanzee adenoviruses.

Subgroup Chimpanzee adenovirus
B AdC8, AdC22, AdC30, AdC37
C AdC11#, AdC3#, AdC17#, AdC19#, AdC31#, AdC20#, AdC24#, Pan1#, Pan2#, Pan3#
E AdC16, AdC26, AdC82, AdC5, AdC7, AdC44, AdC38, AdC43, AdC63#, AdC147#, AdC73, AdC6#, AdC55#, AdC83#, AdC143, AdC144, AdC145, AdC10#, AdC28, AdC9#
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#

represents AdC with high immunological potency. The group C are the most potent and the group B are of low immunogenicity. The group E is divided in two categories: those with high immunological potency (#) and others with lower immunogenicity

Methods for generating chimpanzee Ad vectors

Prior to the application of AdCs in basic research or for clinic use, transforming them into vectors is a vital step. Different strategies have been used to construct recombinant Ad (rAd) vectors. Among these, homologous recombination is the most commonly used method, which can generate rAds in packaging cell lines or bacterial cells such as Escherichia coli. For homologous recombination based on mammalian cell lines, the gene of interest is cloned into a shuttle vector and then co-transfected with the Ad genome into HEK 293 cells20 or other cell lines21 that provide E1 in trans. Recombination between the shuttle vector and the Ad genome replaces the E1 or other target domains with the gene of interest.22 Though this approach has proven extremely useful, the low efficiency of homologous recombination and the need for several rounds of plaque purification requires considerable amounts of time to finish the whole viral production process. Additionally, the unpredictable nature of homologous recombination in mammalian cells has hampered the widespread use of Ad vector technology.23 Another method employs homologous recombination in E. coli, and the commercially available pAdEasy system is based on this method.24 The AdEasy system was shown to achieve a high efficiency of homologous recombination in a specific bacterial strain when combined with selectable antibiotic resistance markers. Using this combination strategy, the generation of rAd vectors can be simplified. However, this method requires a three-step transformation, different plasmid vectors and two kinds of E. coli strains, one of which is a nonconventional host bacterial strain.25-27 These special features make the procedure more complex, and the completion of the full protocol usually takes 4–5 weeks.23

One traditional method for making Ad vector is based on direct cloning of the Ad genome, which can eliminate the potentially contaminating infectious material from the original Ad genome and avoid homologous recombination. However, manipulation of the whole genome in vivo is challenging and inconvenient owing to the relatively large size of the Ad genome, which limits the application of this method. Zhou et al.27 developed a simple and efficient strategy based on improved direct cloning of the Ad genome. In this innovative method, by analyzing and taking advantage of suitable unique restriction sites, which are present in most Ad genomes, a portion of the genome rather than the whole genome can be easily manipulated. The genome can be assembled part by part into one plasmid. Two very rare restriction sites, I-CeuI and PI-SceI, are inserted into the E1-deleted domain, so that the foreign gene of interest can be cloned into the E1-deleted area of the Ad molecular clone. The virus can then be rescued by transfection into packaging cell lines with the linearized recombinant molecular clone.27 With this improved direct cloning method, the generation of new Ad molecular clones and new rAds can be achieved easily and quickly.27

In addition to these approaches, a novel method has been developed that has even higher efficiency. Moreover, nearly any Ad with a known genome sequence can be modified by this method.28 This method relies on isothermal assembly and is a seamless cloning method that provides direct assembly of multiple DNA fragments in a single isothermal reaction. It can be performed without the use of restriction sites, ligases, additional plasmid vectors, or infrequently used E. coli strains. In this sequence independent method, Ad genomes are divided into multiple fragments in an appropriate length randomly, between each adjacent fragments ∼40bp overlaps are designed, and under the function of a chemical enzyme mixture consisting of Taq DNA ligase, a mesophilic exonuclease, and a high-fidelity polymerase,29-31 generation of AdC vectors can be done rapidly and efficiently. In contrast to direct cloning, all fragments in isothermal assembly are amplified by PCR. Thus, the major problem with this method results from mutations that occur when amplifying or assembling fragments from an Ad genome. However, mutation rates can be substantially reduced by using a high-fidelity polymerase. Another point that should be considered in advance for this method is the selection of appropriate fragment lengths and proper overlapping sequences. Other possible issues and troubleshooting approaches were described in a previous study.28 Typically, any foreign genes of interest in which the size of the inserted expression cassette is less than 7.5 kb can be cloned into E1- and E3-deleted Ad vectors for generating recombinant viruses. In addition to cloning foreign genes of interest into the E1- or E3-deleted area, the Ad capsid is always used to incorporate antigen epitopes for display of antigens on the virus surface to elicit high immunity. A method termed as “antigen capsid-incorporation” based on homologous recombination is efficient in capsid modification of Ads and is used in Ad-based vaccine development.32-35

Chimpanzee Ad-based vaccines for infectious diseases

As described above, AdC has many ideal features as a vaccine vector compared to other vaccine vectors even the AdHu5 vector. Though clinical trials based on the AdHu5 vector are still being conducted, increasing numbers of pre-clinical or clinical trials (Table 2). have applied AdC vectors for vaccine development against various infectious diseases, such as Ebola, HIV, HCV, malaria, rabies, and SARS.36,37

Table 2.

