-
Dan H Barouch,
Jinyan Liu,
Lauren Peter, Peter Abbink,
M Justin Iampietro,
Ann Cheung,
Galit Alter,
Amy Chung,
Anne-Sophie Dugast,
Nicole Frahm,
M Juliana McElrath,
Holger Wenschuh,
Ulf Reimer,
Michael S Seaman,
Maria G Pau,
Mo Weijtens,
Jaap Goudsmit,
Stephen R Walsh,
Raphael Dolin,
Lindsey R Baden
[show abstract]
[hide abstract]
ABSTRACT: Background. Adenovirus serotype 26 (Ad26) has been developed as a novel candidate vaccine vector for HIV-1 and other pathogens. The primary safety and immunogenicity data from IPCAVD 001, the first-in-human evaluation of a prototype Ad26 vector-based vaccine expressing clade A HIV-1 Env (Ad26.ENVA.01), is reported concurrently with this manuscript. Here we characterize in greater detail the humoral and cellular immune responses elicited by Ad26.ENVA.01 in humans.Methods. Samples from IPCAVD 001 were utilized for humoral and cellular immunogenicity assays.Results. We observed a dose-dependent expansion of the magnitude, breadth, and epitopic diversity of Env-specific binding antibody responses elicited by this vaccine. Antibody-dependent cell-mediated phagocytosis, virus inhibition, and degranulation functional activity was also observed. Env-specific cellular immune responses induced by the vaccine included multiple CD8+ and CD4+ T lymphocyte memory subpopulations and cytokine secretion phenotypes, although cellular immune breadth was limited. Baseline vector-specific T lymphocyte responses were common but did not impair Env-specific immune responses in this study.Conclusion. Ad26.ENVA.01 elicited a broad diversity of humoral and cellular immune responses in humans. These data support the further clinical development of Ad26 as a candidate vaccine vector.
The Journal of Infectious Diseases 11/2012; · 6.41 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The cellular receptor utilized by adenovirus serotype 26 (Ad26) has remained unclear. Here we show that Ad26 transduction is CD46-dependent and is efficiently blocked by anti-CD46 but not anti-CAR antibodies, demonstrating that Ad26 utilizes CD46 as a primary cellular receptor. Moreover, following Ad26 vaccination of rhesus monkeys, we did not observe sustained activation of peripheral or mucosal vector-specific CD4(+) T lymphocytes. These data contribute to our understanding of Ad26 as a candidate vaccine vector.
Journal of Virology 07/2012; 86(19):10862-5. · 5.40 Impact Factor
-
Dan H Barouch,
Jinyan Liu,
Hualin Li,
Lori F Maxfield, Peter Abbink,
Diana M Lynch,
M Justin Iampietro,
Adam SanMiguel,
Michael S Seaman,
Guido Ferrari, [......],
Maria G Pau,
Hanneke Schuitemaker,
Jerald C Sadoff,
Erik A Billings,
Mangala Rao,
Merlin L Robb,
Jerome H Kim,
Mary A Marovich,
Jaap Goudsmit,
Nelson L Michael
[show abstract]
[hide abstract]
ABSTRACT: Preclinical studies of human immunodeficiency virus type 1 (HIV-1) vaccine candidates have typically shown post-infection virological control, but protection against acquisition of infection has previously only been reported against neutralization-sensitive virus challenges. Here we demonstrate vaccine protection against acquisition of fully heterologous, neutralization-resistant simian immunodeficiency virus (SIV) challenges in rhesus monkeys. Adenovirus/poxvirus and adenovirus/adenovirus-vector-based vaccines expressing SIV(SME543) Gag, Pol and Env antigens resulted in an 80% or greater reduction in the per-exposure probability of infection against repetitive, intrarectal SIV(MAC251) challenges in rhesus monkeys. Protection against acquisition of infection showed distinct immunological correlates compared with post-infection virological control and required the inclusion of Env in the vaccine regimen. These data demonstrate the proof-of-concept that optimized HIV-1 vaccine candidates can block acquisition of stringent, heterologous, neutralization-resistant virus challenges in rhesus monkeys.
