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A Quarter-Century of Indo-U.S. Vaccine Research Collaboration

Working through informal channels 25 years ago, officials built a bilateral vaccine program that continues to support solid research in this field

Edward McSweegan

➤ The Indo-U.S. Vaccine Action Program (VAP) marks its 25th anniversary this year.
➤ Visits to India and chance encounters among leading U.S. and Indian vaccine investigators led them to propose and then establish a joint research program while overcoming numerous obstacles.
➤ With the blessing of national leaders, VAP set up streamlined approaches to supporting joint research projects—at first, on polio, typhoid, cholera, and hepatitis, but later to investigate other infectious diseases.
➤ From the outset, VAP emphasized collegiality, and officials cite that trait anew as they plan for the next round of jointly undertaken vaccine research projects.

Last September, American and Indian scientists met in New Delhi, India, to mark the 25th anniversary of the Indo-U.S. Vaccine Action Program (VAP). The meeting, which featured updates on VAP research projects and clinical trials, also was cause for celebration and self-congratulation for having seen the program through a diffıcult birth and a scientifıc adolescence troubled by fınancial uncertainties, changing research priorities, conflicting bureaucracies, and physical distance. Now at 25 years, many of the people who created the VAP, trained under it, and sustained it with collaborative funds, research, and publications have laid out plans and projects that should carry the program through another quarter century.

Grass Roots Diplomacy Led to Joint U.S.-Indian Vaccine Program

VAP poster
Government-to-government agreements can be ponderous documents, whose contents are known to high-ranking offıcials but which may prove obscure to citizens and scientists alike. The case of the Indo-U.S. VAP, however, may be a unique exception to that general rule. In its favor, it arose from chance meetings between individuals with common interests and a willingness to push new ideas through the labyrinths of their respective governments.

The fırst of these chance meetings came in 1984—and it included Nobel laureate Frederick Robbins, who was then President of the Institute of Medicine in Washington, D.C.; George Curlin, then at the Offıce of International Health (OIH) in the U.S. Department of Health and Human Services (DHHA); and U.S. embassy science attaché Phil Schambra, who later became the director of the Fogarty International Center at the National Institutes of Health (NIH).

Touring India and meeting with Indian offıcials and scientists, Robbins was struck by the country’s enormous need for vaccines. Until  then, India and the U.S. mainly collaborated with vaccines that focused on eradicating smallpox and on childhood immunization programs. The Robbins visit sparked an interest in moving beyond those programs to a more ambitious effort aimed at developing vaccines against infectious diseases important to India and other developing countries.

Yet, U.S.-India collaborations involving science and technology often were jarred by concerns in very different areas, including national security, technology transfer, intellectual property rights, and even Soviet influences. A program on vaccine research, however, seemed likely to strengthen the relationship without getting bogged down in ancillary issues or geopolitical scuffles in Southeast Asia.

A few months after Robbins visited India, a second chance meeting at the World Health Organization in Geneva occurred between George Curlin and Vulimiri Ramalingaswami, the Director- General of the Indian Medical Research Council (ICMR). Ramalingaswami was immediately enthusiastic about a collaborative partnership on vaccine research and development (R&D), and quickly went about promoting the idea within the Indian government.

In April 1985, members of the U.S.-India Science & Technology Subcommission met in New Delhi. William Foege, a former director of the Centers for Disease Control and Prevention (CDC), and Ramalingaswami asked the Subcommission to endorse the concept of a bilateral vaccine research program. With approval from the Subcommission, Curlin, Schambra, Foege and Linda Vogel of OIH briefed Harry Barnes, the U.S. Ambassador to India. Walking up to his offıce, they considered names for the new vaccine collaboration and at some point, the phrase, “Vaccine Action Program,” emerged.

VAP Receives Attention from National Leaders

Within a few months, the VAP received attention from U.S. President Ronald Reagan and Indian PrimeMinister Rajiv Gandhi, and a draft memorandum of understanding (MOU) outlining procedures for the VAP was circulating in Washington and New Delhi by the middle of 1985. Inevitably, perhaps, when a half-dozen agencies and institutes in both countries became involved, progress toward fınalizing the draft plans slowed down.

Yet, two-and-a-half years after Robbins began musing about the state of vaccine development in India, a fıve-year VAP agreement was signed and cofunding was arranged among the U.S. Agency for International Development (USAID), OIH, and the Indian Department of Biotechnology (DBT). Equally important, the Indian Prime Minister gave the new vaccine program “singlewindow project clearance authority,” which greatly reduced the offıcial approval times for personnel, resources, and funds to move into India.

