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

Bradley, Ritu R.; Maxfield, Lori F.; Lynch, Diana M.; Iampietro, M. Justin; Borducchi, Erica N.; Barouch, Dan H.

doi:10.1128/jvi.06165-11

Cited by 85 publications

(79 citation statements)

References 22 publications

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“…Previous studies indicated that epitopes recognized by serotype-specific NAbs may be exposed on the virion surface and reside within the seven HVRs of hexon proteins (1,17). Seven HVRs that reside within HAdV-3 and HAdV-7 hexon proteins were identified by alignment of the available human adenovirus hexon protein sequences (4).…”

Section: Analysis Of Potential Serotype-specific Nab Epitopes Formentioning

confidence: 99%

Serotype-Specific Neutralizing Antibody Epitopes of Human Adenovirus Type 3 (HAdV-3) and HAdV-7 Reside in Multiple Hexon Hypervariable Regions

Qiu

Tian

et al. 2012

J Virol

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bHuman adenovirus types 3 and 7 (HAdV-3 and HAdV-7) occur epidemically and contribute greatly to respiratory diseases, but there is no currently available licensed recombinant HAdV-3/HAdV-7 bivalent vaccine. Identification of serotype-specific neutralizing antibody (NAb) epitopes for HAdV-3 and HAdV-7 will be beneficial for development of recombinant HAdV-3/HAdV-7 bivalent vaccines. In this study, four NAb epitopes within hexon hypervariable regions (HVRs) were predicted for HAdV-3 and HAdV-7, respectively, by using bioinformatics. Eight hexon chimeric adenovirus vectors with the alternation of only one predicted neutralizing epitope were constructed. Further in vitro and in vivo neutralization assays indicated that E2 (residing in HVR2) and E3 (residing in HVR5) are NAb epitopes for HAdV-7, and E3 plays a more important role in generating NAb responses. Cross-neutralization assays indicated that all four predicted epitopes, R1 to R4, are NAb epitopes for HAdV-3, and R1 (residing in HVR1) plays the most important role in generating NAb responses. Humoral immune responses elicited by the recombinant rAdH7R1 (containing the R1 epitope) were significantly and durably suppressed by HAdV-3-specific NAbs. Surprisingly, the rAd⌬E3GFP-specific neutralizing epitope responses induced by rAdMHE3 (R3 replaced by E3) and rAdMHE4 (R4 replaced by E4) were weaker than those of rAdMHE1 (R1 replaced by E1) or rAdMHE2 (R2 relaced by E2) in vitro and in vivo. Furthermore, rAdMHE4 replicated more slowly in HEp-2 cells, and the final yield was about 10-fold lower than that of rAd⌬E3GFP. The current findings contribute not only to the development of new adenovirus vaccine candidates, but also to the construction of new gene delivery vectors.

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Section: Analysis Of Potential Serotype-specific Nab Epitopes Formentioning

confidence: 99%

Serotype-Specific Neutralizing Antibody Epitopes of Human Adenovirus Type 3 (HAdV-3) and HAdV-7 Reside in Multiple Hexon Hypervariable Regions

Qiu

Tian

et al. 2012

J Virol

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“…Both of these properties appear to be mediated primarily by the hexon hypervariable regions (HVRs) (8,(11)(12)(13)(14)(15)(16). HVRs are highly variable among Ad serotypes and represent the primary determinant of neutralization specificity (17)(18)(19)(20).…”

mentioning

confidence: 99%

“…These strategies include HVR chemical modifications, such as PEGylation, HVR sequence modification by poly-His sequence insertion, or replacement of HVRs with those from less prevalent Ad serotypes (12,(21)(22)(23)(24)(25)(26). Our laboratory has described an Ad5 vector with its surface HVRs replaced with those of Ad48, a chimeric vector referred to as Ad5HVR48 (19)(20)(21). This vector evades the majority of preexisting Ad5 neutralizing antibodies and has been evaluated as a human immunodeficiency virus (HIV) vaccine vector in mice, nonhuman primates, and humans in a recent phase I clinical trial (Integrated Preclinical/Clinical AIDS Vaccine Development program [IPCAVD] 002; D. H. Barouch, unpublished data) (19,21).…”

mentioning

confidence: 99%

Hexon Hypervariable Region-Modified Adenovirus Type 5 (Ad5) Vectors Display Reduced Hepatotoxicity but Induce T Lymphocyte Phenotypes Similar to Ad5 Vectors

Teigler

Penaloza-MacMaster

Obeng

et al. 2014

Clin Vaccine Immunol

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“…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). Ad5-based hexon-modified vectors carrying HVRs 1 to 3, HVR 4, or HVR 5 of Ad48 underperformed relative to an Ad5 vector containing all HVRs of Ad48, indicating that modification to multiple HVRs is necessary for full immune avoidance in vivo (65).…”

Section: Discussionmentioning

confidence: 99%

“…However, more recent work indicates that Ad5-, Ad3-, and Ad7-specific NAb target multiple HVRs (65,66). Ad5-based hexon-modified vectors carrying HVRs 1 to 3, HVR 4, or HVR 5 of Ad48 underperformed relative to an Ad5 vector containing all HVRs of Ad48, indicating that modification to multiple HVRs is necessary for full immune avoidance in vivo (65). Our results extend these findings and demonstrate that Ad5 HVRs 1, 2, 4, and 5, or a subset of these, contribute substantially to immune avoidance, whereas HVRs 7 to 9 do not, at least in BALB/c mice.…”

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

Cited by 85 publications

References 22 publications

Serotype-Specific Neutralizing Antibody Epitopes of Human Adenovirus Type 3 (HAdV-3) and HAdV-7 Reside in Multiple Hexon Hypervariable Regions

Serotype-Specific Neutralizing Antibody Epitopes of Human Adenovirus Type 3 (HAdV-3) and HAdV-7 Reside in Multiple Hexon Hypervariable Regions

Hexon Hypervariable Region-Modified Adenovirus Type 5 (Ad5) Vectors Display Reduced Hepatotoxicity but Induce T Lymphocyte Phenotypes Similar to Ad5 Vectors

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

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