Nature 01/2012; 482(7383):89-93. · 36.28 Impact Factor
-
Dan H Barouch,
Sandra V Kik,
Gerrit J Weverling,
Rebecca Dilan,
Sharon L King,
Lori F Maxfield,
Sarah Clark,
David Ng'ang'a,
Kara L Brandariz, Peter Abbink, [......],
Jill Gilmour,
John Hural,
Susan P Buchbinder,
Michael S Seaman,
Raphael Dolin,
Lindsey R Baden,
Angela Carville,
Keith G Mansfield,
Maria G Pau,
Jaap Goudsmit
[show abstract]
[hide abstract]
ABSTRACT: Recombinant adenovirus serotype 5 (rAd5) vaccine vectors for HIV-1 and other pathogens have been shown to be limited by high titers of Ad5 neutralizing antibodies (NAbs) in the developing world. Alternative serotype rAd vectors have therefore been constructed. Here we report Ad5, Ad26, Ad35, and Ad48 NAb titers in 4381 individuals from North America, South America, sub-Saharan Africa, and Southeast Asia. As expected, Ad5 NAb titers were both frequent and high magnitude in sub-Saharan Africa and Southeast Asia. In contrast, Ad35 NAb titers proved infrequent and low in all regions studied, and Ad48 NAbs were rare in all regions except East Africa. Ad26 NAbs were moderately common in adults in sub-Saharan Africa and Southeast Asia, but Ad26 NAb titers proved markedly lower than Ad5 NAb titers in all regions, and these relatively low Ad26 NAb titers did not detectably suppress the immunogenicity of 4×10(10)vp of a rAd26-Gag/Pol/Env/Nef vaccine in rhesus monkeys. These data inform the clinical development of alternative serotype rAd vaccine vectors in the developing world.
Vaccine 05/2011; 29(32):5203-9. · 3.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Post hoc analysis of the phase 2b Step study evaluating a recombinant adenovirus serotype 5 (rAd5)-based HIV-1 vaccine candidate suggested a potential increased risk of HIV-1 acquisition in subjects who were baseline Ad5 seropositive and uncircumcised. These concerns had a profound impact on the HIV-1 vaccine development field, although the mechanism underlying this observation remains unknown. It has been hypothesized that rAd5 vaccination of baseline Ad5-seropositive individuals may have resulted in anamnestic, vector-specific CD4(+) T lymphocytes that could have trafficked to mucosal sites and served as increased targets for HIV-1 infection. Here we show that Ad5-specific CD4(+) T lymphocyte responses at mucosal sites following rAd5-Gag/Pol/Nef vaccination were comparable in rhesus monkeys with and without baseline Ad5 immunity. Moreover, the total cellular inflammatory infiltrates and the CD3(+), CD4(+), HLA-DR(+), Ki67(+), and langerin(+) cellular subpopulations in colorectal and foreskin mucosa were similar in both groups. Thus, no greater trafficking of Ad5-specific CD4(+) T lymphocytes to mucosal target sites was observed following rAd5 vaccination of rhesus monkeys with baseline Ad5 immunity. These findings from this nonhuman primate model provide evidence against the hypothesis that recruitment of vector-specific target cells to mucosal sites led to increased HIV-1 acquisition in Ad5-seropositive, uncircumcised vaccinees in the Step study.
Journal of Virology 10/2010; 84(19):9810-6. · 5.40 Impact Factor
-
Dan H Barouch,
Kara L O'Brien,
Nathaniel L Simmons,
Sharon L King, Peter Abbink,
Lori F Maxfield,
Ying-Hua Sun,
Annalena La Porte,
Ambryice M Riggs,
Diana M Lynch,
Sarah L Clark,
Katherine Backus,
James R Perry,
Michael S Seaman,
Angela Carville,
Keith G Mansfield,
James J Szinger,
Will Fischer,
Mark Muldoon,
Bette Korber
[show abstract]
[hide abstract]
ABSTRACT: The worldwide diversity of HIV-1 presents an unprecedented challenge for vaccine development. Antigens derived from natural HIV-1 sequences have elicited only a limited breadth of cellular immune responses in nonhuman primate studies and clinical trials to date. Polyvalent 'mosaic' antigens, in contrast, are designed to optimize cellular immunologic coverage of global HIV-1 sequence diversity. Here we show that mosaic HIV-1 Gag, Pol and Env antigens expressed by recombinant, replication-incompetent adenovirus serotype 26 vectors markedly augmented both the breadth and depth without compromising the magnitude of antigen-specific T lymphocyte responses as compared with consensus or natural sequence HIV-1 antigens in rhesus monkeys. Polyvalent mosaic antigens therefore represent a promising strategy to expand cellular immunologic vaccine coverage for genetically diverse pathogens such as HIV-1.
