Introduction
The Oxford English Dictionary defines a developing country as a poor or primitive place that is striving to improve economic and social conditions. A more in-depth definition leads to the idea of a country that is deficient in some way, a country that is unfortunate and deserving of sympathy, a country that is not technologically advanced. 'Development' suggests that the country is gradually becoming more mature and organized in terms of the production and consumption of goods and services to the benefit of all the inhabitants of the country. In questioning the utility and feasibility of transferring modern scientific and medical technology to aid in such development, we will take as our example efforts that are being made to alleviate the pandemic of infection with human immunodeficiency virus 1 (HIV-1) in Uganda, East Africa. Why is technology transfer necessary, who should make the transfer, and what may be the eventual benefits in Uganda and for the rest of the developed and developing world?
Uganda
Frederic Courbet
The Uganda Virus Research Institute and the International AIDS Vaccine Initiative vaccine trial unit, Entebbe.
Uganda has gone through long periods of civil unrest and instability that have overturned the whole farming system, leaving most of the population of more than 27 million engaged in subsistence farming, with coffee accounting for the bulk of export revenues. Since the late 1980s, Uganda has rebounded from devastating civil war and may now be considered a developing country, according to its human development index of 0.502 (ref. 1). This index is a combined measure of life expectancy (46 years for men and 47 years for women in Uganda), adult literacy (67% in Uganda), education (87% of Ugandan children are in primary school) and standard of living (85% of the population live on less than US$1 per day, and 35% of the population lives below the poverty line). Development is slow, but it is surely of interest to the arguments to be put forward in this commentary that, whereas a few years ago the average Ugandan villager traveled 2 kilometers to make a telephone call and the average waiting list to access a fixed phone line was 3.6 years, recently there has been an explosion in mobile phone use and there is now a plethora of internet cafes in all major conurbations.
Frederic Courbet
An outreach team sponsored by the International AIDS Vaccine Initiative, conducting HIV testing in the field.
Of chief concern is the fact that the seroprevalence of HIV-1 infection in Ugandan adults hovers around 6%, and one million Ugandans are now living with AIDS. The pandemic is surely hindering Uganda's prospects of development, even though Uganda has been hailed as a rare success story in the fight against HIV and AIDS2. A National AIDS Control program was established early in the epidemic, and in 1992 a 'multi-sectoral AIDS control approach' was established in Uganda. The national HIV-AIDS policy has instigated a succession of open and honest approaches to AIDS education. There has been a sustained, long-term political commitment to this issue at the highest levels of government. However, help from the outside world has been, and is still, necessary.
What has already been accomplished?
The international health funding and research community, such as the Global Fund for AIDS, Tuberculosis and Malaria; the Medical Research Council UK; the International AIDS Vaccine Initiative; the United States Agency for International Development; and many other governmental and nongovernmental organizations, is very active in Uganda. Part of the success in managing HIV and AIDS in Uganda has been due to cooperation between the government and international bodies. Construction, including substantial investment in information technology, and research have been funded, leading, for example, to improved HIV screening and voluntary counseling, free mosquito nets and water purification to prevent opportunistic infections, and free testing and treatment for basic infections of danger to people living with AIDS. For example, since 2004, as part of programs sponsored by the International AIDS Vaccine Initiative in Africa, more than 27,000 people have received voluntary counseling and testing. Several important studies have taken place in Uganda, including a study on the acceptability of male circumcision3, studies examining the utility of preventing mother-to-child transmission of HIV with limited antiretroviral therapy4, and a major economic analysis estimating the cost of an effective 'rollout' of highly active antiretroviral therapy5, coupled with detailed studies of the natural history of the epidemic6. It should be noted that the spectacular success of highly active combined antiretroviral drug therapy for HIV infection has been tempered by inequity in global access7. In this context, for the creation of an evidence base for the development of simple algorithms for antiretroviral therapy in resource-poor regions, the 'DART' trial (Developing Antiretroviral Therapy for Africa), funded by the Medical Research Council (UK), the Rockefeller Foundation and the Department for International Development (UK), has established the largest research cohort of initiation of antiretroviral therapy in Africa, based in Uganda and Zimbabwe. This will be extended for second-line therapy and to address resistance and algorithms for switching treatment.
Our role in Uganda
We have been involved mainly in laboratory expansion to enable large-scale international HIV preventative vaccine trials8. Such trials may of course eventually be of benefit to vulnerable people in both the developed and the developing world. Our aim has always been to encourage self-motivation and to ensure technology transfer wherever possible. Building on the epidemiology and basic science programs at the Uganda Virus Research Institute, an accredited phase I vaccine trial unit has now been developed. We have shown that high-quality trials complying with the standards of the ICH (The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) and good clinical practice, including onsite sophisticated immunogenicity testing, can be done in relatively resource-poor settings such as Uganda. There is an increasing need for laboratories in the developing world (where the HIV pandemic is worst and where vaccines are most sorely needed) to support nationally and internationally initiated and funded trials of vaccine candidates and effective 'rollout' of antiretroviral drugs. It is clear that such countries, including Uganda, wish to take ownership of, or at least be equal partners in, such scientific endeavors. Old fashioned 'parachute science', in which scientists from the developed world fly in, obtain blood from a few patients and immediately return to their country of origin with their samples, is no longer required or acceptable.
