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AAC09 didn't work well at all
Trials in India of AIDS vaccine that collapsed overseas
Sandhya Srinivasan in Mumbai
Why were phase-1 safety trials for an HIV vaccine started in India days before the release of the results of the same trial in Belgium and Germany? And why were phase-2 trials of the same vaccine conducted in Africa?
These are some of the questions that scientists and ethicists knowledgeable about the HIV/AIDS vaccine trials in India are asking about phase-1 trials here of tgAAC09, a recombinant adeno-associated viral vector-based candidate vaccine against HIV infection.
But such questions have been met with a deafening silence from the India office of the International AIDS Vaccine Initiative (IAVI), which has coordinated research and development of the vaccine. Sweta Das, director programme operations, IAVI-India, acknowledged a list of questions sent to her office early this month but did not reply to them.
Some of these questions are asked in an editorial in the Indian Journal of Medical Ethics entitled 'AIDS vaccine trials in India: ethical benchmarks and unanswered questions.' The editorial's authors are Amar Jesani, advisory board member of IAVI, and Lester Coutinho, former consultant with IAVI.
IAVI-India and the National AIDS Research Institute in Pune collaborated to test this vaccine candidate in India. The vaccine was developed, with IAVI funding, by the United States-based Targeted Genetics Corporation (TGC).
IAVI, a nonprofit organisation founded in 1996, states that its mission is to ensure the development of safe, effective, accessible, preventive HIV vaccines for use throughout the world. With offices in New York city and Washington, D.C., and representation in Europe and Africa, IAVI benefited in 2001 from a US 100 million dollar challenge grant from the Bill and Melinda Gates Foundation.
Phase-1 trials for safety and immune response of tgAAC09 were started at NARI in 2005. A total of 30 healthy human volunteers were eventually injected with the vaccine.
But the results of phase-1 trials on 50 volunteers in Belgium and Germany, started in December 2003, were already known unofficially, says C.M. Gulhati, editor of the Monthly Index of Medical Specialities, India and an expert on clinical trials.
"Preliminary results indicated that tgAAC09 was not working well at all," said Gulhati. "The trial had virtually collapsed. Why permit the same phase-1 trials in India?"
The India trials may have been done in the hope that the population here would have a better immune response to the vaccine, says a senior virologist familiar with HIV vaccine research in India, who does not wish to be named. "But at the very least, they should have waited two weeks till the Europe trial results were out."
On Feb. 22, barely two weeks after the India trial started, TGC announced the Europe trial results: "a single administration of the vaccine at the doses evaluated in this initial study did not elicit significant immune responses," though "no safety concerns were identified" either.
The insignificant immune responses were in contrast to expectations when the Europe trial started: "Results to date demonstrate safety and suggest the ability to elicit robust immune responses after a single injection," said Philip Johnson, president of Columbus Children's Research Institute and, with Targeted Genetics, the developer of tgAAC09 and the rAAV technology underlying it, in a press release when the trial was launched in Belgium in 2003.
Did IAVI and Targeted Genetics share the preliminary findings of the Europe trial, ask Jesani and Coutinho in their editorial. Did the Indian collaborators ask to examine the foreign data before starting the India trial?
"This apparent lack of communication raises questions on the nature of the partnership between the Indian and overseas partners," they write.
The Pune site was originally being prepared for TBC-M4 (Modified Vaccinia Ankara HIV-1 multigenic subtype C) to be tested at NARI. The senior virologist suggests that stability problems with the MVA vaccine led to its replacement by the tgAAC09 vaccine. "The NARI site was ready, another vaccine came along and the opportunity was utilised." The MVA trial started two years later in Chennai.
If experts were surprised by the hasty beginning of the NARI trial they were even more shocked to find that in November 2005, phase-2 trials (for immunogenicity) of the vaccine were started - not in Belgium, Germany or India but in Zambia, Uganda and South Africa.
Critics speculate that the Africa sites were chosen because of the lower costs, because there is a large pool of treatment naïve and high risk volunteers - and because these countries would accept phase-1 data from other countries. "They are taking advantage of lax regulations in Africa," Pune-based health activist Anant Phadke told IPS.
"They may also have been driven to test this vaccine in another genetically distinct area - distinct for virus strain as well as human population," says the virologist, conceding that the Africa trial might have some rationale. "Only a dose-escalation phase-2 will actually tell whether the vaccine raises the right types of immunity, and genetic diversity would have a major impact on vaccine-elicited immune responses."
However, "it is not good practice to use safety data from one population to drive phase-2 trials in another population," notes the virologist.
Gulhati opined that ''no one would have permitted phase-2 trials in Germany or Belgium on the basis of the unsatisfactory phase-1 results."
