This month's featured paper is from the Nancy Haigwood lab, and is titled, "Co-Immunization with Multimeric Scaffolds and DNA Rapidly Induces Potent Autologous HIV-1 Neutralizing Antibodies and CD8+ T Cells" It was published in the journal PLos ONE. The research in this paper was conducted by scientists in the OHSU Division of Pathobiology and Immunology, Oregon National Primate Research Center and colleagues*
Mary Stenzel-Poore, PhD:
"Dr. Haigwood has assembled a team of experts in protein biochemistry, immunology and virology---each expertise necessary to solve the very difficult problem of creating effective vaccines against HIV."
According to estimates from UNICEF around 30.6 million adults and 3.4 million children under 15 years were living with HIV at the end of 2010. With no cure on the horizon, HIV vaccines are desperately needed to stem the tide of spread of HIV-1 and the devastation of AIDS worldwide.
The key element in the vaccine that can block the first steps of infection is a type of protein called a neutralizing antibody. For these antibodies to work, they must be present at the time of infection, as a result of vaccination. For this reason, a goal of vaccine makers is to figure out how to make a safe vaccine that produces these types of antibodies quickly and in high amounts.
"During HIV-1 infection, neutralizing antibodies are made in high quantities and are directed to a single protein on the outside of the virus called the Envelope," said Nancy Haigwood, PhD, Adjunct Professor, Department of Molecular Microbiology & Immunology, and ONPRC Director. "More precise mapping studies have shown exactly where on the Envelope protein these antibodies bind, so we know that these regions are the ones we would like to feature in our vaccine."
Previous research showed that there was a self-folding 60-subunit scaffold protein called E2 derived from a thermophilic bacterium (Geobacillus stearothermophilus).The E2 scaffold can display 60 copies of foreign proteins on its surface. Prior work from members of the Haigwood lab had shown that regions of the HIV-1 Gag protein and the enzyme reverse transcriptase could generate antibodies and T cells specific for the HIV-1 proteins.
The Haigwood group found they could use this E2 protein to express regions of the HIV-1 Envelope protein and generate high amounts of neutralizing antibodies in rabbits. The particles they made expressing a loop protein subunit called V3 from the HIV Envelope not only generated strong virus-blocking antibodies in rabbits that received the vaccine, but they also made antiviral T cells in immunized mice.
"The size and shape of the self-folding scaffolds look like virus particles to the immune cells in vivo and can generate T cells through a non-standard method that is still effective," said Dr. Haigwood. "We further demonstrated that the co-administration of DNA plasmids as vaccines along with the E2 particle vaccines made high levels of neutralizing antibodies in all of the rabbits, a novel finding."
Making neutralizing antibodies that are potent and rapidly induced is a benchmark that is important for all vaccines and may be widely applicable. "The vaccines that we are developing are easy and inexpensive to make," said Dr. Haigwood. "And they are very immunogenic in test animals after just a few shots. Results suggest that it is possible to generate immune responses that are potentially protective in a relatively efficient manner."
Dr. Haigwood's team is planning to test this E2 plus DNA approach for other parts of the HIV Envelope to generate different and even more potent neutralizing antibodies that are directed to regions shared by all HIV-1 isolates.To do this work, they will continue their collaboration with Dr. Piergiuseppe DeBerardinis in Naples, Italy, at the Institute for Protein Biochemistry.
"We may also expand our application of this technology to include vaccines for other infectious diseases," said Dr. Haigwood.
Pictured above: Nancy Haigwood, PhD
Juan Pablo Jaworski (1); Shelly J. Krebs1, Maria Trovato (2); Dina N. Kovarik (3); Zachary Brower (1); William F. Sutton (1); Garrett Waagmeester (1); Rossella Sartorius (2); Luciana D’Apice (2); Antonella Caivano (2); Nicole A. Doria-Rose (4); Delphine Malherbe (1); David C. Montefiori (5); Susan Barnett (6); Piergiuseppe De Berardinis (2); Nancy L. Haigwood (1, 3)
- Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon, United States of America
- Institute of Protein Biochemistry, C.N.R., Naples, Italy
- Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, United States of America
- Viral Vaccines Program, Seattle Biomedical Research Institute, Seattle, Washington, United States of America
- Duke University Medical Center, Durham, North Carolina, United States of America
- Novartis, Cambridge, Massachusetts, United States of America
ABOUT THE PAPER OF THE MONTH
The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, PhD.
"These studies offer extreme promise for vaccine strategies that require the generation of potent neutralizing antibodies for protection," said Mary Stenzel-Poore, Senior Associate Dean for Research. "Dr. Haigwood has assembled a team of experts in protein biochemistry, immunology and virology---each expertise necessary to solve the very difficult problem of creating effective vaccines against HIV."
More Published Papers
The entire list of OHSU papers published in February is here