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Vaccine's special issue link -http://www.mdpi.com/journal/vaccines/special_issues/DNA-vaccines
full viewing of it is available now
Andrew Geall and Inovio connection, Andrew Geall is the RNA Vaccine Platform Leader at Novartis
Sep 4, 2012
abstract-Nonviral delivery of self-amplifying RNA vaccines
Andrew J. Geall Novartis Vaccines
ACKNOWLEDGMENTS
We thank the RNA Vaccine Platform Team at Novartis Vaccines and Diagnostics and, in particular, Jacob Archer, Mithra Rothfeder, and Avishek Nandi for their assistance in producing the RNA and DNA for these studies; Michelle Chan for coordinating the delivery of formulations for the animal studies; Alison Curtis and Melissa Sackal for their assistance in conducting the bioluminescence studies in mice; Christine Dong Lee for conducting the RSV-F immunogenicity studies in mice and running the corresponding immunological assays; Kate Broderick (Inovio, San Diego) for providing on-site training using the Elgen DNA Delivery System; Tina Scalzo and Melissa Sackal for conducting the ELISA and lung titer assays in the cotton rat study; Giuseppe Palladino and his serology team; and James Monroe and Kristian Friedrich for assisting in the respiratory syncytial virus neutralization assay. Funding for the HIV studies was provided by HIV Vaccine Research and Design Grant 5P01AI066287.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437863/
22 August 2013
Enhanced Delivery and Potency of Self-Amplifying mRNA Vaccines by Electroporation in Situ
Yen Cu 1,†, Kate E. Broderick 2, Kaustuv Banerjee 1, Julie Hickman 1, Gillis Otten 1, Susan Barnett 1, Gleb Kichaev 2, Niranjan Y.
Sardesai 2, Jeffrey B. Ulmer 1 and Andrew Geall 1,* email
Abstract: Nucleic acid-based vaccines such as viral vectors, plasmid DNA (pDNA), and mRNA are being developed as a means to address limitations of both live-attenuated and subunit vaccines. DNA vaccines have been shown to be potent in a wide variety of animal species and several products are now licensed for commercial veterinary but not human use. Electroporation delivery technologies have been shown to improve the generation of T and B cell responses from synthetic DNA vaccines in many animal species and now in humans. However, parallel RNA approaches have lagged due to potential issues of potency and production. Many of the obstacles to mRNA vaccine development have recently been addressed, resulting in a revival in the use of non-amplifying and self-amplifying mRNA for vaccine and gene therapy applications. In this paper, we explore the utility of EP for the in vivo delivery of large, self-amplifying mRNA, as measured by reporter gene expression and immunogenicity of genes encoding HIV envelope protein. These studies demonstrated that EP delivery of self-amplifying mRNA elicited strong and broad immune responses in mice, which were comparable to those induced by EP delivery of pDNA.
Keywords: antibodies; T cell responses; vaccine; HIV
Publication date Aug 8, 2013
Pegylated liposomes for delivery of immunogen encoding rna
Inventors Andrew Geall, Ayush Verma
Patent-US 20130202684 A1
ABSTRACT
Nucleic acid immunisation is achieved by delivering RNA encapsulated within a PEGylated liposome. The RNA encodes an immunogen of interest. The PEG has an average molecular mass of between 1 kDa and 3 kDa. Thus the invention provides a liposome having a lipid bilayer encapsulating an aqueous core, wherein: (i) the lipid bilayer comprises at least one lipid which includes a polyethylene glycol moiety, such that polyethylene glycol is present on the liposome's exterior, wherein the average molecular mass of the polyethylene glycol is between 1 kDa and 3 kDa; and (ii) the aqueous core includes a RNA which encodes an immunogen. These liposomes are suitable for in vivo delivery of the RNA to a vertebrate cell and so they are useful as components in pharmaceutical compositions for immunising subjects against various diseases.
clip taken from long patent description-
A further study confirmed that the 0.1 µg of liposome-encapsulated RNA gave much higher anti-F IgG responses (15 days post-second dose) than 0.1 µg of delivered DNA, and even was more immunogenic than 20 µg plasmid DNA encoding the F antigen, delivered by electroporation (Elgen™ DNA Delivery System, Inovio).
Monday, September 9, 2013
-conference-
Vaccine Delivery and Stabilization:
Improving the Reach of Vaccines
-presentation-
14:00 – 14:30 Non-viral delivery of self-amplifying mRNA vaccines
Andrew Geall, Novartis, USA
Apr 10, 2013 Inovio Pharmaceuticals & U.S. Army Receive $3.5 Million Biodefense Grant to Further Develop Mass Vaccination Device
This collaboration builds on Inovio's strong relationship with Dr. Schmaljohn and her team at USAMRIID in which Inovio is bringing medical innovation to several biodefense efforts.
The Inovio team of researchers has been collaborating with USAMRIID scientists to advance a DNA vaccine for the Lassa virus, which the DOD has designated as a "Category A" pathogen.The research effort will investigate the novel simultaneous delivery of multiple DNA vaccines — final testing will use the Lassa virus and other arenaviruses
link-http://ir.inovio.com/2013-04-10-Inovio-Pharmaceuticals-U-S-Army-Receive-3-5-Million-Biodefense-Grant-to-Further-Develop-Mass-Vaccination-Device
Inovio is collaborating with Dr. Connie Schmaljohn, Chief Scientist at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID).
August 5
link for more info on her-http://www.washingtonpost.com/local/dc-politics/federal-faces-connie-schmaljohn/2013/08/05/781e76d0-fe21-11e2-96a8-d3b921c0924a_story.html
Publication date Jun 20, 2013
Inovio Pharmaceuticals, Inc, Schmaljohn, Connie applied for a patent and finial publication of this was on Jun 20, 2013 patent title is below
Cross-protective arenavirus vaccines and their method of use
WO 2013055418 A3
ABSTRACT
The invention relates to DNA vaccines that target multiple arenavirus agents singly or simultaneously.
link-http://www.google.com/patents/WO2013055418A3?cl=en
Published: 18 July 2013-
Enhanced Efficacy of a Codon-Optimized DNA Vaccine Encoding the Glycoprotein Precursor Gene of Lassa Virus in a Guinea Pig Disease Model When Delivered by Dermal Electroporation
abstract- Abstract: Lassa virus (LASV) causes a severe, often fatal, hemorrhagic fever endemic to West Africa. Presently, there are no FDA-licensed medical countermeasures for this disease. In a pilot study, we constructed a DNA vaccine (pLASV-GPC) that expressed the LASV glycoprotein precursor gene (GPC). This plasmid was used to vaccinate guinea pigs (GPs) using intramuscular electroporation as the delivery platform. Vaccinated GPs were protected from lethal infection (5/6) with LASV compared to the controls. However, vaccinated GPs experienced transient viremia after challenge, although lower than the mock-vaccinated controls. In a follow-on study, we developed a new device that allowed for both the vaccine and electroporation pulse to be delivered to the dermis. We also codon-optimized the GPC sequence of the vaccine to enhance expression in GPs. Together, these innovations resulted in enhanced efficacy of the vaccine. Unlike the pilot study where neutralizing titers were not detected until after virus challenge, modest neutralizing titers were detected in guinea pigs before challenge, with escalating titers detected after challenge. The vaccinated GPs were never ill and were not viremic at any timepoint. The combination of the codon-optimized vaccine and dermal electroporation delivery is a worthy candidate for further development.
