Introducing new vaccines in the poorest countries: what did we learn from the GAVI experience with financial sustainability?

This paper reviews the experience of the Global Alliance for Vaccines and Immunization (GAVI) in introducing hepatitis B and Haemophilus influenzae type b vaccines in the poorest countries, and explores how financing for immunization has changed since GAVI Fund resources were made available during its first wave of support between 2000 and 2006. The analysis of Financial Sustainability Plans in 50 countries allowed for some of the original funding assumptions of the GAVI approach to be tested against the realities in a wide set of countries, and to highlight implications for future immunization efforts. While the initial GAVI experience with financial sustainability has proved successful through the development of plans, and many countries have been able to both introduce new vaccines and mobilize additional financing for immunization, for future GAVI supported vaccine introduction, some country co-financing of these will be needed upfront for the approach to be more sustainable.

Strengthening immunization in a West African country: Mali.

UNLABELLED: OBJECTIVES AND CONTEXT: This paper describes the preliminary outcomes of a collaborative capacity-building initiative performed in Mali to strengthen the immunization program. METHODS: We conducted baseline assessments, training and post-training assessments in four programmatic areas: vaccine management, immunization safety, surveillance, and vaccine coverage, using adapted World Health Organization (WHO) tools. Impact assessment was done by evaluation of trainee performance, programmatic impact and sustainability. RESULTS: Qualitative and quantitative improvement of trainee performance was seen after the training interventions: some knowledge improvement, greater compliance with vaccine management practices and improved vaccine coverage. Deficiencies in information transfer to the periphery were identified. CONCLUSIONS: The program involves shared responsibility for planning, implementation and financing with national stakeholders while emphasizing the training of leaders and managers to ensure sustainability. Although short-term gains were measured, our initial assessments indicate that sustained impact will require improvements in staffing, financing and guidelines to ensure delivery of information and skills to the periphery.

Regulatory processes and three Rs alternatives.

Previously, the role of the laboratory in the regulation of vaccines and other biological products was key to assuring vaccine quality, where tests for potency and safety in animals were used to predict vaccine efficacy and safety in humans. In the past, regulation of inherently variable biological products depended on the use of inherently variable biological tests. Today, the concepts of regulation are evolving. Systems in place to assure product consistency are required; this is reflected in the need to have Good Manufacturing Practice as a part of quality assurance. Regulation now depends more strongly on experience in the clinic, including large post-marketing studies for safety. It also means that laboratory tests, especially in cases where there are no direct correlates of safety and efficacy, are more properly used for confirmation of consistency. In addition, the products themselves have changed. Many biological products can be produced in a form which allows quantification of characteristics, thus allowing more physical tests to be done. Thus, regulation of biological products in future will probably see a replacement, reduction and refinement (the 3 Rs) of animal testing.

Laboratory testing of whole cell pertussis vaccine: a WHO proficiency study using the Kendrick test.

Whole cell pertussis vaccine (WCV), commonly in combination with vaccines for diphtheria and tetanus, has an important role in reducing morbidity and mortality among children in most parts of the world. Testing to assure the efficacy of such vaccines is essential. We have, therefore, carried out, under the Global Training Network (GTN) of the Department of Vaccines and Biologicals at the World Health Organization (WHO), a proficiency study involving 13 laboratories in 12 countries that routinely test WCV. Two vaccine samples were tested in this study and represented samples which were expected clearly either to pass (sample B, a full strength vaccine) or to fail (sample A, 1/8 strength of vaccine B). Data from this study showed good performance by the majority of participants. Most assays were statistically valid and were carried out to the level of precision achieved for these assays in previous studies. This study also indicated that, relative to the assay precision, the in-house reference (IHR) preparations are in general accurately calibrated. Statistically valid assays of the sub-potent vaccine, A, showed it to fail in all except one laboratory. Statistically valid assays of the potent vaccine, B, showed it to pass in all laboratories. Nevertheless, the between laboratory variability of estimates for vaccine B, and for comparisons of the two vaccine samples suggested that there are some differences in results in different laboratories. The introduction of a common working standard may assist in reducing inter-laboratory variation. This study has shown clearly satisfactory performance by most laboratories. However, a serious problem was detected in one laboratory where the sub-potent vaccine A could have been passed and was not distinguished from the eight-fold more potent vaccine B. There were also indications of possible problems in several other laboratories, where IHR preparation may not be accurately calibrated or where vaccine samples A and B may not be completely distinguished. Although this study provides reassurance that most laboratories perform well, it demonstrates the essential role of ongoing proficiency studies in high-lighting problems.

