[Rotavirus]
[Enterotoxigenic Escherichia coli (ETEC)]
[Technical Assistance and Training Program for Local Vaccine Production and Regulation]
[Other training activities]

Rotavirus
Rotavirus is the most important cause of severe diarrheal disease among infants and children. Each year throughout the world, children suffer an estimated 130 million episodes of rotavirus diarrhea, and at least 600,000 children under 5 years of age die from rotavirus. A recently developed rotavirus vaccine was effective in preventing severe disease due to rotavirus among infants and children. Immunization of infants with this vaccine was shown to be cost-effective. However, this vaccine was withdrawn from the U.S. market because of its association with a potentially fatal intestinal tract complication. Newer rotavirus vaccines are currently under development and evaluation in the United States and elsewhere.

Despite the proven importance of rotavirus as a childhood disease, many countries in Asia, including China, have not undertaken a systematic and comprehensive effort to determine the morbidity, mortality and costs associated with rotavirus. To define the rotavirus disease burden in China, IVI is launching a two-year hospital-based surveillance program that will assess the disease burden in six sentinel hospitals. All infants and children aged < 5 years with diarrhea will be enrolled and parent/guardians will be interviewed by trained clinicians to collect clinical history information. Fecal specimens will be collected and transported to hospital clinical laboratories for detection of rotavirus antigen using an enzyme-linked immunosorbent assay.

Laboratory analysis at two Chinese reference laboratories will be conducted to ascertain the identities of the strains of rotavirus detected in the surveillance. On a regular basis, trained personnel will ship specimens to the WHO Collaborating Center on Rotavirus at the United States Centers for Disease Control and Prevention for laboratory confirmation of identified strains as well as cataloguing strains for the WHO rotavirus reference library.

Enterotoxigenic Escherichia coli
Enterotoxigenic Escherichia coli (ETEC) are the most common bacterial cause of childhood diarrhea in developing countries and are thought to cause about 400,000 deaths annually. The IVI is currently collaborating with SBL Vaccin, Sweden; the U.S. Naval Medical Research Unit-3 in Cairo; the U.S. National Institutes of Health; the University of Gothenburg, Sweden; and WHO on an efficacy trial of a killed oral ETEC vaccine in 6-18 month old infants and children in Egypt. This is the first trial to evaluate the protective efficacy of a new-generation ETEC vaccine in developing country infants and children, the age group accounting for the vast majority of deaths due to ETEC in these settings. Concurrently with this efficacy trial, IVI is collaborating with the same investigators on a study of the safety and immunogenicity of this vaccine when given in the EPI schedule of conventional immunization at 2, 4, and 6 months of age. If promising results are obtained from these two trials, the next step will be to assess the efficacy of the vaccine against ETEC diarrhea when the vaccine is given in the routine EPI schedule.

Technical Assistance and Training Program for Local Vaccine Production and Regulation
Local vaccine production accounts for the majority of all doses of vaccines administered in developing countries. However, mechanisms are often not in place in developing countries to ensure that the manufacturing facilities meet international standards for vaccine production. In addition, an independent and competent National Regulatory Authority/National Control Laboratory (NRA/NCL) is often not fully developed in these countries. A fully functional and competent NRA/NCL is necessary to provide oversight for registration, post-marketing surveillance, lot release, and Good Manufacturing Practices (GMP) inspection, and to establish and enforce appropriate regulations. Therefore, one of IVI's most important mandates is to provide technical assistance and training to local manufacturers and to the NRA/NCLs in vaccine-producing developing countries to upgrade the production, regulation, and control of locally manufactured vaccines. The goal of this program is to develop the competence and requisite skills in vaccine manufacturing and regulatory practices critical to
national needs and priorities.

The program includes the following sequential activities:

1. Vaccine manufacturers
• GMP inspection for status analysis: This activity aims to diagnose the status of vaccine manufacturing facilities and operations, as well as production and quality control/assurance, and to determine the specific areas needing improvement to comply with GMP.
• Short-term, introductory, implementation-oriented GMP training: This course provides trainees with a platform of basic knowledge on the principles and application of GMP.
• GMP facility design: Technical assistance is offered in renovating facilities and/or designing new facilities in accordance with the "clean vs. dirty area"concept and "infectious vs. non-infectious area" concept.
• Long-term extensive hands-on GMP training: This program provides trainees with practical knowledge on the implementation of GMP principles for the manufacture of vaccines. The program focuses on three areas: production, quality control and quality assurance.
• Subsequent training: Occasional short-term visits to vaccine manufacturers are made for further assistance when needed.

2. NRA/NCL

• Inspection for status analysis: To diagnose the status of NRA/NCL, the agencies are assessed and the specific areas to be improved are determined. 

• Introductory Good Laboratory Practice (GLP)/GMP training: The aim of the course is to provide trainees with a platform of basic knowledge on the principles and application of GLP/GMP.

• Facility design: Technical assistance is offered in renovating present facilities and/or designing new facilities.

• Long-term hands-on training on quality control testing and quality assurance is also available.

• Occasional short-term visits to NRA/NCL are made for further assistance when needed.

The above technical assistance and training are provided primarily at local facilities. However when the IVI pilot plant and laboratories are completed, long-term hands-on training will be offered at IVI.

During 2000, the IVI in collaboration with WHO/PAHO conducted a training course for NRA/NCL personnel in Brazil. This training was organized by the Global Training Network (GTN) of WHO, and IVI provided the training course as one of the training centers of the GTN. The Korean Food & Drug Administration has been continuously assisted by IVI staff in the field of the evaluation, research and control of biologics including vaccines and diagnostics. The IVI also provided introductory GMP/QC/QA training courses and inspections/consultancies for the Lanzhou Institute in China, and the National Institute of Hygiene and Epidemiology and the Institute of Vaccines and Biological Substances in Vietnam. Finally, a status analysis was made to plan for specific future assistance and training programs for each institute.

Other Training Activities

The first IVI Inter-national Course on Vaccine Evaluation in Developing Countries took place in late 2000 and was organized in collaboration with The London School of Hygiene and Tropical Medicine and the National Institute of Vaccines and Biological Substances, Nha Trang, Vietnam. The course was co-sponsored by Becton-Dickinson, the Rockefeller Foundation, Sartorious Corp., and GlaxoSmithKline Biologicals. Nha Trang, in the central coast of Vietnam, was the venue and offered a conducive teaching environment. Trainees had direct access to vaccine production facilities and visited the study site of an ongoing large-scale effectiveness trial of a killed oral cholera vaccine.

The course included coordinated lectures, exercises and field visits across the spectrum of vaccine development, introduction and evaluation. Topics included the immunological basis for vaccination; features of vaccination programs in public health; routine surveillance for infectious diseases; assessment of vaccination coverage; Good Clinical Practice principles; Phase 1-2-3 studies; efficacy vs. effectiveness trials; new vaccine regulation and production requirements; surveillance for injection safety; surveillance for vaccine adverse events; serological surveillance; and challenges of evaluating new vaccines against Shigella and malaria.

A total of 21 participants, coming from China, Egypt, Indonesia, Mongolia, Mozambique, Pakistan, and Vietnam, attended the course. Most participants are directly involved in current vaccine evaluations. The IVI plans to provide this course yearly.