Keywords: Lassa fever; Lassa virus; arenavirus; guinea pigs; dermal electroporation; vaccination; vaccine
link-http://www.mdpi.com/2076-393X/1/3/262
http://www.mdpi.com/2076-393X/1/3/384
more research from inovio, one of the things I like about this company is their scientist are always activly involved in research
mrpatinmn- that is a good point
yes September makes a lot of sense in my opinion
"We show here that electroporation can also be used to markedly enhance the delivery and potency of RNA-based vaccines"
It will be interesting to see if they choose not to licence an ep device
also it is interesting they used the elgen opposed to the newer cellectra device not sure the reason for this, possibly protecting their newer technology from competitors while still allowing the company to see the benefits of ep delivery, with all this BP partnership talk it is interesting to see this collaboration come to light right now
Hleg- hey whats going on man ya redondo as in next to manhattan and hermosa,i did review the abstract on the lasa virus and one of the first things i noticed was connie's name, there is currently no treatment available for this virus hopefully further funding for human trials is on its way it appears that way...good find on the conference sep 9th,looks like theyll presenting the work done on the latest study involving novarits and ino
http://www.pharmavoice.com/content/digitaledition.html?pg=80
pharmavoice article on J.Kim
Vaccines, Volume 1, Issue 3 (September 2013)
Kathleen A. Cashman, Kate E. Broderick, Eric R. Wilkinson, Carl I. Shaia, Todd M. Bell, Amy C. Shurtleff, Kristin W. Spik, Catherine V. Badger, Mary C. Guttieri, Niranjan Y. Sardesai and Connie S. Schmaljohn
Article: Enhanced Efficacy of a Codon-Optimized DNA Vaccine Encoding the Glycoprotein Precursor Gene of Lassa Virus in a Guinea Pig Disease Model When Delivered by Dermal Electroporation
Vaccines 2013, 1(3), 262-277; doi:10.3390/vaccines1030262
Received: 31 May 2013; in revised form: 8 July 2013 / Accepted: 10 July 2013 / Published: 18 July 2013
Show/Hide Abstract | Download PDF Full-text (512 KB) | Download XML Full-text
Abstract: Lassa virus (LASV) causes a severe, often fatal, hemorrhagic fever endemic to West Africa. Presently, there are no FDA-licensed medical countermeasures for this disease. In a pilot study, we constructed a DNA vaccine (pLASV-GPC) that expressed the LASV glycoprotein precursor gene (GPC). This plasmid was used to vaccinate guinea pigs (GPs) using intramuscular electroporation as the delivery platform. Vaccinated GPs were protected from lethal infection (5/6) with LASV compared to the controls. However, vaccinated GPs experienced transient viremia after challenge, although lower than the mock-vaccinated controls. In a follow-on study, we developed a new device that allowed for both the vaccine and electroporation pulse to be delivered to the dermis. We also codon-optimized the GPC sequence of the vaccine to enhance expression in GPs. Together, these innovations resulted in enhanced efficacy of the vaccine. Unlike the pilot study where neutralizing titers were not detected until after virus challenge, modest neutralizing titers were detected in guinea pigs before challenge, with escalating titers detected after challenge. The vaccinated GPs were never ill and were not viremic at any timepoint. The combination of the codon-optimized vaccine and dermal electroporation delivery is a worthy candidate for further development.
http://www.mdpi.com/2076-393X/1/3/262
looks like its ICHOR Medical Systems which also uses ep..so its not ino
I just found it online..I haven't confirmed it's ino yet I'm on my phone not my comp so I can't really look it up right now
http://www.ncbi.nlm.nih.gov/m/pubmed/23954384/ expect some pr on this
The volatility continues in Inovovio Pharmaceuticals (INO) today, with the stock rising over 32% on no significant news
Dear seeking alpha,
While some of the recent price rise the last few weeks was due to speculation of partnership. Inovio has released plenty of significant news as of late. You guys continue to publish your short articles with the questionable timing. On the flip side you release a article saying INO could be merck's solution. Thanks for your market games and continued manipulation. Now the fact is a big pharma partnership has been INO's goal for sometime. The CEO speaking in June told investors he expects a partnership in the next few months. The real title of your article should be due to naked shorting and continued spread of misinformation my media sources ino's stock has moved down for no apparent reason.
These significant news releases over the first half of year might have something to with the over all higher share price.
Jan 7, 2013
PATH Malaria Vaccine Initiative and Inovio Pharmaceuticals Partner to Accelerate Development of Malaria Vaccines and Innovative Delivery Technologies
Jan 9, 2013
Inovio Pharmaceuticals to Initiate Clinical Trial for its Hepatitis C Therapeutic Vaccine (INO-8000) Later this Year
Apr 10, 2013
Inovio Pharmaceuticals & U.S. Army Receive $3.5 Million Biodefense Grant to Further Develop Mass Vaccination Device
Apr 18, 2013
Inovio Pharmaceuticals Universal H1N1 Influenza Vaccine Achieves Protective Immune Responses Comparable to Conventional Vaccine in Phase I Study
Apr 18, 2013
Inovio Pharmaceuticals Recognized With "Best Therapeutic Vaccine" and "Best Early Stage Biotech" Awards at World Vaccine Congress 2013
May 14, 2013
Inovio Pharmaceuticals DNA Vaccine Against Ebola and Marburg Filoviruses Provides Complete Protection in Preclinical Challenge Study
Jun 14, 2013
Inovio's Universal H7N9 DNA Vaccine Generates First Protective Antibody Responses Against Virulent H7N9 Virus in 100% of Vaccinated Animals
Jul 8, 2013
Inovio Pharmaceuticals' Universal H7N9 DNA Vaccine Protects 100% of Vaccinated Animals in Challenge Study
Jul 10, 2013
Inovio's CELLECTRA® Electroporation Delivery Technology Powers Durable, Best-in-Class T-Cell Responses from HIV Vaccine in Human Study
Jul 18, 2013
Synthetically Optimized HIF-1 Alpha DNA Delivered with Inovio's Electroporation Technology Provides Significant Therapeutic Effects for Peripheral Arterial Disease in Animal Model
Jul 24, 2013
Inovio Pharmaceuticals' Potent hTERT DNA Cancer Vaccine Shows Potential to Reduce Tumors and Prevent Tumor Recurrence
Aug 15, 2013
Inovio Pharmaceuticals' Malaria DNA Vaccine Demonstrates Robust Immune Responses in Animal Models
(not to mention the 7 conferences their attending in September)
BIO KOREA Sep. 11
Sep. 11 (Wed) 13:00~15:00
KINTEX Exhibition Center II / Rm. 310
This first session will give some perspectives including outcomes and opportunities of vaccine research and development (R & D) with new approaches and target disease. Topics will be provided on vaccine research and development for prevention of co-infection with virus and bacteria, current outcomes and perspectives about new technological approaches such as DNA vaccine, and new vaccine R & D. This session will provide understanding trends of new approaches and challenges in vaccine R & D.
