Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice

Shiratsuchi, Takayuki; Rai, Urvashi; Krause, Anja; Worgall, Stefan; Tsuji, Moriya

doi:10.1172/jci39812

Cited by 49 publications

(84 citation statements)

References 30 publications

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“…Our data contrast with two previous studies that reported substantial evasion of Ad5 immunity by Ad5 vectors in which single HVRs (HVR1, HVR5) were mutated (1,15). In our studies, swapping just HVR1 (Fig.…”

contrasting

confidence: 99%

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Adenovirus Serotype 5-Specific Neutralizing Antibodies Target Multiple Hexon Hypervariable Regions

Bradley

Maxfield

Lynch

et al. 2012

J Virol

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The immunogenicity of adenovirus serotype 5 (Ad5) vectors has been shown to be suppressed by neutralizing antibodies (NAbs) directed primarily against the hexon hypervariable regions (HVRs). We previously reported that replacing all seven HVRs with those from the rare serotype virus Ad48 resulted in a chimeric Ad5HVR48(1-7) vector that largely evaded preexisting Ad5 immunity in mice and rhesus monkeys. In this study, we evaluated the extent to which Ad5-specific NAbs are directed against various HVRs. We constructed partial HVR-chimeric Ad5 vectors with only a subset of HVRs exchanged, and we utilized these vectors in both NAb assays and murine immunogenicity studies with and without baseline Ad5 immunity. Our results demonstrate that Ad5-specific NAbs target multiple HVRs, suggesting that replacing all HVRs is required to optimize evasion of anti-Ad5 immunity. These data have important implications for the development of novel vectors for both vaccines and gene therapy.

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contrasting

confidence: 99%

“…However, the relative importances of the seven individual HVRs as NAb epitopes remain incompletely understood, and recent studies have suggested that Ad5 NAb responses may actually be focused primarily on one specific HVR, such as HVR1 or HVR5 (1,15). In this study, we characterized the contribution of individual hexon HVRs as Ad5 NAb epitopes.…”

mentioning

confidence: 97%

Adenovirus Serotype 5-Specific Neutralizing Antibodies Target Multiple Hexon Hypervariable Regions

Bradley

Maxfield

Lynch

et al. 2012

J Virol

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“…Incorporation of identical or distinct epitopes in multiple hexon HVRs or multiple capsid proteins is possible and may enhance the magnitude or breadth of an antibody response to capsid display recombinants. We and others have demonstrated induction of robust T-cell responses against antigens delivered by live adenovirus recombinants that express whole proteins as transgenes (17,18,36). Recombinants that both contain a transgene and display a relevant epitope on the capsid therefore might effectively induce both humoral and cellular immunity.…”

Section: Discussionmentioning

confidence: 99%

“…Adenoviruses that display exogenous epitopes on the surfaces of their capsids (capsid display recombinants) are potently immunogenic in mice (10)(11)(12)17). Capsid display recombinants that expressed either the central repeat B-cell epitope (NANP) 5 or a combined B-and T-cell epitope NANPNVDP(NANP) 4 induced high-titer P. falciparum CSP antibodies, and serum from (NANP) 5 -immunized mice (the only ones examined) neutralized sporozoites in an in vitro assay (11).…”

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confidence: 99%

A Replicating Adenovirus Capsid Display Recombinant Elicits Antibodies against Plasmodium falciparum Sporozoites in Aotus nancymaae Monkeys

et al. 2015

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bDecades of success with live adenovirus vaccines suggest that replication-competent recombinant adenoviruses (rAds) could serve as effective vectors for immunization against other pathogens. To explore the potential of a live rAd vaccine against malaria, we prepared a viable adenovirus 5 (Ad5) recombinant that displays a B-cell epitope from the circumsporozoite protein (CSP) of Plasmodium falciparum on the virion surface. The recombinant induced P. falciparum sporozoite-neutralizing antibodies in mice. Human adenoviruses do not replicate in mice. Therefore, to examine immunogenicity in a system in which, as in humans, the recombinant replicates, we constructed a similar recombinant in an adenovirus mutant that replicates in monkey cells and immunized four Aotus nancymaae monkeys. The recombinant replicated in the monkeys after intratracheal instillation, the first demonstration of replication of human adenoviruses in New World monkeys. Immunization elicited antibodies both to the Plasmodium epitope and the Ad5 vector. Antibodies from all four monkeys recognized CSP on intact parasites, and plasma from one monkey neutralized sporozoites in vitro and conferred partial protection against P. falciparum sporozoite infection after passive transfer to mice. Prior enteric inoculation of two animals with antigenically wild-type adenovirus primed a response to the subsequent intratracheal inoculation, suggesting a route to optimizing performance. A vaccine is not yet available against P. falciparum, which induces the deadliest form of malaria and kills approximately one million children each year. The live capsid display recombinant described here may constitute an early step in a critically needed novel approach to malaria immunization.

