Vaccination to Conserved Influenza Antigens in Mice Using a Novel Simian Adenovirus Vector, PanAd3, Derived from the Bonobo Pan paniscus

Vitelli, Alessandra; Quirion, Mary R.; Lo, Chia-Yun; Misplon, Julia A.; Grabowska, Agnieszka; Pierantoni, Angiolo; Ammendola, Virginia; Price, Graeme E.; Soboleski, Mark R.; Cortese, Riccardo; Colloca, Stefano; Nicosia, Alfredo; Epstein, Suzanne L.

doi:10.1371/journal.pone.0055435

Cited by 45 publications

(34 citation statements)

References 48 publications

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“…A major cause of the need for product-specific optimisation of adenovirus vector production processes is the fact that some transgenes have a marked impact upon the growth of adenovirus vectors [20]. We and others have previously reported that viruses carrying such 'toxic' transgenes can be rescued by incorporating 'tet operator' elements in the transgene promoter and growing the virus in cells such as HEK293 T-Rex (ThermoFisher) and Procell 92 which repress expression from such modified promoters [20,21,32,33]. Unfortunately however, such cell lines have not been widely accessible for GMP manufacture in suspension culture.…”

Section: Vectors Of Three Serotypes Carrying Three Antigen Transgenesmentioning

confidence: 99%

Simian adenovirus vector production for early-phase clinical trials: A simple method applicable to multiple serotypes and using entirely disposable product-contact components

Fedosyuk¹,

Merritt²,

Peralta-Álvarez³

et al. 2019

Vaccine

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a b s t r a c tA variety of Good Manufacturing Practice (GMP) compliant processes have been reported for production of non-replicating adenovirus vectors, but important challenges remain. Most clinical development of adenovirus vectors now uses simian adenoviruses or rare human serotypes, whereas reported manufacturing processes mainly use serotypes such as AdHu5 which are of questionable relevance for clinical vaccine development. Many clinically relevant vaccine transgenes interfere with adenovirus replication, whereas most reported process development uses selected antigens or even model transgenes such as fluorescent proteins which cause little such interference. Processes are typically developed for a single adenovirus serotype -transgene combination, requiring extensive further optimization for each new vaccine.There is a need for rapid production platforms for small GMP batches of non-replicating adenovirus vectors for early-phase vaccine trials, particularly in preparation for response to emerging pathogen outbreaks. Such platforms must be robust to variation in the transgene, and ideally also capable of producing adenoviruses of more than one serotype. It is also highly desirable for such processes to be readily implemented in new facilities using commercially available single-use materials, avoiding the need for development of bespoke tools or cleaning validation, and for them to be readily scalable for later-stage studies.Here we report the development of such a process, using single-use stirred-tank bioreactors, a transgene-repressing HEK293 cell -promoter combination, and fully single-use filtration and ion exchange components. We demonstrate applicability of the process to candidate vaccines against rabies, malaria and Rift Valley fever, each based on a different adenovirus serotype. We compare performance of a range of commercially available ion exchange media, including what we believe to be the first published use of a novel media for adenovirus purification (NatriFlo Ò HD-Q, Merck). We demonstrate the need for minimal process individualization for each vaccine, and that the product fulfils regulatory quality expectations. Cell-specific yields are at the upper end of those previously reported in the literature, and volumetric yields are in the range 1 Â 10 13 -5 Â 10 13 purified virus particles per litre of culture, such that a 2-4 L process is comfortably adequate to produce vaccine for early-phase trials. The process is readily transferable to any GMP facility with the capability for mammalian cell culture and aseptic filling of sterile products.

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Section: Vectors Of Three Serotypes Carrying Three Antigen Transgenesmentioning

confidence: 99%

Simian adenovirus vector production for early-phase clinical trials: A simple method applicable to multiple serotypes and using entirely disposable product-contact components

Fedosyuk¹,

Merritt²,

Peralta-Álvarez³

et al. 2019

Vaccine

View full text Add to dashboard Cite

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“…Moreover, a single immunization with ChAd68 induced long-lasting protection against rabies virus by the induction of neutralizing antibodies in nonhuman primates (47). The Ad vector PanAd3, which was isolated from bonobos and which was engineered to express an influenza A virus matrix 1 and nucleoprotein fusion antigen, provided significant protection against a lethal dose of a highly pathogenic challenge influenza virus in mice (48). The novel rhesus monkey adenovirus vectors described in the present study represent a new class of vaccine vectors with unique advantages and distinct biology.…”

