Policymakers’ views regarding the introduction of new-generation vaccines against typhoid fever, shigellosis and cholera in Asia

Abstract

Face-to-face interviews and meetings with more than 160 policymakers and other influential professionals in seven large Asian countries (Bangladesh, China, India, Indonesia, Pakistan, Thailand and Vietnam) were conducted to survey opinions regarding the need for, and potential uses of new-generation vaccines against cholera, typhoid fever and shigellosis. Despite several barriers to their uptake—notably uncertainty of the burden of enteric diseases; preference for water, sanitation and other environmental improvements over vaccination for disease control; and high prices of the current vaccines relative to basic EPI vaccines, and their moderate protection levels—considerable interest was found in the targeted use of Vi typhoid vaccine in most countries, followed by (future) Shigella and oral cholera vaccines. The introduction of these vaccines in Asia could be greatly facilitated by country-specific evidence of disease burden, local or regional vaccine production, field studies demonstrating their safety and efficacy in local populations, evidence of potential economic savings from vaccination, and effective dissemination of research results to all those who make or influence immunization policy.

Introduction

The past 5 years have seen increasing efforts—funded largely by the Gates Foundation—to accelerate the development and use of vaccines needed mainly in developing countries, but not viewed by the major vaccine producers as sufficiently profitable to justify the considerable research and development investments that are required. These projects include: the Malaria Vaccine Initiative (MVI), the International AIDS Vaccine Initiative (IAVI), the Meningitis Vaccine Project (to develop an appropriate meningococcal conjugate vaccine for Africa), the Rotavirus Vaccine Program and the Pneumococcal Vaccines Accelerated Development and Introduction Plan (Pneumo ADIP).

One of the earlier projects of this kind was the Diseases of the Most Impoverished (DOMI) Program, launched in 1999 to accelerate the development and use of current and future new-generation vaccines against three serious enteric diseases responsible for many deaths in developing countries: typhoid fever, cholera and shigellosis. DOMI aims to achieve this goal by providing country-specific, multi-faceted data—on disease burden, vaccine safety and field effectiveness, vaccine cost-effectiveness, and private demand and willingness-to-pay for these vaccines—through a comprehensive, field research programme. The intent, therefore, is to translate solid, country-specific data into rational decisions regarding the use of new- and future-generation typhoid, cholera and Shigella vaccines.

But will the DOMI Program's research results necessarily lead to decisions by country-level policymakers to introduce a vaccine and to allocate sufficient resources to do so—even if the data provide powerful epidemiological and economic arguments for vaccine introduction? How will these diseases and vaccines fit in with the disease control priorities of policymakers in the target countries? How are these priorities determined and who determines or influences them? What factors or criteria do policymakers weigh in making decisions about a new vaccine? Are there other unforeseen obstacles to introducing these vaccines? What introduction strategies—in terms of vaccine source, distribution channels, financing and delivery mechanisms—are most likely to succeed for each of these vaccines? And finally, what specific types of data will be most critical to policymakers in making decisions regarding vaccine introduction and how and to whom can these data be disseminated to most effectively translate into policy decisions?

DOMI believed that answering these questions would help ensure that its research and advocacy programme meets the needs of those who make or influence vaccine introduction decisions—thus enhancing the likelihood that it will actually lead to vaccine introduction in countries where the data present a compelling case. Exploring these questions becomes increasingly important as government juggle decisions regarding a growing list of available and upcoming vaccines and technologies, while faced with many pressing health priorities and often severe budgetary constraints.

The DOMI Program, therefore, decided to conduct, at an early stage, a survey of policymakers and other influential professionals in the seven participating countries (Bangladesh, China, India, Indonesia, Pakistan, Thailand and Vietnam). The survey, consisting of face-to-face interviews and meetings, represents the first systematic effort to explore the views of policymakers and opinion leaders in developing countries concerning the need for and possible uses of new-generation enteric vaccines. This study was conceived not as a comprehensive stakeholder analysis, but rather as a rapid means to initially identify prevailing views, issues and data needs of policymakers in order to inform the DOMI Program's research agenda, information dissemination and advocacy activities and to begin the policy dialogue regarding these diseases and vaccines.