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“…Substitution of Ad5 HVRs 7, 8, and 9 with Ad43 HVRs had minimal impact on the immune avoidance phenotype and did not reduce vector yields in complementing cells. Earlier published studies showed that Ad5 vectors with modifications to only HVR1 (63) or HVR5 (64) avoided Ad5 NAb in vitro and could induce transgene-specific immune responses in animals previously exposed to Ad5. However, more recent work indicates that Ad5-, Ad3-, and Ad7-specific NAb target multiple HVRs (65,66).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Suppressor Mutation That Improves the Yields of Hexon-Modified Adenovirus Vectors

Bruder

Chen

Семенова

et al. 2013

J Virol

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We have generated hexon-modified adenovirus serotype 5 (Ad5) vectors that are not neutralized by Ad5-specific neutralizing antibodies in mice. These vectors are attractive for the advancement of vaccine products because of their potential for inducing robust antigen-specific immune responses in people with prior exposure to Ad5. However, hexon-modified Ad5 vectors displayed an approximate 10-fold growth defect in complementing cells, making potential vaccine costs unacceptably high. Replacing hypervariable regions (HVRs) 1, 2, 4, and 5 with the equivalent HVRs from Ad43 was sufficient to avoid Ad5 preexisting immunity and retain full vaccine potential. However, the resulting vector displayed the same growth defect as the hexon-modified vector carrying all 9 HVRs from Ad43. The growth defect is likely due to a defect in capsid assembly, since DNA replication and late protein accumulation were normal in these vectors. We determined that the hexon-modified vectors have a 32°C cold-sensitive phenotype and selected revertants that restored vector productivity. Genome sequencing identified a single base change resulting in a threonine-to-methionine amino acid substitution at the position equivalent to residue 342 of the wild-type protein. This mutation has a suppressor phenotype (SP), since cloning it into our Ad5 vector containing all nine hypervariable regions from Ad43, Ad5.H(43m-43), increased yields over the version without the SP mutation. This growth improvement was also shown for an Ad5-based hexon-modified vector that carried the hexon hypervariable regions of Ad48, indicating that the SP mutation may have broad applicability for improving the productivity of different hexon-modified vectors.A denovirus vectors are considered a leading viral vector platform for vaccines because of their robust immunogenicity and manufacturing feasibility. The most potent adenovirus vectors for use as vaccines are based on adenovirus serotype 5 (Ad5) (1-6). Ad5 vectors can be grown to very high yields in bioreactors and can be purified efficiently with reasonable cost-of-goods estimates for vaccines. Adenovirus-based vectors are capable of generating robust and protective T cell and antibody responses in animal models (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), and clinical data conclusively show that Ad5 vectors can induce potent CD8 ϩ and CD4 ϩ T cell and antibody responses in vaccinated volunteers (18)(19)(20)(21)(22)(23)(24)(25). Most encouragingly, the protective capacity of a DNA prime-Ad5 boost regimen expressing two malaria antigens demonstrated sterile protection from malaria in 27% of test subjects (26). However, the high prevalence of Ad5-specific neutralizing antibodies (NAb) in human populations, especially in sub-Saharan Africa, has the potential to limit the effectiveness of Ad5-based vaccines (23,(27)(28)(29)(30).Hexon is the most abundant adenoviral structural protein, and studies show that it is the major target for NAb in vivo (23,31,32). These NAbs target the nine hypervariable regions that form the exposed ...

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Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice

Cited by 49 publications

References 30 publications

Adenovirus Serotype 5-Specific Neutralizing Antibodies Target Multiple Hexon Hypervariable Regions

Adenovirus Serotype 5-Specific Neutralizing Antibodies Target Multiple Hexon Hypervariable Regions

A Replicating Adenovirus Capsid Display Recombinant Elicits Antibodies against Plasmodium falciparum Sporozoites in Aotus nancymaae Monkeys

Identification of a Suppressor Mutation That Improves the Yields of Hexon-Modified Adenovirus Vectors

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