EV01: A phase I trial in healthy HIV negative volunteers to evaluate a clade C HIV vaccine, NYVAC-C undertaken by the EuroVacc Consortium

Bart, Pierre‐Alexandre; Goodall, Ruth; Barber, Tristan; Harari, Alexandre; Guimarães-Walker, A.; Khonkarly, Mona; Sheppard, Neil C.; Bangala, Yolanda; Frachette, Marie-Joelle; Wagner, Ralf; Liljeström, Peter; Kraehenbuhl, Jean–Pierre; Girard, Marc; Goudsmit, Jaap; Esteban, Mariano; Heeney, Jonathan L.; Sattentau, Quentin J.; McCormack, Sheena; Babiker, Abdel; Pantaleo, Giuseppe; Weber, Jonathan

doi:10.1016/j.vaccine.2008.03.083

Cited by 55 publications

(58 citation statements)

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“…While the order of vector administration had only minor effects on the magnitude of the IgG response, increasing priming doses of rAd5 led to significantly higher response rates of binding Env-specific IgG after the NYVAC-B boost for consensus A Env gp140 (P = 0.0013), consensus C Env gp140 (P < 0.0001), ConS gp140 (P < 0.0001), A244 gp120 (P = 0.0005), and p24 NYVAC group had 2 participants with erythema and/or induration of greater than 9 cm in diameter after receipt of the fourth vaccination. Overall, the reactogenicity profile was similar to that observed in prior studies of the NYVAC and rAd5 vaccines used in this study (11,12,21).…”

Section: Resultssupporting

confidence: 82%

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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Section: Resultssupporting

confidence: 82%

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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“…The specific T cell response was evaluated by measuring the percentage of IFN-g-producing CD8 T cells by flow cytometry as above or using the IFN-g ELISPOT assay as previously described (27). The functional avidity of the T cell responses was assessed by determining the peptide concentration capable of inducing half-maximal responses (EC 50 ).…”

Section: Functional Avidity Of T Cell Recognitionmentioning

confidence: 99%

Large TCR Diversity of Virus-Specific CD8 T Cells Provides the Mechanistic Basis for Massive TCR Renewal after Antigen Exposure

Miconnet

Marrau

Farina

et al. 2011

The Journal of Immunology

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Ex vivo analysis of virus-specific CD8 T cell populations by anchored PCR has shown that the CD8 TCR repertoire was less oligoclonal (seven to nine clonotypes per individual epitope) than previously thought. In the current study, TCR diversity was investigated by assessing both the overall TCR β-chain variable regions usage as well as the CDR3 regions in ex vivo-isolated CMV- and EBV-specific CD8 T cells from 27 healthy donors. The average number of clonotypes specific to most single viral epitopes comprised between 14 and 77. Changes in the CD8 TCR repertoire were also longitudinally assessed under conditions of HIV-1 chronic infection (i.e., in patients with suppressed virus replication and after treatment interruption and Ag re-exposure). The results showed that a large renewal (≤80%) of the TRB repertoire occurred after Ag re-exposure and was eventually associated with an increased T cell recognition functional avidity. These results demonstrate that the global CD8 TCR repertoire is much more diverse (≤9-fold) than previously estimated and provide the mechanistic basis for supporting massive repertoire renewal during chronic virus infection and Ag re-exposure.

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“…In particular, priming with DNA-vectored vaccines prior to the application of the viral vector, mostly by employing adenoviruses or poxviruses, has repeatedly been shown to considerably increase cellular and humoral immune responses compared to those obtained with the viral vector alone (8)(9)(10). In the context of the EuroVacc clinical trials EV01 and EV02 (11,12), we tested HIV clade C antigens (GagPolNef and gp120) delivered via the poxvirus New York vaccinia virus (NYVAC), with or without priming with a DNA encoding the same set of antigens. These vectors previously showed promising immunogenicity profiles in preclinical assays and protective efficacy in primates against simian-human immunodeficiency virus SHIV89.6 challenge (13,14).…”

