Typhoid Fever Coordinator : R.

Leon Ochiai Background Typhoid fever is a major cause of morbidity with an estimated global incidence of approximately 21 million cases each year. According to one conservative estimate, there were approximately 216,000 deaths from typhoid world-wide in the year 2000 and other estimates are as high as 600,000 typhoid-related deaths each year. Multidrug-resistant Salmonella typhi has spread to many parts of the world, limiting the ability to treat typhoid fever with available antibiotics. Typhoid is both a waterborne and food-borne gastrointestinal infection, with incidence approaching one percent of the population annually in endemic areas. In the absence of affordable programs to assure safe water and better sanitation conditions in less developed countries, short and medium-term efforts need to be directed towards prevention through vaccines. The heat-phenol-inactivated whole-cell typhoid vaccine, which provides approximately 65% protection, has limited usefulness because of the adverse reactions it evokes. In contrast, two new-generation typhoid vaccines promise protection without significant side effects. These are the live, attenuated oral vaccine, Ty21a, and the injectable subunit vaccine, Vi polysaccharide. Both Ty21a and Vi have been shown to be safe. Because of its more consistent efficacy results across countries, its single-dose regimen and relative heat stability, Vi vaccine is felt by most public health experts to be the new-generation typhoid vaccine best suited for use in public health programs in developing countries. Consequently, DOMI has focused on Vi vaccine for accelerated introduction in typhoidendemic countries. In addition, the vaccine is being produced locally by an increasing number of producers in developing countries, including Vietnam, China, India and Cuba, increasing the cost-competitive global supply of the vaccine.

A girl with her father waits for immunization against typhoid fever in Kolkata, India. Despite the fact that the World Health Organization, in its position paper on Typhoid Vaccines in 2000 [Weekly Epidemiological Record 2000, No. 32 (75):257-264] has

recommended immunization against typhoid fever using new-generation vaccines "in areas where typhoid fever is a significant public health problem, and particularly where antibiotic resistant S. typhi strains are prevalent", the use of these vaccines in public health programs in typhoid-endemic countries had been very limited at the start of the DOMI Program. Apart from clinical trials, typhoid vaccination (using Vi) was taking place only in a few high-incidence provinces for school children in China and among 310 year olds in some high-risk districts in Vietnam. The DOMI Typhoid Program was established to address this disparity between the availability of improved, modern typhoid vaccines and their use in typhoid-endemic countries. Characteristics of Vi Vaccine Vaccine type: Route of administration: Number of doses: Efficacy (from clinical field trials): Age of effectiveness: Heat stability: Rate of side effects: Potential for local production in developing countries: Vaccine sources (examples): purified Vi capsular polysaccharide injectable one 64-72% at 17 months 55% at 3 years 2 years old high low high (due to low production costs and lack of patent protection) GSK, sanofi-pasteur, IVAC (Vietnam), several producers in China, Bharat Biotech (India), BioMed (India), Finlay(Cuba)

Goals The goals of the DOMI Typhoid Program are to:

Generate and disseminate the evidence needed by policymakers to rationally introduce existing, licensed Vi PS vaccine, including evidence of disease burden; vaccine effectiveness; vaccine demand, cost-effectiveness, and acceptability; and the analysis of policy strategies for vaccine introduction; Help develop a consensus at the regional, national, and international levels on the use of vaccines against typhoid fever;

Assure an adequate and cost-competitive supply of Vi PS vaccine by assisting the transfer of production technologies to qualified producers in Asia and by providing training in vaccine production and regulation; and Ensure that the pipeline of newer-generation experimental vaccines against typhoid is exploited by accelerating the development of new vaccine candidates and evaluating these in endemic settings.

Projects Multi-disciplinary field research projects: The DOMI Typhoid Program has established field research sites in five countries to gather evidence needed by policymakers to inform decisions about the control of typhoid fever. These sites are: Hechi City in Guangxi Province, China; slum areas of Kolkata, India, North Jakarta, Indonesia, and Karachi, Pakistan; and the entire city of Hue in central Vietnam. The program in each site was designed to generate evidence of the disease burden and severity of typhoid fever; rates of antibiotic resistance; the private and public costs of typhoid illness; knowledge, attitudes, and beliefs among the population about the seriousness, risks, and causes of the disease, as well as their attitudes toward vaccination against typhoid; and estimates of the willingness of populations at risk to pay for typhoid vaccines if they are made available. The design of the typhoid field research program in these sites is shown in the figure below. Design of the typhoid field research program in China, India, Indonesia, Pakistan and Vietnam

These studies, described in a paper published in Tropical Medicine and International Health include the following:

