Comparative Analysis of Simian Immunodeficiency Virus Gag-Specific Effector and Memory CD8
            <sup>+</sup>
            T Cells Induced by Different Adenovirus Vectors

Tan, Wendy G.; Jin, Hyun Tak; West, Erin E.; Penaloza-MacMaster, Pablo; Wieland, Andreas; Zilliox, Michael J.; McElrath, M. Juliana; Barouch, Dan H.; Ahmed, Rafi

doi:10.1128/jvi.02055-12

Cited by 77 publications

(100 citation statements)

References 38 publications

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“…Our results are in accordance with previous studies that have shown that waiting a longer time between prime and boost enhances the secondary effector response (7,47,50). The 3-week interval required before boosting after a VREP prime is, however, substantially shorter than for adenovirus vectors, for which a minimum of 8 weeks is required after prime (47,50). In a flu vaccine clinical trial comparing different intervals between a DNA prime and monovalent inactivated influenza booster, the responses were optimized by waiting a minimum of 12 weeks before the booster was administered (51).…”

Section: Discussionsupporting

confidence: 83%

“…Moreover, waiting longer than 3 weeks between prime and boost did not increase the booster effect. Our results are in accordance with previous studies that have shown that waiting a longer time between prime and boost enhances the secondary effector response (7,47,50). The 3-week interval required before boosting after a VREP prime is, however, substantially shorter than for adenovirus vectors, for which a minimum of 8 weeks is required after prime (47,50).…”

Section: Discussionsupporting

confidence: 82%

“…Similarly, the live yellow fever virus and smallpox vaccines, two highly successful human vaccines, induce CD8 ϩ T cell responses that peak rapidly within 2 weeks and have contracted by 4 weeks after vaccination (45,46). This is in contrast to adenovirus 5 (Ad5), which induces a response peaking between days 15 and 25, depending on the specific dose (47,48). Also, T cells induced by a single immunization of Ad5 do not contract but rather remain at a high level and are of predominantly Te and Tem phenotypes (3,49).…”

Section: Discussionmentioning

confidence: 90%

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Kinetic and Phenotypic Analysis of CD8 ⁺ T Cell Responses after Priming with Alphavirus Replicons and Homologous or Heterologous Booster Immunizations

Knudsen

Ljungberg

Kakoulidou

et al. 2014

J Virol

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Alphavirus replicons are potent inducers of CD8؉ T cell responses and thus constitute an attractive vaccine vector platform for developing novel vaccines. However, the kinetics and memory phenotype of CD8 ؉ T cell responses induced by alphavirus replicons are not well characterized. Furthermore, little is known how priming with alphavirus replicons affects booster immune responses induced by other vaccine modalities. We demonstrate here that a single immunization with an alphavirus replicon, administered as viral particles or naked DNA, induced an antigen-specific CD8 ؉ T cell response that had a sharp peak, followed by a rapid contraction. Administering a homologous boost before contraction had occurred did not further increase the response. In contrast, boosting after contraction when CD8؉ IMPORTANCEAlphavirus replicons are promising vaccine candidates against a number of diseases and are by themselves developed as vaccines against, for example, Chikungunya virus infection. Replicons are also considered to be used for priming, followed by booster immunization using different vaccine modalities. In order to rationally design prime-boost immunization schedules with these vectors, characterization of the magnitude and phenotype of CD8 ؉ T cell responses induced by alphavirus replicons is needed. Here, we demonstrate how factors such as timing and dose affect the phenotypes of memory T cell populations induced by immunization with alphavirus replicons. These findings are important for designing future clinical trials with alphaviruses, since they can be used to tailor vaccination regimens in order to induce a CD8 ؉ T cell response that is optimal for control and/or clearance of a specific pathogen.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 90%

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Kinetic and Phenotypic Analysis of CD8 ⁺ T Cell Responses after Priming with Alphavirus Replicons and Homologous or Heterologous Booster Immunizations

Knudsen

Ljungberg

Kakoulidou

et al. 2014

J Virol

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“…Our study also demonstrated the importance of IL-2 signals in vaccineinduced CD4 T cell responses, implicating the potential of manipulating IL-2 signaling to drive favorable vaccine-induced CD4 T cell responses. Additionally, it will be interesting to examine CD4 T cell responses after immunization with alternative serotype Ad vectors in comparison to Ad5, as the vectors have different biological properties and have been shown to elicit distinct immune responses (30,31).…”

