EV02: A Phase I trial to compare the safety and immunogenicity of HIV DNA-C prime-NYVAC-C boost to NYVAC-C alone

McCormack, Sheena; Stöhr, Wolfgang; Barber, Tristan; Bart, Pierre‐Alexandre; Harari, Alexandre; Moog, Christiane; Ciuffreda, Donatella; Cellerai, Cristina; Cowen, Miranda; Gamboni, Romilda; Burnet, Séverine; Legg, Ken; Brodnicki, Elizabeth; Wolf, Hans; Wagner, Ralf; Heeney, Jonathan L.; Frachette, Marie-Joelle; Tartaglia, Jim; Babiker, Abdel; Pantaleo, Giuseppe; Weber, Jonathan

doi:10.1016/j.vaccine.2008.02.072

Cited by 92 publications

(97 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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“…Building on the experience from the EuroVacc clinical trials EV01 to EV03 (11,12,19), as well as parallel confirmatory immunogenicity studies performed with rhesus macaques (22), we set out to refine several parameters of our vaccine concept to further augment the strength and quality of the anti-HIV-1 immune response, with a special emphasis on enhancing T cell responses. Optimized antigens were assessed in different immunization schedules.…”

Section: Resultsmentioning

confidence: 99%

“…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%

“…The clinical trials demonstrated that the vaccine candidates were safe and well tolerated and that DNA priming dramatically improved the T cell responses elicited by NYVAC. Both the proportion of responders and the number of HIV-specific T cells, as measured by enzymelinked immunosorbent spot (ELISpot) analysis of gamma interferon (IFN-␥)-secreting cells, increased 2-to 4-fold (12,15). Other studies have shown even better augmentation (16).…”

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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%

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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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Vaccine-Induced HIV Seropositivity/Reactivity in Noninfected HIV Vaccine Recipients

Cooper

Metch

Dragavon

et al. 2010

JAMA

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Context Induction of protective anti-HIV immune responses is the goal of an HIV vaccine. However, this may cause a reactive result by routine HIV testing in the absence of HIV infection. Objective This study evaluated the frequency of vaccine-induced seropositivity/reactivity (VISP) in HIV vaccine trial participants. Design, Setting, and Participants A routine diagnostic HIV algorithm was used for participants who completed 25 phase 1 and two phase 2 vaccine trials from 2000–2010 conducted in the United States, South America, Thailand, and Africa. Main Outcome Measures Three common FDA-approved enzyme immunoassay (EIA) HIV antibody kits were used to determine VISP. VISP was defined as being reactive on ≥ 1 EIA test, HIV-1 negative by nucleic acid testing, and Western blot negative, indeterminate, or atypical positive (profile consistent with vaccine product). Results Among 2176 HIV uninfected participants who received a vaccine product, 908 (41.7%; 95% confidence interval [CI], 39.6–43.8%) had VISP, but the occurrence of VISP varied substantially across different HIV vaccine product types: 399 of 460 (86.7%; 95% CI, 83.3–89.7%) adenovirus 5 product recipients, 295 of 552 (53.4%; 95% CI, 49.2–57.7%) recipients of poxvirus alone or as a boost, and 35 of 555 (6.3%; 95% CI, 4.4–8.7%) of DNA alone product recipients developed VISP. Overall, the highest proportion of VISP (40.9%; 891 of 2176 tested) occurred with the HIV 1/2 (rDNA) EIA compared to the rLAV EIA (21.4%; 150 of 700 tested), HIV-1 Plus O Microelisa System (14.7%; 193 of 1309 tested), and HIV 1/2 Peptide and HIV 1/2 Plus O (8.8%; 189 of 2150 tested) kits. Only 17 (1.9%) of the 908 participants with VISP tested nonreactive using the HIV 1/2 (rDNA) kit. All recipients of a gp140 vaccine (n= 70) had VISP, with 94.3% tested reactive to all three EIA kits tested. Among 901 participants with VISP and a Western blot result, 92 (10.2%) had a positive Western blot (displaying an atypical pattern consistent with vaccine product) and 592 (65.7%) had an indeterminate result. Only 8 participants with VISP received a vaccine not containing an env insert. Conclusions The induction of VISP in HIV vaccine recipients is common especially with vaccines containing both the HIV-1 envelope and gag proteins. Development and detection of VISP appear to be associated with the immunogenicity of the vaccine and the EIA assay used.

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EV02: A Phase I trial to compare the safety and immunogenicity of HIV DNA-C prime-NYVAC-C boost to NYVAC-C alone

Cited by 92 publications

References 11 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

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

Vaccine-Induced HIV Seropositivity/Reactivity in Noninfected HIV Vaccine Recipients

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