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A shot of good news

Promising results from clinical trials presented at this year's AIDS Vaccine conference

The near thousand researchers who gathered at the start of the annual AIDS Vaccine Conference in Amsterdam from August 29 to September 1 were greeted with a spirit of optimism that has become quite unusual for this field. Lawrence Corey of the HIV Vaccine Trials Network in Seattle called 2006 "a vintage year for vaccine development" when he gave a presentation on the AIDS vaccine pipeline at the conference's opening plenary session.

The source of Corey's enthusiasm was the data from several ongoing clinical trials showing that some AIDS vaccine candidates are inducing promising levels of cellular immune responses. "A few years ago it was hardly possible to stimulate T-cell responses with vaccination," said Andrew McMichael of the University of Oxford, UK, so this was a welcome shot of good news for a field that has struggled to develop candidates that are immunogenic in humans. Now Phase I and II trials with candidates based on adenovirus or poxvirus vectors are providing more encouraging results.

While efforts to stimulate a neutralizing antibody response with immunization are still largely unsuccessful, researchers have been able to increasingly improve the level of cellular immune responses. Those induced by the current crop of candidates are three times greater than was possible just a couple of years ago, said Corey. He is hopeful that this progress will continue over the next few years and that further improvements of candidates that induce potent cellular responses may bring the field closer to a partially-effective AIDS vaccine. This type of vaccine may either prevent HIV infection or, perhaps more likely, slow disease progression in those who do become HIV infected and lower the likelihood of them transmitting the virus to others.

But many researchers still question how effective an AIDS vaccine will be if it doesn't also induce neutralizing antibodies. Jaap Goudsmit of the Netherlands-based biotechnology company Crucell reminded researchers that there is yet to be a vaccine, for any disease, licensed solely on the basis of cellular immune responses. Therefore vaccines that induce neutralizing antibodies remain a focus of ongoing research.

Vintage data

Much of the promising immunogenicity data presented at the conference came from trials administering two different vaccine candidates sequentially in a prime-boost combination. Several different research groups are utilizing DNA plasmid vaccines for the initial immunization, which seem to effectively prime the immune system.

One of the earliest presentations on a DNA vaccine candidate was by Eric Sandström of the Karolinska Institute, Sweden, who presented for the first time immunogenicity data from a Phase I trial that is ongoing in Stockholm with a DNA vaccine developed at the institute in collaboration with the Swedish Institute for Infectious Disease Control (seeVAX April 2006 Spotlight article, Clinical trials march on). Forty volunteers in the trial were randomized to receive three injections with one of three doses of the DNA vaccine administered either intramuscularly with a traditional injection or intradermally via the needle-less system developed by Bioject, a US-based biotechnology company.

Six months after the third DNA immunization all but two volunteers also received a booster immunization with a modified vaccinia Ankara (MVA)-based vaccine candidate developed by the US National Institutes of Allergies and Infectious Diseases. Vaccine recipients reported experiencing fatigue and general flu-like symptoms after the DNA prime and only mild adverse events were reported after the MVA injection.

After the third DNA immunization, 11 of the 38 volunteers were considered to have positive immune responses. But after receiving the booster immunization, 33 of 36 participants had positive results. Based on the impressive immunogenicity of these candidates, Sandström and colleagues are preparing for a larger Phase I/II trial in Tanzania with the same vaccine candidates.

Results from a Phase I trial conducted by the European Vaccine consortium (EuroVacc) with another DNA plasmid vaccine tested in combination with a modified poxvirus vector vaccine, known as NYVAC, were also presented. A total of 40 volunteers—20 male, 20 female—were recruited at two sites in the UK and in Switzerland. Half of the participants received two injections of a DNA plasmid vaccine followed by two doses of NYVAC. Of the 20 volunteers who received the DNA/NYVAC prime-boost combination, 90% had positive immune responses.

