Population impact of Vi capsular polysaccharide vaccine

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KEYWORDS: effectiveness • efficacy • fever • Salmonella Typhi • typhoid • Vi polysaccharide. Population impact of Vi capsular polysaccharide vaccine.
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Population impact of Vi capsular polysaccharide vaccine Expert Rev. Vaccines 9(5), 485–496 (2010)

M Imran Khan1, R Leon Ochiai1 and John D Clemens†1 International Vaccine Institute, Seoul, 151-919, Republic of Korea † Author for correspondence: Tel.: +82 2872 2801 Fax: +82 2881 1164 [email protected] 1

Development of a safe and efficacious vaccine against typhoid fever has been the mainstay of enteric vaccinology since production of the first parenteral whole-cell typhoid vaccine in 1896. The new-generation Vi polysaccharide single-dose injectable typhoid vaccine developed in the 1980s is widely used in countries where it is locally produced, such as China, and in travelers from industrialized countries to typhoid-endemic settings. However, Vi vaccine use is limited to private practice at a small scale by residents of high-burden countries such as India, Pakistan and Bangladesh. Recognition of the public health importance of typhoid fever prevention has significantly increased due to the emergence of antimicrobial-resistant strains of Salmonella enterica serovar Typhi in recent years. Recent evidence of herd protection conferred by the Vi  vaccine has highlighted the significance of the vaccine’s effects beyond the vaccinated population. The large-scale use of this vaccine can yield protective benefits to a larger population and can reduce the epidemiologic and economic burden of typhoid fever in endemic countries. Keywords : effectiveness • efficacy • fever • Salmonella Typhi • typhoid • Vi polysaccharide

Typhoid fever is a systemic disease caused by the bacterium, Salmonella enterica serovar Typhi (S.  Typhi) [1] . S.  Typhi is commonly spread through oral transmission of food or water contaminated with the feces of an infected person and is limited to humans. The clinical presentation of typhoid fever ranges from mild fever to severe manifestation, including toxic shock, intestinal hemorrhage and intestinal perforation  [1] . For patients presenting with fever, it may be difficult for the clinician to differentiate typhoid fever from other febrile illnesses such as malaria  [2] . Misdiagnosis of typhoid fever may lead to prolongation of fever and result in complications such as encephalopathy and disseminated intravascular coagulation, which can consequently lead to death [3] . Overall, 10–15% of typhoid patients develop severe clinical disease  [4] . Typhoid fever cases may become an asymptomatic carrier of S.  Typhi, having no apparent clinical symptoms but capable of infecting others. Approximately 5% of the typhoid fever patients are assumed to become chronic carriers and they are usually elderly females [5] . Even though typhoid fever has been nearly eradicated in the developed world through major improvements in hygiene and sanitation, the disease continues to be a significant public health problem in the developing world. The nonavailability of clean and safe drinking water, www.expert-reviews.com

10.1586/ERV.10.43

abundance of street vendors selling unhygienic food and high population density in the urban settings increase the risk of contracting typhoid fever in the developing world [6–8] . While hygiene and sanitation are critical measures to prevent typhoid fever, these are long-term solutions that require financial investment, political will and behavioral change, which are difficult goals to attain for a developing country typically facing economic, political and social instability. Thus, vaccines are considered as an effective short- to medium-term intervention for the prevention and control of typhoid fever. Early-generation typhoid vaccines

Typhoid fever vaccines have been used since 1896 when the first injectable, killed whole-cell (WC) typhoid vaccine was introduced [9] . Although production was poorly standardized, the vaccine showed a considerable reduction in typhoid fever incidence in British and US soldiers where it was used at large scale [10–12] . Efforts in improving the typhoid vaccine continued with development of oral and parental inactivated WC vaccines, attenuated strains of live oral vaccine and other modified forms. However, these vaccines could not enter the market due to concerns of safety and poor immune response. For vaccines that were safe, efficacy estimates were lower than the existing vaccines [11] . The WHO sponsored field