Prospective disease surveillance studies conducted in all five sites, involving a total surveillance population of nearly 440,000 persons. The studies, conducted for at least one year prior to and two or more years following vaccination demonstration projects, employed standardized surveillance, clinical and microbiological methods across sites, including the use of blood cultures to confirm typhoid cases. Surveillance in each site involved the participation of public health facilities, and in some countries, private health facilities as well, while, in the case of Karachi, Pakistan and Kolkata, India, special clinics were set up in the slum sites for the surveillance. The surveillance has found high rates of typhoid fever in the large urban slum sites of Kolkata, Karachi and North Jakarta especially in children - and lower rates in Hechi City and Hue, Vietnam. Blood culture rates among 5-15 year olds were 400-500/100,000 per year in Karachi and Kolkata and 180/100,000 in North Jakarta. The actual rates of typhoid incidence are likely to be double these rates, given that blood cultures are found to be only around 50% sensitive. Children less than five years of age were also found to have high rates of typhoid in Kolkata and Karachi, giving further evidence to the fact that the disease is not limited to school-aged children. The study also found antibiotic resistant strains of S. typhi to be a growing threat in several countries, especially Pakistan, India and Vietnam. High rates of multi-drug resistance were found in these three countries, rendering all three first-line antibiotics (ampicillin, chloramphenicol and co-trimoxozole) ineffective. In addition, resistance to nalidixic acid, an indicator of reduced effectiveness of ciprofloxacin and other quinolones often used as second-line treatment, greatly limit the options for

treating typhoid, making it more difficult and costly. The differing patterns of typhoid incidence by geographic area, age group, and level of antibiotic resistance suggest that tailor-made packages of evidence are needed for each country and data generated in one country will not be readily accepted by decision-makers in neighboring countries.(Bulletin of World Health Organization, Ochiai et al. April 2008, 86 (4)) Cost-of-illness studies, which tracked the costs of culture-positive cases found through the surveillance in each sites, including both the out-of-pocket costs and indirect costs (lost wages) borne by families and the costs at public sector treatment facilities borne by governments. The studies found that the cost of hospitalized cases - which ranged from 8% of cases in Karachi to 23-40% in Indonesia, China and Vietnam - was quite burdensome, especially to families. Out-of-pocket expenditures averaged nearly an entire month's income for the average household in Karachi and 3.5 months income in North Jakarta. A study of typhoid costs, conducted in the slums of Delhi, India with the All India Institute of Medical Sciences (AAIMS), found that a blood- culture-confirmed case of typhoid cost, on average, $101 and that hospitalized cases, which accounted for 11% of culture-confirmed cases in the study, cost an average of $511 (Journal of Health Population and Nutrition).

Children wearing ID cards are instructed by a health worker during a school-based typhoid vaccine demonstration project in Indonesia. Vi vaccination demonstration projects, through which nearly 195,000 persons were vaccinated in all five DOMI sites. With the exception of Indonesia, the demonstrations were cluster-randomized controlled trials in which participants received either Vi vaccine or a control vaccine (e.g., group A meningococcal polysaccharide vaccine or Hepatitis A vaccine). This will allow the estimation of field effectiveness of Vi in each of these populations. The vaccination campaigns in Indonesia and Vietnam were school-based, while those in China, India and Pakistan took place in community settings and, in the case of China and India, targeted adults as well as children (see table). All five demonstration projects found Vi vaccination to be feasible in both school and community settings,

acceptable to the population, and relatively inexpensive to deliver. Vaccination coverage rates ranged from 58% in Vietnam to 91% in North Jakarta, Indonesia. Articles have been published that summarize the results of the demonstration projects in Indonesia (Public Health), Pakistan (Trials), Vietnam (Southeast Asian J Trop Med Public Health) and China (BMC Public Health). Site-specific Vi effectiveness rates in sites where randomized controlled demonstrations took place will be available in mid-2007. Vi Vaccine Demonstration Projects in the DOMI Program Hechi, China Setting Urban and rural N. Jakarta, Indonesia Urban slum Kolkata, India Karachi, Pakistan Hue, Vietnam Urban(entire city)

Urban slum Urban slum

Design Vaccine delivery Target population Number of persons vaccinated Vaccination Coverage

Randomized Randomized Randomized Randomized Mass controlled controlled controlled controlled immunization trial trial trial trial CommunityCommunity- CommunitySchool-based School-based based based based 5 to 60 years 2 years and 2 to 15 years Grades 1 to 5 old above old 92,476 78% 4,828 91% 37,686 69% 27,236 68% Grades 1 to 12 32,267 58%

