Cost of production of live attenuated dengue vaccines: a case study of the Instituto Butantan, Sao Paulo, Brazil.

BACKGROUND: A vaccine to prevent dengue disease is urgently needed. Fortunately, a few tetravalent candidate vaccines are in the later stages of development and show promise. But, if the cost of these candidates is too high, their beneficial potential will not be realized. The price of a vaccine is one of the most important factors affecting its ultimate application in developing countries. In recent years, new vaccines such as those for human papilloma virus and pneumococcal disease (conjugate vaccine) have been introduced with prices in developed countries exceeding $50 per dose. These prices are above the level affordable by developing countries. In contrast, other vaccines such as those against Japanese encephalitis (SA14-14-2 strain vaccine) and meningitis type A have prices in developing countries below one dollar per dose, and it is expected that their introduction and use will proceed more rapidly. Because dengue disease is caused by four related viruses, vaccines must be able to protect against all four. Although there are several live attenuated dengue vaccine candidates under clinical evaluation, there remains uncertainty about the cost of production of these tetravalent vaccines, and this uncertainty is an impediment to rapid progress in planning for the introduction and distribution of dengue vaccines once they are licensed. METHOD: We have undertaken a detailed economic analysis, using standard industrial methodologies and applying generally accepted accounting practices, of the cost of production of a live attenuated vaccine, originally developed at the US National Institutes of Health (National Institute of Allergy and Infectious Diseases), to be produced at the Instituto Butantan in Sao Paulo, Brazil. We determined direct costs of materials, direct costs of personnel and labor, indirect costs, and depreciation. These were analyzed assuming a steady-state production of 60 million doses per year. RESULTS: Although this study does not seek to compute the price of the final licensed vaccine, the cost of production estimate produced here leads to the conclusion that the vaccine can be made available at a price that most ministries of health in developing countries could afford. This conclusion provides strong encouragement for supporting the development of the vaccine so that, if it proves to be safe and effective, licensure can be achieved soon and the burden of dengue disease can be reduced.

Cost of immunization with a locally produced, oral cholera vaccine in Viet Nam.

Policy decisions regarding whether to incorporate new vaccines into routine public health practice in developing countries will depend in part on the costs of vaccine purchase and of vaccine delivery. In March, 1997, a large-scale effectiveness trial of a locally produced, orally administered bivalent vaccine against Vibrio cholerae 01 and 0139 began in Viet Nam. Empirical data obtained from the trial was used to determine the costs of the immunization campaign from the government perspective. The study population, including the children less than one year of age and pregnant women who were ineligible for immunization, was 353926. A total of 289041 persons received two doses of vaccine, and 13340 persons received one dose of vaccine. Two-dose vaccine coverage was 83.4%. The total cost of vaccine delivery during the immunization campaign was $66527. The cost of each dose of vaccine was $0.31. Therefore, the total cost of the immunization campaign was $0.44 per dose administered, and $0.91 per fully immunized person. Attempts to reduce the cost per dose of vaccine (e.g. the use of a monovalent vaccine against serogroup 01) are likely to have a large impact on the cost of future similar immunization campaigns.

The introduction of new vaccines into developing countries II. Vaccine financing.

The development of new vaccines for important childhood diseases presents an unparalleled opportunity for disease control but also a significant problem for developing countries: how to pay for them. To help address this problem, the William H. Gates Foundation has established a Global Fund for Children's Vaccine. In this paper, we discuss the allocation of this and other similar funds, which we call Global Funds. We propose that allocation of the Global Funds to individual countries be guided in part by a Vaccine Procurement Baseline (VPB). The VPB would set a minimum of 0.01% of gross national product (GNP) as an amount each developing country would devote to its own vaccine procurement. When this amount is not sufficient to procure the vaccines needed by a developing country, the Global Funds would meet the shortfall. The amount required of donors to maintain the Global Funds would be about $403 million per year for both existing EPI vaccines as well as for a hypothetical group of five new vaccines costing $0.50 per dose and requiring three doses per child. Including program costs, poor developing countries currently spend about 0.13% of GNP on EPI immunizations. In contrast, the United States, as one example donor country, spends about 0.035% of GNP for childhood immunization including several new vaccines. This paper analyzes the Global Funds requirements for hepatitis B and Haemophilus influenzae type b (Hib) vaccines. After a ramp-up period, needier countries would eventually require about $62 million for hepatitis B and $282 million for Hib at current prices. Various additional criteria could be used to qualify countries for participation in the Global Funds.