Rick Koup also presented an update on the DNA plasmid vaccine and adenovirus serotype 5 (Ad5) vector-based vaccine developed by the Vaccine Research Center (VRC) at the US National Institutes of Health (NIH) that are currently in Phase I/II clinical trials in a prime-boost regimen (see VAX April 2006 Spotlight article, Clinical trials march on). Enrollment for these trials is now two-thirds complete but is still ongoing at HIV Vaccine Trials Network (HVTN) sites in North and South America and South Africa and at Walter Reed Army Institute of Research (WRAIR) sites in Africa. In the meantime the VRC, WRAIR, and IAVI are preparing to move these candidate vaccines into a Phase IIb test-of-concept trial, known as PAVE 100, which should commence next year.

Nature's adjuvant

Adenovirus-based vaccine candidates have produced the most impressive cellular immune responses seen so far, and Gary Nabel of the VRC referred to the viral vector as "nature's adjuvant," (see VAX October 2004 Primer onUnderstanding Vaccine Adjuvants). Another advantage of this vector is that it can be administered at much higher doses than other viral vectors—1000 to 10,000—fold more viral particles than can be safely used with MVA, for example.

But results from a Phase I safety trial, HVTN 054, indicate that vaccination with higher doses of Ad5 results in more severe side effects without any further gain in immunogenicity. Laurence Peiperl of the University of California, San Francisco presented data from this trial that evaluated a single injection of the VRC's Ad5 vaccine candidate at a low and high dose. Flu-like symptoms or reactions at the injection site were reported in four volunteers, all of whom received the higher dose. These side-effects peaked one or two days following injection and subsided within a week. Although none of the serious adverse events were considered related to the vaccine, Peiperl concluded that the safety profile of the lower dose seemed more favorable. Additionally the immune responses were actually higher in volunteers who received the higher dose—95% were considered responders compared to 90% at the lower dose. "It appears that less is more for immune responses to adenovirus," said Robert Seder of the VRC.

Merck is currently evaluating the immunogenicity of the lower dose of their Ad5 vaccine candidate in the company's ongoing Phase IIb test-of-concept trial in collaboration with the HVTN (see VAX October 2005 Spotlight article, AIDS vaccine researchers find promise). The highly anticipated efficacy data from this trial won't be available until 2008 but Michael Robertson of Merck provided some preliminary information about the safety of the vaccine candidate. The majority (74%) of volunteers reported mild or moderate adverse events, most of which were headache, fever, fatigue, or pain at the injection site. Serious adverse events occurred in 13 individuals and 3 of these were attributed to the vaccine, including a severe case of fever, diarrhea, and a report of a possible allergic reaction.

Another focus of his presentation was on the experiences of conducting the trial in individuals at high risk of HIV infection either through sexual activity or injection drug use. Conducting trials in these populations will allow researchers to get preliminary efficacy results with smaller, faster, and less expensive studies, a strategy advocated in IAVI's AIDS Vaccine Blueprint 2006 (see VAX September 2006 Global News). But some have speculated that it will be more difficult to both recruit and retain high-risk individuals in long-term vaccine trials, said Robertson. So far, at least, this has not been Merck's experience. Almost 2000 volunteers—1329 male and 668 female—were enrolled in the study at the end of July and, overall, 95% of scheduled visits have been completed. Robertson expects enrollment of the intended 3000 total volunteers to be completed on target by the end of this year.

Merck is gathering information on the risk behaviors of potential volunteers and Robertson presented some of this data. Across all sites, male volunteers screened so far for the Phase IIb study reported having a median of six different sexual partners in the last six months, and 12% of them reported having unprotected anal intercourse with a partner who they knew was HIV infected. Women reported having an average of 28 different sexual partners over the previous 6 months and 5% said they had unprotected vaginal intercourse with an HIV-infected partner. Also, 15% percent of the women reported having another sexually-transmitted disease in this same time period, which can enhance their risk of becoming HIV infected. During the screening process the HIV prevalence rates among males was 4% and around 3% for females, though Robertson explained that these figures vary greatly from site to site.

The AIDS vaccine field is eagerly anticipating the results of this and other ongoing trials to answer some of the critical questions about cellular immunity. "The next few years are going to be very interesting in this field," said Robertson. "There is a lot of energy right now about new prevention strategies and hopefully we will have good news on T-cell based vaccines."