Nature medicine 02/2010; 16(3):319-23. · 27.14 Impact Factor
-
Dan H Barouch,
Jinyan Liu,
Diana M Lynch,
Kara L O'Brien,
Annalena La Porte,
Nathaniel L Simmons,
Ambryice M Riggs,
Sarah Clark, Peter Abbink,
David C Montefiori,
Gary Landucci,
Donald N Forthal,
Steven G Self,
Angela Carville,
Keith Mansfield,
Jaap Goudsmit
[show abstract]
[hide abstract]
ABSTRACT: Rare serotype and chimeric recombinant adenovirus (rAd) vectors that evade anti-Ad5 immunity are currently being evaluated as potential vaccine vectors for human immunodeficiency virus type 1 and other pathogens. We have recently reported that a heterologous rAd prime-boost regimen expressing simian immunodeficiency virus (SIV) Gag afforded durable partial immune control of an SIV challenge in rhesus monkeys. However, single-shot immunization may ultimately be preferable for global vaccine delivery. We therefore evaluated the immunogenicity and protective efficacy of a single immunization of chimeric rAd5 hexon hypervariable region 48 (rAd5HVR48) vectors expressing SIV Gag, Pol, Nef, and Env against a homologous SIV challenge in rhesus monkeys. Inclusion of Env resulted in improved control of peak and set point SIV RNA levels following challenge. In contrast, DNA vaccine priming did not further improve the protective efficacy of rAd5HVR48 vectors in this system.
Journal of Virology 07/2009; 83(18):9584-90. · 5.40 Impact Factor
-
Jinyan Liu,
Kara L O'Brien,
Diana M Lynch,
Nathaniel L Simmons,
Annalena La Porte,
Ambryice M Riggs, Peter Abbink,
Rory T Coffey,
Lauren E Grandpre,
Michael S Seaman,
Gary Landucci,
Donald N Forthal,
David C Montefiori,
Angela Carville,
Keith G Mansfield,
Menzo J Havenga,
Maria G Pau,
Jaap Goudsmit,
Dan H Barouch
[show abstract]
[hide abstract]
ABSTRACT: A recombinant adenovirus serotype 5 (rAd5) vector-based vaccine for HIV-1 has recently failed in a phase 2b efficacy study in humans. Consistent with these results, preclinical studies have demonstrated that rAd5 vectors expressing simian immunodeficiency virus (SIV) Gag failed to reduce peak or setpoint viral loads after SIV challenge of rhesus monkeys (Macaca mulatta) that lacked the protective MHC class I allele Mamu-A*01 (ref. 3). Here we show that an improved T-cell-based vaccine regimen using two serologically distinct adenovirus vectors afforded substantially improved protective efficacy in this challenge model. In particular, a heterologous rAd26 prime/rAd5 boost vaccine regimen expressing SIV Gag elicited cellular immune responses with augmented magnitude, breadth and polyfunctionality as compared with the homologous rAd5 regimen. After SIV(MAC251) challenge, monkeys vaccinated with the rAd26/rAd5 regimen showed a 1.4 log reduction of peak and a 2.4 log reduction of setpoint viral loads as well as decreased AIDS-related mortality as compared with control animals. These data demonstrate that durable partial immune control of a pathogenic SIV challenge for more than 500 days can be achieved by a T-cell-based vaccine in Mamu-A*01-negative rhesus monkeys in the absence of a homologous Env antigen. These findings have important implications for the development of next-generation T-cell-based vaccine candidates for HIV-1.
