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Posted: 22 Sep 2011
30 years in 30 weeks, 2001

Vaccine development traditionally used antibody titers as indicators of immunogenicity. However, the challenge of developing an HIV vaccine led researchers to explore other approaches. The paper presented this week describes one of the first efforts to elicit T cell responses and carefully document them after vaccination – both a technological and a conceptual advancement at the time (2001). Today, T cell assays are routinely used in HIV vaccine trials to assess immunogenicity.

Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine.
Science. 2001 Apr 6;292(5514):69-74.
Amara RR, Villinger F, Altman JD, Lydy SL, O'Neil SP, Staprans SI, Montefiori DC, Xu Y, Herndon JG, Wyatt LS, Candido MA, Kozyr NL, Earl PL, Smith JM, Ma HL, Grimm BD, Hulsey ML, Miller J, McClure HM, McNicholl JM, Moss B, Robinson HL.

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2000 < All years > 2002

Commentary by Drs. Robinson and Amara

Dr. Harriet Robinson
When we published this paper, we had not anticipated that it would be one of the most cited papers in 2001; but we were pleased with our results and excited about the potential of T cells to control immunodeficiency virus infections.  Our vaccine, which combined a DNA prime with a recombinant modified vaccinia Ankara (rMVA) boost, had not prevented infection of rhesus macaques with SHIV, but had controlled infection with a response recalled from long-term memory. Importantly, the vaccine, which had been inoculated parenterally, had controlled a mucosal challenge.

The experiment was our 3rd major trial in macaques and my first as a new Chief of Microbiology and Immunology at the Yerkes National Primate Research Center.  On arrival at Yerkes we had consolidated sequences previously expressed from 5 different DNAs into one DNA by using subgenomic splicing to express multiple proteins from a single RNA. Our very first macaque trial had shown that DNA vaccines, alone, would not provide protection1; our second had shown  that a DNA prime plus a poxvirus boost would be superior to a DNA prime plus a protein boost2.  I went to Bernie Moss, Chief of the Laboratory of Viral Diseases at the National Institutes of Health, whose laboratory was the first to develop poxvirus vectors, to seek council on poxvirus boosts. He recommended MVA, based on its safety record in humans, track record of eliciting good vaccine responses, and capacity to deliver gag-pol as well as env sequences. He also agreed to construct MVA vectors to be used as boosts for our DNA vectors, a collaboration that has lasted to this day.

Our 2001 study was one of the first to undertake detailed analyses of T cell responses using the new technologies of tetramer and intracellular cytokine staining. Rama Amara, a fellow, brought a green thumb to these analyses, which were made possible by the availability of the latest advances in flow cytometry at the Emory Vaccine Center.  Yerkes, with Harold McClure at the lead, enabled the non-human primate portions of the study.

Based on the results in the study, I co-founded GeoVax Labs Inc. for the commercialization of the DNA/MVA concept.  Currently the GeoVax clade B DNA/MVA vaccine is advancing in human clinical trials through the HIV Vaccine Trials Network (HVTN). A 120 participant Phase 1 trial has completed3 and a 300 person Phase 2a trial is near completion. In both trials the vaccine has shown good safety and elicited both T cell and antibody responses.  Recently, we advanced our initial concept by co-expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) in the DNA component of the vaccine.  The co-expressed GM-CSF enhanced the ability of SIV prototypes of the vaccine to prevent, not just control, infection in rhesus macaques4.  A GM-CSF co-expressing version of our clade B HIV vaccine is under production for testing by the HVTN and a GM-CSF co-expressing clade C vaccine is under development. Thus, we remain excited by the vaccine concept in the 2001 study and are actively pursuing its potential to provide the world a much needed HIV/AIDS vaccine.

  1. Lu, S., et al. Simian immunodeficiency virus DNA vaccine trial in macaques. Journal of Virology 70, 3978-3991 (1996).
  2. Robinson, H.L., et al. Neutralizing Antibody-Independent Containment of Immunodeficiency Virus Challenges by DNA Priming and Recombinant Pox Virus Booster Immunization. Nature Medicine 5, 526-534 (1999).
  3. Goepfert, P.A., et al. Phase 1 safety and immunogenicity testing of DNA and recombinant modified vaccinia Ankara vaccines expressing HIV-1 virus-like particles Journal of Infectious Disease 203, 610-619 (2011).
  4. Lai, L., et al. Prevention of Infection by a Granulocyte-Macrophage Colony-Stimualting Factor Co-Expressing DNA/Modified Vaccinia Ankara  Simian Immunodeficiency Virus Vaccine. The Journal of Infectious Diseases 204, 164-173 (2011).

About the author: Harriet L. Robinson is Chief Scientific Officer at GeoVax Labs, Inc. and Professor Emeritus at Emory University.

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