· Synthetic Vaccines: DNA Vaccines
David B. Weiner, Professor, Professor of Pathology and Laboratory Medicine,University of
Pennsylvania School of Medicine
Sep. 13 (Fri)
KINTEX Exhibition Center II / Rm. 303
Nowadays, most of basic technologies originated in academia and research Instiutions. Start-up companies drive the commericialization under their development strategy and in the process, they often initiate the collaborations with other pharmaceutical company. Sharing the stories of experiences in both sides of the collaboration partners (Pharmaceutical & bioventure companies)
Session Chair
To be Updated
Speaker
· External Opportunity in Asia : Key Consideration in Early Stage Collaboration; Big Pharma
Perspective
Yuan-Hua Ding, Senior Director, External R&D Innovation(ERDI)-Asai/Pacific, Pfizer
· Licensing Case : Partnering with Big-Pharma
To be Updated
· Early Stage Opportunities in Merck : Merck Initiatives for New Target INT
To be Updated
6/28/2013
Comparison of intradermal and intramuscular delivery followed in vivo electroporation of SIV Env DNA in macaques
Viraj Kulkarni, Margherita Rosati, Jenifer Bear, Guy R Pilkington, Rashmi Jalah, Cristina Bergamaschi, Ashish K Singh, Candido Alicea, Bhabadeb Chowdhury, Gen-Mu Zhang, Eun-Young Kim, Steven M Wolinsky, Wensheng Huang, Yongjun Guan, Celia LaBranche, David C Montefiori, Kate E Broderick, Niranjan Y Sardesai, Antonio Valentin, Barbara K Felber*, George N Pavlakis*
https://www.landesbioscience.com/journals/vaccines/article/25473/
this is older but hopefully more updates in the next few months with improved ep device
IL-12 DNA as molecular vaccine adjuvant increases the cytotoxic T cell responses and breadth of humoral immune responses in SIV DNA vaccinated macaques
Rashmi Jalah
Human Retrovirus Pathogenesis Section; Frederick National Laboratory for Cancer Research, Frederick, MD, USA
Vainav Patel
Human Retrovirus Section, Vaccine Branch, CCR, Frederick National Laboratory for Cancer Research, Frederick, MD USA
Viraj Kulkarni
Human Retrovirus Pathogenesis Section; Frederick National Laboratory for Cancer Research, Frederick, MD, USA
Margherita Rosati
Human Retrovirus Section, Vaccine Branch, CCR, Frederick National Laboratory for Cancer Research, Frederick, MD USA
Candido Alicea
Human Retrovirus Pathogenesis Section; Frederick National Laboratory for Cancer Research, Frederick, MD, USA
Brunda Ganneru
Human Retrovirus Section, Vaccine Branch, CCR, Frederick National Laboratory for Cancer Research, Frederick, MD USA
Agneta von Gegerfelt
Human Retrovirus Section, Vaccine Branch, CCR, Frederick National Laboratory for Cancer Research, Frederick, MD USA
Wensheng Huang
Institute of Human Virology, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD USA
Yongjun Guan
Institute of Human Virology, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD USA
Kate E. Broderick
Inovio Pharmaceuticals, Inc.; Blue Bell, PA USA
Niranjan Y Sardesai
Inovio Pharmaceuticals, Inc.; Blue Bell, PA USA
Celia LaBranche
Department of Surgery, Laboratory for AIDS Vaccine Research and Development, Duke University Medical Center; Durham, NC USA
David C. Montefiori
Department of Surgery, Laboratory for AIDS Vaccine Research and Development, Duke University Medical Center; Durham, NC USA
George N. Pavlakis
*Corresponding author: pavlakig@mail.nih.gov
Human Retrovirus Section, Vaccine Branch, CCR, Frederick National Laboratory for Cancer Research, Frederick, MD USA
Barbara K. Felber
*Corresponding author: felberb@mail.nih.gov
Human Retrovirus Pathogenesis Section; Frederick National Laboratory for Cancer Research, Frederick, MD, USA
Submitted
5.18.2012
Revised
7.3.2012
Accepted
7.8.2012
Published Online
8.16.2012
Abstract
Intramuscular injection of macaques with an IL-12 expression plasmid (0.1 or 0.4 mg DNA/animal) optimized for high level of expression and delivered using in vivo electroporation, resulted in the detection of systemic IL-12 cytokine in the plasma. Peak levels obtained by day 4–5 post injection were paralleled by a rapid increase of IFN-?, indicating bioactivity of the IL-12 cytokine. Both plasma IL-12 and IFN-? levels were reduced to basal levels by day 14, indicating a short presence of elevated levels of the bioactive IL-12. The effect of IL-12 as adjuvant together with an SIVmac239 DNA vaccine was further examined comparing two groups of rhesus macaques vaccinated in the presence or absence of IL-12 DNA. The IL-12 DNA-adjuvanted group developed significantly higher SIV-specific cellular immune responses, including IFN-?+ Granzyme B+ T cells, demonstrating increased levels of vaccine-induced T cells with cytotoxic potential, and this difference persisted for 6 mo after the last vaccination. Coinjection of IL-12 DNA led to increases in Gag-specific CD4+ and CD4+CD8+ double-positive memory T cell subsets, whereas the Env-specific increases were mainly mediated by the CD8+ and CD4+CD8+ double-positive memory T cell subsets. The IL-12 DNA-adjuvanted vaccine group developed higher binding antibody titers to Gag and mac251 Env, and showed higher and more durable neutralizing antibodies to heterologous SIVsmE660. Therefore, co-delivery of IL-12 DNA with the SIV DNA vaccine enhanced the magnitude and breadth of immune responses in immunized rhesus macaques, and supports the inclusion of IL-12 DNA as vaccine adjuvant.
https://www.landesbioscience.com/journals/vaccines/article/21407/
Malaria vaccine capable of mass vaccination, Anthony Fauici of the NIH publicly noted last week the us Goverment is seeking one...INO has one and there next new generation delivry device will be capable of delivering two vaccines at once..safe,cut cost, rapidly able to respond..Inovios future remains has breakthroughs written all over it..go long
increased my shares today.
There was some talk this week about the company that developed a malaria vaccine "it was reported a breakthrough not by fda but by the editors of the article
Here is the article name
Early promise for malaria vaccine that mimics bug bites
Aug 9, 2013, 11.07AM IST
(here is a clip from the article)
After a week, volunteers were checked for infection, and those who were infected were treated for malaria. The team found that those who got the higher doses of the vaccine were far less likely to develop malaria that those who got lower doses or were not vaccinated.
In the study, only three of 15 participants who received higher dosages of the vaccine became infected, compared to 16 of 17 participants in the lower dosage group who became infected. Among the 12 participants who were not vaccinated, 11 became infected after exposure to infected mosquitoes.
Manufacturing the vaccine was itself an achievement. The company that produced it, Sanaria of Rockville, Maryland, was able to expose sterile mosquitoes to the malaria-infected blood, irradiate them to weaken the parasites that cause the disease and then - and this is the hard part - dissect the tiny insects to extract those parasites. Only then could they make the vaccine.
"The speed with which they were able to get enough material surprised me," Fauci said. "I thought they would never be able to do it. And they did it - and they did it very quickly and in a large amount."
The current vaccine is delivered intravenously and not through injections, which could be impractical for use in a widespread vaccination program.
"Now we've got to figure out a way to deliver it in a way that's practical for mass vaccination programs," Fauci said.
Scientists from the Walter Reed Army Institute of Research and the Naval Medical Research Center participated in the study, which also holds out hope for finally shielding US military personnel stationed in areas with the disease.
A statement from the Navy said malaria was responsible for "a greater loss of manpower than enemy fire in all conflicts occurring in tropical regions during the 20th century."
Notice the quote
"Now we've got to figure out a way to deliver it in a way that's practical for mass vaccination programs," Fauci said.