Doubts have been raised about the vaccine itself. "This is a weak vaccine and should not be pursued in a phase-2," says the virologist. "A vaccine with any hope for even partial success should aim to achieve more than a '20 per cent modest immune response'. Also consider that this vaccine construct has only one HIV gene (gag). It is clear from literature that the breadth of immune response is important, i.e. a response to multiple HIV proteins."
Targeted Genetics' own press release reports a "modest" immune response against gag, the principal HIV protein encoded by tgAAC09. Though animal trials elicited both T- and B-cell responses, only HIV-specific T-cell responses were observed in the human trials, and that too in barely one in five participants receiving the highest dose of tgAAC09 tested; antibody responses were not observed.
Preparations for the HIV vaccine trial involved extensive consultations and negotiations, establishing ethical benchmarks for all clinical trials in India, acknowledge Jesani and Coutinho in their editorial.
"The informed consent and participant information documents disclosed all known risks and clearly stated the right to withdraw from the trial at any stage. Guidelines for recruitment prevented coercion and exploitation of the poor and uneducated. Participants who became HIV positive during the trial would receive free access to care, support and treatment, including anti-retroviral therapy, for five years, and, all participants were insured for care, treatment and compensation for trial-related injuries."
Few argue with the desperate need for an HIV vaccine in India, which sees hundreds of thousands of new HIV infections each year. Jesani and Coutinho also ask why there is no systematic effort to develop a therapeutic vaccine to reduce the viral load in those already infected with the virus. It would pose fewer ethical challenges, they write, and it would also be cheaper to vaccinate infected people alone.
They conclude with food for thought on the driving forces behind vaccine research today: "The field of vaccine development today is shaped as much by philanthropy as by competitive market interests, global institutional arrangements of intellectual property rights, patents, scientific capacities (or the lack thereof), and the interests of investors and shareholders."
[Sandhya Srinivasan is executive editor of the Indian Journal of Medical Ethics published from Mumbai]
- Inter Press Service
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All political systems have inherent flaws
Mohammad Anwarul Kabir
The incumbent Army Chief Lt General Moeen U Ahmed has been gradually revealing his political ideology since the installation of the present interim government on January 11 this year. First, on the eve of our Independence Day he has expressed view with lamentation that 36 years after the independence, the nation has failed to pay due homage to Sheikh Mujib, the founding father of the country. He has also raised issue of war criminals and possible trial for their heinous crimes in 1971.
As the general's bold and vibrant utterance has coincided with the aspiration of the common people, many of them are really excited. Some members of the civil society, political parties and conscious citizens of the country have appreciated the Army Chief's sincere and honest expression without pointing at whether his official position as a chief of the armed forces allows him to express his political view.
It is true that every conscious citizen of the country has his/her personal political ideology and there is nothing wrong in it as long as it does not do any harm to the norm of the society. So, like other conscious citizens of the country General Moeen has his own political ideology.
General Moeen attended the seminar as Chief of the Armed Forces and disclosed his political ideology by presenting a paper in an academic manner. In this seminar, he sought for indigenous brand of democracy for our country. According to him rather than Westminster type parliamentary democracy, a hybrid democracy by increasing the power of the titular president under the parliamentary system should be introduced.
At the policy level, especially at this present critical juncture of the political scenario of the country the Army Chief's opinion has a significant impact. Already, Barrister Moinul Husein, the Law and Information Adviser to the government, has stated to the media that the general's proposition would get priority for consideration.
Parliamentary form
In this context, it can be argued that nothing is wrong with our constitutionally defined parliamentary form of government. The Westminster style parliamentary form of government works well in the UK, India and some other countries. Why should it not be suitable for our country? In fact, due to the failure of our politicians the nation has failed to see the real essence of the parliamentary democracy. So, rather blaming any system we should deplore the people who have corrupted the system.
Every system has its inherent merits and demerits: and both presidential and parliamentary systems are no exception. Even the hybrid system for which the General is advocating, if one properly investigates, will find inherent flaws in it. In Pakistan, this sort of hybrid system has failed to produce any effective democracy.
We must admit that to devise a perfect system - be it physical or social system - is quite impossible. Physicists have postulated that nothing in the universe is perfect and no system can ever be produced without any flaw. There must be a system loss (or flaw) in every system. This postulate of physics is not only true for any physical system but it is also true for any social system. In fact, social systems are more complex than physical systems as the major constituent of any social system is the human having very complex psychological dimensions. So, whatever the system the people have invented so far (e.g. democracy, socialism) to govern the society can never be termed as perfect and all of these systems have merits and demerits.
