Immunotherapy Against HPV16/18 Generates Potent TH1 and Cytotoxic Cellular Immune Responses.

Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA.
Science translational medicine (Impact Factor: 14.41). 10/2012; 4(155):155ra138. DOI: 10.1126/scitranslmed.3004414
Source: PubMed

ABSTRACT Despite the development of highly effective prophylactic vaccines against human papillomavirus (HPV) serotypes 16 and 18, prevention of cervical dysplasia and cancer in women infected with high-risk HPV serotypes remains an unmet medical need. We report encouraging phase 1 safety, tolerability, and immunogenicity results for a therapeutic HPV16/18 candidate vaccine, VGX-3100, delivered by in vivo electroporation (EP). Eighteen women previously treated for cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) received a three-dose (intramuscular) regimen of highly engineered plasmid DNA encoding HPV16 and HPV18 E6/E7 antigens followed by EP in a dose escalation study (0.3, 1, and 3 mg per plasmid). Immunization was well tolerated with reports of mild injection site reactions and no study-related serious or grade 3 and 4 adverse events. No dose-limiting toxicity was noted, and pain was assessed by visual analog scale, with average scores decreasing from 6.2/10 to 1.4 within 10 min. Average peak interferon-γ enzyme-linked immunospot magnitudes were highest in the 3 mg cohort in comparison to the 0.3 and 1 mg cohorts, suggesting a trend toward a dose effect. Flow cytometric analysis revealed the induction of HPV-specific CD8(+) T cells that efficiently loaded granzyme B and perforin and exhibited full cytolytic functionality in all cohorts. These data indicate that VGX-3100 is capable of driving robust immune responses to antigens from high-risk HPV serotypes and could contribute to elimination of HPV-infected cells and subsequent regression of the dysplastic process.

Download full-text


Available from: Matthew P Morrow, Feb 15, 2014
1 Follower
  • Source
    • "Until recently, the DNA platform has been used primarily in prime-boost strategies along with viral vectors and proteins, thus creating an inordinately long testing and development window for addressing emerging pandemics rapidly. In order to address the technical hurdles associated with weak vaccine-induced immunity, we have recently applied many synthetic DNA design strategies, including codon/RNA optimization, the addition of highly efficient immunoglobulin leader sequences [24] [25] [26], use of 'centralized' immunogens to broaden immunity and remove dependence on any individual viral sequence [27] [28], new formulations [29] combined with highly efficient DNA delivery methods such as in vivo electroporation (EP) [30] [31], to improve the induction of immune responses induced by DNA vaccines in small animals, macaques [31] [32], and most recently and importantly, in humans [33] [34]. Here we present the first adaptation of this newly developed synthetic platform deployed to approach the feasibility of developing a protective vaccine against a rapidly emerging pathogen in real time. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite an intensive vaccine program influenza infections remain a major health problem, due to the viruses' ability to change its envelope glycoprotein hemagglutinin (HA), through shift and drift, permitting influenza to escape protection induced by current vaccines or natural immunity. Recently a new variant, H7N9, has emerged in China causing global concern. First, there have been more than 130 laboratory-confirmed human infections resulting in an alarmingly high death rate (32.3%). Second, genetic changes found in H7N9 appear to be associated with enabling avian influenza viruses to spread more effectively in mammals, thus transmitting infections on a larger scale. Currently, no vaccines or drugs are effectively able to target H7N9. Here, we report the rapid development of a synthetic consensus DNA vaccine (pH7HA) to elicit potent protective immunity against the H7N9 viruses. We show that pH7HA induces broad antibody responses that bind to divergent HAs from multiple new members of the H7N9 family. These antibody responses result in high-titer HAI against H7N9. Simultaneously, this vaccine induces potent polyfunctional effector CD4 and CD8T cell memory responses. Animals vaccinated with pH7HA are completely protected from H7N9 virus infection and any morbidity associated with lethal challenge. This study establishes that this synthetic consensus DNA vaccine represents a new tool for targeting emerging infection, and more importantly, its design, testing and development into seed stock for vaccine production in a few days in the pandemic setting has significant implications for the rapid deployment of vaccines protecting against emerging infectious diseases.
    Vaccine 03/2014; 32(24). DOI:10.1016/j.vaccine.2014.02.038 · 3.49 Impact Factor
  • Source
    Clinical Immunology 01/2010; 135. DOI:10.1016/j.clim.2010.03.336 · 3.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Identification of human papillomavirus (HPV) as the etiologic factor of cervical, anogenital, and a subset of head and neck cancers has stimulated the development of preventive and therapeutic HPV vaccines to control HPV-associated malignancies. Excitement has been generated by the commercialization of two preventive L1-based vaccines, which use HPV virus-like particles (VLPs) to generate capsid-specific neutralizing antibodies. However, factors such as high cost and requirement for cold chain have prevented widespread implementation where they are needed most. Areas covered: Next generation preventive HPV vaccine candidates have focused on cost-effective stable alternatives and generating broader protection via targeting multivalent L1 VLPs, L2 capsid protein, and chimeric L1/L2 VLPs. Therapeutic HPV vaccine candidates have focused on enhancing T cell-mediated killing of HPV-transformed tumor cells, which constitutively express HPV-encoded proteins, E6 and E7. Several therapeutic HPV vaccines are in clinical trials. Expert opinion: Although progress is being made, cost remains an issue inhibiting the use of preventive HPV vaccines in countries that carry the majority of the cervical cancer burden. In addition, progression of therapeutic HPV vaccines through clinical trials may require combination strategies employing different therapeutic modalities. As research in the development of HPV vaccines continues, we may generate effective strategies to control HPV-associated malignancies.
    Expert Opinion on Emerging Drugs 11/2012; 17(4). DOI:10.1517/14728214.2012.744393 · 3.28 Impact Factor
Show more