Inovio is working on solving that very big problem
Inovio Pharmaceuticals & U.S. Army Receive $3.5 Million Biodefense Grant to Further Develop Mass Vaccination Device
Inovio to Advance Painless Device to Simultaneously Deliver Multiple Vaccines Using Electroporation Technology
Apr 10, 2013
BLUE BELL, Pa., April 10, 2013 /PRNewswire/ -- Inovio Pharmaceuticals, Inc. (NYSE MKT: INO) has been selected to receive a $3.5 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) to advance the development of its next generation DNA vaccine delivery device capable of simultaneously administering multiple synthetic vaccines via skin surface electroporation. Inovio is collaborating with Dr. Connie Schmaljohn, Chief Scientist at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). The goal of this public/private partnership is to develop a device that would facilitate rapid vaccination of U.S. troops stationed around the world against multiple infectious diseases and protect civilian populations from pandemic threats.
Dr. J. Joseph Kim, Inovio's president & CEO, said, "This new device would provide a means to rapidly and painlessly deliver multiple vaccines simultaneously to large groups of people. This collaboration builds on Inovio's strong relationship with Dr. Schmaljohn and her team at USAMRIID in which Inovio is bringing medical innovation to several biodefense efforts. Moreover, the advancements from this project will enable rapid and efficient delivery of Inovio's SynCon® vaccines for universal flu, HIV, and other infectious diseases on a mass scale."
The Inovio team of researchers has been collaborating with USAMRIID scientists to advance a DNA vaccine for the Lassa virus, which the DOD has designated as a "Category A" pathogen. In previous testing, an optimized DNA vaccine for the Lassa virus delivered by surface electroporation demonstrated complete protection against a virus challenge in both guinea pig and non-human primate disease models. Although prior results are highly encouraging and electroporation delivery is very tolerable from a patient perspective, improvements are still needed to make the technology more suitable for multiple vaccine administrations and mass vaccinations.
This NIAID grant builds on a 2011 Small Business Innovation Research Grant in which Inovio demonstrated a delivery device that was designed to deliver two separate DNA vaccines simultaneously. In this new program, Inovio will develop the multi-vaccine electroporation delivery device to address biodefense vaccine targets – notably to advance the Lassa virus vaccine through to clinical studies.
The research effort will investigate the novel simultaneous delivery of multiple DNA vaccines — final testing will use the Lassa virus and other arenaviruses — at distinct spatial sites while avoiding immune interference between vaccines. In addition, this new device platform could significantly increase the dose of vaccine delivered at one time which is a current limitation in vaccine delivery to the skin. The new skin surface device resulting from this research will leverage Inovio's latest surface DNA vaccine delivery technology, based on the company's proprietary electroporation delivery platform which uses millisecond electrical pulses to dramatically improve cellular uptake of the vaccine and resulting immune responses. Inovio vaccines delivered with electroporation devices for cancer and infectious diseases have previously demonstrated best in class T-cell and antibody responses in clinical studies.
FDA's chief drug tester Dr. Janet Woodcock discusses the "breakthrough" designation program that's winning praise from drug-makers
http://www.bloomberg.com/video/america-s-drug-approver-QyPUT8OBQXCdIoEiA3gTQw.html
Making vaccines “on demand”: A potential solution for emerging pathogens and biodefense? Published 2013-07-22
this is not an ino abstract but this study re confirms ino's potential future role in stockpiling biodefense vaccines which i believe will be there fastest way to profitability
http://www.landesbioscience.com/article/25611/full_text/#load/info/all
Anne S De Groot, 1, 2, * Leo Einck, 1 Leonard Moise, 1 Michael Chambers, 3 John Ballantyne, 3 Robert W Malone, 4 Matthew Ardito, 1 William Martin 1
Abstract
The integrated US Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) has made great strides in strategic preparedness and response capabilities. There have been numerous advances in planning, biothreat countermeasure development, licensure, manufacturing, stockpiling and deployment. Increased biodefense surveillance capability has dramatically improved, while new tools and increased awareness have fostered rapid identification of new potential public health pathogens. Unfortunately, structural delays in vaccine design, development, manufacture, clinical testing and licensure processes remain significant obstacles to an effective national biodefense rapid response capability. This is particularly true for the very real threat of “novel pathogens” such as the avian-origin influenzas H7N9 and H5N1, and new coronaviruses such as hCoV-EMC. Conventional approaches to vaccine development, production, clinical testing and licensure are incompatible with the prompt deployment needed for an effective public health response. An alternative approach, proposed here, is to apply computational vaccine design tools and rapid production technologies that now make it possible to engineer vaccines for novel emerging pathogen and WMD biowarfare agent countermeasures in record time. These new tools have the potential to significantly reduce the time needed to design string-of-epitope vaccines for previously unknown pathogens. The design process—from genome to gene sequence, ready to insert in a DNA plasmid—can now be accomplished in less than 24 h. While these vaccines are by no means “standard,” the need for innovation in the vaccine design and production process is great. Should such vaccines be developed, their 60-d start-to-finish timeline would represent a 2-fold faster response than the current standard.
The Problem: Delayed Response to Emerging Infections and Biowarfare Attacks
According to the Commission on the Prevention of Weapons of Mass Destruction (WMD) Proliferation and Terrorism, medical counter-measures such as vaccines are critically important for protecting first-responders and non-combatant (civilian) populations from the consequences of a bioterror attack. In 2008, Bob Graham (D-FL) and Jim Talent (R-MO), chairs of the WMD commission and authors of World at Risk, reported that the United States was “seriously lacking” in this vital capability.1 The 2009 H1N1 influenza pandemic highlighted continued weaknesses in the national preparedness system; as a consequence, Graham and Talent gave US bio-defense preparedness an “F” in their follow-up report, published in 2010.2 The Governmental Accounting Office (GAO) also reported poor inter-agency coordination on biodefense.3,4 As a result of renewed emphasis on biodefense, the United States government has expended substantial resources on protecting the nation against a potential bioterror attack, creating specialized units for planning and preparedness within the Departments of Health and Human Services, Defense, Homeland Security, Agriculture, Commerce and State.
4
Vaccine production infrastructure has also improved due to significant investments by the Federal government. For example, there are now several federally subsidized “Advanced Development and Manufacturing” production facilities distributed in different regions of the country that are capable of producing millions of doses of protein-based vaccines.5 Unfortunately, despite these important advances in the strategic preparedness of US agencies for biodefense, vaccine design remains a significant obstacle to national biodefense. This is particularly true for the very real threat of as-yet-undetermined pathogens for which little is known about their critical antigenic determinants and correlates of immunity, the key parameters used in vaccine design for conventional pathogens.
1
A Proposed Solution: Design and Delivery of “Vaccines on Demand”
Recent reports6 of a novel H7N9 avian influenza virus emerging in China have led to even greater scrutiny of methods used to respond to infectious disease public health threats and have, in turn, provided for a “live fire” assessment of novel approaches. In 2009–2010, the FastVax group began to discuss whether existing tools and vaccine production platforms could be used to accelerate the development of vaccines for emerging infectious diseases, as illustrated in Figure 1. Traditional vaccine development for previously unknown pathogens takes place on the time scale of years. The accelerated process, as proposed by our group, would begin with analysis of the genomic sequence of an emerging pathogen with immunoinformatics tools, followed by rapid design of an epitope-based vaccine containing the most immunogenic components, using an integrated in silico approach illustrated in Figure 2. Once the vaccine is designed, production and testing would involve a four-step process undertaken by the FastVax consortium arrangement, as described below.
2
1
Several constraints affecting the proposed approach bear mentioning; each of these is addressed in turn.