Section: Discussionmentioning

confidence: 99%

Adenovirus Serotype 5 Vaccination Results in Suboptimal CD4 T Helper 1 Responses in Mice

Lee

Hashimoto

et al. 2017

J Virol

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Adenovirus serotype 5 (Ad5) is one of the most widely used viral vectors and is known to generate potent T cell responses. While many previous studies have characterized Ad5-induced CD8 T cell responses, there is a relative lack of detailed studies that have analyzed CD4 T cells elicited by Ad5 vaccination. Here, we immunized mice with Ad5 vectors encoding lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) and examined GP-specific CD4 T cell responses elicited by Ad5 vectors and compared them to those induced by an acute LCMV infection. In contrast to LCMV infection, where balanced CD4 T helper 1 (Th1) and T follicular helper (Tfh) responses were induced, Ad5 immunization resulted in a significantly reduced frequency of Th1 cells. CD4 T cells elicited by Ad5 vectors expressed decreased levels of Th1 markers, such as Tim3, SLAM, T-bet, and Ly6C, had smaller amounts of cytotoxic molecules like granzyme B, and produced less interferon gamma than CD4 T cells induced by LCMV infection. This defective CD4 Th1 response appeared to be intrinsic for Ad5 vectors and not a reflection of comparing a nonreplicating vector to a live viral infection, since immunization with a DNA vector expressing LCMV-GP generated efficient CD4 Th1 responses. Analysis at early time points (day 3 or 4) after immunization with Ad5 vectors revealed a defect in the expression of CD25 (interleukin-2 [IL-2] receptor alpha chain) on Ad5-elicited CD4 T cells, and administration of exogenous IL-2 following Ad5 immunization partially restored CD4 Th1 responses. These results suggest that impairment of Th1 commitment after Ad5 immunization could be due to reduced IL-2-mediated signaling.IMPORTANCE During viral infection, generating balanced responses of Th1 and Tfh cells is important to induce effective cell-mediated responses and provide optimal help for antibody responses. In this study, to investigate vaccine-induced CD4 T cell responses, we characterized CD4 T cells after immunization with Ad5 vectors expressing LCMV-GP in mice. Ad5 vectors led to altered effector differentiation of LCMV GP-specific CD4 T cells compared to that during LCMV infection. CD4 T cells following Ad5 immunization exhibited impaired Th1 lineage commitment, generating significantly decreased Th1 responses than those induced by LCMV infection. Our results suggest that suboptimal IL-2 signaling possibly plays a role in reduced Th1 development following Ad5 immunization. KEYWORDS CD4 T cell responses, T helper 1 (Th1), T follicular helper (Tfh), adenovirus serotype 5, vaccination R ecombinant adenovirus (Ad) vectors are one of the most favorable vaccine platforms as they have certain potential advantages, such as strong immunogenicity, large transgene capacity, and good safety profile. Ad-based vaccine vectors can induce

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“…Recent HIV vaccine strategies have progressively focused on viral vector-based vaccines in order to induce potent cellular as well as humoral responses. Recombinant adenovirus-vectored (rAd-vectored) HIV vaccines have been extensively studied in preclinical (2) and clinical studies, both alone (3, 4) and in primeboost regimens preceded by DNA (5), demonstrating excellent immunogenicity. Following the disappointing outcome of the rAd5-vectored Step Study (3) and the more promising results obtained in the RV144 trial (6) with a canarypox-containing regimen, poxvirus vectors have seen a surge in interest over the past few years.…”

Section: Introductionmentioning

confidence: 99%

HIV-specific humoral responses benefit from stronger prime in phase Ib clinical trial

