Triple vaccine strategy stimulates
strong HIV-specific immune response in monkeys
09 Jul 2004
Researchers at The Wistar Institute and the University of Pennsylvania report success in monkeys of an innovative triple-vaccine strategy aimed at creating an effective anti-HIV vaccine regimen. In a test of the new approach, the scientists sought to maximize the immune response to a truncated HIV gene called Gag and succeeded in dramatically stimulating the production of CD8+ T cells responsive to Gag. Many scientists believe that CD8+ T cells will be an important key to creating an effective HIV vaccine.
"For a variety of reasons, it may not be possible to create a vaccine that generates antibodies able to neutralize HIV," says Hildegund C.J. Ertl, M.D., professor and immunology program leader at Wistar and senior author on the report published in the July issue of the Journal of Virology. "The next best thing may be to develop a vaccine that stimulates the production of anti-HIV CD8+ T cells, which have been shown in other studies to reduce viral load, although they do not prevent infection. The new vaccine regimen we tested induced unprecedented levels of CD8+ T cells in monkeys."
The experimental vaccines developed by Ertl and her colleagues take advantage of sophisticated bioengineering technologies and the special characteristics of a class of viruses called adenoviruses to create a series of three vaccines that, when given in sequence, build on each other to generate a stronger immune response than might otherwise be possible.
Many current vaccine development programs rely on human adenoviruses engineered to include elements from disease-causing agents, in part because adenoviruses are relatively easy to manipulate in the laboratory and readily enter a wide variety of cells, including important cells of the immune system, to stimulate a vigorous, long-lasting immune response.
A number of these vaccines based on common strains of human adenoviruses, including some against HIV, have returned positive results in early clinical trials. An unaddressed problem with this vaccine-development approach, however, is that many people are exposed to adenoviruses in childhood and carry neutralizing antibodies against the viruses that would interfere with the effectiveness of any vaccine based on them.
About 45 percent of adults in the United States, for example, have pre-existing immunity to the most prevalent strains of adenovirus, and similar or higher levels have been reported in other parts of the world.
To circumvent this potential difficulty, the researchers at The Wistar Institute and the University of Pennsylvania developed a series of vaccine vectors based on chimpanzee adenovirus strains, which possess the immunological strengths of human adenoviruses without their drawbacks. Previously published proof-of-principle studies in mice showed that the new vectors were able to avoid the problem of pre-existing immunity.
In the current study, the scientists created three vaccines, each with a different adenovirus as a backbone but all containing the same truncated HIV gene, Gag. Two of the vaccines were based on chimpanzee adenoviruses, and the third was based on a human adenovirus. The vaccines were administered to two groups of four rhesus macaques each.
One group received the human adenovirus vaccine first, followed by the two chimpanzee adenovirus vaccines. The other group received one of the chimpanzee adenovirus vaccines first, followed by the other chimpanzee adenovirus vaccine and then the human adenovirus vaccine.
Both triple immunization regimens sparked high frequencies of CD8+ T cells against Gag that remained remarkably stable over time, demonstrating the potential of the new strategy. For eventual clinical use, vaccines incorporating more elements of HIV would be needed to elicit sufficiently broad T-cell responses to be fully effective.
Call for greater involvement of
developing world scientists in fight against AIDS
09 Jul 2004
During the past two decades, HIV/AIDS has had a devastating impact on the health and social and economic well-being of populations in many parts of the developing world. In 2003 alone, the disease caused the death of more than three million people, mostly in sub-Saharan Africa. Despite the best efforts of some of the world's most prominent scientists, a vaccine that would protect against the disease is still a long way from reality. Drugs that help fight the virus and alleviate the disease symptoms are available, but are expensive and unavailable to many sufferers living in the world's developing countries. In addition, many countries are still failing to tackle the social issues that lead to the further spread of the disease.
Against this background, and on the eve of AIDS 2004, the XV International AIDS Conference in Bangkok, Thailand, the Third World Academy of Sciences (TWAS) and the African Academy of Sciences (AAS) have issued a Joint statement on HIV/AIDS in the developing world, calling for greater involvement of developing world scientists in research initiatives designed to treat and mitigate the disease. Both organizations are particularly keen to enlist African scientists in this campaign.