T cell epitope-based vaccines provide the minimal, essential information required for protective immunity T cell epitopes are critical mediators of cellular immunity. They are derived from a pathogen’s proteins via two pathways: (1) intracellular proteins are processed, and their constituent peptides are loaded onto major histocompatability complex (MHC) class I molecules; and (2) exogenous proteins are processed in the proteolytic compartment, and their constituent peptides are loaded onto MHC class II molecules. MHC class I and class II-peptide complexes are then transported to the surface of an APC, where they are exposed to interrogation by passing T cells (CD8+ and CD4+ T cells, respectively). From these different antigen processing and presentation pathways, two distinct T cell responses are generated: (1) a CD8+ cytotoxic T lymphocyte immune response that is critical for pathogen clearance, and (2) a CD4+ T helper immune response that is essential for robust and sustained antibody and cytotoxic T lymphocyte responses. After initial exposure to pathogen, memory T cells are established that respond more rapidly and efficiently upon subsequent exposure.
Because epitopes provide the essential information needed to trigger a protective immune response, epitope-based vaccines can be developed to recreate this response. Given the lengthy process that is usually associated with the development of killed, live-attenuated and whole-subunit vaccine approaches, an epitope-based strategy is one rational alternative, particularly when no vaccine exists and an emerging pathogen threatens human health on a global scale.
T cell epitopes do not protect against infection; however, they may protect against disease
There is published evidence demonstrating that epitope-based vaccines can be protective. Vaccination with peptide epitopes stimulates protective immune responses in a range of animal models, including complete protection of BALB/c mice against RSV challenge,8 partial protection of BALB/c mice against Plasmodium yoelii sporozoite challenge,9 partial protection of BALB/c and CBA mice against encephalitis following intracerebral challenge with a lethal dose of measles virus,10 complete protection of BALB/c mice from intraperitoneal HSV challenge,11 high degree of protection of BALB/c mice against infection with malaria or influenza A virus,12 full protection of sheep against BLV,13 and full protection of horses against West Nile Virus.14 Furthermore, experts are generally in agreement that cross-reactive T cell epitopes were responsible for the limited morbidity and mortality associated with pandemic H1N1 in 2009.15-17 The absence of T cell epitopes may be contributing to the rapid spread and significant mortality rate of H7N9 in China.18 T cell epitope-related immune responses appear to be critically important for reducing morbidity and mortality in human infectious disease.19
11
No “Fast Track” to vaccine-on-demand approval is currently possible under existing FDA regulations
Epitope-driven vaccines offer distinct advantages that should contribute to a reconsideration of the current vaccine approval process for emergency use. Multiple epitopes derived from more than one antigen can be packaged together in a single cassette. In this way, a broad-based immune response directed against multiple antigenic proteins associated with the pathogen can be elicited without the need to manufacture and administer large quantities of protein, much of which will be immunologically irrelevant or potentially even reactogenic. This is likely to reduce formulation challenges, decrease cost and accelerate the development process. The use of epitopes also helps to mitigate potential safety concerns stemming from the use of intact recombinant proteins that may have undesired biological activity (e.g., enzymes, immunomodulators, cross-reactivity, toxins, etc.). For example, the NP protein of Lassa has been associated with immune-suppressive activity.20 Genome sequencing, immunoinformatics tools and the epitope-driven approach now make it possible to develop vaccines on demand in response to emerging pathogens.
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A Four-Step Process to Design and Deliver “Vaccines On Demand”
Step one: Genome-derived, epitope-driven vaccine strategy (GD-EDV)
The first step to making “faster vaccines” is to design vaccine immunogens directly from pathogen genomes.21 For example, for emerging influenza strains, the vaccine “payload” is constructed in silico using the pathogen genome sequence provided by the World Health Organization (WHO) or posted on GISAID (http://platform.gisaid.org/). T cell epitope-mapping algorithms that are integrated in a “vaccine design toolkit” developed by Martin and De Groot are applied to the genome sequences.22 These tools derive and concatenate those epitopes that have a high likelihood of driving an effective T cell response into a “string-of-beads” format for insertion into a vaccine delivery vehicle. The process can be performed in less than 24 h; the exact length of time required for the analysis depends on whether comparisons have to be performed to other existing genomes and epitopes. Tools for carrying out the task have been applied to the development of vaccine candidates for SARS,23 2009 H1N1 pandemic influenza,24 smallpox,25 and a number of other emergent and biowarfare agents, such as West Nile Virus, H. pylori and Burkholderia.7,26-28 Most recently, the tools were applied in May 2013 to the design of a vaccine for H7N9, an emerging avian-origin influenza (Fig. 2).29 The integration of epitope mapping into a step-by-step vaccine design process makes it possible to design vaccines in the shortest time possible once the DNA sequence from the emerging infectious disease or biowarfare pathogen is available. Should errors later be found in the sequence, they may impact one or two epitopes. For an epitope-based string of beads vaccine, the overall impact would be minimal, since T cell epitopes are linear; in contrast, sequence variations may compromise the structural integrity of a whole protein vaccine with negative effects on immunogenicity.
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How many epitopes?
Available evidence from animal studies suggests that the number of vaccine components (epitopes) required for full protection against disease is a small and definable subset that can be discovered using state-of-the-art computer programs such as the ones described and validated by EpiVax.30,31 We have proposed that any FastVax vaccine would include a minimum of 100 broadly reactive T cell epitopes in several strings, designed to induce multi-functional immune responses that are essential for protective immunity.32 Careful selection of the vaccine components, comprising epitopes covering most common HLA, can provide greater than 99% coverage of diverse human populations.33
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Need for adjuvants?
Currently, MF59 and AS03, both oil-in-water emulsions, and virosome, a liposome formulation, are three adjuvants licensed for use in seasonal, pre-pandemic and pandemic influenza vaccines. No influenza vaccines containing adjuvant are FDA approved. T cell epitope vaccine responses may be enhanced through genetic immunization.34 DNA vaccines are self-adjuvanting through co-encoded sequences, and thus many such vaccines do not incorporate traditional adjuvants in their final formulation. A number of strategies that are currently being evaluated may improve DNA vaccine potency for humans, including use of more efficient promoters and codon optimization, addition of traditional or genetic adjuvants, electroporation and intradermal delivery.35
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Step two: Manufacturing and production
Reliable, reproducible methods for producing vaccines are currently available. The FastVax consortium favors DNA vaccines because production is scalable, the vaccines are stable at room temperature, manufacturing can be easily distributed to different geographic locations, and the production method is more rapid than many other vaccine manufacturing technologies. Alternative scalable and rapid production methods for accelerated vaccine production include plant-derived vaccines, phage-based vaccines and recombinant vaccines produced in cell culture. Proteins produced using each of these systems have been approved by the FDA for use in humans.
Rapid production of DNA vaccines
The initial vaccine sequence designed in silico can be electronically provided to a production facility, where a cassette representing the vaccine genetic construct(s) is then synthesized and inserted into a standardized DNA vaccine plasmid. A cGMP seed lot of bacteria containing the vaccine plasmid with cassetted payload can be rapidly produced and vialed using existing SOPs for release and characterization assays. An initial manufacturing lot of plasmid vaccine would be produced from the seed lot and used to initiate safety studies. To reduce time to produce sufficient vaccine product, multiple scale-up facilities could be located in different regions of the US. Using current methods of DNA vaccine development, seed lot production would take one to three weeks. Scale-up for DNA production is much more rapid than traditional vaccine designs; only three to four weeks would be required to produce one million doses per facility. See below for discussion of Biological Agents Research Defense Agency (BARDA) appropriations for the construction of distributed vaccine production facilities.
