NYVAC immunization induces polyfunctional HIV‐specific T‐cell responses in chronically‐infected, ART‐treated HIV patients

Abstract

We report the results of the Theravac-01 phase I trial, which was conducted to evaluate the safety and immunogenicity of a poxvirus-based vector, NYVAC, expressing Gag, Pol, Nef, and Env from an HIV clade B isolate. NYVAC-B vaccine was injected intramuscularly into ten HIV-infected patients successfully treated with antiretroviral therapy, twice on day 0 and again at week 4. Safety and immunogenicity were monitored for 48 weeks. HIV-specific T-cell responses following immunization were quantitatively analyzed using an IFN-γ ELISPOT assay and qualitatively characterized for their functional profile (including multiple cytokines secretion plus cytotoxic and proliferation capacity) by polychromatic flow cytometry. Our results indicate that the NYVAC-B vaccine is safe and highly immunogenic, as indicated by increased HIV-specific T-cell responses in virtually all vaccinees. Interestingly, both an expansion of preexisting T-cell responses, and the appearance of newly detected HIV-specific CD4 + and CD8 + T-cell responses were observed. Furthermore, immunization mostly induced an increase in Gag-specific T-cell responses. In conclusion, NYVAC-B immunization induces broad, vigorous, and polyfunctional HIV-specific T-cell responses, suggesting that poxvirus-based vaccine regimens may be instrumental in the therapeutic HIV vaccine field. Eur. J. Immunol. 2012. 42: 3038-3048 Clinical immunology 3039 IntroductionThe development of antiviral therapy has dramatically changed the course and the prognosis of HIV infection. More than 30 antiviral drugs available offer many therapeutic options for the patients and some of these drugs used in combination are able to induce long-term suppression of virus replication as indicated by the persistence of levels of viremia below the limit of detection of highly sensitive PCR assays [1]. The antiviral therapy-mediated suppression of virus replication has resulted in dramatic reduction of morbidity and mortality, and HIV infection has shifted from being a life threatening to a chronic viral disease [2]. In this regard, recent studies have estimated a life expectancy of 25-30 years for subjects with HIV infection [3,4]. Despite the long-term suppression of virus replication and the normalization of a series of immunological parameters, which are not limited to the CD4 + T-cell counts but also to the recovery of a series of antigen-specific (including HIV) immunological functions, the interruption of antiviral therapy is almost invariably associated to virus rebound [1,5]. These observations indicated that the long-term suppression of virus replication does not result in the generation of an effective HIV-specific immune response [6].For these reasons, a number of immunological interventions have been investigated in the past and are currently being investigated to stimulate HIV-specific immune responses that may efficiently control HIV replication also in the absence of antiviral therapy. Among these interventions, particular attention has been given to the development of therapeutic v...

Comparison of Immunogenicity in Rhesus Macaques of Transmitted-Founder, HIV-1 Group M Consensus, and Trivalent Mosaic Envelope Vaccines Formulated as a DNA Prime, NYVAC, and Envelope Protein Boost

“…The DNA and NYVAC vectors used in the present study generate both CD4 ϩ and CD8 ϩ T lymphocyte immune responses (31,44). While mosaic immunogens have been shown to improve the cross-reactivity of both CD8 ϩ and CD4 ϩ T lymphocyte vaccine responses (26), the mosaic advantage in earlier studies was far more pronounced for CD8 ϩ T-cell responses (26,27).…”

“…We evaluated their antigenicities and their immunogenicities in a DNA prime, recombinant NYVAC (rNYVAC), and Env protein boost immunization protocol (31).…”

Head-to-Head Comparison of Poxvirus NYVAC and ALVAC Vectors Expressing Identical HIV-1 Clade C Immunogens in Prime-Boost Combination with Env Protein in Nonhuman Primates

“…A similar NYVAC-based HIV/AIDS therapeutic vaccine candidate expressing Env and Gag-Pol-Nef HIV-1 antigens from clade B (NYVAC-B) has been evaluated in HIV-1-infected patients on antiretroviral therapy in a phase I clinical trial (Theravac-01). In HIV-infected individuals, this NYVAC immunogen induced broad, polyfunctional HIV-1-specific T-cell responses, triggering both an expansion of preexisting T-cell immune responses and the appearance of newly detected HIV-1-specific CD4 ϩ and CD8 ϩ T-cell responses (14). Importantly, the novel poxvirus vectors NYVAC-C and ALVAC-C express HIV-1 antigens from clade C, the most broadly distributed HIV-1 subtype, reinforcing the use of these combined vectors as HIV/AIDS vaccine candidates in those geographical regions where HIV-1 clade C is most prevalent.…”

“…In particular, recombinant NYVAC vectors expressing HIV-1 Env, Gag, Pol, and Nef antigens from clade B or C elicited strong, broad, and polyfunctional T-cell immune responses in mice, nonhuman primates, and humans, together with varied levels of humoral re-sponses against HIV-1 gp120 (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)). An additional feature is that the current NYVAC vectors preferentially trigger CD4 ϩ T-cell responses (13,14,24,25) in both humans and macaques, inferring immunologically the recruitment of stronger B-cell responses than ALVAC-based vectors. In an effort to enhance the magnitude and scope of T-and B-cell responses to HIV-1 antigens delivered by a poxvirus vector, we recently characterized two novel attenuated NYVAC vectors expressing HIV-1 clade C trimeric soluble gp140 or Gag-Pol-Nef as a polyprotein processed into Gag-derived virus-like particles (VLPs) which triggered specific innate responses in human cells and elicited in mice polyfunctional Envspecific CD4…”

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

“…Both rAd5 and NYVAC-B had previously been tested in humans and have been shown to elicit both humoral and cellular responses (21,25), but the combination of an adenoviral vector with a poxvirus vector had only been tested in NHPs, in which it showed superior protection from acquisition compared with that of homologous poxvirus vectors (20). The rAd5 vaccine used in Interestingly, we found that Env-specific IgA production was mainly restricted to NYVAC/Ad5 hi ( Figure 3D for clade B gp140, P = 0.003 for response rates in NYVAC/Ad5 hi vs. Ad5 hi /NYVAC; Supplemental Figure 4 for clades A and C as well as ConS gp140).…”