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confidence: 99%

“…Specifically, the major optimization comprises modified antigens, mainly in regard to the weak Gag-specific responses observed in nonhuman primate (NHP) and clinical studies (EV01 to EV03) (11,12,15,19). For this purpose, the original GagPolNef antigen, consisting of a 160-kDa fusion protein with modifications introduced for increased safety (i.e., abrogated myristoylation, lack of IN, inactivation of PR, splitting of RT, and scrambling of Nef [25]), was refined further to allow for efficient production and release of virus-like particles and to better balance the relative expression of Gag and PolNef antigens.…”

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confidence: 99%

Potential To Streamline Heterologous DNA Prime and NYVAC/Protein Boost HIV Vaccine Regimens in Rhesus Macaques by Employing Improved Antigens

Asbach

Kliche

Köstler

et al. 2016

J Virol

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In a follow-up to the modest efficacy observed in the RV144 trial, researchers in the HIV vaccine field seek to substantiate and extend the results by evaluating other poxvirus vectors and combinations with DNA and protein vaccines. Earlier clinical trials (EuroVacc trials 01 to 03) evaluated the immunogenicity of HIV-1 clade C GagPolNef and gp120 antigens delivered via the poxviral vector NYVAC. These showed that a vaccination regimen including DNA-C priming prior to a NYVAC-C boost considerably enhanced vaccine-elicited immune responses compared to those with NYVAC-C alone. Moreover, responses were improved by using three as opposed to two DNA-C primes. In the present study, we assessed in nonhuman primates whether such vaccination regimens can be streamlined further by using fewer and accelerated immunizations and employing a novel generation of improved DNA-C and NYVAC-C vaccine candidates designed for higher expression levels and more balanced immune responses. Three different DNA-C prime/NYVAC-C؉ protein boost vaccination regimens were tested in rhesus macaques. All regimens elicited vigorous and well-balanced CD8 ؉ and CD4 ؉ T cell responses that were broad and polyfunctional. Very high IgG binding titers, substantial antibody-dependent cellular cytotoxicity (ADCC), and modest antibody-dependent cell-mediated virus inhibition (ADCVI), but very low neutralization activity, were measured after the final immunizations. Overall, immune responses elicited in all three groups were very similar and of greater magnitude, breadth, and quality than those of earlier EuroVacc vaccines. In conclusion, these findings indicate that vaccination schemes can be simplified by using improved antigens and regimens. This may offer a more practical and affordable means to elicit potentially protective immune responses upon vaccination, especially in resource-constrained settings. IMPORTANCEWithin the EuroVacc clinical trials, we previously assessed the immunogenicity of HIV clade C antigens delivered in a DNA prime/NYVAC boost regimen. The trials showed that the DNA prime crucially improved the responses, and three DNA primes with a NYVAC boost appeared to be optimal. Nevertheless, T cell responses were primarily directed toward Env, and humoral responses were modest. The aim of this study was to assess improved antigens for the capacity to elicit more potent and balanced responses in rhesus macaques, even with various simpler immunization regimens. Our results showed that the novel antigens in fact elicited larger numbers of T cells with a polyfunctional profile and a good Env-GagPolNef balance, as well as high-titer and Fc-functional antibody responses. Finally, comparison of the different schedules indicates that a simpler regimen of only two DNA primes and one NYVAC boost in combination with protein may be very efficient, thus showing that the novel antigens allow for easier immunization protocols.

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EV01: A phase I trial in healthy HIV negative volunteers to evaluate a clade C HIV vaccine, NYVAC-C undertaken by the EuroVacc Consortium

Cited by 55 publications

References 5 publications

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

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

Large TCR Diversity of Virus-Specific CD8 T Cells Provides the Mechanistic Basis for Massive TCR Renewal after Antigen Exposure

Potential To Streamline Heterologous DNA Prime and NYVAC/Protein Boost HIV Vaccine Regimens in Rhesus Macaques by Employing Improved Antigens

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