The DNA vaccine delivery platform and rational in silico design provide for a strong safety profile. The DNA vaccine manufacturing process, particularly the efficient and stringent release criteria, allow for a highly pure and well-characterized final product. Rational design permits in silico analysis of the vaccine sequence for identification of potential unfavorable immune responses including regulatory sequences or cross-reactive immune responses. A fundamental principle of rapid biodefense vaccine production is that safety and speed are paramount for eliciting a protective immune response prior to the epidemic.
Delivery vehicle
The bulk vaccine product would then be coated onto pre-manufactured micro-needle patches that provide direct delivery to the dermis, or would be delivered using another skin-based method such as “scarification.” A number of self-applied patch delivery systems have already been developed. These would be optimal in bioterror and pandemic scenarios, because patches can be pre-manufactured and stored in bulk and do not require refrigeration for delivery or trained practitioners for administration.36 Vaccination centers would not be required, which would minimize transmission of the biothreat organism between patients and health care providers. Alternatively, previously approved electroporation delivery methods37 could be used, though this would take more time and increase the need for vaccine administration personnel training, leading to an escalation of the vaccine administration expense and more protracted timelines.
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Step three: Clinical trials
While there are no Phase III or FDA-approved DNA vaccines, there are more than 30 Phase II trials listed in clinicaltrials.gov. FDA approval of a DNA vaccine appears to be on the horizon, but until then, the FastVax DNA vaccine may encounter an additional FDA-associated barrier. Implementation of a previously untested vaccine is only possible after rapidly completing initial clinical testing to the point that “emergency use authorization” can be invoked by the Secretary of Health and Human Services (HHS). In some biodefense scenarios, approximate correlates of protection may have been previously identified; such is the case with Lassa Fever, Ebola, the encephaloviruses, and a number of other “Category A, B and C” biodefense pathogens. In some cases, correlates of protection are unknown, and either an antibody-focused or a T cell-driven vaccine may prove effective. Where antibody-mediated immunity is critically important, T cell-driven vaccines still merit attention as potential adjuncts to more traditional whole-antigen (B cell-driven) approaches, since T cell help drives higher titer, higher affinity antibody responses. Especially in settings where challenge studies cannot be performed in advance of use in humans, licensure may be possible by means of the “Two Animal Rule” in lieu of a human correlate. Rapid clinical testing can be achieved using existing commercial clinical research organizations and clinical site networks such as the Medical Countermeasures Clinical Studies Network currently envisioned by ASPR/BARDA. Emergency use authorization approval can be based on achievement of “correlates” such as induction of broadly protective T cell or antibody responses, provided an allowed Investigational New Drug (IND) Application is in hand.
One problem facing T cell-driven vaccines that are designed to stimulate HLA-restricted human immune responses is that testing for correlates of immunity as described in the “Two Animal Rule” may not demonstrate the true efficacy of the product. Thus alternative approaches may need to be considered.
The MIMIC assay, a comprehensive measurement of localized reactogenicity, could be utilized for initial safety studies and to qualify release of the actual vaccine intended for emergency use.38 Additionally, in pandemic response simulations, “mock up” or example vaccines (in a specific DNA plasmid backbone) and patch delivery system could be submitted for approval by the FDA, and this formulation would be evaluated in the clinic for immunogenicity that recapitulates the influenza correlates of protective immunity already defined by CBER and EMA. Correlates of protective immunity for currently approved influenza vaccines will not serve as a basis for regulatory approval of a DNA vaccine. The FDA would require correlates to be determined for a new influenza vaccine and will not rely on related, but different, vaccines already approved. Advance trials will establish correlates of protection for a FastVax influenza vaccine to serve as a basis for regulatory review in an emergency. In a pandemic, a novel FastVax sequence composition might be rapidly tested in a small, swiftly completed safety and immunogenicity trial, much like EMA precedence for annual influenza vaccine updates.
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Step four: Approval and emergency use authorization
One means of obtaining initial FDA review, experience and oversight for the FastVax vaccine-on-demand system would be to firmly establish the immunogenicity of an existing, clinical-trial-ready DNA influenza virus vaccine in a patch or scarification delivery system. Demonstration that the vaccine candidate meets influenza correlates of protection criteria with an acceptable profile in human trials would inform regulatory review for products of similar composition, much as current regulatory policy supports annual marketing re-authorization despite changes in influenza subunit vaccine composition (from trivalent to quadrivalent) to reflect seasonal shifts and drifts.
Timely approval by the FDA to allow distribution of product in response to a rapidly emerging threat would require close cooperation between the vaccine manufacturer and the Agency. The manufacturer can assist by providing clinical safety and efficacy data for a variety of vaccine products based on standardized vaccine platform, manufacturing, specifications, operating procedures and method of delivery. If the manufacturer can establish predictable immunogenicity of epitopes in a demonstrated safe and reproducible vaccine platform and rapidly perform Phase I and Phase II trials establishing safety and immunogenicity in terms of a surrogate endpoint that predicts clinical benefit, the Agency may be able to provide a rapid review and emergency use allowance/authorization; release of the vaccine would then be possible through emergency use authorization by the HHS Secretary.
Scale up
To reduce the time to vaccine production, manufacturing sites could be pre-inspected and maintained at a state of operational readiness. While this would involve redundancy and higher costs, it would allow for the rapid production and scale-up of vaccines at any given moment. Each site would need to utilize the same manufacturing process to ensure consistency across vaccine batches, and entities would need to be willing to share their specific methodologies to harmonize an approach. One site would create the master cell bank (MCB), and then generate the manufacturer's working cell bank (MWCB) for distribution to all other sites. In order to reduce production time by two weeks, this step would be performed “at risk,” meaning MWCBs would be distributed prior to the completion of testing on either the MCB or MWCB. Sequencing on the MCB could likely be completed before the MWCB goes into fermenter starters. Assuming that a dose would constitute 0.2 mg of DNA vaccine and that each site has several 240 L fermenters (either as back-ups or for parallel growth), one million doses (200 g) per site could be produced in a three- to four-week period. BARDA recently invested hundreds of millions of dollars in distributed influenza vaccine production; adapting these facilities for DNA vaccine production would be an added but not insurmountable expense (as compared with the initial investment).39
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An in vitro assay like the MIMIC system could serve as a release characteristic of the multi-site lots that would run in parallel with the patch loading, preventing a single problematic DNA vaccine batch from impeding the release of patches generated with other batches. If the backbone-host system is proven to be rugged with virtually any type of insert, a pilot run would no longer be necessary. Conversely, if the system is not shown to be rugged, then pilot runs would be important, as some inserts can greatly influence stability and growth characteristics. Such pilot runs would need to be undertaken at every facility, most likely with different methods tested, to maximize the likelihood of determining the best method for production.
Summary
A number of technological advances are moving T cell-driven vaccines to the foreground with lessons applicable to influenza T cell-driven vaccine development. Perhaps the most prominent example of this new focus is the expanding use of T cell-driven immunotherapy as an adjunct to cancer therapy. Many of the barriers to effective T cell-driven vaccine development are being addressed and surmounted in clinical cancer trials. For example, dendritic-cell pulsing vaccines using tumor antigens have moved into clinical use.40,41 Outcomes of these types of vaccination protocols have improved as MHC class II epitopes (CD4+ T cell help) were included42 and antibodies against cytotoxic T lymphocyte antigen-4 (anti-CTLA-4; see ref. 43) and other anti-T regulatory cell (Treg) agents have been added to the conditioning regimen.
