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

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.

HIV Epidemic in Asia: Implications for HIV Vaccine and Other Prevention Trials

“…[134][135][136][137] HIV vaccine clinical development came to a halt and shifted to designing immunogens able to induce HIV-specific broadly neutralizing antibodies (www.iavi.org). The prioritization of trialrelated financial and healthcare provisions, including access to an efficacious vaccine posttrial, among MSM in India indicates the importance of trials providing such services, as well as the value of formative research in identifying key concerns among participating communities in resourcelimited settings.…”

Experiences in recruiting volunteers through community based initiatives in Phase-1 vaccine trials in India

“…18 Both the institutes that conducted the three HIV vaccine trials in India worked with locally constituted Community Advisory Boards (CAB). 8,9 Contribution of Community Advisory Board members in discussions regarding the type of population to be targeted for enrollment, in creating "community literacy" among researchers and in development of informed consent forms as well as study information material in a non-technical and community language was crucially important. During CAB consultations to discuss trial recruitment strategies, investigators in Pune had proposed approaching blood donors as potential trial participants following the Thailand model.…”

“…In a span of 6 y, a total of 94 healthy volunteers were recruited in three phase I trials in India. 8,10,18 At Pune site, 30 and 16 enrollments made were in the first (AAV) and third (DNA-MVA prime boost) HIV vaccine trials by reaching out to 8349 and 5881 individuals respectively. At the Chennai site, 32 and 16 volunteers were recruited in the second (MVA) and third (DNA-MVA prime boost) HIV vaccine trials by approaching 13 920 and 14 080 respectively.…”

“…The safety data of all the three trials conducted in Pune and Chennai have already been published. [8][9][10] The processes followed and experiences gained while implementing various community based initiatives for recruitment of healthy volunteers during the three HIV vaccine trials in India are described.…”

Deletion of the Vaccinia Virus N2L Gene Encoding an Inhibitor of IRF3 Improves the Immunogenicity of Modified Vaccinia Virus Ankara Expressing HIV-1 Antigens

“…Numerous MVA vectors expressing different HIV-1 antigens have been produced and tested in human clinical trials (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25), revealing that MVA vectors are safe and elicit humoral and cellular immune responses to HIV-1 antigens (for reviews, see references 3, 6, and 7), regardless of its limited replication in human and most mammalian cell types. However, MVA still contains several immunomodulatory VACV genes that counteract the host antiviral innate immune response, particularly those genes encoding proteins that inhibit the Toll-like receptor (TLR) signaling pathway (26), an important route that plays a fundamental role in the defense against pathogens through the induction of proinflammatory cytokines and type I interferon (IFN) but also in modeling adaptive immune responses to patho-gens (27)(28)(29).…”