Promising results from clinical trials presented at this year's AIDS Vaccine conference
Researchers at Makerere University in Kampala, Uganda, in collaboration with Johns Hopkins University in the US, recently initiated the first Phase I trial of an AIDS vaccine aimed at preventing the transmission of HIV from mother to child during breastfeeding. According to the World Health Organization breastfeeding remains one of the major routes of HIV transmission to infants in developing countries. In many settings alternatives to breastfeeding, such as liquid formula or powdered milk, are either prohibitively expensive or impractical because they require access to clean water. In many cultures where breastfeeding is common practice, HIV-infected women who do not breastfeed their babies are also subjected to stigma.
Several studies have shown that treating HIV-infected women with antiretrovirals during late pregnancy, labor, and through the breastfeeding period is an effective way to prevent HIV transmission to infants, but not all women have access to these drugs (see VAX February 2005 Spotlight article, Preventing mother-to-child transmission). A vaccine that could effectively protect babies during the period they are breast fed would be a major advance.
The current trial will enroll 50 infants born to HIV-infected mothers at Mulago Hospital in Kampala and evaluate the safety of the vaccine candidate ALVAC-HIV vCP1521 as compared to placebo. Forty of the infants will receive four doses of the vaccine over three months and will be followed by researchers for two and a half years. The vaccine candidate, based on a canarypox virus carrying genetic pieces of HIV, was developed by Sanofi Pasteur and was already tested in a safety trial in Uganda involving adult volunteers and in another study involving infants in the US. No serious safety issues were reported in either of these previous trials.
ALVAC vCP1521 is also now being tested in a Phase III efficacy trial in Thailand to see if it can protect adults against HIV infection. The Thai trial recently completed enrolling volunteers but final results will not be available for a few years.
For more information on these and other ongoing trials, go to the IAVI database of AIDS vaccines in human trials.
Grant recipients through the Grand Challenges in Global Health Initiative, a US$436.6 million program funded by theBill & Melinda Gates Foundation to increase research on diseases that primarily affect developing countries, recently convened their annual meeting in Washington, DC to highlight progress on the 48 ongoing projects. Grantees include scientists from 33 countries who are working to tackle either scientific or technological challenges that could enhance global public health. The plans for this innovative funding mechanism were initially announced at the World Economic Forum in 2003 and the first round of grants were awarded last year in collaboration with the US National Institutes of Health.
The Gates Foundation also recently awarded the Keystone Symposia on Molecular and Cellular Biology, a US non-profit organization that hosts many high-profile scientific conferences, a three-year grant of $2.6 million to further expand their offerings of conferences that focus on global health. Keystone already sponsors several conferences concerning infectious diseases, including the annual symposia on HIV Pathogenesis and HIV Vaccines that are held in conjunction each spring.
With this new grant Keystone will add a meeting focused on vaccines called "Challenges of Global Vaccine Development," which will be held either immediately before or after the next Grand Challenges in Global Health Meeting. The first annual conference will take place from October 8-13 next year in Cape Town, South Africa and will involve 300 scientists, many of whom are investigators on one of the Grand Challenges projects. The Keystone Symposia will also use part of the grant to provide scholarships and travel awards to researchers from developing countries, and specifically to graduate students and post-doctoral fellows who are completing their studies in Africa.
Other meetings that will be launched next year with this new funding include, "HIV Vaccines from Basic Research to Clinical Trials" and "Molecular and Cellular Determinants of HIV Pathogenesis."
All articles written by Kristen Jill Kresge
How are AIDS vaccine candidates tested for safety and immunogenicity before they enter clinical trials?
Clinical trials are a stepwise process to determine the safety and immunogenicity of AIDS vaccine candidates in human volunteers. The earliest trials (Phase I and II) are designed primarily to evaluate safety, while the later stage trials (Phase IIb and III) are when researchers determine if the vaccine candidate is effective. Each Phase involves a progressively larger number of volunteers and conducting clinical trials is a time-consuming and expensive process. The conduct of these trials is closely monitored by regulatory agencies, like the US Food and Drug Administration or the European Union's European Agency for the Evaluation of Medicinal Products, to ensure that a vaccine candidate meets necessary safety standards.