© 2010 Expert Reviews Ltd

ISSN 1476-0584

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Khan, Ochiai & Clemens

trials with the killed WC vaccine, which showed an efficacy of 51–80% in children and young adults with duration of protection up to 7 years. Vaccination was associated with a high frequency of adverse events, which included fever (6–30%), headache (~10%) and pain at the injection site (~35%). In additionally, vaccine recipients lost at least 1 day from either school or work after vaccination. Currently, killed WC vaccines continue to be on the market but they are produced by only a few manufacturers, and are used in a limited number of countries [13,14] . New-generation typhoid vaccines

Reports of S. Typhi strains resistant to first-line antimicrobial therapy brought attention to typhoid vaccines and, thus, triggered efforts to develop new safe and effective vaccines [15–21] . As a result, a live attenuated, orally administered vaccine, Ty21a, was developed in the late 1980s. This vaccine consists of a mutant strain of S. Typhi Ty2, which was isolated after chemical mutagenesis. Immune response to the vaccine starts 14 days after vaccination, which is mediated by mucosal (IgA), serum (IgG) and cell-mediated antibodies. The overall protective efficacy for a three-dose regimen ranged between 67 and 80% in large-scale efficacy trials, conducted in the 1980s in Chile [22,23] . Another trial in Santiago, Chile also provided evidence of indirect protection. Currently licensed as a live oral typhoid vaccine, Ty21a is presented as enteric-coated capsules or as a liquid formulation (2–10 × 109). One capsule is taken per day for 3 alternate days [23] . Around the same time, scientists at the US NIH were continuing research on the capsular polysaccharide, Vi, for its use as a vaccine antigen. Vi elicits anti-Vi serum IgG antibodies in 85–95% of adults or in children older than 2 years of age [24] . The serum antibody response is not boosted through administration of additional doses of the Vi vaccine [25,26] and Vi causes a T-cellindependent immune response, hence, it elicits a poor response in infants and young toddlers, and it does not elicit long-term immunity through the induction of memory cells [27] . However, the Vi was further developed as another new-generation vaccine against typhoid fever (vide infra). Currently, both Ty21a and Vi vaccines are licensed and used worldwide, but at a much lesser scale considering the global burden. Ty21a vaccine is not used in routine public health programs in typhoid-endemic countries, while Vi vaccine has been introduced in China, Vietnam and the State of Delhi in India. A recent recommendation issued by the WHO states that countries severely affected by typhoid should consider the programmatic use of typhoid vaccines in order to control the disease [28] . As the Vi vaccine is currently being produced by both international and emerging producers from India and China, and in light of the WHO recommendation, it is an appropriate time to seriously consider the Vi vaccine for further widespread introduction into public health programs of typhoid-endemic countries. Here, we review existing evidence from the literature on the contemporary disease burden of typhoid, the programmatic feasibility and acceptability of using Vi vaccine, Vi vaccine’s protective effectiveness, and the cost–effectiveness of Vi vaccine when used in public health programs. 486

Disease & economic burden of typhoid fever

A recent review of published reports estimates 21.6 million typhoid fever episodes with 216,000 deaths globally in the year 2000 [29] . The vast majority of reported cases are from countries of South and Southeast Asia [29–32] . However, the WHO estimates are based on only 22 studies from 13 countries – highlighting a gap in the country-specific typhoid burden [33] . A retrospective study in an urban hospital in Kathmandu, Nepal, assessed the frequency of Salmonella isolation from outpatients and inpatients over the period of 1993–2003. Among 82,467 blood cultures performed, Salmonella accounted for 74.5% (9124) of all growths (71% were S. Typhi and 29% were S. Paratyphi A). When comparing the period of 1997–2000 with the period of 2000–2003 for the proportion of total blood cultures that were taken, Salmonella septicemia rates significantly increased from 6.2 to 13.6% between those two periods [34] . There is variation in the affected age group geographically but most studies report high burden in younger age groups. In some instances the incidence of typhoid fever is as high as 10–19 per 1000 individuals per year [31,35] . More recently, a coordinated, population-based, multi­ centric study in Asia reported annual incidence rates of blood culture-confirmed typhoid fever of 494, 413 and 180 cases per 100,000 individuals among school-aged children in the slum areas of Kolkata, India; Karachi, Pakistan; and North Jakarta, Indonesia, respectively. In addition, the rates among 2–4-yearolds in Kolkata, Karachi and North Jakarta, respectively, were 573, 340 and 149 cases per 100,000 individuals per year [36] . Considering the relative sensitivity of 50% for blood culture with bone marrow as gold standard, these rates provide conservative estimates of typhoid fever incidence in these communities [37–39] . Impact of antimicrobial-resistant strains

