Safety and immunogenicity of an HIV-1 gag DNA vaccine with or without IL-12 and/or IL-15 plasmid cytokine adjuvant in healthy, HIV-1 uninfected adults

Spyros A Kalams, Scott Parker, Xia Jin, Marnie Elizaga, Barbara Metch, Maggie Wang, John Hural, Michael Lubeck, John Eldridge, Massimo Cardinali, William A Blattner, Magda Sobieszczyk, Vinai Suriyanon, Artur Kalichman, David B Weiner, Lindsey R Baden, NIAID HIV Vaccine Trials Network, Spyros A Kalams, Scott Parker, Xia Jin, Marnie Elizaga, Barbara Metch, Maggie Wang, John Hural, Michael Lubeck, John Eldridge, Massimo Cardinali, William A Blattner, Magda Sobieszczyk, Vinai Suriyanon, Artur Kalichman, David B Weiner, Lindsey R Baden, NIAID HIV Vaccine Trials Network

Abstract

Background: DNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity. DNA plasmid cytokine adjuvants have been shown to augment immune responses in small animals and in macaques.

Methodology/principal findings: We performed two first in human HIV vaccine trials in the US, Brazil and Thailand of an RNA-optimized truncated HIV-1 gag gene (p37) DNA derived from strain HXB2 administered either alone or in combination with dose-escalation of IL-12 or IL-15 plasmid cytokine adjuvants. Vaccinations with both the HIV immunogen and cytokine adjuvant were generally well-tolerated and no significant vaccine-related adverse events were identified. A small number of subjects developed asymptomatic low titer antibodies to IL-12 or IL-15. Cellular immunogenicity following 3 and 4 vaccinations was poor, with response rates to gag of 4.9%/8.7% among vaccinees receiving gag DNA alone, 0%/11.5% among those receiving gag DNA+IL-15, and no responders among those receiving DNA+high dose (1500 ug) IL-12 DNA. However, after three doses, 44.4% (4/9) of vaccinees receiving gag DNA and intermediate dose (500 ug) of IL-12 DNA demonstrated a detectable cellular immune response.

Conclusions/significance: This combination of HIV gag DNA with plasmid cytokine adjuvants was well tolerated. There were minimal responses to HIV gag DNA alone, and no apparent augmentation with either IL-12 or IL-15 plasmid cytokine adjuvants. Despite the promise of DNA vaccines, newer formulations or methods of delivery will be required to increase their immunogenicity.

Trial registration: Clinicaltrials.gov NCT00115960 NCT00111605.

Conflict of interest statement

Competing Interests: ML was an employee of Wyeth (now Pfizer, Inc.) during the course of the trial. JE was formerly employed by Wyeth (now Pfizer), is currently employed by Profectus BioSciences (PB), and holds stock or options in both companies. PB has licensed a portfolio of issued and pending patents from Pfizer in the area of DNA vaccines, is actively developing DNA IL-12 as a product, and support for that development has been provided by the Natinal Institutes of Health under contract HHSN 80062C awarded to JE. The remaining authors have declared that no competing interests exist. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Allocation, follow-up, and analysis cohorts…
Figure 1. Allocation, follow-up, and analysis cohorts for HVTN 060 and HVTN 063.
Figure 2. Study schema for HVTN 060/063.
Figure 2. Study schema for HVTN 060/063.
N3-5 – Number of participants randomized to either 3 dose or 5 dose regimen; N5 – Number of participants randomized to a 5 dose regimen.
Figure 3. Severity of vaccine reactions.
Figure 3. Severity of vaccine reactions.
Panel A shows the maximum severity of pain or tenderness at the injection site and Panel B the maximum severity of systemic reactogenicity symptoms. Systemic symptoms include malaise and/or fatigue, myalgia, headache, nausea, vomiting, chills and arthralgia. Data for vaccinations 1–3 and for vaccinations 4–5 are combined. Data for adjuvants at a dose of 100 or 500 ug are also combined (labeled as low). Abbreviation PL = placebo.

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