Nature 12/2008; 457(7225):87-91. · 36.28 Impact Factor
-
Jinyan Liu,
Bonnie A Ewald,
Diana M Lynch,
Matthew Denholtz, Peter Abbink,
Angelique A C Lemckert,
Angela Carville,
Keith G Mansfield,
Menzo J Havenga,
Jaap Goudsmit,
Dan H Barouch
[show abstract]
[hide abstract]
ABSTRACT: Recombinant adenovirus serotype 5 (rAd5) vaccine vectors for human immunodeficiency virus type 1 (HIV-1) and other pathogens have been shown to elicit antigen-specific cellular immune responses. Rare serotype rAd vectors have also been constructed to circumvent preexisting anti-Ad5 immunity and to facilitate the development of novel heterologous rAd prime-boost regimens. Here we show that rAd5, rAd26, and rAd48 vectors elicit qualitatively distinct phenotypes of cellular immune responses in rhesus monkeys and can be combined as potent heterologous prime-boost vaccine regimens. While rAd5-Gag induced primarily gamma interferon-positive (IFN-gamma(+)) and IFN-gamma(+)/tumor necrosis factor alpha(+) (TNF-alpha(+)) T-lymphocyte responses, rAd26-Gag and rAd48-Gag induced higher proportions of interleukin-2(+) (IL-2(+)) and polyfunctional IFN-gamma(+)/TNF-alpha(+)/IL-2(+) T-lymphocyte responses. Priming with the rare serotype rAd vectors proved remarkably effective for subsequent boosting with rAd5 vectors. These data demonstrate that the rare serotype rAd vectors elicited T-lymphocyte responses that were phenotypically distinct from those elicited by rAd5 vectors and suggest the functional relevance of polyfunctional CD8(+) and CD4(+) T-lymphocyte responses. Moreover, qualitative differences in cellular immune responses may prove critical in determining the overall potency of heterologous rAd prime-boost regimens.
Journal of Virology 06/2008; 82(10):4844-52. · 5.40 Impact Factor
-
Peter Abbink,
Angelique A C Lemckert,
Bonnie A Ewald,
Diana M Lynch,
Matthew Denholtz,
Shirley Smits,
Lennart Holterman,
Irma Damen,
Ronald Vogels,
Anna R Thorner,
Kara L O'Brien,
Angela Carville,
Keith G Mansfield,
Jaap Goudsmit,
Menzo J E Havenga,
Dan H Barouch
[show abstract]
[hide abstract]
ABSTRACT: Recombinant adenovirus serotype 5 (rAd5) vector-based vaccines are currently being developed for both human immunodeficiency virus type 1 and other pathogens. The potential limitations associated with rAd5 vectors, however, have led to the construction of novel rAd vectors derived from rare Ad serotypes. Several rare serotype rAd vectors have already been described, but a detailed comparison of multiple rAd vectors from subgroups B and D has not previously been reported. Such a comparison is critical for selecting optimal rAd vectors for advancement into clinical trials. Here we describe the construction of three novel rAd vector systems from Ad26, Ad48, and Ad50. We report comparative seroprevalence and immunogenicity studies involving rAd11, rAd35, and rAd50 vectors from subgroup B; rAd26, rAd48, and rAd49 vectors from subgroup D; and rAd5 vectors from subgroup C. All six rAd vectors from subgroups B and D exhibited low seroprevalence in a cohort of 200 individuals from sub-Saharan Africa, and they elicited Gag-specific cellular immune responses in mice both with and without preexisting anti-Ad5 immunity. The rAd vectors from subgroup D were also evaluated using rhesus monkeys and were shown to be immunogenic after a single injection. The rAd26 vectors proved the most immunogenic among the rare serotype rAd vectors studied, although all rare serotype rAd vectors were still less potent than rAd5 vectors in the absence of anti-Ad5 immunity. These studies substantially expand the portfolio of rare serotype rAd vectors that may prove useful as vaccine vectors for the developing world.
Journal of Virology 06/2007; 81(9):4654-63. · 5.40 Impact Factor
-
Anna R Thorner,
Ronald Vogels,
Jorn Kaspers,
Gerrit J Weverling,
Lennart Holterman,
Angelique A C Lemckert,
Athmanundh Dilraj,
Lisa M McNally,
Prakash M Jeena,
Soren Jepsen, Peter Abbink,
Anjali Nanda,
Patricia E Swanson,
Andrew T Bates,
Kara L O'Brien,
Menzo J E Havenga,
Jaap Goudsmit,
Dan H Barouch
[show abstract]
[hide abstract]
ABSTRACT: We assessed neutralizing antibody titers to adenovirus serotype 5 (Ad5) and six rare adenovirus serotypes, serotypes 11, 35, 50, 26, 48, and 49, in pediatric populations in sub-Saharan Africa. We observed a clear age dependence of Ad5-specific neutralizing antibody titers. These data will help to guide the development of Ad vector-based vaccines for human immunodeficiency virus type 1 and other pathogens.