Bottom-up Science

The newly signed agreement called for “cooperation across the entire spectrum of vaccine-related technology, including research to develop new and improved vaccines and vaccine-related diagnostic methodology, vaccine fıeld trials, quality control, and vaccine delivery methodology.” Initially, collaborative vaccine studies would focus on “diarrheal diseases, viral hepatitis, rabies, and others as may be mutually identifıed.” Two governments had signed the VAP agreement and infused it with startup funds, but it would take individual investigators and investigator- initiated research proposals to make the program work as advertised. Toward that end, Indian and American offıcials formed a VAP Joint Working Group (JWG) of scientists and policymakers, who met in March 1988 to work out the bureaucratic details of long-distance collaborative research. The JWG appointed two agencies—DBT in India and OIH in the U.S.—to serve as “secretariats” for handling the day-today business of soliciting grant proposals, arranging peer review, making awards, and monitoring progress.

The U.S. VAP Secretariat announced the new VAPgrants program by mailing letters and applications to 149 medical schools and 22 public health schools. Twenty-two proposals came back in response. At the second meeting of the JWG in October 1988, four projects on polio, typhoid, cholera, and hepatitis were approved for funding. Indo-U.S. collaborative vaccine research had begun in earnest.

Dollars, Rupees, and Programs to Develop a Variety of Vaccines

Since those fırst awards in 1988, the VAP has supported almost 60 collaborative projects with more than $10 million plus an equivalent amount in Indian rupees. Investigators from U.S. universities and federal agencies worked with scientists from Indian universities and government agencies. Several hundred researchers, students, and technicians traveled between India and the U.S. for training, meetings, and related project work. Since 1989, 30 workshops and expert consultations on vaccines and infectious diseases have been organized. In addition, almost 300 peerreviewed publications emerged from VAP projects and collaborations, some of which continue long after specifıc projects ended.

The productivity and longevity of VAP led to changes in personnel and practices on the U.S. side. For example, the U.S. VAP was funded initially with $4 million from the USAID Vaccine and Immunodiagnostic Development Project (VIDX). When that funding ended, the Starr Foundation donated $2 million. Eventually, the U.S. VAP Secretariat relied on NIH grants and supplements, and Indian rupees that accumulated under an agricultural aid program called the Special Foreign Currency Program. In the absence of dedicated funds, NIH grants supported VAP research projects in the U.S. while U.S.-held rupees paid for travel to and from India.

Along with the loss of set-aside funds, there were repeated changes in management. For example, USAID withdrew from the VAP, and Embassy Health Offıce staff left India for other assignments. The U.S. Secretariat functions and records moved from OIH in DHHS to the National Institute of Allergy and Infectious Diseases (NIAID) at NIH.

While the U.S. side of VAP went through a series of funding and management changes, the Indian side of the program was largely spared similar changes. Thus, the Indian DBT continued to serve as the Secretariat, and a line item in the DBT annual budget provided a stable source of funding for VAP projects and travel.

Yet, for all the changes in personnel and funding, the VAP continued to support new projects and provide a springboard for long-term collaborative research. For example, in the early 1990s, small VAP grants were awarded to Roger Glass at CDC, Harry Greenberg at Stanford University, Maharaj Kishan Bhan at the All India Institute of Medical Science (AIIMS) and C. Durga Rao at the Indian Institute of Science to study neonatal, nonpathogenic strains of Indian rotavirus as possible vaccine candidates. Two more such grants were awarded to Bhan, Glass, and Yvonne Maldonado at Stanford.

By 2003, these two rotavirus projects merged and acquired new funding from a large NIAID cooperative agreement. Since then the scope of the project expanded to include clinical trials funded by a variety of international partners, including DBT, CDC, the Program for Appropriate Technology in Health (PATH), the Society for Applied Sciences (SAS) in New Delhi, Bharat Biotech International in Hyderabad, Stanford University, and the government of Norway.

The rotavirus vaccine project led to three dozen peer-reviewed publications and provided years of training opportunities in everything from recombinant DNA technologies to clinical trials design and biostatistics. If eventually licensed, the vaccine could prevent 100,000 annual pediatric deaths in India. Fogarty International Center Director Roger Glass wrote in the VAP Silver Jubilee Commemorative publication that it also will be the “fırst totally new vaccine developed entirely in India for more than a century, made with an Indian strain, an Indian manufacturer, Indian clinical trials, through an Indo-U.S. partnership initiated by the VAP. . . .”

Similarly, two early VAP projects on rabies and typhoid eventually led to a new rabies vaccine that was licensed and is marketed in India as well as a typhoid vaccine that is manufactured by Bharat Biotech. In addition, an Indian dengue subunit vaccine is being tested in mice with support from NIAID and the involvement of investigators in Boston, Texas, and North Carolina.

