Bacteriophages in live virus vaccines: lack of evidence for effects on the genome of rhesus monkeys.

Four juvenile rhesus monkeys were inoculated with 10(12) plaque-forming units of the bacteriophage phiV1 isolated from live virus vaccines. After phiV1 had been cleared from the blood, DNA's were isolated from the livers and kidneys and analyzed for the presence of bacteriophage by plaque assays, and for the presence of phiV1 DNA by DNA-DNA reassociation kinetics. No evidence was found for persistence of the bacteriophage or for replication of the phage genome in these rhesus monkeys.

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.

Safety of viral vaccine cell substrates: a reevaluation.

Primary cultures of African green monkey kidney and rabbit kidney as well as diploid cell lines WI-38 and DBS-FRhL-2 were examined for evidence of tumorigenicity and latent RNA tumor viruses. Cells inoculated into immunosuppressed newborn hamsters and rhesus monkeys were not tumorigenic. Cells treated with 2'-deoxy-5-iodouridine to induce the production of latent viruses were examined by electron microscopy, density gradient centrifugation, and the reverse transcriptase enzyme assay. No evidence was found for RNA tumor viruses by the biochemical or biophysical methods used. The results indicated that each type of mammalian cell currently used in the production of virus vaccines would be acceptable for these parameters of safety if similar control procedures were applied at the time the vaccines were manufactured.

Adverse reactions reported following receipt of Haemophilus influenzae type b vaccine: an analysis after 1 year of marketing.

An analysis of adverse reactions occurring after receipt of Haemophilus influenzae type b vaccine and reported to the Food and Drug Administration during the first year of marketing of the product was performed. During the period April 1985 to May 1986, adverse reaction reports on 152 patients, excluding those of vaccine failure and concurrent infection, were received. Several adverse reactions not previously recognized, including convulsions, allergic reactions such as anaphylactoid-like and serum sickness-like reactions, and vomiting were received. The vast majority of adverse reactions were benign. Because there are many biases that result in the reporting of or failure to report an adverse reaction, it is not possible to derive a rate of reactions from these data. Furthermore, causality cannot be inferred from any single report. The data, however, indicate that, in light of widespread use of the vaccine, its use appears to be safe.

Neonatal anuria with maternal angiotensin-converting enzyme inhibition.

The use of angiotensin-converting enzyme inhibitors as antihypertensives has increased rapidly since the introduction of captopril in 1981. Seven cases of neonatal renal failure have been reported in patients with exposure to angiotensin-converting enzyme inhibitors that continued to the time of delivery. Two cases resulted in death of the newborn; the other five patients recovered after peritoneal dialysis. Because the relative frequency of normal outcomes is unknown, these data are insufficient for incidence-rate estimates or risk/benefit analyses. However, given the potential neonatal morbidity and mortality associated with late-pregnancy exposure to angiotensin-converting enzyme inhibitors, alternative therapies in the third trimester should be given consideration. If these drugs must be used in this context, the clinician should be prepared to deal with renal failure and hypotension in the newborn. The Food and Drug Administration invites reports of adverse pregnancy outcomes associated with such exposure.

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.

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.

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.

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.

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.

Tests for RNA tumor viruses in cell substrates used in virus vaccine production.

Test to detect RNA tumor viruses in cell substrates were reviewed with respect to advantages and disadvantages. Viral induction, electron microscopy, reverse transcriptase assays, density gradient centrifugation, and radioimmunoassays were performed on several cell substrates now in use or being considered for use in vaccine production. RNA tumor viruses were not detected by any of the methods except in the positive control cultures.

An oligonucleotide affinity column for RNA-dependent DNA polymerase from RNA tumor viruses.

Columns of (dT)(12-18)-cellulose provide a one-step enrichment procedure for RNA-dependent DNA polymerase. The enzyme of the virus from RD-114 cells, as well as that from Rauscher murine leukemia virus, have been purified in this way. The preference of viral as compared to cellular DNA polymerases for (dT)(12-18) as a primer is reflected in the fact that the DNA polymerases of uninfected cells do not bind to this column. Viral enzymes have been purified and identified from crude cellular extracts.

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.

Quality control of BCG vaccine by WHO: a review of factors that may influence vaccine effectiveness and safety.

WHO oversees the quality control of BCG vaccine via a system that includes regular testing of products by in vitro methods and clinical trials. Three parent strains of BCG (Glaxo-1077, Tokyo-172, and Pasteur-1173P2) account for over 90% of the vaccines currently in use worldwide. Important characteristics of the vaccine preparations are summarized here, along with their physical-chemical properties. In instances where diagnostic criteria for tuberculosis are stringent, there is no evidence that when administered to newborns different preparations of BCG vaccine exhibit different efficacies; however, the incidence of BCG-associated adverse reactions does correlate with the type of preparation. Other factors, including dose, administration technique, and recipient characteristics are also important in determining vaccine-associated reactions.