In the pre-antimicrobial era, typhoid was a debilitating disease with a mortality rate as high as 30% [40,41] . Case fatality fell dramatically to less than 1% with the discovery and application of antimicrobials. Chloramphenicol followed by ampicillin and cotrimoxazole were the antibiotics of choice [21] , S. Typhi strains resistant to all first-line antimicrobials were identified, which raised the specter of typhoid re-emerging as a fatal disease [16–20] . Furthermore, the resulting use of new-generation antimicrobials has increased the cost of treatment [42] . The distribution of cost of illness in different settings is given in Table 1. Cost of treatment increased with hospitalization of the cases due to resultant nonresponse to oral antimicrobials and replacement by injectable cephalosporin [43] . Typhoid fever was found to exert a devastating financial impact on families in several of the low-income communities studied, since much of the cost of illness is borne privately (Figure 1) . Vi capsular polysaccharide vaccine: development to licensure

The Vi antigen on the surface of S. Typhi was first discovered in the 1930s [44] . Vi is a capsular polysaccharide surface antigen composed of a linear homopolymer of a(1–4)-d-GalpANAc Expert Rev. Vaccines 9(5), (2010)

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Population impact of Vi capsular polysaccharide vaccine

Table 1. Total cost of blood culture-confirmed typhoid fever illness by type of patient and study site in the Diseases of the Most Impoverished Program. Type of patients and costs

Hechi, China Delhi, India† Kolkata, India

North Jakarta, Karachi, Indonesia Pakistan‡

Hue, Vietnam

Sample size (n)

58

98

79

107

66

16

Ages (years) included in surveillance

5–60

All ages

All ages

All ages

2–15

5–18

Total costs for hospitalized patients 215 (2005 US$)

820

129

432

210

157

Total costs for outpatients (2005 US$)

67

95

13

57

38

38

Hospitalization rate (%)

40

12

2

20

10†

28

Weighted average costs (hospital + outpatient) Private costs (2005 US$)

126

79

11

106

53

38

Direct (2005 US$)

100

43

6

61

44

33

Indirect (2005 US$)

26

36

5

45

9

5

Public costs (2005 US$)

0

101

4

26

2

33

Total weighted average costs

126

182

15

132

55

71

Average household monthly income in sample (2005 US$)

121

N/A

N/A

207

158

84

Families that borrowed money for treatment (%)

14

N/A

49

24

N/A

18

Study conducted by All India Institute of Medical Sciences (AIIMS) in 1996 and re-analyzed by Diseases of the Most Impoverished (DOMI) Program (Bahl et al., 2004) [42]. Results from Karachi are based on local expert opinion and reflect the costs of disease in children aged 2–15 years. N/A: Not applicable. †



variably O acetylated at C-3 [45] . Virtually all S. Typhi isolated from the blood of patients with typhoid fever are encapsulated with Vi antigen. The Vi antigen interferes with the effectiveness of the host immune response, thereby enabling the bacteria to survive and grow, which can result in a more severe form of the disease [46,47] . Parenteral WC vaccines that retain high levels of Vi antigen (acetone-inactivated and designated as the ‘K-type’) were more protective than other inactivated vaccines, suggesting a protective role for the Vi antigen [48] . The Vi polysaccharide has since been purified, and the vaccine was developed using subunit technology [27,49,50] . A Vi polysaccharide, extracted from Citrobacter freundii, was prepared in the 1950s, but it failed to elicit Vi antibodies in human volunteer studies [51] . It is believed that the reflux treatment depolymerizes the Vi polysaccharide, and removes all of its O-acetyl and some of its N-acetyl moieties, resulting in reduced immunogenicity in vivo. Subsequently, a modern approach to purifying Vi polysaccharide was developed at the NIH in which S. Typhi was treated with hexadecyltrimethylammonium bromide, resulting in nondenaturing of the Vi antigen [46] and, thus, an improved vaccine. The safety and immunogenicity of the improved Vi vaccine has been reported in a series of studies [24,52–54] . Immune response, defined as fourfold rise (standard rise in geometric mean titer) in serum anti-Vi antibodies was reported in 75% of the study parti­ cipants 1 month after vaccination [55] . The immunological response to the vaccine was consistent both in populations of endemic, as well as nonendemic areas [26,56–58] . In addition, simultaneous www.expert-reviews.com