The introduction of new vaccines into developing countries.

The development and introduction of new vaccines is a costly and time consuming process. Unfortunately, those most in need--individuals in developing countries--are the last to receive these powerful disease preventing products. From the time a vaccine is first licensed in a developed country to the time most of the poor in developing countries have access to the vaccine can be 20-30 years. This delay is unacceptable. There is a great need to reduce this time span. This paper examines five ways of reducing the time span. Each of the five is essential and achieving success on all five will require a heightened level of international effort and coordination.

Cost of plasma-derived hepatitis B vaccine production.

It is generally accepted that the introduction of hepatitis B vaccine to national programmes of immunization in developing countries is desirable, but it has so far been constrained by the high cost of the vaccine. To determine the potential minimal costs of the vaccine, a study has been carried out of the production of the vaccine in a developing country with a population of approximately 50 million. The study concludes that the manufacture of a plasma-derived hepatitis vaccine in some developing countries may be reasonable. A detailed financial evaluation using the best available information leads to several conclusions. In the hypothetical 50-million population country, a plasma-derived hepatitis B vaccine could be manufactured and made available at a price of approximately US$0.50 per dose packed in 10-dose vials if approximately 4 million doses per year are procured. An important condition of achieving this price level is that approximately 8% of total production is sold in the private sector for a profit. To establish these facilities, an initial capital investment of approximately US$3.7 million would have to be made. The minimal prices for hepatitis B vaccine that could be achieved in very large production facilities manufacturing many tens of millions of doses per year have also been estimated. Extension of the model to such quantities (10 to 20 million doses per year) suggests that the vaccine can be sold for less than US$0.10 per dose, thereby placing it in the same cost range as other EPI vaccines. Thus, hepatitis B vaccine may reach these cost levels when large-scale procurement is undertaken by governments and international donor agencies.

Attitudes toward the rhythm method in the Philippines.

Two sets of focus group discussions on the advantages and disadvantages of the rhythm method were carried out in the Philippines in 1980 and 1981. The first discussions were held among 30 women and nine men 21-40 years of age, and the second among eight women 25-35 years of age who had voluntary pregnancy terminations after the method had failed. Among the perceived advantages of rhythm were that it permits spontaneous intercourse on the safe days and has no bad side effects. Among the perceived disadvantages were that it is ineffective, especially for women with irregular periods, and it requires abstinence. The women who had had voluntary pregnancy terminations discussed their motivations and rationales and the methods that they had used. The information obtained from the discussions formed the basis for support materials that are now used throughout the country.

PIP: 2 sets of focus group discussions on the advantages and disadvantages of the rhythm method were carried out in the Philippines in 1980 and 1981. The 1st discussions were held among 30 women and 9 men 21-40 years of age, and the 2nd among 8 women 25-35 years of age who had voluntary pregnancy terminations after the method failed. Among the perceived advantages of rhythm were that it permits spontaneous intercourse on the safe days and has no bad side effects. Among the perceived disadvantages were that it is ineffective, especially for women with irregular periods, and it requires abstinence. Traditional methods for terminating a pregnancy were jumping on logs while working in the forest, eating roots of the chico tree, drinking quinine extracted from a white cheesewood tree, and drinking the juice/tea made from roots. Women personalize the decision to have an abortion with only secondary reference to external moral or legal systems. They have a clear set of perceptions about the nature of the fetus; they justify an abortion on the basis of the fetus's stage of development. The information obtained from these discussions formed the basis for support materials that are now used throughout the country.