Each year, an estimated 1.1 million people world-wide die from shigellosis, more than 200,000 from typhoid fever, and 120,000 from cholera—the majority of them children in developing countries [1], [2], [3]. The overall toll of these diseases is considerable—with an estimated 5–7 million cases of cholera, 21 million cases of typhoid fever and up to 165 million cases of shigellosis occurring each year [1], [2], [3]. Outbreaks of all three diseases also cause severe disruptions in less developed countries. In addition, rapidly rising rates of antibiotic resistance are increasing the cost and difficulty of treating both typhoid fever and shigellosis in many countries.

New-generation vaccines have been developed in the past three decades to replace the old injectable killed whole-cell cholera and typhoid vaccines, which produced high rates of side effects and, in the case of cholera vaccine, were minimally effective. These newer vaccines include typhoid Vi polysaccharide—an injectable one-dose vaccine developed by the US National Institutes of Health with proven effectiveness of 64–72% in persons 2 years and older for at least 17 months following vaccination and 55% protection for at least 3 years [4], [5], [6]—and oral killed whole-cell based (WC) cholera vaccines, both with and without the cholera toxin B subunit. The B subunit killed WC cholera vaccine has been demonstrated to confer around 60% protection after two doses to populations naturally exposed to cholera [7], [8], [9] for 2 years and is effective in persons 2 years and older. Both typhoid Vi and oral cholera vaccines are considered appropriate for use in public sector programmes in developing countries because of their proven effectiveness in populations at risk, their low rates of side effects, their relative ease in use, and their potential for low-cost production by local manufacturers. In addition, Vi vaccine, since it was developed in the US public sector, does not have patent protection and its technology is readily transferable to high-quality vaccine producers throughout the world.

The only Shigella vaccine in use to date is an oral live-attenuated Shigella flexneri 2a-Shigella sonnei (“FS”) vaccine, developed and licensed in China since 1999. The vaccine has a demonstrated efficacy of 60–70% and requires a regimen of three doses taken within a 2-week period [10], [11]. Its use in China has been limited thus far because it has not been licensed for children under 5 years of age—who accounts for an estimated 60% of Shigella-related deaths [1]—and because of its relatively high price (reportedly up to US$ 9.60 per series). Other Shigella vaccine candidates currently under development include oral, live, genetically attenuated vaccine strains [12], injectable polysaccharide-protein conjugate vaccines [13] and proteosome oral or intranasal vaccines [14]. The concept of ribosomal Shigella vaccines [15] is also being revisited.

Vi polysaccharide vaccine has been licensed in more than 40 countries, including many Asian countries, where it is mainly available in the private sector and used for school-aged children. Thus far, the vaccine has been used by a national immunization programme, either for universal or targeted use, only in Vietnam, which has provided the vaccine to a limited number of 3–10 year olds in high-incidence districts each year since 1997. In addition, in China, where six local vaccine production institutes produce the vaccine, following technology transfer from US NIH, several provincial or district governments in high-incidence areas have encouraged its use through school-based campaigns financed by reasonable user fees (e.g. US$ 0.36–0.60 per dose). Local Vi production also began in Vietnam in 2003 and development and production efforts are currently underway in Indonesia and India (the latter in the private sector).

Oral cholera vaccine has been licensed in few developing countries to date and only in Vietnam, where a state-run vaccine company produces a version of the vaccine without the B subunit, is it provided by the national immunization programme for targeted use. Although the government's long-term goal is to immunize all 2–5 year olds in high-risk areas of the country, immunization has thus far been limited to around 300,000 children each year—a fraction of its target population—and for emergencies, such as floods, because of financial constraints.

Thus, despite the existence of new-generation typhoid and cholera vaccines for several years and the presumed need in many developing countries, their use remains extremely limited. The DOMI Program was established to speed up the introduction and use of these new-generation vaccines, where most needed, as well as to stimulate the development and testing of newer, improved enteric vaccines, such as conjugate Vi and Shigella vaccines that could theoretically have increased efficacy and be effective in infants.