Clinical trials based on chimpanzee adenoviral vectors.

Disease Phase stage Vaccine vector Antigen Safety Immune response Reference*
Ebola Phase I/Ib AdC3 GP of Zaire strain+ GP of Sudan strain Safe CD4+ and CD8+ T cell responses NCT0223186638
Phase I/II AdC3 GP of Zaire strain Safe CD4+ and CD8+ T cell responses NCT0228902739
Phase Ib AdC3 GP of Zaire strain Safe CD4+ and CD8+ T cell responses NCT0226710938
Phase I AdC3/MVA GP of Zaire strain+ GP of Sudan strain No published data No published data NCT02368119
Phase I/Ib GP of Zaire strain Safe CD4+ and CD8+ T cell responses NCT0224087541
/NCT0240891340
Phase Ib Safe CD4+ and CD8+ T cell responses NCT0248591241
Phase II AdC3/VSV GP of Zaire strain Safe B cell responses NCT0234440742
Malaria Phase I/II AdC63/MVA ME-TRAP Safe CD3+, CD4+ and CD8+ T cell responses NCT01658696 / NCT0109505543/ NCT0188360944
Phase I/II ChAdOx1 Malaria liver-stage dual antigen LS2 (LSA1 and LSAP2) fused with the transmembrane domain from shark invariant chain No published data No published data NCT03203421
HIV Phase I DNA/AdC63/ MVA HIVconsv, a T cell immunogen from conserved regions of HIV proteome
 Safe CD8+ T cell responses NCT01712425/ NCT0115131945
HCV Phase I AdC3/Ad6 HCV antigens (NS region) Safe CD4+ and CD8+ T cell responses NCT01070407 / NCT0109487346
Crohn Disease Phase I ChAdOx2 ahpC/gsd/p12/mpa No published data No published data NCT03027193
Respiratory Syncytial Virus (RSV) Phase I PanAd3/ MVA F (fusion protein), N (nucleocapsid protein) and M2–1 (matrix protein) Safe CD4+ and CD8+ T cell responses NCT0180592147
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*

ClinicalTrial.gov Identifier can be found at https://clinicaltrials.gov/

The first replication-defective AdC vector tested in humans was derived from AdC63, an AdC that belongs to group E and has a very low seroprevalence in many populations.11 It has been engineered to encode different antigens as vaccine candidates for different diseases (Table 2). In Phase I studies, AdC63 was proved to be safe and effective. In addition to AdC63, AdC3 has also been evaluated in a Phase I clinical trial among healthy volunteers. Its safety and immunogenicity were comparable to that of AdHu5, while its immune response can be boosted efficiently by heterologous boosting strategies.38

The pandemic of Ebola virus (EBOV) has posed serious threats to human health. For the prevention of EBOV infection, several AdC-based EBOV vaccines are being tested in clinical trials, one of which is based on AdC339. In a phase 1/2a study, a vaccine candidate termed as AdC3-EBO-Z was tested, in which glycoprotein (GP) from the Ebola Zaire strain was cloned into an AdC3 vector. In this trial, GP-specific IgG responses were elicited in 96% of participants in both the high-dose and low-dose groups, with no significant difference in antibody titer between these two groups. Regarding specific T-cell responses, 61% of the participants developed GP-specific CD4 T-cell responses in the low-dose group, whereas the percentage in the high-dose group was 57%. Additionally, 67% and 69% of participants in the low- and high-dose groups developed CD8 T-cell responses, respectively. Vaccine-induced memory T-cell responses showed the same trend and were distributed equally between CD4 and CD8 T-cells.39 In another clinical trial that involved boosting with a heterologous MVA vaccine, virus-specific antibody responses increased 12-fold in all 30 participants and GP-specific CD8+ T-cells responses increased 5-fold. After 6 months of vaccination, virus-specific antibody responses were significantly higher in the participants who had been boosted with MVA than in those primed with AdC3 only, although antibody responses in the group primed with AdC3 alone were still positive.41 Heterologous prime-boost with Ad6 and AdC3 vector-based HCV vaccines induced broad and sustained T-cell responses in humans.46

As malaria is one of the globally infectious and fatal diseases, a vaccine for malaria is urgently needed. In a phase 2a trial in which vaccine candidates involving AdC63- or MVA-expressing ME-TRAP were tested, the participants received a series of trials including vaccine injection and repeat controlled human malaria infection (CHMI) was performed. In this trial, 75%–82.4% of subjects were protected by different vaccination regimens. After repeat CHMI, 83.3%–87.5% participants remained protected. Both antibody responses and T-cell responses were induced in vaccinated subjects and contributed to the protection against malaria parasite infection.44 The prime-boost vaccine regimen demonstrated a significantly reduced risk of malaria infection.

As expanding numbers of AdC vectors enter clinical trials, the advantages of AdCs are becoming increasingly apparent, which should further broaden the use of AdC vectors in pre-clinic or clinic studies in the future.

