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Working towards an HIV/AIDS vaccine

Biology in central Massachusetts. My first move in 1988 was from the Worcester Foundation, which did not have facilities for work with HIV, to the nearby University of Massachusetts Medical Center that had appropriate biocontainment facilities. While at the Worcester Foundation I had used recombinant avian retroviruses to deliver foreign genes to chickens. One series of experiments had used a recombinant with the avian influenza hemagluttinin (H5) gene to vaccinate chickens against “bird flu.” The vaccine trial, conducted in collaboration with Dr. Robert Webster, who had the appropriate containment facilities for a bird flu challenge, met with high success.3 All of the chickens survived the lethal challenge. One of the phenomena that intrigued me about the trial was the very low dose of a replication-defective retrovirus vector (~1 x 105 infectious units) that had achieved protection. Retroviruses exist in two forms: the viral form in which the genetic information is RNA; and the infected cell form, where the genetic information is DNA. I had used the viral form for the initial vaccine trials. It now struck me that I might be able to achieve sufficient antigen expressing cells using the DNA form. If all I needed was 105 antigen-expressing cells to vaccinate, I should be able to inject ~1013 DNA molecules (~100 ug of DNA representing the DNA form of the vaccine) and achieve 105 antigen expressing cells. We made as much of the DNA form as we could practically produce and sent it to Webster for testing. I knew this first test of a “DNA vaccine” had worked when I received the message from Webster: “Send More Vaccine.” We had protected all of the chickens against the lethal bird flu challenge. We initially kept our finding that DNA could be used to vaccinate very quiet to get patents filed and the paper accepted. We did not want anyone stealing our new method of vaccination. This proved to be a false concern. When we did try to publish, nobody believed that DNA could vaccinate. The grants to support this new avenue of research came back rejected. I came the closest to losing my career that I ever have in my life. Fortunately, my Department chair, a pathologist, saw the interest in what I was doing and supported me until I obtained funding. Meanwhile, the scientific community, although not ready to fund us, was interested, and I traveled the world, helping name the technology at the World Health Organization, and becoming lifelong friends with a remarkable group of co-pioneers in the use of DNA vaccines. I signed up to teach immunology so that I could learn immunology to better understand the responses we were raising. Experimentally, the disease I focused on was HIV/AIDS. Retroviruses were the viruses that I best understood. The initial AIDS infections were becoming a pandemic. Is an HIV/AIDS vaccine possible? Given we could grow HIV-1 in culture and have known the sequence of HIV-1 for more than 25 years, why has the development of an AIDS vaccine been so difficult? The two AIDS vaccines that have progressed to efficacy trials have failed. The first of these was designed to elicit antibody (Ab) against the gp120 subunit of the viral envelope glycoprotein (Env).1 This vaccine elicited high titer Ab to gp120 but failed to elicit protective Ab. The second shifted the emphasis from raising protective Ab to eliciting protective T cells and used a replication defective adenovirus 5 vector (Ad5) to elicit cytolytic T cells against three internal HIV proteins: Gag, Pol, and Nef.2 Trials of this vaccine were halted at the first meeting of its Data Safety Monitoring Board due to “futility” (no promise for protection) and an alarming possibility of increased infections in those receiving the vaccine. The vaccine I am working on is designed to elicit both Ab and T cells. It is a DNA/MVA vaccine which uses recombinant DNA to prime the immune response and recombinant modified vaccinia Ankara (MVA) to boost the primed response. Both the DNA and MVA express the three major proteins of HIV-1: Gag, Pol, and Env and form non-infectious virus like particles that bud from vaccineexpressing cells. These particles bear native forms of Env on their surface. The vaccine, developed at the Emory Vaccine Center, Inc. has been licensed to GeoVax, Inc., a company for which I was a co-founder, and is currently entering phase 2a trials through the HIV Vaccines Trials Network (HVTN), a network funded and supported by the US National Institutes of Health (NIH). Of the more than 80 protocols the HVTN has developed for testing candidate HIV vaccines in phase 1, only five have progressed to phase 2. We are the fifth. The story of the GeoVax DNA/MVA vaccine is in many senses my story and the story that outside of my family has been the adventure of my life. I have made three institutional moves to enable my work on HIV/AIDS vaccines. After completing a postdoctoral fellowship working with Rous sarcoma virus, an avian retrovirus, at the University of California, Berkeley, I spent 10 years as a full-time mother while I raised three sons to school age. On my return to