Progress Made In HIV Vaccine Development

Barney S. Graham, MD, PhD, and colleagues from the National Institutes of Health IH Vaccine Research Center in Maryland, the Fred Hutchinson Cancer Research Center in Seattle, and GenVec Incorporated tested two possible HIV vaccines with the hope of producing an immune response in healthy, uninfected adults. One was a plasmid DNA-based vaccine expressing genes from three dominant HIV subtypes, and the second used recombinant adenovirus serotype 5 (rAd5) as a vector to deliver similar HIV strains.

"Both approaches operate by gene delivery of customized vaccine antigens that are produced by host cells to initiate an immune response. DNA is simple and does not have the problem of anti-vector immunity. However, DNA may be less potent than vector-based gene delivery strategies. Replication-defective rAd5 has the advantage of targeted, efficient gene delivery and high potency, but may be susceptible to anti-vector immunity," said Graham.

Both vaccines were tested in healthy uninfected adult volunteers. The DNA vaccine was found safe and well-tolerated. By week 12 following immunization, 97.5% of vaccinees experienced positive CD4 T cell responses and 40% experienced positive CD8 T cell responses.

The recombinant vector vaccine was also well-tolerated, but higher doses led to some adverse events such as pain and fever. By week 4 following immunization, 93.3% of vaccinees experienced positive CD4 T cell responses, and 60% experienced positive CD8 T cell responses.

"HIV-specific CD8 cell responses clear virus infected cells, and appear during the declining viremia following acute infection," explained Graham. "HIV-specific CD4 responses also peak early in infection; however this response diminishes soon after seroconversion. Maintenance of a functional HIV-specific CD4 T cell response correlates with long term non-progression of HIV disease."

Harriet L. Robinson, PhD, from Emory University and Kent J. Weinhold, PhD, from Duke University commented on the impact of these results in their accompanying editorial. "The DNA studies are a landmark for DNA-based vaccines in that they are the first to demonstrate a DNA vaccine successfully eliciting immune responses in essentially all vaccinated volunteers," they said. "The Ad5 recombinant HIV vaccine had both a higher percentage of responders and, overall, a higher magnitude of responses than the DNA vaccine."

The next step, according to Graham, is "to evaluate the combination of DNA priming and rAd5 boosting. Combining these distinct gene-delivery vaccination approaches has the potential to induce higher levels of T cell responses and a different quality of response than either approach by itself."

As Robinson and Weinhold add, the idea behind combining strategies is that "the vaccine uses DNA to prime the immune response and a replication defective recombinant adenovirus serotype 5 vector to boost responses."