Auto-disable syringes for immunization: issues in technology transfer

It reviews issues in technology transfer for the use of auto-disable syringes for immunization. Document in pdf format; Acrobat Reader required.

Ensuring vaccine safety in immunization programmes--a WHO perspective.

Ever since vaccines were firstly used against smallpox, adverse events following immunization have been reported. As immunization programmes expand to reach even the most remote communities in the poorest countries, it is likely that many more events will be temporally linked with vaccine administration. Furthermore, the profound shift in the general public and media interest in adverse events may lead to undue concerns and allegations which may ultimately jeopardize immunization programmes world-wide. While the health professional has understood this issue for some time, the public and the media have now also become all too aware of the significance of vaccine-related adverse events. The familiar vaccines, well-tested over decades, have not changed--but the perception regarding their safety has shifted. Claims outrageous or reasonable are being made against both the old and the newly-introduced vaccines. At the same time, the immunological and genetic revolution of the last decade may well bring to our notice some hypothetical risks that need to be addressed at pre-clinical level. WHO has been at the leading edge to guarantee vaccine safety for the last 30 years and will continue to do so. The Organization's plans for the next decade and beyond include the Safe Injection Global Network (SIGN), the development and introduction of safer technologies, and the prevention, early detection and management of AEFIs. The new technologies include needle-containing injection devices such as the autodisable syringe, as well as mucosal and transcutaneous immunization. Training will continue to be at the centre of WHO's efforts, limiting human error to a minimum. Mechanisms have been set in place to detect and respond to new and unforeseen events occurring. Above all, there is a willingness to respond to new climates and new technologies so that the Organization is in the best position to ensure safe immunization for all the world's children.

New challenges in assuring vaccine quality.

In the past, quality control of vaccines depended on use of a variety of testing methods to ensure that the products were safe and potent. These methods were developed for vaccines whose safety and efficacy were based on several years worth of data. However, as vaccine production technologies have developed, so have the testing technologies. Tests are now able to detect potential hazards with a sensitivity not possible a few years ago, and an increasing array of physicochemical methods allows a much better characterization of the product. In addition to sophisticated tests, vaccine regulation entails a number of other procedures to ensure safety. These include characterization of starting materials by supplier audits, cell banking, seed lot systems, compliance with the principles of good manufacturing practices, independent release of vaccines on a lot-by-lot basis by national regulatory authorities, and enhanced pre- and post-marketing surveillance for possible adverse events following immunization. These procedures help assure vaccine efficacy and safety, and some examples are given in this article. However, some contaminants of vaccines that can be detected by newer assays raise theoretical safety concerns but their presence may be less hazardous than not giving the vaccines. Thus risk-benefit decisions must be well informed and based on scientific evidence.

Developing a national system for dealing with adverse events following immunization.

Although vaccines are among the safest of pharmaceuticals, the occasional severe adverse event or cluster of adverse events associated with their use may rapidly become a serious threat to public health. It is essential that national monitoring and reporting systems for vaccine safety are efficient and adequately coordinated with those that conventionally deal with non-vaccine pharmaceuticals. Equally important is the need for an enlightened and informed national system to be in place to deal with public concerns and rapid evaluation of the risk to public safety when adverse events occur. Described in this article is the outcome of efforts by the WHO Global Training Network to describe a simple national system for dealing with vaccine safety and with emergencies as they arise. The goals of a training programme designed to help develop such a system are also outlined.