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Quite a few T cell-driven vaccines are currently in human clinical trials (reviewed by Gilbert in 2012; see ref. 44). While it is true that infectious disease T cell-driven vaccines have lagged behind T cell-driven vaccines for cancer, the regulatory pathway for T cell vaccines is improving, since more than 250 cancer vaccines that are based on T cell-driven immune responses are in clinical trials.a Furthermore, recent challenge studies have shown that humoral immunity is not required for protection against all human pathogens. This was demonstrated in the case of influenza, following vaccination of study participants with a multi-antigen vaccine. Following exposure to live influenza virus, two of 11 vaccinees and five of 11 control subjects developed laboratory-confirmed influenza (symptoms plus virus shedding). Symptoms of influenza were less pronounced in the vaccinees and there was a significant reduction in the number of days of virus shedding in those vaccinees who developed influenza (mean of 1.09 d in controls, 0.45 d in vaccinees, p = 0.036)45,46 for a final efficacy of 60%, which is better than many vaccines currently available.
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This is a major milestone for T cell vaccines for infectious disease, as it is one of the first vaccines to reach a Phase 2 clinical trial and none have reached Phase 3. While one cannot directly extrapolate from this trial nor the many cancer T cell-driven immunotherapy trials to state that the approach will work for all types of vaccines against infectious disease, successful implementation of the T cell-driven approach in a range of contexts suggests that it is worth pursuing.
Immunome-mining (computational immunology) tools have played a major role in the design and development of T cell-driven vaccines for infectious diseases. The process was first termed “vaccinomics” by Brusic and Petrovsky in 2002,47 then “reverse vaccinology” by Rappuoli in 2003,48 and more recently, “immunome-derived or genome-derived vaccine design” by Pederson,49 De Groot and Martin,50 and Doytchinova, Taylor, and Flower.51 The concept behind these descriptors is that a minimal set of antigens that induces a competent immune response to a pathogen or neoplasm can be discovered using immunoinformatics, and that administration of these epitopes in the right delivery vehicle and with the correct adjuvant will result in a degree of protection against infection by the pathogen. In short, the T cell-driven approach to developing vaccines is based on these fundamental principles: Payload + Adjuvant + Delivery vehicle = Vaccine.
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T cell-driven vaccines also offer some significant advantages over conventional vaccines for infectious diseases. For example, despite strain-to-strain variation at the protein level, immunoinformatics tools can be used to identify highly conserved T cell epitopes that are immunogenic and broadly representative or universal, covering a wide range of variant strains; our group has published results for TB, HIV, smallpox, HCV and H. pylori,16,52-58 and additional evidence can be found in literature published by other gene-to-vaccine researchers (e.g., Sette and Newman, Brusic, Petrovsky, Reche, and He). Concatenation of multiple epitopes, either from a single organism or from multiple pathogens in a single delivery vehicle, has been shown to elicit broad-based immune response directed at the epitopes and is associated with improved efficacy when compared with the whole organism (lysate) in animal challenge studies.59,60 Furthermore, epitope-based vaccines limit the antigenic load, diminishing the need to manufacture and administer large quantities of immunogen, much of which is immunologically irrelevant. In an important advance for T cell-driven vaccines, new tools (e.g., JanusMatrix; see ref. 61) may enable vaccine developers to select potent T effector epitopes, and to differentiate these from Treg-activating epitopes and/or self-cross-reactive epitopes that may lead to immunopathogenic responses (Losikoff P, et al. Forthcoming).62-64
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Over the past five years, the authors of this report have advanced a number of T cell-driven vaccines described to the point of formulation and delivery studies. Vaccines for many of the high-priority biodefense pathogens and emerging or re-emerging infectious diseases under development are not currently available, and evidence that T cell-mediated immune response is critically important for protection against these pathogens is emerging.
Members of the FastVax consortium are well aware that there are many obstacles to overcome before the proposed “rapid response” or FastVax platform for biodefense vaccines can be implemented. Nonetheless, there is a critical national need for an accelerated vaccine design, development and production process that can be accomplished in weeks, not months, in the event of a serious infectious disease outbreak or biowarfare attack. The development of a rapid response to emerging infectious disease threats, using best-in-class technologies to provide a first line of defense, will contribute to greater biodefense preparedness and a significant improvement in the ability of the US to protect its citizens against pandemic infectious diseases. The need for new vaccines for protecting against bioterror pathogens and emerging infectious disease is great, and we would argue that, for the reasons cited above, the time to advance these vaccines to the clinic is now.
Your correct the ichor device was used in that study
http://www.landesbioscience.com/article/25611/full_text/#load/info/all
your welcome please read this article, it will shed light on why many big government contracts will be coming in the following years
http://www.washingtonpost.com/politics/federal_government/at-the-forefront-of-vaccine-research-to-safeguard-the-military/2013/08/05/cd45151e-fe18-11e2-96a8-d3b921c0924a_story.html
here is the link above...below is a link on her connection with inovio
http://vaccinenewsdaily.com/news/323919-inovio-pharmaceuticals-receives-3-5-million-niaid-grant-for-mass-vaccination-device/
Updated: Tuesday, August 6, 3:00 AM
At the forefront of vaccine research to safeguard the military
Connie Schmaljohn(Inovio's partner in the goverment)
Since she was a young girl, Connie Schmaljohn knew she wanted a career that involved saving lives. More than 30 years ago, she started down the professional path toward achieving that dream by becoming an Army research scientist and working on vaccines to prevent diseases not typically found in this country, but which afflict members of the military overseas.
Schmaljohn, now an internationally recognized expert on Hantaviruses and hemorrhagic fever with renal syndrome, uses molecular biology tools to develop and test vaccines for a range of viruses. She and the scientists in her lab use recombinant DNA, a form of artificial DNA, to take the genes out of potentially deadly viruses so they are no longer infectious.
“We like to call them next-gen vaccines,” said Schmaljohn, a senior research scientist for the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) in Frederick, Md.
Research scientists at USAMRIID were among the first to use these DNA vaccines. “We’re always in the forefront of what the technological state of the art is and then we push it further,” Schmaljohn said.
Schmaljohn’s expertise enabled her and her colleagues to identify what was going on when the number of cases of Hantavirus Pulmonary Syndrome (HPS) exploded in the southwestern part of United States in the 1990s. Previously, the severe, sometimes fatal, respiratory illness due to Hantavirus infections was not known to cause disease in the Western hemisphere, and Hantaviruses had only been associated with kidney failure diseases in Asia and Europe.
But then HPS started felling people here.
“Because of the groundwork she had done, she was able to identify the outbreak in the Four Corners as Hantavirus,” said Jean Patterson, chairman of Virology and Immunology at the Texas Biomedical Research Institute in San Antonio, referring to a region comprising parts of Arizona, Colorado, New Mexico and Utah. “It was the first time it was identified in America.”
Historically, USAMRIID has blazed medical trails, since the military serves all over the world and comes into contact with viruses not found in the United States and therefore aren’t widely studied here, said Colleen Jonsson, director of the Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases at the University of Louisville.
“They were the frontline for exotic pathogens predominantly because soldiers serve in many, many countries,” she said. After 9/11, the National Institutes of Health also started sponsoring research to study these agents, she added.
