Against HIV strains in North America & Europe


Phase I

  • HIV uninfected subjects
  • HIV infected subjects

Milestone

Data published in the Journal of Infectious Diseases in July 2013

Description
PENNVAX®-B is a DNA vaccine that was designed for the prevention and treatment of the HIV subtype prevalent in North America and Europe. The vaccine consists of SynCon® immunogens targeting HIV gag, pol, and env proteins from HIV subtype, or clade, B. It is delivered with Inovio’s CELLECTRA® electroporation device. 

Development Status
In March 2012, Inovio reported that in an open label, phase I clinical trial (HIV-001) of PENNVAX-B in 12 adult HIV-positive volunteers, the vaccine generated significant T-cell immune responses. These responses were predominately antigen-specific CD8+ T-cells, which are considered to be paramount in clearing chronic viral infections and an important performance measure. There were no significant adverse events. In this study, four doses of PENNVAX-B were delivered with the CELLECTRA electroporation device. The study was conducted at the University of Pennsylvania Medical Center.

In a prior phase I study (HVTN-080) of 48 healthy patients, PENNVAX-B demonstrated best-in-class immune responses.

These results indicated the potency of Inovio’s synthetic vaccine technology platform, raising the potential for the development of therapeutic vaccines against HIV.

Knowledge from the PENNVAX-B HIV program has been incorporated into the design of our multi-clade, globally oriented PENNVAX®-GP vaccine, which is now our lead preventive and therapeutic vaccine that broadly targets global HIV strains. Inovio will not further develop PENNVAX-B.

Disease State
More than 36 million people have died from HIV-related causes and 35 million are living with HIV1. Although a highly active antiretroviral therapy regimen has dramatically transformed the treatment of the disease in developed countries, effective HIV vaccines are needed to stop the spread of disease and reduce the need for antiretroviral treatments, which can have harsh side effects and lose their efficacy over time.

1Joint United Nations Programme on HIV/AIDS (UNAIDS)



Clinical Trials

Clinical Trials

Two clinical studies have been completed:

HVTN-080 in uninfected patients:

In October of 2009, Inovio initiated a phase I study for PENNVAX-B to assess the safety and immunogenicity of this DNA-based vaccine, with or without IL-12 DNA plasmid, delivered using Inovio’s CELLECTRA electroporation delivery device in 48 HIV-1 uninfected adults. PENNVAX-B consists of SynCon immunogens targeting HIV gag, pol, and env proteins from HIV subtype B commonly found in North America and Europe

Of the 48 total volunteers, eight subjects received a placebo, 10 subjects received a 3 mg dose (1 mg dose of each of three DNA plasmids – gag, pol, env) of Inovio's SynCon PENNVAX-B vaccine, and 30 subjects received a 3 mg dose of PENNVAX-B along with 1 mg of GENEVAX™IL-12 DNA. All volunteers received vaccine or placebo administered via intramuscular injection with electroporation at months 0, 1, and 3.

Phase 1 study data from this trial was published in the peer-reviewed Journal of Infectious Diseases in the article, "Safety and comparative immunogenicity of an HIV-1 DNA vaccine in combination with plasmid IL-12 and impact of intramuscular electroporation for delivery."

This randomized, double-blind, multi-center study was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), an agency of the National Institutes of Health, and conducted by the NIAID-funded HIV Vaccine Trials Network (HVTN) at several clinical sites.

Knowledge gained from this study has been used in the design of PENNVAX-GP, Inovio’s global preventive and therapeutic HIV DNA vaccine targeting clades A,C, and B.

Go to study protocol


HIV-001 in infected patients:

HIV-001 was an open label, phase I study that assessed safety and immunogenicity generated by Inovio's PENNVAX-B vaccine delivered with its CELLECTRA electroporation device in 12 HIV-positive adults. This vaccine consists of SynCon immunogens targeting HIV gag, pol, and env proteins from HIV subtype B commonly found in North America and Europe.

Study volunteers were required to be on a highly active antiretroviral therapy (HAART) regimen, have undetectable plasma viral load (<75 copies/mL), and have CD4 T lymphocyte counts above 400 cells/µL with nadirs over 200 cell/µL. Twelve (12) eligible subjects were administered a four dose series (day 0, weeks 4, 8 and 16) of PENNVAX-B containing 3 mg of DNA/dose via intramuscular electroporation.

The study was sponsored by Inovio Pharmaceuticals and conducted at the University of Pennsylvania Medical Center. 

Go to study protocol

Study Data

Study Data

PENNVAX®-B HIV Vaccine

Inovio previously reported best-in-class, antigen-specific T-cell immune responses to the PENNVAX-B vaccine in healthy adults in a preventive setting. In that study (HVTN-080), T-cell responses were generated in 89% of the subjects that received three vaccinations of PENNVAX-B, which consisted of 1 mg of each of three DNA plasmids (encoding for HIV gag, pol, and env proteins) in addition to 1 mg of IL-12 DNA plasmid, followed by intramuscular electroporation with Inovio's CELLECTRA device. Three or four vaccinations with a 2 mg dose of each PENNVAX-B plasmid plus 1.5 mg of IL-12 DNA generated fewer responses when delivered without electroporation.

A 45% point or, 7-fold increase (7% to 52%), in the generation of CD8 T-cells was found when patients received only half the vaccine dose delivered using CELLECTRA electroporation, and three doses instead of four compared to subjects that received a full vaccine dose without electroporation. In the three-vaccination regimen with electroporation, 88.9% (24/27) of subjects developed a robust CD4 or CD8 response. Six months after vaccination, T-cell response rates remained strong and persistent in the subjects that received only three doses delivered by CELLECTRA EP. Of 24 positive CD4 or CD8 T-cell responders following the third and last vaccination in month 3, 79% (19/24) showed persistent CD4 or CD8 T-cell responses at month 9.

