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.

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.

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.

Development of a more thermostable poliovirus vaccine.

In 1991, a goal of improved thermostability of oral poliovirus vaccine (OPV) was set, and the Product Development Group was established under the Children's Vaccine Initiative to achieve this goal. Several initial research strategies were unsuccessful. The substitution of deuterium oxide for water in the final blending stage of vaccine production resulted in a significantly more stable product at temperatures of > or = 37 degrees C. A large body of clinical data shows the safety of deuterium at the dosage that would be given with this vaccine. However, reservations about the public acceptability of the vaccine, combined with the progress achieved in polio eradication with the current vaccine and the availability of vaccine vial monitors to indicate time and temperature exposure of every vial of OPV, have resulted in a recommendation that vaccine development cease. This product development activity has been instructive for the process of introduction of new vaccines.

Global DTP manufacturing capacity and capability. Status report: January 1995.

A recently completed survey of 63 manufacturers of diphtheria-tetanus-pertussis (DTP) vaccine and its components in 42 countries shows that there is potentially a large excess installed capacity for DTP production. However, many manufacturers are not producing to capacity, and demand and supply for this vaccine are not matched in individual countries. About half of all countries producing DTP vaccine and its components do not have fully functional national control systems, and some countries are performing none of the critical functions for an effective control of quality. Thus, potential for export of excess capacity is limited. The data collected indicate much homogeneity in the preparation of diphtheria and tetanus toxoids. Nearly all manufacturers use the same seeds and similar purification methods, but there is variability in whether purification is done before or after conversion of toxin to toxoid. About 10% of all manufacturers do not meet WHO-defined standards of purity for these toxoids. There is much more heterogeneity in the pertussis seed strains and the methods of purification used. The formulation of DTP vaccine differs considerably among producers. Potency testing is not being done by the WHO-recommended method by about 50% of manufacturers on lots of diphtheria and tetanus toxoids for release. Testing of irreversibility of conversion of toxin to toxoid, a WHO-specified safety test, is also not being done on each lot of diphtheria toxoid by 15% of manufacturers surveyed nor on each lot of tetanus toxoid vaccine by 30% of manufacturers surveyed. Access to technology to develop new DTP-based combination vaccines will be delayed if these manufacturers cannot ensure consistent high quality vaccine for their target populations. The results and conclusions suggest areas for future activities to strengthen the supply and quality of DTP and DTP-based combination vaccines.

Regulatory considerations for new stabilised poliovaccines.

As the least heat stable vaccine used by national immunization programmes, oral poliovaccine (OPV) is a target for improved stability. Dilution of OPV trivalent bulk vaccines meeting all international requirements in 87% deuterium oxide results in a significant stability increase of up to 1000-fold after incubation for one week at 45 degrees C. Regulatory considerations for a new formulation focus generally on the safety, potency and efficacy of the individual components (OPV and deuterium oxide) and ruling out any untoward and unexpected interactions between them. As the characteristics of OPV and deuterium oxide are well established, preclinical and clinica, data should address potential interactions. Because this stabilised vaccine is under development by two European manufacturers, initial regulatory discussions are being conducted with the European Medicines Evaluation Agency and its Committee on Proprietary Medicinal Products.

Performance and potency of tetanus toxoid: implications for eliminating neonatal tetanus.

Neonatal tetanus (NT) is a major cause of mortality in developing countries, with over 400,000 deaths estimated to occur annually. WHO has adopted the goal of eliminating NT worldwide, and a major strategy for its prevention is the administration of at least two properly spaced doses of tetanus toxoid (TT) to women of childbearing age in high-risk areas to protect passively their newborns at birth. In certain countries the locally produced TT vaccine has been shown to be subpotent, while other countries have reported NT among infants born to vaccinated women. An extensive review of production and quality control procedures was carried out between 1993 and 1995 in 8 of 22 TT-producing countries that also report NT cases, with a more superficial assessment being carried out in the remaining 14 countries. Only 4 of the 22 countries have a functioning national control authority to monitor TT production and vaccine quality. A total of 80 TT lots from 21 manufacturers in 14 of the 22 NT-reporting countries were tested for potency. Of these, 15 lots from eight manufacturers in seven countries had potency values below WHO requirements. TT potency can also be compromised by improper vaccine handling. To eliminate neonatal tetanus worldwide requires assurance that all doses of TT meet WHO production and quality requirements and that the field effectiveness of TT is monitored through systematic NT case investigations and assessment of coverage.

PIP: Neonatal tetanus (NT) causes an estimated 400,000 deaths annually in developing countries. One major way to prevent NT is to administer at least two properly spaced doses of tetanus toxoid (TT) to women of childbearing age in high-risk areas in order to passively protect their newborns at birth. However, locally-produced TT vaccine in some countries has been found to be subpotent, while other countries have reported NT among infants born to vaccinated women. An extensive review of production and quality control procedures was conducted between 1993 and 1995 in 8 of 22 TT-producing countries which also report NT cases. A less exhaustive examination was conducted in the other 14 countries. Among the 22 countries which both report NT cases and produce TT, only Brazil, India, Indonesia, and Mexico have fully functioning national control authorities to monitor TT production and vaccine quality. 80 TT lots from 21 manufacturers in 14 of the 22 countries were tested for potency. 15 lots from 8 manufacturers in 7 countries had potency values below World Health Organization (WHO) requirements. TT potency can also be compromised by improper vaccine handling. If NT is going to be eliminated worldwide, all doses of TT must meet WHO production and quality requirements. Moreover, the field effectiveness of TT must be monitored through systematic NT case investigations and the assessment of coverage.