VAP funds supported research between staff scientists at the U.S. Food and Drug Administration (FDA) and the Indian Institute of Pathology to identify parasite genes that may serve as vaccine candidates and drug targets against leishmaniasis. Another VAP grant on the genetic diversity of Indian strains of Helicobacter pylori helped start collaborations between researchers at Washington University in St. Louis and the National Institute of Cholera and Enteric Diseases in Kolkata. A grant to the University of Alabama and AIIMS helped fund research on rapid, low-cost diagnostics for influenza and other respiratory pathogens. All three grants have long since ended, but the collaborations started under the VAP continue through other means, including NIH grants.

Since the VAP provided an offıcial conduit for cooperation, funding, and clearing government hurdles, it made sense for investigators to use the VAP to work in India. Yet, one NIH grant on HIV/AIDS in India awarded to Robert Bollinger of Johns Hopkins University and his Indian colleagues had a major impact on the VAP without being part of it. A 10-year review of the VAP noted, “The DBT is not sponsoring or fınancing the project under the VAP, however, this project, and especially Dr. Bollinger’s 1994 scientifıc presentation, convinced JWGmembers to recognize the importance of AIDS within VAP, and thus HIV/AIDS was added as a VAP priority. . . .”

When the VAP was renewed in 1997, HIV/AIDS was added to the list of targeted diseases. Since then, VAP reviewed and funded four projects on HIV infection and HIV vaccine candidates. Moreover, in October 2011, offıcials from HHS and the Indian Ministry of Health and Family Welfare expanded bilateral AIDS cooperation by signing a separate agreement called the Joint Statement on Collaboration on Prevention of Sexually Transmitted Diseases and HIV/AIDS.

A Collegial Program

The original language of the VAP agreement called for each side to designate a secretariat “to assure that the VAP operates smoothly between Joint Working Group meetings, and to help sustain the collegial nature of this joint program.” For the fırst decade or so, the two VAP Secretariats operated very much like a typical granting agency: inviting scientists to write letters of intent, screening proposals, soliciting peer reviews, scoring applications, awarding funds, and tracking progress. Over the years, however, some formalities waned with growing experience, confıdence, and familiarity with the agencies and individuals on both sides. What once required lengthy proposals, reviews, and formal meetings may be done through a few phone calls or e-mail exchanges between NIAID and the DBT, along with some outside advice. That flexibility enables the VAP quickly to supplement grants, provide travel funds for visiting scientists, supply reagents and technical advice for ongoing projects, and add new grants or research topics to the program.

While the September 2012 meeting allowed VAP participants to look back at 25 years of international cooperation, it also was an opportunity to identify new areas for research and ways to support it. For example, a Human Immunology Project Consortium run by NIAID will cofund new projects with India on human immunology and infectious diseases. NIAID will contribute $1 million per year, which the DBT in India will match. A second cooperative grant program that focuses on tuberculosis will also be jointly funded, but will be managed through the nonprofıt entity CRDF Global of Virginia. VAP investigators are also considering ways to collaborate on studies of the human microbiome.

The VAP is a small but important venue for international vaccine research. It has been an important source of funding, resources, and expertise for U.S. and Indian scientists, and it is likely to remain so during the next 25 years. As AIIMS Professor and VAP founding member Prakash Narain Tandon wrote in the VAP commemorative booklet, “The most cherished aspects of the VAP are its spirit, trust, and mutual confıdence it has generated over the years. All this has built up a genuine friendship, a feeling of belonging to a unique family.” Imagination, chance encounters, and joint funding enabled VAP to take shape during the 1980s, but perhaps the qualities Professor Tandon described are what will keep it going into the future.

Edward McSweegan is at the National Institute of Allergy and Infectious Diseases in Bethesda, Md.

Suggested Reading

Indo-U.S. Vaccine Action Program. Available online at: http://www.niaid.nih.gov/about/organization/dmid/indo

Indo-U.S. Science and Technology Forum. A brief history of bilateral collaboration and cooperation in science and technology. Available online at: http://www .indousstf.org/fullstory.aspx?storyheadline_History &prevmytitle_About%20IUSSTF&sectionid_S150

Raymond, S. Designing and implementing a multiagency project: the Vaccine Action Program in India. Task Force on Development Organizations of the Carnegie Commission on Science, Technology, and Government, in New York City, October 1990. http://pdf.usaid. gov/pdf_docs/PCAAA520.pdf

U.S. Agency for International Development. India: Vaccine and Immunodiagnostic Development (386-0503), April 17, 1987. Available online at: http:// pdf.usaid.gov/pdf_docs/PDAAV736.pdf.

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