Journal of Clinical Microbiology 11/2006; 44(10):3781-3. · 4.15 Impact Factor
-
Diane M Roberts,
Anjali Nanda,
Menzo J E Havenga, Peter Abbink,
Diana M Lynch,
Bonnie A Ewald,
Jinyan Liu,
Anna R Thorner,
Patricia E Swanson,
Darci A Gorgone,
Michelle A Lifton,
Angelique A C Lemckert,
Lennart Holterman,
Bing Chen,
Athmanundh Dilraj,
Angela Carville,
Keith G Mansfield,
Jaap Goudsmit,
Dan H Barouch
[show abstract]
[hide abstract]
ABSTRACT: A common viral immune evasion strategy involves mutating viral surface proteins in order to evade host neutralizing antibodies. Such immune evasion tactics have not previously been intentionally applied to the development of novel viral gene delivery vectors that overcome the critical problem of anti-vector immunity. Recombinant, replication-incompetent adenovirus serotype 5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 and other pathogens have proved highly immunogenic in preclinical studies but will probably be limited by the high prevalence of pre-existing anti-Ad5 immunity in human populations, particularly in the developing world. Here we show that rAd5 vectors can be engineered to circumvent anti-Ad5 immunity. We constructed novel chimaeric rAd5 vectors in which the seven short hypervariable regions (HVRs) on the surface of the Ad5 hexon protein were replaced with the corresponding HVRs from the rare adenovirus serotype Ad48. These HVR-chimaeric rAd5 vectors were produced at high titres and were stable through serial passages in vitro. HVR-chimaeric rAd5 vectors expressing simian immunodeficiency virus Gag proved comparably immunogenic to parental rAd5 vectors in naive mice and rhesus monkeys. In the presence of high levels of pre-existing anti-Ad5 immunity, the immunogenicity of HVR-chimaeric rAd5 vectors was not detectably suppressed, whereas the immunogenicity of parental rAd5 vectors was abrogated. These data demonstrate that functionally relevant Ad5-specific neutralizing antibodies are focused on epitopes located within the hexon HVRs. Moreover, these studies show that recombinant viral vectors can be engineered to circumvent pre-existing anti-vector immunity by removing key neutralizing epitopes on the surface of viral capsid proteins. Such chimaeric viral vectors may have important practical implications for vaccination and gene therapy.
Nature 06/2006; 441(7090):239-43. · 36.28 Impact Factor
-
Anjali Nanda,
Diana M Lynch,
Jaap Goudsmit,
Angelique A C Lemckert,
Bonnie A Ewald,
Shawn M Sumida,
Diana M Truitt, Peter Abbink,
Michael G Kishko,
Darci A Gorgone,
Michelle A Lifton,
Ling Shen,
Angela Carville,
Keith G Mansfield,
Menzo J E Havenga,
Dan H Barouch
[show abstract]
[hide abstract]
ABSTRACT: Preexisting immunity to adenovirus serotype 5 (Ad5) has been shown to suppress the immunogenicity of recombinant Ad5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 (HIV-1) in both preclinical studies and clinical trials. A potential solution to this problem is to utilize rAd vectors derived from rare Ad serotypes, such as Ad35. However, rAd35 vectors have appeared less immunogenic than rAd5 vectors in preclinical studies to date. In this study, we explore the hypothesis that the differences in immunogenicity between rAd5 and rAd35 vectors may be due in part to differences between the fiber proteins of these viruses. We constructed capsid chimeric rAd35 vectors containing the Ad5 fiber knob (rAd35k5) and compared the immunogenicities of rAd5, rAd35k5, and rAd35 vectors expressing simian immunodeficiency virus Gag and HIV-1 Env in mice and rhesus monkeys. In vitro studies demonstrated that rAd35k5 vectors utilized the Ad5 receptor CAR rather than the Ad35 receptor CD46. In vivo studies showed that rAd35k5 vectors were more immunogenic than rAd35 vectors in both mice and rhesus monkeys. These data suggest that the Ad5 fiber knob contributes substantially to the immunogenicity of rAd vectors. Moreover, these studies demonstrate that capsid chimeric rAd vectors can be constructed to combine beneficial immunologic and serologic properties of different Ad serotypes.
Journal of Virology 12/2005; 79(22):14161-8. · 5.40 Impact Factor
