By Kristen Jill Kresge
Clinical Trials Yield Promising Results from Two Adenovirus-based Vaccines
Enrollment in Merck's ongoing Phase IIb "test of concept" trial with the trivalent adenovirus serotype 5 (Ad5)-based vaccine, MRKAd5, was recently expanded to include double the number of volunteers originally planned at sites in North America, South America, Australia, and the Caribbean. The 1500 additional volunteers will include individuals with Ad5 vector-specific antibody titers greater than 1:200 who were originally screened out of the trial (see Renewed promise).
Merck's decision to include volunteers with high levels of pre-existing immunity to the Ad5 vector was based on the results of now completed studies that showed MRKAd5, when given at a high dose of 3x1010 viral particles, can elicit strong immune responses even in individuals with substantial antibody titers. Robin Isaacs of Merck says that the vaccine seems to still be immunogenic in volunteers with antibody titers over 1:1000. The trivalent vaccine expresses Gag, Pol, and Nef proteins of subtype B HIV and is being evaluated in the Step study, a collaboration between Merck, the HIV Vaccine Trials Network (HVTN), and the National Institutes of Allergy and Infectious Diseases. This trial started in January of this year and final results are expected in 2008.
Another Ad5-based vaccine candidate developed at the Vaccine Research Center (VRC) is now in Phase II testing in partnership with the HVTN (see Renewed promise). This trial uses a 4-plasmid DNA prime vaccination comprised of a fused gag/pol/nef construct from subtype B, the primary viral strain found in Europe and North America, and HIV env genes from subtypes A, B, and C, which are the subtypes most common in Africa and parts of Asia. This is followed by a boost vaccination with an Ad5 recombinant containing gag, pol, nef, and env genes. This study, HVTN 204, seeks to enroll 480 volunteers at 13 HVTN sites in North and South America, Africa, and the Caribbean to determine safety and immunogenicity.
The VRC has seen an improved response when the DNA and Ad5 are administered in a prime/boost protocol and results from a Phase I trial indicate that the approach produced a robust cellular and antibody response. In the Phase I study there was a 26 month interval between receipt of the prime and boost, but the Phase II trial will evaluate a more typical vaccination schedule. Volunteers that are randomly selected to receive the DNA/Ad5 candidate will receive 3 injections of the DNA and a single Ad5 boost over a period of 6 months. Half of the trial participants will be enrolled at HVTN sites in the Americas as well as in Haiti and Jamaica, while the other half will be at sites in South Africa and Botswana.
This vaccine is the first developed at the VRC to move into the second stage of clinical testing. "Clearly what's different about this candidate is that it is responding to the global epidemic," says Gary Nabel, director of the VRC. "It's important to evaluate a vaccine that could have a broad response." The US-based company Vical is manufacturing the DNA portion of the vaccine and the adenovirus vector was developed by the VRC in collaboration with GenVec. Researchers at the VRC also hope to get around the problem of pre-existing immunity to the Ad5 vector by using a higher dose.
This candidate will also be evaluated further in a series of Phase I and II clinical trials in Kenya and Rwanda in cooperation with IAVI and at sites in Uganda, Kenya, and Tanzania in partnership with the US Military HIV Research Program, pending regulatory approvals in these countries. Nabel says these partnerships will allow the VRC to learn more about the immune response to the vaccine approach in diverse groups of volunteers. "Each of these organizations has some special strength that they bring to the research and I'm really excited and pleased that they have taken the considerable effort to harmonize their trial plans," he adds.
US Senators Introduce Bill to Accelerate AIDS Vaccine Research
US senators John Kerry of Massachusetts and Richard Lugar of Indiana introduced legislation in Congress recently that calls for increased funding to accelerate the research and development of vaccines for AIDS, tuberculosis, and malaria, as well as other infectious diseases. The proposal, called the "Vaccines for the New Millennium Act of 2005", highlights several ways that both the US government and private industry can develop a comprehensive strategy for bringing new and important vaccines to the people in greatest need.