However, relying upon the goodwill of the individuals who are part and parcel of the system, a faulty social system can also produce good result as in democracy, which, despite its limitations, is acting efficiently and effectively to govern the people in the Western countries.
In this context, we can take example of system loss in electricity transmission system. Like any other physical systems, electricity generating and transmission system is not flawless and in this case the system loss (loss of electricity due to systems' own resistance) is obvious. In Western countries the rate of this system loss is at its tolerable level - not more than a few percentage point. However, in our country, although similar technology has been adopted for electricity generation and transmission systems, the system loss we incur is more than 25 per cent. What is the reason behind this? Of course this is not due to the inherent flaw of the system. In fact this undesirable high system loss is due to the corrupt individuals who are involved in our PDB (or DESA).
In fact, the efficiency of a system largely depends on the individuals who are integral parts of that system. So, if we can elect right people to run our country following our constitutionally defined democracy then eventually we will get an effective parliament which in turn will produce good governance aligning the aspiration of the common people. For this, the first and foremost responsibility of the present interim government is to arrange a free and fair general election within the shortest possible time as it has already adopted one of its prime agenda. Any sort of fresh constitutional debate centering forms of the government may jeopardise this goal.
M. Anwarul Kabir is a teacher and freelance writer, working at the American International University-Bangladesh.
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CAMPUS CAPERS
Whistle-blower
Rayyan Kamal
Richard C. Levin is the longest serving Ivy League president and is recognized as one of the leaders of American higher education. Prior to assuming the presidency in 1993, he was Dean of Yale's Graduate School of Arts and Sciences. A distinguished economist, he has served as Chair of Yale's Economics Department and has been a member of Yale's faculty since 1974.
The internationalization of Yale has been one of President Levin's priorities during his leadership. During his tenure, he launched the Yale Center for the Study of Globalization headed by former President of Mexico, Ernesto Zedillo; created the Yale World Fellows Program that is building and training a world-wide network of emerging leaders; and introduced a new financial aid policy to provide international students with the same generous financial aid awarded to U.S. students. Yale announced in Spring 2005 that it will provide every undergraduate student the opportunity to go abroad for study, research or internships at least once during their four years of college. For students on financial aid, additional funding will be granted to make these overseas opportunities possible.
President Levin has focused on China as the University's internationalization efforts have developed. He has traveled to China five times in the last four years. In 2001, he chose to give his Tercentennial Address on "The Global University" on the campus of Peking University, and he met with China's President Jiang Zemin in Beijing. In subsequent conversations with senior government officials, Yale was chosen to sponsor an Advanced University Leadership Program for the presidents and vice presidents of China's fourteen leading universities. That program was held during both the summers of 2004 and 2005. Similarly, Yale was chosen to sponsor an executive education program for the most senior cohort of Chinese government officials to study outside the country; that program was devoted to exploring how the Rule of Law could be further extended in China and occurred on Yale's campus in June 2005.
President Levin holds an Honorary Degree from Peking University and was awarded an Honorary Professorship from Fudan (Shanghai) University in late 2005. He gave remarks at Fudan's Centennial Celebration on that occasion.
President Levin's other international trips included visits to Japan, South Korea, India and Mexico as part of Yale's expansion of research and educational ties around the world. He delivered the Sir Purshotamdas Thakurdas Memorial Lecture on "Patents in Global Perspective" in Mumbai in January 2005.
Under President Levin's leadership, Yale completed a $1.7 billion fundraising campaign, and invested more than $2 billion in campus renovation and building programs. To ensure Yale's preeminence in research and discovery, he has committed $1 billion to renovating and expanding Yale's medical and science facilities, including the construction of five new science and engineering buildings; one of the largest new medical research facilities in the United States has opened recently.
President Levin has developed an effective partnership with the City of New Haven to expand commercial activity near the campus and increase the number of new local companies based on Yale research. During President Levin's term more than $1.5 billion has been invested in Yale spin-off companies, and Yale has directly contributed $100 million to improvements in the City of New Haven since 1993. As a part of President Levin's commitment to community development, Yale also supports numerous programs that provide New Haven with the expertise and services of faculty and students.
President Levin serves as a trustee of the William and Flora Hewlett Foundation, one of the largest philanthropic organizations in the United States. President Levin is also a director of American Express, and Satmetrix. He served on Presidential Commissions reviewing the U.S. Postal Service and the effectiveness of U.S. intelligence operations. As a member of the board on Science, Technology and Economic Policy at the National Academy of Science, President Levin co-chaired a committee that examined the effects of intellectual property rights policies on economic and scientific progress and made recommendations for reform of the patent system that are currently under active consideration by the U.S. Congress. In addition he was on the Blue Ribbon Panel on Baseball Economics.