Section: Figmentioning

confidence: 99%

Construction and Evaluation of Novel Rhesus Monkey Adenovirus Vaccine Vectors

Abbink

Maxfield

Ng’ang’a

et al. 2015

J Virol

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Adenovirus vectors are widely used as vaccine candidates for a variety of pathogens, including HIV-1. To date, human and chimpanzee adenoviruses have been explored in detail as vaccine vectors. The phylogeny of human and chimpanzee adenoviruses is overlapping, and preexisting humoral and cellular immunity to both are exhibited in human populations worldwide. More distantly related adenoviruses may therefore offer advantages as vaccine vectors. Here we describe the primary isolation and vectorization of three novel adenoviruses from rhesus monkeys. The seroprevalence of these novel rhesus monkey adenovirus vectors was extremely low in sub-Saharan Africa human populations, and these vectors proved to have immunogenicity comparable to that of human and chimpanzee adenovirus vaccine vectors in mice. These rhesus monkey adenoviruses phylogenetically clustered with the poorly described adenovirus species G and robustly stimulated innate immune responses. These novel adenoviruses represent a new class of candidate vaccine vectors. IMPORTANCEAlthough there have been substantial efforts in the development of vaccine vectors from human and chimpanzee adenoviruses, far less is known about rhesus monkey adenoviruses. In this report, we describe the isolation and vectorization of three novel rhesus monkey adenoviruses. These vectors exhibit virologic and immunologic characteristics that make them attractive as potential candidate vaccine vectors for both HIV-1 and other pathogens. R ecombinant adenoviruses (Ads) are currently being explored as candidate vaccine vectors for multiple pathogens (1-6), as a result of their safety profile, manufacturability, and ability to induce broad and strong immune responses (7-16). Multiple human and chimpanzee adenovirus vectors have been developed to date (8,9,(11)(12)(13). The majority of these adenovirus vectors are from species B, C, D, and E. Adenovirus vectors from avian, bovine, and other species have also been constructed, but their different genomic structures may necessitate the development of a novel manufacturing platform for clinical development (17, 18). Old World monkey adenoviruses have been hypothesized to be distinct from both human and chimpanzee adenoviruses and may offer unique advantages, such as the ability to more efficiently bypass preexisting immunity to human adenoviruses (12,(19)(20)(21)(22)(23)(24), while maintaining the genomic structure and growth properties of human adenoviruses.We isolated simian adenoviruses from fecal samples from rhesus monkeys (Macaca mulatta) that were positive for adenoviruses by metagenomics sequencing (25). We performed whole-genome sequencing of these novel adenoviruses and determined their phylogeny in comparison with that of other human and simian adenoviruses. The basic genetic structure of these novel rhesus monkey adenoviruses proved similar to that of human adenoviruses (7,16,26). We vectorized three rhesus monkey adenoviruses and then assessed humans in sub-Saharan Africa for seroprevalence of these adenoviruses and ...

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“…In addition to the use of rare species human Ads, the issue of high seroprevalence of NAbs to Ad5 in humans can be circumvented by using non‐human Ads, such as those derived from non‐human primates [50,51]. Although there is a high degree of phylogenetic relatedness between Ads derived from different primate hosts,[52] sequence homology within the hypervariable regions (HVRs) of the hexon, the major antigenic target of NAb to Ads[39,53] is more divergent,[54] allowing them to evade pre‐existing immunity in humans.…”

Section: Adenoviral Vectorsmentioning

confidence: 99%

Adenoviral vectors as novel vaccines for influenza

Coughlan

Mullarkey

Gilbert

2015

Journal of Pharmacy and Pharmacology

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Objectives Influenza is a viral respiratory disease causing seasonal epidemics, with significant annual illness and mortality. Emerging viruses can pose a major pandemic threat if they acquire the capacity for sustained human-to-human transmission. Vaccination reduces influenza-associated mortality and is critical in minimising the burden on the healthcare system. However, current vaccines are not always effective in at-risk populations and fail to induce long-lasting protective immunity against a range of viruses. Key findings The development of 'universal' influenza vaccines, which induce heterosubtypic immunity capable of reducing disease severity, limiting viral shedding or protecting against influenza subtypes with pandemic potential, has gained interest in the research community. To date, approaches have focused on inducing immune responses to conserved epitopes within the stem of haemagglutinin, targeting the ectodomain of influenza M2e or by stimulating cellular immunity to conserved internal antigens, nucleoprotein or matrix protein 1. Summary Adenoviral vectors are potent inducers of T-cell and antibody responses and have demonstrated safety in clinical applications, making them an excellent choice of vector for delivery of vaccine antigens. In order to circumvent pre-existing immunity in humans, serotypes from non-human primates have recently been investigated. We will discuss the pre-clinical development of these novel vectors and their advancement to clinical trials.

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Vaccination to Conserved Influenza Antigens in Mice Using a Novel Simian Adenovirus Vector, PanAd3, Derived from the Bonobo Pan paniscus

Cited by 45 publications

References 48 publications

Simian adenovirus vector production for early-phase clinical trials: A simple method applicable to multiple serotypes and using entirely disposable product-contact components

Simian adenovirus vector production for early-phase clinical trials: A simple method applicable to multiple serotypes and using entirely disposable product-contact components

Construction and Evaluation of Novel Rhesus Monkey Adenovirus Vaccine Vectors

Adenoviral vectors as novel vaccines for influenza

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