Bart¹,

Huang²,

Karuna³

et al. 2014

J. Clin. Invest.

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BACKGROUND. Vector prime-boost immunization strategies induce strong cellular and humoral immune responses. We examined the priming dose and administration order of heterologous vectors in HIV Vaccine Trials Network 078 (HVTN 078), a randomized, double-blind phase Ib clinical trial to evaluate the safety and immunogenicity of heterologous prime-boost regimens, with a New York vaccinia HIV clade B (NYVAC-B) vaccine and a recombinant adenovirus 5-vectored (rAd5-vectored) vaccine. METHODS.NYVAC-B included HIV-1 clade B Gag-Pol-Nef and gp120, while rAd5 included HIV-1 clade B Gag-Pol and clades A, B, and C gp140. Eighty Ad5-seronegative subjects were randomized to receive 2 × NYVAC-B followed by 1 × 10 10 PFU rAd5 (NYVAC/Ad5 hi ); 1 × 10 8 PFU rAd5 followed by 2 × NYVAC-B (Ad5 lo /NYVAC); 1 × 10 9 PFU rAd5 followed by 2 × NYVAC-B (Ad5 med /NYVAC); 1 × 10 10 PFU rAd5 followed by 2 × NYVAC-B (Ad5 hi /NYVAC); or placebo. Immune responses were assessed 2 weeks after the final vaccination. Intracellular cytokine staining measured T cells producing IFN-γ and/or IL-2; cross-clade and epitope-specific binding antibodies were determined; and neutralizing antibodies (nAbs) were assessed with 6 tier 1 viruses. RESULTS. CD4+ T cell response rates ranged from 42.9% to 93.3%. NYVAC/Ad5 hi response rates (P ≤ 0.01) and magnitudes (P ≤ 0.03) were significantly lower than those of other groups. CD8+ T cell response rates ranged from 65.5% to 85.7%. NYVAC/Ad5 hi magnitudes were significantly lower than those of other groups (P ≤ 0.04). IgG response rates to the group M consensus gp140 were 89.7% for NYVAC/Ad5 hi and 21.4%, 84.6%, and 100% for Ad5 lo /NYVAC, Ad5 med /NYVAC, and Ad5 hi /NYVAC, respectively, and were similar for other vaccine proteins. Overall nAb responses were low, but aggregate responses appeared stronger for Ad5 med /NYVAC and Ad5 hi /NYVAC than for NYVAC/Ad5 hi . CONCLUSIONS. rAd5 prime followed by NYVAC boost is superior to the reverse regimen for both vaccine-induced cellular and humoral immune responses. Higher Ad5 priming doses significantly increased binding and nAbs. These data provide a basis for optimizing the design of future clinical trials testing vector-based heterologous prime-boost strategies.TRIAL REGISTRATION. ClinicalTrials.gov NCT00961883.FUNDING. NIAID, NIH UM1AI068618, AI068635, AI068614, and AI069443.

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Comparative Analysis of Simian Immunodeficiency Virus Gag-Specific Effector and Memory CD8 ⁺ T Cells Induced by Different Adenovirus Vectors

Cited by 77 publications

References 38 publications

Kinetic and Phenotypic Analysis of CD8 ⁺ T Cell Responses after Priming with Alphavirus Replicons and Homologous or Heterologous Booster Immunizations

Kinetic and Phenotypic Analysis of CD8 ⁺ T Cell Responses after Priming with Alphavirus Replicons and Homologous or Heterologous Booster Immunizations

Adenovirus Serotype 5 Vaccination Results in Suboptimal CD4 T Helper 1 Responses in Mice

HIV-specific humoral responses benefit from stronger prime in phase Ib clinical trial

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Comparative Analysis of Simian Immunodeficiency Virus Gag-Specific Effector and Memory CD8 + T Cells Induced by Different Adenovirus Vectors

Cited by 77 publications

References 38 publications

Kinetic and Phenotypic Analysis of CD8 + T Cell Responses after Priming with Alphavirus Replicons and Homologous or Heterologous Booster Immunizations

Kinetic and Phenotypic Analysis of CD8 + T Cell Responses after Priming with Alphavirus Replicons and Homologous or Heterologous Booster Immunizations

Adenovirus Serotype 5 Vaccination Results in Suboptimal CD4 T Helper 1 Responses in Mice

HIV-specific humoral responses benefit from stronger prime in phase Ib clinical trial

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Product

Resources

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Comparative Analysis of Simian Immunodeficiency Virus Gag-Specific Effector and Memory CD8 ⁺ T Cells Induced by Different Adenovirus Vectors

Kinetic and Phenotypic Analysis of CD8 ⁺ T Cell Responses after Priming with Alphavirus Replicons and Homologous or Heterologous Booster Immunizations

Kinetic and Phenotypic Analysis of CD8 ⁺ T Cell Responses after Priming with Alphavirus Replicons and Homologous or Heterologous Booster Immunizations