In-house development and research is an effective and efficient way forward. It is gratifying to realize that there are now many state-of-the-art, qualified laboratories, staffed by local scientists and technologists, supporting AIDS vaccine trials in these regions, including Uganda, although there remains a challenging need to develop this capacity further. The standardization of all tests is important so that data can be pooled and compared across multiple sites and products. The recent development of high-quality programs, including 'GCLP' (good clinical laboratory practice), to ensure reproducibly high standards and safety has been key to ensuring that data are reliable and meets the requirements of regulatory bodies9. The laboratory in Uganda sponsored by the International AIDS Vaccine Initiative, along with those in South Africa, India, Zambia and Kenya, has reached this status. It has also been necessary to develop new diagnostic tests for example, to distinguish true HIV infection from vaccine-induced antibodies10.
Many laboratory tests are required during AIDS vaccine clinical trials (Table 1). Along with validated tests to quantify the potential immunogenicity of any vaccine, for complete assessment, common diagnostic tests must be available, including hematology, clinical chemistry, urinalysis, expert microscopy for parasitic diseases, microbiology for sexually transmitted diseases, and detection assays for tuberculosis and hepatitis, for example. Local reference ranges for healthy young adults should be set, as these may be of great importance to trial enrollment as well as in the interpretation of safety data from volunteers during clinical trials, ensuring that adverse events are managed appropriately11.
We have recognized the importance of a central 'supporting' laboratory to successful laboratory development in Uganda and elsewhere and to the sound comparison of results from different vaccine candidates being tested at various sites. The role of this central laboratory has been fully described elsewhere12, but the delivery of specific laboratory training programs and standard reagents are of particular importance. We feel that substantial investment in the training of laboratory and managerial staff and provision of sustained ongoing support needs to be made.
The future?
It is absolutely essential that technology continues to be transferred and shared in an altruistic way. Western governments and international funding agencies must make long-term commitments to this goal. Capacity building and the training of future generations of scientists and doctors onsite in new technologies must continue. Not only facilities and equipment but also trained and motivated 'in-country' staff must be maintained and sustained. It is most important to 'input' the capacity to train the trainers to ensure that knowledge is shared and developed 'in country'. Local laboratory and clinical reference ranges need to be validated, and other country-specific parameters should be set. Laws and regulatory guidelines to cover laboratory services supporting such research must be developed and implemented. Clinical governance issues and ethical matters must also be addressed.
It is very important to provide support for suitable tertiary education 'in country' to train the leaders of tomorrow. Consideration must be given to providing lecturers in universities and colleges in developing countries; access to 'distance learning' in partnership with Western universities is also useful. Ensuring that clinical disciplines are physically located together, along with academic strength, will enable scientific growth. In turn, this will ensure developing countries not only conduct clinical trials and epidemiology studies but also provide state-of-the-art research that might contribute to the discovery phase.
In terms of the specific problem of HIV, which we have addressed here, the development of substantial international programs must be ensured to test new interventions, including microbicides and vaccines. An HIV vaccine must be part of a complete treatment and prevention package. Good examples of such initiatives are those funded through the European Commission Framework 6 such as 'Europrise' and 'Gisheal'. In that context, the ability to study mucosal immunity, especially around the genital tract and the gut and intestinal mucosa, may yield important information13, 14. New laboratory technology, general skills and clinical methodology must be transferred through in-house accessible training and the delivery of courses.
In Uganda we have not only focused on HIV vaccine trials. In partnership with our colleagues at the Uganda Virus Research Institute, we have undertaken cutting-edge research to enable better understanding of the pathological mechanisms underlying HIV infection and disease progression6. Such understanding may lead to new interventions for the treatment and prevention of diseases such as HIV. Other important diseases are being studied, and the capacity to study emerging diseases such as Ebola must be ensured. We have been able to link our clinical research with population-based information research. As in the developed world, we feel that a strong foundation in basic science is essential to any 'translational' research program. Publications in high-ranking journals from adequately funded, highly qualified scientists in the developing world are of paramount importance. First-author papers from a cadre of trained scientists, who have the capacity to conduct exciting and important research, may halt the 'brain drain' from the developing to the developed world15, 16, 17, 18, 19, 20, 21.
Finally, it must not be forgotten that HIV is not the only problem in Uganda or elsewhere in the developing world. The present crisis caused by devastating floods22 has resulted in the displacement of two million people from their homes in the most rural parts of Uganda, with the real prospect of hunger and disease to follow. Funds must be in place to alleviate suffering after such natural disasters. Technology transfer and 'in-country' research are also urgently needed to improve crop and livestock production, to deal with deforestation and to improve water purification. Problems related to global warming need to be addressed. Most importantly, training and education need to be strengthened, and in particular the development of women and girls must be considered. To paraphrase Tony Blair (General Election Manifesto; http://www.psr.keele.ac.uk/area/uk/man/lab97.htm), 'education, education, education' will surely result in a confident and well-equipped cadre of African scientists able to set up a scientific infrastructure to facilitate research and development and to lead the way in the future.
Conclusion
The need for the development of an effective preventative HIV vaccine is compelling. Vaccine trials must be done in the areas where the epidemic is worst to ensure that clinical trials are done as rapidly as possible (with the highest-incidence groups), which will also facilitate rapid access to vaccines. To undertake clinical trials 'in country', clinical diagnostic laboratories must be established on site to ensure appropriate enrollment of volunteers and to ensure their safety during interventional trials. This is relevant for all vaccine and drug trials; we are confident that resources and capacity will be shared within the country, regionally and worldwide. Our job is far from finished. In partnership, people of all parts of the world have the responsibility to work for mutual benefit and to make the planet a better, safer place for the future generations.
This article is part of the Global Theme on Poverty and Human Development, organized by the Council of Science Editors. All articles from the Nature Publishing Group are available free at www.nature.com/povhumdev. The content from all participating journals can be found at http://www.councilscienceeditors.org/globalthemeissue.cfm
