New DNA Weapon Against Avian Flu Identified

This approach could allow for the build up of vaccine reserves that could be easily and effectively dispensed in case of an epidemic.

"This is the first study to show that a single DNA vaccine can induce protection against strains of pandemic flu in many animal models, including primates," says David B. Weiner, Ph.D., Professor of Pathology and Laboratory Medicine. "With this type of vaccine, we can generate a single construct of a pandemic flu vaccine that will give much broader protection."

Traditional vaccines expose a formulation of a specific strain of flu to the body so it can create immune responses against that specific strain. Conversely, a DNA vaccine becomes part of the cell, giving it the blueprint it needs to build antigens that can induce responses that target diverse strains of pandemic flu.

Avian flu is tricky. Not only is it deadly, but it mutates quickly, generating different strains that escape an immune response targeted against one single strain. Preparing effective vaccines for pandemic flu in advance with either live or killed viruses, which protect against only one or few cross-strains, is therefore very difficult. How to predict which strain of avian flu may appear at any time is difficult. "We are always behind in creating a vaccine that can effectively protect against that specific strain," notes Weiner.

Instead of injecting a live or killed virus, Penn researchers injected three different species of animal models with synthetic DNA vaccines that are not taken from the flu microbe, but trick the immune system into mounting a broad response against pandemic flu, including strains to which the immune system was never exposed. Antibodies induced by the vaccine rapidly reached protective levels in all three animal species.

"The synthetic DNA vaccines designed in this study customize the antigen to induce more broad immune responses against the pathogen," says Weiner.

Researchers found evidence of two types of immune responses -- T lymphocytes and antibodies -- in all three types of animal models. Two types of animal models (mice and ferrets) were protected from both disease and mortality when exposed to avian flu.

To ensure increased DNA delivery, the researchers administered the vaccine in combination with electroporation, a small, harmless electric charge that opens up cell pores facilitating increased entry of the DNA vaccine into cells.

If proven in humans, this research could lead the way to preparing against an outbreak of avian flu. Because these synthetic DNA vaccines are effective against multiple cross strains, vaccines could be created, stockpiled, prior to a pandemic, and thus be delivered quickly in the event of an outbreak, surmise the researchers.

This study has shown other advantages of DNA vaccines. On one hand, killed vaccines, which involve the injection of a dead portion of a virus, are relatively safe but usually effective at producing only a strong cellular immunity. Live vaccines, which involve the injection of a form of a live virus, can have increased manufacturing and some safety issues. Both of these vaccine strategies may have concerns in persons with certain allergies (egg for example) as current manufacturing methods rely on egg based production technologies. On the other hand, DNA vaccines preclude the need to create live tissue samples, which presents risk to those working with the virus.

"DNA vaccines have the benefits and avoid many conceptual negatives of other types of traditional vaccines," says Weiner.

This research also has implications for non-avian types of flu. Every year, scientists try to guess what strain of the year will be that creates the common flu. Sometimes their educated guess is wrong, which is why last year's influenza vaccine worked only 30 percent of the time. Designing traditional vaccines in combination with the DNA platform may be a partial solution to this dilemma, predicts Weiner.

In addition to Weiner, Dominick J. Laddy, Jian Yan and Michele Kutzler from Penn; Darwyn Kobasa of the Public Health Agency of Canada; Gary P. Kobinger of the Public Health Agency of Canada and the University of Manatoba; Amir S. Khan, Ruxandra Draghia-Akli and Niranjan Y. Sardesai of VGX Pharmaceuticals; and Jack Greenhouse of Bioqual, Inc. were co-authors. VGX Pharmaceuticals and the National Institute of Allergy and Infectious Diseases provided partial funding for this research.

Dr. Weiner sits on the scientific advisory board of VGX, and collaborates with Wyeth, Merck, BMS, Althea, and Virxsys, as well as other companies on DNA vaccine technologies.

This study was published during the last week of June 2008 in

PLoS One

.

The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors [Hospital of the University of Pennsylvania;Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.