Specifically, TWAS and AAS believe that the discovery and development of new drugs and vaccines to combat HIV/AIDS should also be conducted through South-South collaboration, using the expertise present in the many centres of scientific excellence in the developing world.
"Such a programme of support would not only allow the enormous potential of developing countries' flora and fauna to be investigated for novel pharmaceutical products, but would also help stem the 'brain drain' – a major problem for the development of scientific capacity in the South, and especially in sub-Saharan Africa," says Gideon Okelo, Professor of Medicine at the University of Nairobi, Kenya, and AAS Secretary General and Executive Director.
"It would also offer potential avenues of investigation that have yet to be explored because of the dominance of Northern scientists in the design and implementation of AIDS-related research," says Ahmed A. Azad, Director of Research at the Faulty of Health Sciences, University of Cape Town, South Africa.
Azad and Okelo, both of whom are TWAS fellows, were the two lead authors of the TWAS/AAS joint statement, which has been approved by the TWAS Council and AAS Governing Council.
Founded in 1983 by the Nobel Prize-winning Pakistani physicist Abdus Salam, TWAS counts more than 700 eminent scientists among its membership, most of whom are working in developing countries. Among the main aims of the Academy is to help build the scientific and technological capacities of developing countries as a means to promoting sustainable economic development. TWAS is headquartered in Trieste, Italy.
AAS was established in 1985 as a non-profit organization of scientists with the aim of developing into a continent-wide forum to champion science-led development in Africa. Headquartered in Nairobi, Kenya, it has a current membership of more than 130.
Full text of Joint Statement on HIV/AIDS in the Developing World
Third World Academy of Sciences (TWAS)
African Academy of Sciences (AAS)
Trieste, Italy / Nairobi, Kenya
During the past two decades HIV/AIDS has had a devastating impact on the health and social and economic well-being of populations in many parts of the developing world.
In 2003 alone, HIV/AIDS caused the death of more than three million people.1 That made it the number one killer among all infectious diseases.
The vast majority of the 40 million people living with HIV/AIDS – indeed some 34 million or nearly 85 percent of the total number of people afflicted with the disease – live in Africa, Asia and Latin America, among countries that are least able to manage the epidemic or afford the costly combination of antiretroviral drugs which have dramatically reduced AIDS-related morbidity and mortality rates in developed countries.
Sub-Saharan Africa, on its own, accounts for about two-thirds of all HIV/AIDS-related deaths. The region also accounts for about two-thirds of the number of people living with HIV/AIDS.
The number of people afflicted with HIV/AIDS in Africa, particularly in sub-Saharan Africa, is truly daunting. More than 26.5 million Africans currently live with HIV/AIDS – 3.2 million of whom were infected in 2003.
The HIV/AIDS-related yearly death toll in sub-Saharan Africa has reached 2.3 million in 2003. Experts expect that the total number of deaths due to the disease will reach 55 million by 2020 unless aggressive measures are taken to prevent and treat disease.
The HIV/AIDS epidemic, however, is by no means restricted to the African continent. South Africa has the highest number of HIV-infected people – some 5 million people or 20 percent of the population. But India has the second highest count in terms of absolute numbers (an estimated 2 to 5 million people) and the incidence of infection is also rising at an alarming rate in China.
Failure to arrest the spread of the disease in the developing world, particularly in the world's two most populous countries that account for more than one-third of the world's population, could have disastrous consequences for the entire human race.
The enormous challenges posed by the HIV/AIDS epidemic has aroused a rising chorus of global concern for combating the disease. In September 2000, representatives at the Millennium Summit of the United Nations classified HIV/AIDS as one of the world's most pressing problems.
In June 2001, the United Nations Special Session of the General Assembly cited the fight against HIV/AIDS as a global priority and issued a 'Declaration of Commitment' in which member states pledged to vigorously address the public health and social issues engendered by the epidemic. In April 2001, at the African Summit on HIV/AIDS, Tuberculosis and Other Related Infectious Diseases, held in Abuja, Nigeria, Kofi Annan, the Secretary General of the United Nations, issued a global call for action in the fight against HIV/AIDS in which he implored political and business leaders to respond to the challenge. The Secretary General's urgent request led to the creation of the Global Fund Against AIDS, Tuberculosis and Malaria in 2001.
