New vaccines prevent potentially deadly diarrheal disease in infants
In a final report, leaders of the G8 nations who gathered in St. Petersburg, Russia from July 15-17 pledged continued support for HIV prevention, treatment, and care, highlighting in particular the development of AIDS vaccines and microbicides as priorities in the fight against the pandemic. The need for vaccines to prevent other diseases that increase an individual's risk of HIV infection was also emphasized.
Other strategies promoted in the document on infectious diseases, one of the three areas considered during the meeting, included expanding the partnerships with developing countries to bolster capacity for research and development and ensuring that qualified healthcare workers are available in these regions. The leaders also endorsed the Russian proposal to form a regional center in Eastern Europe and Central Asia to promote AIDS vaccine development.
Russia also announced that it would repay US$270 million that it received from the Global Fund to Fight AIDS, Tuberculosis, and Malaria, to further provision of treatment and care to HIV-infected individuals in developing countries. The Fund is currently in need of $1 billion to meet its present commitments.
Malawi recently launched a nation-wide campaign to encourage the country's citizens to undergo voluntary counseling and testing (VCT) for HIV infection (see November 2005 Primer on Understanding HIV Testing). The aim of this week-long testing drive, announced by the Health Minister, is to increase access to the available HIV prevention, treatment, and care services, and was initiated after surveys found that only 15% of the 12 million people in the country have already received VCT.
The campaign is expected to reach over 50,000 people. To date 47,000 HIV-infected individuals in Malawi have received antiretrovirals (ARVs) through the Global Fund, but estimates are that another 178,000 are still in need of treatment.
Malawi's new campaign follows Lesotho's announcement last year of a comprehensive VCT program, which is going door-to-door throughout the country offering testing to all citizens (see June 2006 Primer on Understanding Home-Based Voluntary Counseling and Testing Services). Former US President Bill Clinton also recently called for all African governments to actively encourage HIV testing in order to identify those in need of ARVs.
The Bill & Melinda Gates Foundation awarded US$287 million in grants over the next five years to 16 different research teams, encompassing 165 investigators from 19 countries, to support innovative approaches to overcoming the scientific obstacles in AIDS vaccine research and to accelerate the development of new candidates. These grants are the Foundation's largest contribution to date for HIV/AIDS research and bring together many of the leading teams that are currently working to develop an effective vaccine.
Five of the grants are to laboratories that focus on research into vaccines that can elicit broadly-neutralizing antibodies against HIV. The largest of these grants, $25.3 million, was awarded to Robin Weiss of the University College London in the UK. Among the other recipients was Barton Haynes of Duke University in the US, who leads a team of researchers that was recently awarded a $300 million grant from the US National Institute of Allergy and Infectious Diseases to form the Center for HIV/AIDS Vaccine Immunology (CHAVI).
Another six grants were issued to laboratories or consortia working on vaccine candidates aimed at inducing cellular immune responses to the virus. IAVI was the recipient of a $23.7 million grant in this category. Other grantees include David Ho of the Aaron Diamond AIDS Research Center in New York City and Juliana McElrath of the Fred Hutchinson Cancer Research Center in Seattle.
A main point of these grants was to facilitate cooperation and coordination of data between vaccine discovery teams. The acceptance of this new funding is therefore contingent upon all awardees working through a network of standardized laboratories to test their vaccine candidates. The remaining five grants were provided to researchers who will form these centralized facilities for vaccine candidate evaluation and will be involved in measuring the immune responses generated by candidates developed through the vaccine discovery programs, as well as handling the data collection.
All articles written by Kristen Jill Kresge
How does the genetic diversity of HIV affect AIDS vaccine design?
A key concern for AIDS vaccine researchers is the tremendous genetic diversity of HIV. The majority of global HIV infections are caused by a single group of virus, which is divided into nine different subtypes, or clades, designated by the letters A through K. Further complicating matters are the viral recombinants that occur when viruses from different clades combine segments of their genome, forming a hybrid. These occur in several regions of the world where more than one HIV clade is circulating.