A native of San Francisco, President Levin received his bachelor's degree in history from Stanford University in 1968 and studied politics and philosophy at Oxford University, where he earned a Bachelor of Letters degree. In 1974 he received his Ph.D. in economics from Yale and was named to the Yale faculty. He holds honorary degrees awarded by Peking, Harvard, Princeton, and Oxford Universities. He is a Fellow of the American Academy of Arts and Sciences.
President Levin maintains his involvement with students through regular meetings, meals in student dining halls, and regular attendance at sporting events. He and his wife, Jane, are longtime New Haven residents. They have four children and one grandchild.
Article obtained from http://www.yale.edu/opa/president/biography.html
Rayyan Kamal is a sophomore at Yale University.
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Urban air pollution in megacities
killing residents
Asim Khan
The freshness of the air in one's environment has a most fundamental and direct impact on the quality and length of one's life. Air is more a necessity of life than either food or water.
Imagine you live in a city where a grey-brown noxious haze of smog permeates the streets in your district. Imagine that these streets are filled with jam-packed traffic, a slow moving assembly of automobiles which blow out unhealthy exhaust fumes of carbon monoxide and other harmful chemicals. You cover your nose and mouth with a handkerchief to avoid excess exposure to dust and chemical particulates in the air. The air is not pleasant to inhale in deeply, and it gives you breathing trouble, making you cough and wheeze. In addition, your eyes water, your nose runs, and you have headaches and irritated eyes regularly when you are outdoors. As you walk on a street in this particular city on a weekday afternoon, a jogger passes by you wearing a face mask, and you observe children playing in a nearby school, inside a giant glass bubble to shield them from the city air.
Imagine this scene and you have in your mind the current state of affairs in Mexico City, a city whose air was recently ranked by the World Health Organization (WHO) as the most contaminated in the world. WHO studies indicate that it is unhealthy for human beings to breathe air with more than 100 to 120 parts per billion (ppb) of ozone contaminants for more than one day a year. Yet Mexico City residents breathe this level, or more, for over 300 days a year. Over a five-day emergency period last November - the longest continuous period in six years since the establishment of the emergency warning system - readings rose above 250 ppb, and city hospitals and clinics reported 400,000 pollution-related patients and 300 deaths.
Over one million of the 18 million Mexico City residents suffer permanent breathing difficulties, headaches, coughs and eye irritations. New studies suggest that children living in neighbourhoods with the worst air could suffer permanent alterations to cells in their nose and throat linings which could lead to cancer later in life.
In 1974 the Global Environment Monitoring System (GEMS) was created by the World Health Organization and The United Nations Environment Programme (UNEP) to monitor air pollution in large cities of the world. Indeed, urban air pollution could become a public health and environmental problem of crisis proportion early in the next century, if this is not already the case. The network monitors levels of suspended particulate matter concentration, lead, carbon monoxide, nitrogen dioxide, sulphur dioxide and ozone in the air.
Although air pollution is only one of the many environmental hazards in urban centres of the world, along with water contamination, hazardous wastes, overcrowding, congestion, and so on, it is a unique problem as it affects every resident, it is seen by every resident, and is caused by nearly every resident.
Of foremost concern in monitoring air quality in large cities is the health and well being of urban residents. The concentration of ambient air pollutants in many of the cities are high enough to cause increased mortality, disease prevalence, deficits in pulmonary function and cardiovascular and neurobehavioral effects. Indoor sources of air pollution, such as cooking fires and tobacco smoking, have contributed toward general human exposure as well. Air pollution is seriously damaging also to the material resources of cities, such as buildings and various works of art. Its impact on vegetation is also of concern.
The most recent WHO/UNEP report on air quality in 1992 focused on 20 of the 24 megacities of the world. Megacities were defined for the purpose of the study as urban agglomerations with current or projected populations of 10 million or more by the year 2000. The urban areas chosen include cities in all parts of the world - two in North America (Los Angeles, New York), four in Central and South America (Rio de Janeiro, Sao Paulo, Buenos Aires, Mexico City), one in Africa (Cairo), 11 in Asia (Bangkok, Beiji ng, Bombay, Calcutta, Delhi, Jakarta, Karachi, Manila, Seoul, Shanghai, Tokyo) and two in Europe (London, Moscow).
The UN estimates that by 2000 there will be 59 "supercities" having over five million population and many of these will reach megacity status by the next century. The study of air pollution problems in the 20 megacities is intended to guide efforts to solve and prevent some of these problems from occurring in emerging megacities. Preventing pollution problems before they occur is usually the most cost-effective method for dealing with air pollution.
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