Prior to testing in humans, vaccine candidates are developed and tested extensively by researchers in the laboratory and then in different animal models. Data from these pre-clinical studies give researchers important information about how vaccine candidates might work in people and are carefully reviewed by regulators when they are granting approval to an organization or company to proceed with a Phase I clinical trial.
Before a vaccine candidate is tested using animal models, researchers fully characterize the engineered vaccine in the laboratory—whether it is a viral vector, protein subunit, or DNA-based vaccine that will be used to present HIV protein to the immune system. For candidates that use viral vectors (see VAX September 2004 Primer, Understanding Viral Vectors), scientists will already have an extensive body of knowledge about how the naturally-occurring virus acts both biologically and immunologically so that they have an idea of how it will act in humans. This allows researchers to generate a well-informed hypothesis about the types of immune responses the vaccine candidate might induce in humans.
Other pre-clinical evaluations
Even with a strong hypothesis, laboratory studies can only give researchers a vague idea of how the vaccine will work in the complex environment within the human body. To try to gauge the safety and immunogenicity of a vaccine candidate, therefore, scientists have to conduct research in animal models. Usually the vaccine candidate will first be tested in mice and then in non-human primates, most often rhesus macaques.
Researchers start by administering the vaccine candidate to macaques and then characterizing the immune response it induces. This includes a detailed analysis of the cellular responses, especially in T cells, and measuring the level and type of antibody responses. Based on these results researchers can alter the vaccine candidate to try to enhance its immunogenicity and then re-test it in macaques. Working with animal models allows researchers to obtain extensive data that would be impossible to collect from human volunteers.
Next researchers usually use challenge studies to evaluate vaccine candidates. In these studies the vaccine candidate is administered to macaques that are later infected with simian immunodeficiency virus (SIV), which naturally infects many species of non-human primates. Challenge studies are only conducted in animal models, never in human volunteers. In this type of study researchers can determine how many macaques are protected by the vaccine candidate from becoming infected with SIV. They can also determine how long this protection lasts by challenging the macaques again later. Challenge studies may also provide clues on what type of immune responses (specific types of antibodies or cellular responses) are responsible for this protection, an idea referred to as correlates of protection.
This data gives researchers critical information about the vaccine candidate and helps them determine if it is safe and immunogenic enough to move into clinical trials involving human volunteers. Many of the vaccine candidates that are evaluated in pre-clinical studies never actually advance into clinical trials because they are not immunogenic enough to explore further.
One important limitation with these animal studies is that the vaccine is not being tested against an HIV challenge. Researchers must evaluate the vaccine candidate's immunogenicity against SIV, which is a closely-related but different virus, because HIV does not infect non-human primates. To more closely mimic HIV infection in humans, researchers have tried running challenge studies with an engineered virus that contains both SIV and HIV genes—known as SHIV—but this is generally seen as an even less satisfactory model than SIV for predicting how a vaccine will work in humans.
Another limitation is that researchers have to also modify the vaccine candidate to carry SIV genes, rather than HIV genes, to match the virus being used in the challenge studies. Using a different challenge virus and a different vaccine candidate in a different animal species makes pre-clinical evaluation more difficult. This is just one of the many complications researchers face in developing an effective AIDS vaccine.
For many years, therefore, researchers have sought ways to improve their ability to evaluate candidates in pre-clinical studies and find a better animal model for HIV infection. Recently researchers have developed an engineered mouse model where human cells are transplanted into mice that have their own immune systems depleted. This allows mice to grow human immune cells that can be infected by HIV. With refinement this type of model may be useful to researchers as an initial screen for AIDS vaccine candidates to help determine if a candidate is immunogenic enough to pursue in human clinical trials.
Scientists are also studying the genetic factors that allow non-human primates to fend off HIV infection. This research might one day enable scientists to engineer an HIV strain that can productively infect an animal model and therefore more closely mimic human infection.