The advent of clades
The diversity of HIV and the development of clades stems from the ability of HIV to produce billions of viral particles daily. The enzyme involved in viral replication, reverse transcriptase, is not precise and sometimes incorporates mistakes into the viral genome, resulting in genetic mutations. The more HIV replicates, the more likely it is to make mistakes, increasing the potential for genetic variation.
Each of HIV's genes develops mutations at a different rate. The genetic sequence of the envelope gene (env), for example, which encodes the HIV surface protein that attaches the virus to human cells, can vary by as much as 35% in virus samples from different clades. Others, such as the gag gene that encodes the internal core of the virus, remain more conserved, varying by less than 10% from one clade to another. Overall, the genetic makeup between all clades deviates by approximately 30%.
HIV clades also vary in prevalence throughout the world. For example, HIV clade B is found mostly throughout North America and Europe, while the epidemic in South Africa and India is due to HIV clade C. Researchers are therefore trying to develop an AIDS vaccine candidate that offers the broadest possible protection.
But there are still many unanswered questions about the significance of viral diversity for AIDS vaccine design. Scientists do not yet know whether immune responses induced by a preventive AIDS vaccine would be able to protect against only one particular HIV clade or against several. Most clinical trials of AIDS vaccine candidates have occurred in communities where the antigen in the vaccine comes from the same HIV clade as the one circulating in the region, a concept known as clade or genetic matching. The key for an effective AIDS vaccine is to elicit the kind of immune response that would be effective against the circulating virus in the region, but this is not well predicted by clade alone. Clade classification refers to the different protein sequences that distinguish the circulating viruses and not the way the human immune system recognizes or reacts to HIV, so the importance of such matching is still in question. Scientists are also still trying to determine the type and magnitude of immune response required for protection, so clinical trials to determine the immunogenicity of vaccine candidates in relevant populations remain critical.
Implications for vaccine design
When the first AIDS vaccine trials were initiated, vaccine development efforts focused mostly on candidates from isolates of HIV clade B, found in North America, parts of South America, Western Europe, and Australia, and currently responsible for approximately 12% of global infections. Later, candidates with antigens from clades A and D, both common in parts of Africa, were brought to clinical trials. Several others were also developed based on clade C, the subtype circulating in Southern Africa, India, and China, which is responsible for over 50% of all HIV infections worldwide.
As more candidates entered clinical testing different approaches to vaccine development have emerged to tackle HIV diversity. One strategy aimed at eliciting cellular immune responses involves the use of the most conserved regions of HIV or widely recognized protein pieces from different parts of HIV to develop an AIDS vaccine candidate.
A different vaccine strategy that aims to elicit broadly-neutralizing antibodies against several clades uses a combination vaccine with env genes from several clades. A third approach, which is not yet in clinical trials, compares the sequences of HIV genomes from different clades to create a computer-generated sequence that best matches the highest number of strains, with the hope that any protective immune response that the vaccine elicits would confer protection against infection by different HIV clades.
Informing the field
Merck and the HIV Vaccine Trials Network (HVTN) are now completing site preparations in South Africa for a second Phase IIb "test of concept" trial with the company's clade B-based adenovirus serotype 5 (Ad5) vaccine candidate, known as MRKAd5. The candidate is currently being evaluated in another Phase IIb trial in North America, South America, the Caribbean, and Australia. The addition of a South African trial marks the first time this candidate will be evaluated in a population where the circulating clade of HIV, clade C, does not match that in the vaccine.
In 2003 the African AIDS Vaccine Programme came out strongly in favor of planning trials to give clear answers about protection across different clades as long as there is evidence that the vaccine candidate induces immune responses against the most commonly circulating virus, regardless of clade classification. Preclinical data for MRKAd5 show reactivity between the vaccine antigens and the predominant virus found in South Africa. The Merck trial therefore offers an opportunity to test this in a "proof of concept" trial that may provide preliminary answers about a vaccine's efficacy while answering crucial questions for vaccine design.