Availability of quality fixed-dose combinations for the treatment of tuberculosis: what can we learn from studying the World Health Organization's vaccine model?

SETTING: In efforts to promote the use of fixed-dose combinations (FDCs) for the treatment of tuberculosis (TB), the World Health Organization (WHO) and partners address the issue of quality assurance. OBJECTIVE: To provide guidance for the development of strategies for quality assurance of FDCs. DESIGN: This review examines the WHO strategies for and experience with quality assurance and supply of vaccines. RESULTS: Several elements in the strategies for quality assurance and supply of vaccines may be applicable for FDCs. At national level, the important strategies are to strengthen National Regulatory Authorities (NRA) and procurement systems and develop planning activities. Stressing quality assurance of FDCs in training activities for regulatory personnel and recommending that aid agencies require adherence to quality assurance policies as conditions for support would promote the implementation of quality assurance of FDCs at country level. At the global level, pre-qualification of manufacturers of FDCs should be explored as a mechanism to assure quality. The pre-qualification process should include evaluation of product files, initial testing for compliance and consistency of specifications, and site visits to producers and NRAs. The vaccine model defines criteria for reassessment that can be used for FDCs.

Alternatives and developing countries.

Alternative tests have a role in vaccine testing, especially to confirm production consistency. Given the characteristics of these alternative tests and of the products for which they may be used, there are several factors which will influence their use. These include a good understanding of the test and the product to be tested, strong national regulatory infrastructure, a laboratory run in accordance with the principles of laboratory quality systems, and the ability to validate the alternative method. This means that national regulatory authorities will need strong expertise in epidemiology and quality assurance to complement laboratory experience.

Auto-disable syringes for immunization: issues in technology transfer.

WHO and its partners recommend the use of auto-disable syringes, "bundled" with the supply of vaccines when donor dollars are used, in all mass immunization campaigns, and also strongly advocate their use in routine immunization programmes. Because of the relatively high price of auto-disable syringes, WHO's Technical Network for Logistics in Health recommends that activities be initiated to encourage the transfer of production technology for these syringes as a means of promoting their use and enhancing access to the technology. The present article examines factors influencing technology transfer, including feasibility, corporate interest, cost, quality assurance, intellectual property considerations, and probable time frames for implementation. Technology transfer activities are likely to be complex and difficult, and may not result in lower prices for syringes. Guidelines are offered on technology transfer initiatives for auto-disable syringes to ensure the quality of the product, the reliability of the supply, and the feasibility of the technology transfer activity itself.

PIP: This article examines the factors influencing technology transfer, including feasibility, corporate interest, cost, quality assurance, intellectual property considerations, and probable time frames for implementing the use of auto-disable (AD) syringes. WHO and its partners recommend the use of AD syringes, "bundled" with a supply of vaccines when donor dollars are used in all mass immunization campaigns, and also strongly advocate their use in routine immunization programs. Due to the relatively high price of AD syringes, WHO's Technical Network for Logistics in Health recommends that activities must be initiated to encourage the transfer of production technology for these syringes as a means of promoting their use and enhancing its access to it. Technology transfer activities are likely to be complex and difficult and may not result in lower prices for syringes. Guidelines are offered on technology transfer initiatives for AD syringes to ensure the quality of the product, the reliability of the supply, and the feasibility of the technology transfer activity.

A systematic method for evaluating the potential viability of local vaccine producers.

Vaccine production exists in > 55 countries, but many production facilities cannot assure a reliable supply of existing or new vaccines. By analysing the characteristics of successful producers, we have identified seven critical elements for viability, each defined by several indicators. Each indicated weakness implies an investment to correct it. Thirty-one manufacturers were assessed based on these viability indicators and the implied investment costs. Three general groupings were found. 'Viable' producers scored well in all seven categories. Those with a 'low probability' of viability are weak in all areas. Facilities regarded as 'potentially viable' may produce sufficient vaccine to meet national needs, but must develop appropriate structures to effectively manage change. This analysis provides a logical system for governments and donors to evaluate the potential effectiveness of further investment in local vaccine production.