In other study arms that did not achieve statistical significance, the use of IL-12 DNA appeared to positively impact T-cell response rates. The increased response rate only occurred when IL-12 DNA was delivered with electroporation. This effect may be further investigated in Inovio’s PENNVAX-GP HIV vaccine study.

Overall, the investigators in this study concluded that PENNVAX-B + IL-12 plasmid delivered via electroporation led to frequencies and magnitudes of cellular immune responses equal to or greater than those reported from current vector-based HIV vaccines such as adenovirus or traditional DNA vaccination without electroporation. This data was published in the peer-reviewed Journal of Infectious Diseases in the article, "Safety and comparative immunogenicity of an HIV-1 DNA vaccine in combination with plasmid IL-12 and impact of intramuscular electroporation for delivery."

Knowledge from this HIV program has been incorporated into the design of our multi-clade PENNVAX-GP vaccine, which is now our lead preventive and therapeutic vaccine that broadly targets global HIV strains. PENNVAX-B will not be developed further.
 

Phase I Study in a Therapeutic Setting (Infected Patients)
Inovio achieved strong T-cell immune responses in a Phase I clinical study of PENNVAX-B, its product for the treatment of the HIV subtype prevalent in North America and Europe, in HIV-positive subjects.

The HIV-001 open label, Phase I study enrolled 12 adult HIV-positive volunteers to assess safety and levels of immune responses generated by Inovio's PENNVAX-B vaccine delivered with its CELLECTRA electroporation device. PENNVAX-B consists of SynCon immunogens targeting HIV gag, pol, and env proteins from HIV subtype B commonly found in North America and Europe.

Study volunteers were required to be on a highly active antiretroviral therapy (HAART) regimen, have undetectable plasma viral load (<75 copies/mL), and have CD4 T lymphocyte counts above 400 cells/µL with nadirs over 200 cell/µL. Twelve (12) eligible subjects were administered a four dose series (day 0, weeks 4, 8 and 16) of PENNVAX-B containing 3 mg of DNA/dose via intramuscular electroporation.

All 12 subjects completed the four dose vaccination regimen. There were no significant adverse events or vaccine related grade 3 or 4 adverse events noted in the study and the vaccine was found to be generally well tolerated. Reported injection site reactions were mild to moderate and did not require treatment to resolve. T-cell responses were measured using a validated ELISpot assay at the U Penn Immunology Core Facility.

Overall, significant vaccine-specific T-cell responses were observed in 75% (9 out of 12) of subjects against at least one of the three vaccine antigens (gag. pol, or env) following vaccination. Fifty percent of the subjects (6 out of 12) had strong vaccine induced antigen-specific responses above the pre-vaccination levels to at least two of the antigens. Importantly, the responses induced by vaccination were predominantly antigen-specific (i.e. gag, pol and env) CD8+ T-cells, which are considered to be paramount in clearing chronic viral infections and an important measurement of the performance of a therapeutic vaccine. These results are in stark contrast to previously reported studies with other DNA vaccines delivered without electroporation that yielded poor overall T-cell immune responses.

Preclinical Data
In June 2010, the peer-reviewed journal Molecular Therapy published a paper entitled "Comparative Analysis of Immune Responses Induced by Vaccination With SIV Antigens by Recombinant Ad5 Vector or Plasmid DNA in Rhesus Macaques." The paper, co-authored by researchers from Merck, University of Pennsylvania School of Medicine, and Inovio Pharmaceuticals, described that in a head-to-head comparison with an adenovirus serotype 5 (Ad5) vaccine considered to be the most immunogenic among viral vectors, Inovio's optimized SynCon DNA vaccine delivered using its proprietary electroporation technology demonstrated numerous advantages in both magnitude and breadth of immune responses produced in non-human primates. Compared to Ad5, the SynCon DNA vaccine resulted in:

  • Significantly stronger antigen-specific cellular immune responses, in particular CD8+ T cells. T-cells are considered instrumental in clearing cancerous or infected cells from the body. Such responses are therefore imperative to achieving sufficient potency in new vaccines against cancers and chronic infectious diseases such as HIV and hepatitis C virus. Importantly, Ad5 immunizations failed to boost immune responses following the first immunization, whereas immune responses from DNA vaccination were continually boosted even after four immunizations.
  • Increased breadth of T-cell-based immune responses. CD4+ and CD8+ T-cell immune responses produced with DNA vaccination were broader and produced multiple immune molecules called cytokines (IFN, IL-2, TNF-a, and CD107a). Broad immune responses are considered an important potential marker for vaccine efficacy.
  • Immune responses were long-lasting and maintained at high levels.

These data were considered to be a pivotal outcome in displaying the progress and potential of synthetic vaccine delivered using electroporation.

More Information

More Information

Human immunodeficiency virus (HIV) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS), a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells.

AIDS has spread relentlessly since its identification in the early 1980s, causing one of the most devastating pandemics ever recorded in human history. More than 36 million people have died from HIV-related causes and roughly 35 million are living with HIV. The annual rate of new HIV infections has declined from an estimated 3.1 million in 1999 to roughly 2.5 million in 2011. However, AIDS remains the fourth leading cause of death in low-income countries, and every day more than 7,100 people worldwide become newly infected with HIV.

Although a highly active antiretroviral therapy regimen has dramatically transformed the treatment of the disease in developed countries, effective HIV vaccines are needed to stop the spread of disease and reduce the need for antiretroviral treatments, which can have harsh side effects and lose their efficacy over time.