The bill calls for an increase in the number of public-private partnerships as one strategy for achieving this objective, and mentions in particular IAVI, the Malaria Vaccine Initiative, and the Global TB Drug Facility as examples of these partnerships. Other strategies mentioned include exploring improved regulatory procedures or economic incentives—such as tax credits—for private companies to increase their involvement in the research and development of vaccines that target diseases primarily affecting developing countries. According to the bill only 10% of the world's research and development capacity is focused on diseases that affect 90% of the global population. Other incentives for industry participation suggested in the bill are Advance Market Commitments (seeIf you build it, they will pay, IAVI Report 9, 3, 2005), by which governments, foundations or other players in the global health community ensure a market through agreeing to buy vaccines for developing countries at guaranteed prices.
Within the legislation, senators Kerry and Lugar refer to immunization as a "cheap, reliable, and effective" way to have a profound impact on global health throughout the world. The co-authors cite several examples of this including the eradication of smallpox, the elimination of polio in many areas of the world, and vaccines for diseases like measles and tetanus that have drastically reduced rates of childhood mortality. The proposed legislation is yet to receive approval by the US government.
Merck's HPV Vaccine Shines in Phase III Trials
A vaccine to protect women from infection with human papilloma virus (HPV)— which causes cervical and anal cancer, as well as genital warts—was found 100% effective at preventing high-grade cervical pre-cancers as well as non-invasive cervical cancers associated with the strains of the virus that are contained in the vaccine. This is the first report from a large-scale efficacy trial with Merck's HPV vaccine, known as Gardasil.
This Phase III trial (FUTURE II) enrolled 12,167 women aged 16-26 at 90 sites in Brazil, Colombia, Denmark, Finland, Iceland, Mexico, Norway, Peru, Poland, Singapore, Sweden, the UK, and the US. Women in the trial received three injections of Gardasil, which is a virus-like particle vaccine containing the L1 nucleocapsid protein of 4 HPV strains delivered with an aluminum adjuvant. Two of the strains (16 and 18) are responsible for over 70% of cervical cancer cases worldwide, while the other two strains (6 and 11) cause more than 90% of genital warts, a benign manifestation of genital HPV infection.
A secondary endpoint analysis showed that one immunization with the vaccine reduced the risk of developing high-grade pre-cancer and non-invasive cervical cancer due to infection with strains 16 and 18 by 97%. This result provides a more realistic example of how the vaccine may be used since people often do not return for all three courses of a vaccine. There was only a single observed case of pre-cancerous cervical lesions in the vaccine group compared to 36 in those who received placebo. The sustainability of the immune response is yet to be determined as the participants in this trial were followed only for an average of two years. These results were presented at the annual meeting of the Infectious Disease Society of America that took place recently in San Francisco.
Merck submitted an application to the US Food and Drug Administration for approval and licensure to market and sell the first cervical cancer vaccine based on the results of this study and other efficacy trials in more than 25,000 women and men in 33 countries. The company expects to receive a license early next year. Merck has also formed a joint venture with Sanofi Pasteur to license and market the vaccine in Europe and the application was recently submitted to the European Medicines Agency.
There are still ongoing studies to evaluate Gardasil's ability to prevent the incidence of anal cancer in men who have sex with men and as a way of creating herd immunity to further reduce the disease burden in women, but the company has not reported any results yet in male volunteers.
"Where the vaccine is really needed is in developing countries," says Jessica Kahn of the Cincinnati Children's Hospital. "It could have a tremendous impact there on mortality rates." Cervical cancer is one of the leading cancers among women and worldwide it causes more than 290,000 mortalities annually. The vast majority of these deaths occur in developing countries because there are few screening programs to provide women with regular Pap tests. HPV is one of the most common sexually-transmitted infections among sexually active individuals and a 100% effective vaccine promises to greatly reduce the associated disease burden.
Another HPV vaccine developed by GlaxoSmithKline Biologicals in Rixsensart, Belgium is also in Phase III clinical trials. This candidate, known as Cervarix, is also a virus-like particle vaccine but it only contains L1 proteins from HPV strains 16 and 18. Cervarix also utilizes a proprietary adjuvant known as AS04. The company is currently conducting 5 efficacy trials in 28,000 women worldwide but no results have yet been reported. In a Phase II study the vaccine was found to be 100% effective at preventing persistent HPV infection in women that received three injections of the vaccine. This candidate is expected to be submitted to the European regulatory authorities for licensure in the first half of 2006.