Schmaljohn’s work on dangerous pathogens may be aimed at protecting military personnel, but the benefits spill over into the civilian population, as the Hantavirus outbreak demonstrated.
Her lab works on two types of vaccines: those that protect against medical infectious diseases and those that defend against agents that could be used as weapons in biological warfare.
Researchers at USAMRIID were the first to start testing DNA vaccines for biodefense, using a method of delivering DNA vaccines with a short electrical burst. The first study of this electroporation method dispensed a vaccine to muscle in a clinical study at Walter Reed Army Medical Center with two vaccines for Hantaviruses.
The next study will deliver the vaccine to the skin instead of muscle, a less invasive, less painful method. Schmaljohn hopes the immune response will be even better.
Schmaljohn decided early on she wanted help save lives. She calls the story silly now, but she was watching a TV show, in which a little girl’s mother died from a disease. “I said, ‘That’s not right.’ ”
At first she thought she was going to be a doctor, but realized she preferred the broader reach of medical research. “I wanted people to not die of disease,” she said.
Schmaljohn describes the experiments she performed—and planned, designed and tested—as the highlight of her career. “Every top moment has to do with an experiment,” she said. “I don’t know how many years I’ve gone to parties or dinners and said, ‘I have to go check my experiment.’ It was a rollercoaster of emotion. Did it work? Did it not work?”
Schmaljohn now mostly manages other scientists, but experiences “vicarious happiness,” through the people who work for her, she said. She continues to focus on keeping soldiers healthy and safe.
“My job is to bring the newest technology to the Army and improve our science, and make us be at the very front of what we can do to protect the military from disease.”
This article was jointly prepared by the Partnership for Public Service, a group seeking to enhance the performance of the federal government, and washingtonpost
ya this is the 2nd part of the study the therapeutic side,im under the impression this data will be released via peer review or pr..this was just a poster from that mtg analysis of this info is what were waiting for
March 5th at the CROI conference 2013
Potent Cellular Immune Responses Induced after Therapeutic Immunization of HIV+ Patients with PENNVAX-B DNA Vaccine Delivered by Electroporation
Lorenzo Ramirez*1, T Arango1, D Shah2, M Morrow2, J Lee2, M Naji1, K Maffei3, M Bagarazzi2, P Tebas3, and J Boyer1
1Univ of Pennsylvania Perelman Sch of Med, Philadelphia, US; 2Inovio Pharmaceuticals, Blue Bell, PA, US; and 3Univ of Pennsylvania, Philadelphia, US
Background: The goal of eradicating the HIV reservoir has renewed interest in immunotherapeutic approaches to boost T cell responses against HIV+ cells. However, individuals chronically infected with HIV respond poorly to T cell vaccines. We evaluated the use of PENNVAX-B vaccine (a gag, pol, and env combination DNA vaccine) delivered by in vivo electroporation (EP) that has proven immunogenic in HIV– individuals (HVTN 080).
Methods: We conducted a phase 1 study in well controlled, ART treated, HIV+ individuals (HIV RNA <75 copies/mL, current CD4 >400/µL, and nadir CD4 cells >200 cells/µL). Subjects received 4 doses (at day 0, weeks 4, 8, and 16) of 3 mg PENNVAX-B (consisting of consensus sequence HIV gag, pol, and env immunogens) intramuscularly followed by EP. Standard IFN-? ELISpot assays were performed. Positive responses were determined using a one-way ANOVA followed by Dunnett’s test, comparing each time-point to baseline. We measured the potential of cells to lyse HIV-1+ cells by measuring CD8+CD107a+ Perforin+ Granzyme B+ responses, by standard flow cytometry. Subjects were considered responders to the vaccine if responses were 50% greater than baseline. Also, the subjects’ pre-vaccination cytokine profiles were examined using a 30 cytokine Luminex plasma assay. We compared baseline cytokine profiles of the subjects who responded via ELISpot or Flow assays to those who did not respond.
Results: 12 subjects were included. 92% were male and 58% black. The vaccine was safe and well tolerated. 10 of the 12 subjects (83%) showed significant vaccine-specific T cell responses in the form of IFN-? ELISpot to at least 1/3 vaccine antigens (gag, pol, or env) throughout the immunizations. ELISpot responses were primarily mediated by CD8+ T cells. 9/11 subjects tested showed a positive CD8+CD107a+ Perforin+ Granzyme B+ response. HIV-1+ individuals, despite having well-controlled viral replication showed significantly different cytokine profiles compared to healthy controls. Importantly, baseline IL-12 p70, and MCP-1 levels were directly associated with response to the HIV-1 therapeutic vaccine.
Conclusions: PENNVAX-B induced HIV-specific CTL responses in well-controlled HIV+ individuals. The pre-vaccination cytokine environment may provide the necessary signals for T cells to respond to therapeutic vaccination, suggesting that the cytokines examined could serve as potential adjuvants in a therapeutic vaccine strategy.
go their website spend a few days there learn a little bit
Tom..what if any insight do you have regarding if inovio has or plans on applying for breakthrough status for any of there treatments or any other kind of of special fda status? I thought you might have some good insight on this or an a opinion? As always thanks for your informative post.
ABSTRACT
A vaccine candidate that elicits humoral and cellular responses to multiple sporozoite and liver-stage antigens may be able to confer protection against Plasmodium falciparum (Pf) malaria, however, a technology for formulating and delivering such a vaccine has remained elusive. Here, we report the preclinical assessment of an optimized DNA vaccine approach that targets four Pf antigens: circumsporozoite protein (CSP), liver stage antigen 1 (LSA1), thrombospondin-related-anonymous-protein (TRAP), and cell-traversal protein for ookinetes and sporozoites (CelTOS). Synthetic DNA sequences were designed for each antigen with modifications to improve expression, and were delivered using in vivo electroporation (EP). Immunogenicity was evaluated in mice and non-human primates (NHPs) and assessed by ELISA, IFN? ELISpot, and flow cytometry. In mice, DNA+EP delivery induced antigen-specific IFN? production as measured by ELISpot and IgG seroconversion against all antigens. Sustained production of IFN?, IL-2 and TNFa was elicited in both the CD4+ and CD8+ T cell compartments. Furthermore, hepatic CD8+ lymphocytes produced LSA1-specific IFN?. The immune responses conferred in mice by this approach translated to the NHP model showing cellular responses by ELISPOT assay and intracellular cytokine staining. Notably, antigen-specific CD8+ Granzyme B+ T cells were observed in NHPs. Collectively, the data demonstrate that delivery of gene sequences by DNA/EP encoding malaria parasite antigens is immunogenic in animal models and can harness both the humoral and cellular arms of the immune system.
Inducing humoral and cellular responses to multiple sporozoite and liver stage malaria antigens using pDNA
B. Ferraro1, K.T. Talbott1, A. Balakrishnan1, N. Cisper1, M.P. Morrow3, N.A. Hutnick1, D.J. Myles1, D.J. Shedlock1, N. Obeng-Adjei1, J. Yan3, A. Kayatani4, N. Richie4, W. Cabrera4, R. Shiver1, A.S. Khan3, A.S. Brown3, M. Yang3, U. Wille-Reece2, A.J. Birkett2, N.Y. Sardesai3 and D.B. Weiner1?
- Author Affiliations
1University of Pennsylvania School of Medicine, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA, 19104
2PATH Malaria Vaccine Initiative, 455 Massachusetts Avenue, Suite 1000, Washington, DC 20001
3Inovio Pharmaceuticals, Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422
4US Military Malaria Vaccine Program, Division of Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910