The Third World Academy of Sciences (TWAS) and the African Academy of Sciences (AAS) acknowledge the enormity of the problems caused by HIV/AIDS in the developing world and recognize the pressing need to stem the spread of the epidemic through public awareness and education, universal access to both condoms and antiretroviral drugs, development of more effective, affordable and safer therapies, and the need for additional investment in the research and development of vaccines. In Africa, more than 4 million people would benefit from anti-retroviral drugs, but only 50,000 people are receiving such therapies.
To help achieve these objectives, TWAS and AAS are eager to join UN agencies and government and non-government organizations in support of on-going research in the following areas:
1. Disease management and care of AIDS sufferers and HIV-infected individuals, including AIDS orphans.
2. Efforts to lower the cost of antiretroviral drugs and to make these drugs universally available to prevent mother-to-child transmission of HIV and to lower viral count in infected individuals.
3. Vaccine development through South-South and South-North research collaboration.
4. Public education and awareness of the disease process that would help reduce the incidence of HIV infection. Such campaigns should be intensified, together with efforts to increase universal access to condoms, as key preventative measures. Existing sources of indigenous knowledge, as well a in-depth assessments of prevailing cultural attitudes and beliefs concerning HIV/AIDS, should be identified as part of a larger effort to improve public awareness of the disease and its consequences.
5. Examination of the use of traditional herbal medicines in HIV/AIDS management and analyses of indigenous flora and fauna as potential sources of less expensive antiretroviral drugs. The role of traditional healers in preventing and treating HIV/AIDS should also be examined. The South is richly endowed with natural products that contain potential immune-boosting ingredients. Such products may prove particularly valuable in HIV/AIDS treatments, particularly for infants and for adults during early stages of infection.
TWAS and AAS are aware of the shortcomings of antiretroviral drugs currently in use and, therefore, recognize the need for additional research that could lead to the discovery and development of new drugs that are more effective, affordable and patient friendly.
The enormous potential of the flora and fauna present in the developing world, combined with the pooling of expertise and resources within the South, could help promote the discovery and development of new antiretroviral and other drugs that prevent the destruction of the immune system or that boost existing immunity to arrest the progression of AIDS.
Vaccination is the cheapest and most effective way to prevent infection by HIV in the first place and to manage the disease over the long term. Despite two decades of intense international effort, no effective vaccine has been produced and none is likely to be discovered in the near future.
The difficulty of producing effective vaccines is compounded by the enormous genetic diversity found among HIV strains. There is also an urgent need for therapeutic vaccines to arrest the progression of HIV in infected individuals. TWAS and AAS, therefore, encourage and support research leading to the development of cross-protective prophylactic vaccines to prevent new infections as well as therapeutic vaccines for the millions of individuals who have already contracted HIV.
TWAS and AAS believe that research, leading to the discovery and development of new drugs and vaccines to combat HIV/AIDS, should be conducted not only through collaboration with institutions in developed countries, but also through South-South collaboration, especially among centres of excellence in the developing world that possess complementary expertise. The latter efforts would not only help promote relevant and focused multidisciplinary research but would contribute to building scientific capacity in the developing world and thus serve to counter the 'brain drain' phenomenon. Such efforts could provide a unique opportunity for TWAS and AAS to become involved in efforts that have long-lasting benefits for people living in HIVAIDS-affected areas both in sub-Saharan Africa and throughout the developing world.
Transfusion of unscreened blood that may be contaminated with HIV represents an insidious yet efficient method of HIV transmission. Although countries in the South are aware of this problem, the transfusion of unscreened blood is still a common occurrence in many developing countries. TWAS and AAS urge all governments in the South to ensure that only properly screened blood is used in blood transfusions and that all medical laboratories in the developing world have the necessary equipment and skilled personnel to perform safe and reliable transfusion procedures.