A separate study was conducted in Guangxi, China to evaluate the effectiveness of Vi vaccination to control outbreaks that are underway. When given during a typhoid outbreak to students not previously vaccinated against typhoid, Vi was associated with nearly the same level of protection (71%) as that found among students vaccinated routinely a year earlier (73%). This study - the first to measure the effectiveness of Vi in controlling typhoid outbreaks - highlights the value of Vi vaccination both in preventing endemic disease through routine immunization and in controlling current outbreaks (JID). Socio-behavioral surveys involving interviews with nearly 3,400 household heads or their spouses in all five study sites, which assess the local populations' knowledge, beliefs and practices regarding typhoid fever, its prevention and treatment, as well as potential interest in typhoid vaccination. Knowledge and concern about typhoid fever was, logically, highest in places where the disease surveillance studies showed the highest incidence, such as Karachi, Pakistan, where 47% of respondents claimed past experience with typhoid in their

households, and in Kolkata and North Jakarta. Interest in having their children vaccinated against the disease was universally high (87-98%) across study sites, even in lower incidence areas, such as Guilin, China and Hue, Vietnam. See a paper on the results of these studies in Vietnam (Trop Med Int Health).

Market demand studies among both low- and middle-income residents in the five countries to quantify the private demand for new-generation typhoid vaccines. The studies found considerable demand across countries for typhoid vaccination, especially for children. The description of the methodology and results have been published for Hue, Vietnam in Health Policy and Planning.

Developing a consensus on use of vaccine against typhoid fever: To provide national policymakers with realistic options for typhoid immunization programs, DOMI health economists analyzed possible program options developed with country collaborators - in terms of their potential impact on reducing typhoid incidence, their cost and cost-effectiveness and their financial sustainability. The analyses use the DOMI study results from each field site on disease incidence, cost-of-illness, Vi vaccination program costs and market demand surveys. Thus far, financial analyses have been conducted for three locations (Karachi, Pakistan; all of Vietnam; and North Jakarta, Indonesia) and presented at an international meeting in Hanoi in 2005, co-hosted by Vietnam's Ministry of Health. Plans are currently underway to conduct pilot Vi vaccination programs in these three countries, with support from national and local governments, as a first step in the phased introduction of typhoid vaccination in high-risk areas. Following the achievements of the DOMI Typhoid program and other advances in the field, a session on typhoid vaccination was included in the WHO Strategic Advisory Group of Experts (SAGE) meeting of November 2007. The SAGE drafted a strong recommendation that typhoid endemic countries to consider the use of typhoid vaccines in their public health programs. (Wkly Epidemiol Rec. 2008 Jan 4;83(1):1-15) The SAGE also recommended that a new WHO Position Paper on typhoid vaccines be issued that provides updated information (e.g. on incidence, vaccine effectiveness in young children and herd effects), and that gives specific programmatic guidance to countries on such issues as choice of vaccine, delivery strategy, and age groups to vaccinate. (Wkly Epidemiol Rec. 2008 Feb 8;83(6):49-59) Training, technology transfer and new vaccine development IVI is helping to transfer the production technology for Vi PS vaccine to qualified producers in Asia. IVI scientists discovered a way to produce higher yield of Vi PS using new methods. (J Biotechnol. 2008 May 20;135(1):71-7) They are also developing a Vi conjugate vaccine at IVI's laboratories, in the aim of transferring the technology of a safe, effective and low-cost Vi conjugate vaccine to qualified local producers in developing countries. Unlike the Vi polysaccharide vaccine, the conjugate vaccine has the potential to be effective in children under two years of age and therefore to be included in the

infant EPI schedule in endemic areas. The conjugate vaccine being developed at IVI used diphtheria toxoid (DT) as the carrier protein. New Projects resulting from the DOMI Typhoid Program Based on the observation from the DOMI program that S. paratyphi A is an important emerging pathogen and cause of enteric fever, IVI was awarded a grant by the UBS Optimus Foundation to conduct further studies of paratyphoid fever in the DOMI field site in Hechi, China. This project, named ParaChina, is further evaluating the disease burden, epidemiological patterns, and economic costs of this emerging pathogen in the DOMI program's Hechi field site. In addition, the Wellcome Trust awarded a grant to support clinical studies of a new, genetically attenuated live oral typhoid vaccine, M01ZH09, in typhoid-endemic areas. IVI scientists will collaborate with Emergent Biosolutions, the producer of M01ZH09, the Tropical Disease Unit of the Wellcome Trust in Ho Chi Minh City, Vietnam, and National Institute of Cholera and Enteric Diseases in Kolkata, India on Phase II and Phase III studies of the vaccine. M01ZH09 is one of the most advanced and promising of new generation, live oral typhoid vaccine candidates. It has already undergone successful inpatient studies in the UK and inpatient and outpatient studies in the US.