Chimpanzee adenovirus for cancer therapy

Among all the anti-cancer viruses, Ad has been considered as the most promising one for cancer therapy as it shows huge success in some cases given its specificity to cancer cells and fewer safety concerns.48 The popularity of Ad in cancer therapy is mainly because it is naturally oncolytic and has been found to be safe in several human trials.49 Moreover, Ad can be easily produced in large quantities, is genetically stable, can be manipulated very easily, and has no record of integration into the host genome during treatment.50 ONYX-015 is the first reported oncolytic Ad.49 Later in 2005, the marketing of the genetically modified oncolytic AdH101 was also approved, which is based on AdHu551. Although AdHu5 is commonly used in cancer therapy studies, the major drawback of AdHu5 is that it can be easily affected by pre-existing neutralizing antibodies resulting from prior infection.51 Moreover, the AdHu5 hexon can be recognized by blood coagulation factor X (FX) in liver cells, resulting in excessive sequestration of AdHu5 in the liver. Because AdC is antigenically distinct from AdHu5, AdC-based vectors could be minimally neutralized by anti-AdHu5 immunity52 and thus might be the ideal vectors for oncolytic virotherapy. The first AdC-based oncolytic virus originated from AdC7, termed as AdC7-SP/E1A-ΔE3,53 in which the E1a promoter was replaced by the tumor specific survivin promoter (SP) and the E3 region was deleted. The major advantage of the AdC7 oncolytic virus is that the AdC7 hexon protein does not interact with FX receptors in liver cells,54 which overcomes the extensive liver sequestration issue of Ads. Further improvement of AdC7 oncolytic vectors can be accomplished by increasing their selectivity in targeting of cancer cells through genetic modification of the fiber protein55 or by inserting specific peptides into the hexon region.56 According to the report, AdC7-SP/E1A-ΔE3 showed significant anti-tumor effects in certain cancer cells as well as in tumor-bearing mice. Further investigation showed that AdC7-SP/E1A-ΔE3 induced cell death through apoptosis rather than by autophagy.53 In the treated cells, apoptosis occurred in a p53-independent manner and via the proapoptotic protein Bad-mediated mitochondrial pathway.53

Cetuximab (CTB), a murine-human chimeric anti-EGFR monoclonal antibody used to treat patients with metastatic colorectal cancer (mCRC), head and neck squamous cell carcinoma (HNSCC), and non-small-cell lung cancer (NSCLC), has remained a very expensive treatment option and also involves complicated treatment techniques.57 Recently, cheaper forms of cetuximab have been generated by using Ad vectors, AdC68 or AdHu5, that express the cetuximab monoclonal antibody gene.57 Single administration of both recombinant Ads effectively suppressed tumor growth in NCI-H508- or DiFi-inoculated nude mice. The plasma levels of CTB in Adc68-CTB treated mice were above 30 µg/mL, which was within the effective therapeutic limits of 3–30 µg/mL.58 Applying the same strategy, other effective monoclonal antibodies such as the PD-1 antibody, PD-L1 antibody, CTLA-4 antibody, etc. can be incorporated by AdCs and employed for efficient, low-cost clinical cancer treatment. Thus, anti-tumor therapeutic antibodies mediated by AdC might be considered as a novel strategy for cancer immunotherapy. The application of chimpanzee Ad vectors in cancer therapy is summarized in Table 3.

Table 3.

Chimpanzee adenoviral vectors in cancer research.

Adenovirus Vector Features Anti-tumor effects
AdC7 AdC7-SP/E1A-ΔE3 Replication-selective; Induces cell death through apoptosis via the pro-apoptotic protein BAD mediated mitochondrial pathway Showed significant anti-tumor effects in some certain cancer cells as well as in tumor-bearing mice
AdC68 AdC68-CTB Replication-defective; Expresses cetuximab that is an anti-EGFR monoclonal antibody against cancer Effectively suppressed tumor growth in NCI-H508 or DiFi- inoculated nude mice
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Further prospects and conclusions

AdCs' low seroprevalence, high capacity for loading foreign genes, and the ability to induce abundant immunoreactions, make them a competitive candidate for use as vaccine vectors. Different strategies have been developed for constructing Ad vectors; among them, methods of improved direct cloning of the Ad genome and isothermal assembly are the most efficient, reliable, and practical techniques, which promote the applications of AdC. When AdC is employed as a vaccine against infectious diseases, compared to prime only, heterologous prime-boost regimens combining different AdCs (or AdCs combined with other vectors) might be the best choice for raising higher immunity and improving protection efficacy. AdC-based oncolytic virotherapy or immunotherapy approaches have already showed promising results in laboratory studies and can be further improved and moved into clinic settings. Overall, it can be concluded that, although the use of AdC vectors has been promoted in the prevention and control of infectious diseases and cancer as well as for use as an efficient tool in basic research, the enormous potential of AdC vectors still needs to be further explored.

Funding Statement

This work was supported by grants from the National Natural Science Foundation (U1303203) and partly by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDPB030405).

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed

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