A Phase 1 Study to Evaluate the Safety and Immunogenicity of a Recombinant HIV Type 1 Subtype C-Modified Vaccinia Ankara Virus Vaccine Candidate in Indian Volunteers

Tuberculosis Research Centre, Chennai, India.
AIDS research and human retroviruses (Impact Factor: 2.46). 11/2009; 25(11):1107-16. DOI: 10.1089/aid.2009.0096
Source: PubMed

ABSTRACT A recombinant modified vaccinia Ankara virus vaccine candidate (TBC-M4) expressing HIV-1 subtype C env, gag, tat-rev, and nef-RT genes was tested in a randomized, double-blind, dose escalation Phase I trial in 32 HIV-uninfected healthy volunteers who received three intramuscular injections of TBC-M4 at 0, 1, and 6 months of 5 x 10(7) plaque-forming units (pfu) (low dosage, LD) (n = 12) or 2.5 x 10(8) pfu (high dosage, HD) (n = 12) or placebo (n = 8). Local and systemic reactogenicity was experienced by approximately 67% and 83% of vaccine recipients, respectively. The reactogenicity events were mostly mild in severity. Severe but transient systemic reactogenicity was seen in one volunteer of the HD group. No vaccine-related serious adverse events or events suggesting perimyocarditis were seen. A higher frequency of local reactogenicity events was observed in the HD group. Cumulative HIV-specific IFN-gamma ELISPOT responses were detected in frozen PBMCs from 9/11 (82%), 12/12 (100%), and 1/8 (13%) volunteers after the third injection of the LD, HD, and placebo groups, respectively. Most of the responses were to gag and env proteins (maximum of 430 SFU/10(6) PBMCs) persisting across multiple time points. HIV-specific ELISA antibody responses were detected in 10/11, 12/12, and 0/8 volunteers post-third vaccination, in the LD, HD, and placebo groups, respectively. No neutralizing activity against HIV-1 subtype C isolates was detected. TBC-M4 appears to be generally safe and well-tolerated. The immune response detected was dose dependent, modest in magnitude, and directed mostly to env and gag proteins, suggesting further evaluation of this vaccine in a prime-boost regimen.

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    • "Among poxviruses, the highly attenuated modified vaccinia virus Ankara (MVA) strain is one of the most promising vectors to be used as an effective vaccine against HIV- 1 (Esteban, 2009; Pantaleo et al., 2010). A great number of MVA vectors expressing different HIV-1 antigens have been generated and tested in different animal models and in several clinical trials in humans (Cebere et al., 2006; Currier et al., 2010; Goepfert et al., 2011; Gomez et al., 2011a; Goonetilleke et al., 2006; Keefer et al., 2011; Kutscher et al., 2010; Ramanathan et al., 2009; Sandstrom et al., 2008; Vasan et al., 2010), showing that they are safe, able to induce high levels of expression of HIV-1 antigens, and to trigger strong, broad, polyfunctional and durable HIV-1-specific immune responses. In our lab we have constructed an HIV/AIDS vaccine candidate termed MVA-B (Fig. 1A), based in a recombinant MVA expressing Env, as monomeric gp120, and the codon-optimized polyprotein Gag-Pol-Nef (GPN) of HIV-1 from clade B (Gomez et al., 2007). "
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    ABSTRACT: MVA-B is an attenuated poxvirus vector expressing human immunodeficiency virus type 1 Env, Gag, Pol, and Nef antigens from clade B, and is considered a promising HIV/AIDS vaccine candidate. Recently, a phase I clinical trial in human healthy volunteers has shown that MVA-B is safe and highly immunogenic, inducing broad, polyfunctional, and long-lasting CD4(+) and CD8(+) T cell responses to HIV-1 antigens, with preference for effector memory T cells; and it also triggers the induction of specific antibodies to Env in most of the vaccines. While MVA recombinants expressing HIV-1 antigens are being used or plan to use in therapeutic clinical trials, little is known on the effect of HIV-1 highly active antiretroviral therapy in MVA life cycle. To define this role, here we have evaluated in established cell cultures and human dendritic cells to what extent different HIV-1 protease inhibitors affect virus replication and expression of HIV-1 antigens during MVA-B infection. The results obtained revealed that the most commonly used HIV-1 protease inhibitors (atazanavir, ritonavir, and lopinavir) had no effect on MVA-B virus growth kinetics, even at higher concentrations than those normally used on HAART. Furthermore, expression of gp120 and the fused Gag-Pol-Nef polyprotein in permissive and non-permissive cells infected with MVA-B were also not affected. These findings are relevant information for the therapeutic use of MVA-B as an HIV-1/AIDS vaccine.
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    • "These have appeared to be safe and well tolerated [10] [11] [12]. However, limited immunogenicity has been usually reported when MVA is used alone [11] [12] [13] [14] [15] [16]. This low level of response is similar to other poxvirus used alone [17] [18] [19]. "
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    ABSTRACT: To investigate the safety and immunogenicity of a modified vaccinia virus Ankara vector expressing HIV-1 antigens from clade B (MVA-B), a phase-I, doubled-blind placebo-controlled trial was performed. 30 HIV-uninfected volunteers at low risk of HIV-1 infection were randomly allocated to receive 3 intramuscular injections (1×10(8)pfu/dose) of MVA-B (n=24) or placebo (n=6) at weeks 0, 4 and 16. All volunteers were followed 48 weeks. Primary end-points were adverse events and immunogenicity. A total of 169 adverse events were reported, 164 of grade 1-2, and 5 of grade 3 (none related to vaccination). Overall 75% of the volunteers showed positive ELISPOT responses at any time point. The magnitude (median) of the total responses induced was 288SFC/10(6)PBMC at week 18. Antibody responses against Env were observed in 95% and 72% of vaccinees at week 18 and 48, respectively. HIV-1 neutralizing antibodies were detected in 33% of volunteers. MVA-B was safe, well tolerated and elicited strong and durable T-cell and antibody responses in 75% and 95% of volunteers, respectively. These data support further exploration of MVA-B as an HIV-1 vaccine candidate. Clinical identifier: NCT00679497.
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    ABSTRACT: The Indian HIV epidemic has not reached the predicted proportions even after more than 25 years since the first case of HIV infection was detected in Chennai. An estimated 2.4 million adults were living with HIV in 2009 and an adult prevalence of HIV was 0.3%. The disease burden is geographically diverse and has spread to rural areas also. HIV viruses circulating in India predominantly belong to HIV-1 subtype C although recombinant strains and HIV-2 infections have been identified. Tuberculosis is the commonest opportunistic infection reported from various parts of the country and HIV-TB co-infection is a public health challenge. Government of India launched free antiretroviral treatment (ART) programme 6 years back which has shown good clinical and immunological response in HIV infected individuals. Though the drug resistance monitoring survey has reported effectiveness of regimen in the programme, adherence remains the key issue for minimizing the drug resistance. In addition to the ongoing prevention efforts, India should be poised to accept and scale up newer preventive tools in a manner acceptable and feasible in our socio-cultural context in order to sustain and consolidate the gains that we have achieved so far.
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