TWAS and AAS should involve the Network of African Science Academies (NASAC) to fully engage the entire scientific community in Africa in research on HIV/AIDS. AAS and TWAS should also work closely with national governments in Africa, the New Partnership for Africa's Development (NEPAD), the African Union (AU) and all relevant UN agencies – UNAIDS, the World Health Organization (WHO), the United Nations Development Programme (UNDP), and the United Nations Children's Fund (UNICEF) – in developing a pan-African strategy to combat an epidemic that now threatens the well-being not only of Africa but, increasingly, all other parts of the developing world. Similar organizations in Asia and Latin America should also be engaged.
TWAS and AAS should examine ongoing efforts in countries throughout the South for potential opportunities to collaborate as the basis of a larger effort to promote joint action to combat the HIV/AIDS epidemic in the South.
Approved by TWAS Council and AAS Governing Council
Notes 1. All figures cited are based on UNAIDS, WHO and CDC data.
World Leaders Are Scarce as AIDS
Conference Opens in Bangkok
By LAWRENCE K. ALTMAN
BANGKOK, July 11 - The 15th International AIDS Conference began on a disturbing note here on Sunday with the cancellation of a summit meeting of world leaders invited to discuss AIDS, one of the worst epidemics in history.
The summit meeting, a Thai initiative, was to be held as a closed session on Monday. Invitations were sent to nine national leaders - Botswana, Brazil, Canada, China, India, Nigeria, Russia, Rwanda and Uganda and the head of the European Commission.
Only one, President Yoweri Museveni of Uganda, accepted, said Dr. Peter Piot, the director of United Nations AIDS, an organizer of the conference.
The record of national leaders attending and addressing past AIDS conferences has been inconsistent.
Former presidents Bill Clinton and Nelson Mandela, as well as Denzel Douglas, the prime minister of St. Kitts and Nevis, and Paul Kagame, president of Rwanda, played prominent roles in the last International AIDS Conference, in Barcelona, Spain in 2002. Spain's prime minister did not attend. President Thabo Mbeki of South Africa spoke at the opening of the conference in Durban, South Africa, in 2000.
In opening the Bangkok meeting, Prime Minister Thaksin Shinawatra of Thailand said, "Alarmingly enough, it seems that H.I.V. is still in its infancy and is likely to continue to spread, rather than go away by itself."
Kofi Annan, the secretary general of the United Nations, said: "AIDS is far more than a health crisis. It is a threat to development itself." He added, "We are not doing nearly well enough."
Mr. Annan urged "stronger leadership at every level - including at the top" to break "the deadly wall of silence that continues to surround the epidemic."
Dr. Piot said in an interview that he was disappointed that more heads of state were not at the conference because experience had shown that strong political will at a national level was critical to marshaling efforts needed to more effectively control AIDS.
Although political leadership on AIDS has improved in recent years, it "is still too weak in many parts of the world,'' Dr. Piot said.
Dr. Piot's United Nations group has stressed the need to put AIDS on the agendas of political meetings like those of the Group of 8. At the same time, Dr. Piot and others have tried to get leaders to attend meetings like this one to combine politics and public policy with AIDS science.
Mr. Douglas is representing not only St. Kitts and Nevis but also other Caribbean countries.
The plan for a summit meeting here was aimed at getting heads of state to commit to the efforts on prevention and treatment needed to raise a young generation free of H.I.V., Dr. Piot said. But, he added wistfully, "Here they would have preached to the converted."
One meeting organizer said, though, that the invitations had been sent out late and that some leaders declined because they faced elections and other domestic issues.
Prime Minister Manmohan Singh of India is not coming because his administration is just starting and is involved in budget debates this week, Dr. Piot said. Sonia Gandhi, the leader of the Congress Party, which leads the governing coalition in India, and Mr. Mandela are expected to speak at the close of the conference.
Prime Minister Wen Jiabao of China has sent a videotape that will be shown on Monday.
In Barcelona, heckling by activists prevented the United States Secretary of health and human services, Tommy G. Thompson, from delivering his speech. That humiliating experience, Dr. Piot said, may be a reason why some heads of state did not want to risk coming to Bangkok.
Dr. Piot said he was encouraged that nearly 100 ministers of health, education, finance, defense and foreign affairs are to attend this conference. That is about double the number of those who went to Barcelona.