administration of the Vi vaccine with other vaccines has been shown to be safe, and there was no interference of the immune responses between the Vi vaccine and the concomitantly administered vaccines [59,60] . A study conducted among Malaysian air force recruits compared the safety of the improved Vi vaccine with the traditional killed WC typhoid vaccine. The study showed that the Vi vaccine was immunogenic and safe, and had significantly fewer adverse reactions compared with the conventional killed WC typhoid vaccine [54] . The efficacy of the Vi vaccine produced by an international vaccine manufacturer was tested in two individual randomized, double-blind, placebo-controlled studies in Nepal and South Africa [55,57] . The trial in Nepal randomly assigned 6907 residents from five villages near Kathmandu to receive either the Vi vaccine or pneumo­ coccal vaccine. The target subject age ranged from 5 to 44 years. After 17 months of follow-up, the incidence rate of typhoid was 16.2 cases per 1000 person-years in the control group, and 4.1 cases per 1000 person-years in the group immunized with the Vi vaccine. The overall protective efficacy of Vi vaccine was found to be 72% (95% CI: 41–87%) when using blood culture as an outcome, and 80% when a clinical definition of typhoid fever was used [55] . The study in South Africa assessed the protective efficacy of a single intramuscular injection of 25 µg of the Vi polysaccharide. A total of 11,384 school-aged children were followed for 3 years after vaccination. The control groups received a bivalent meningococcal A + C polysaccharide vaccine. Protective efficacy was 487

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The Vi vaccine is currently available as a solution containing 25 µg of Vi polysaccharide in 0.5 ml of isotonic buffer. The 800 Private costs vaccine is administered as a single-dose, Costs borne by public sector 700 intra­muscular or deep subcutaneous injection. It was first registered in France by 600 sanofipasteur, Lyon, France (then Pasteur Vaccins) in 1988, followed by the registra500 tion in the USA in 1994. There are at least 432 eight current producers of Vi, including 400 three producers that sell their vaccine on 300 the international market: sanofipasteur, 215 GlaxoSmithKline Biologicals (Rixensart 210 200 Belgium) and Bharat Biotech (India). 157 129 sanofipasteur’s Typhim Vi is registered 100 in 114  countries, including 82  low- and middle-income countries where typhoid 0 Hechi, Delhi, Kolkata, N. Jakarta, Karachi, Hue, is considered endemic. GlaxoSmithKline’s China India† India(2%) Indonesia Pakistan Vietnam Typherix ® is registered in 73  countries, (40%) (12%) (20%) (10%) (28%) including 43  low- and middle-income countries, and Bharat’s TypBar ® vaccine Study site (hospitalization rate) is licensed in India, as well as in six other countries. More than one Vi vaccine is Figure 1. Cost (2005 US$) of blood culture-confirmed typhoid illness for registered in at least 38 countries. Vi vachospitalized cases in six Asian settings in the Diseases of the Most Impoverished Program. cine is licensed in most countries for use † Study conducted by All India Institute of Medical Sciences (AIIMS) in 1996 and in persons aged 2 years and older [Box 1] . reanalyzed by the Diseases of the Most Impoverished (DOMI) Program. Revaccination is recommended every found to be 55% (95% CI: 30–71%) 3 years after vaccination. 2–3 years, which has been shown to be safe [63] . Efficacy estimates varied from 61% in the first year to 50% in The Vi vaccine is widely used by travelers from developed counthe third year. Vaccination was associated with minimum local tries going to typhoid-endemic regions [64] . The cost of the vaccine side effects and an increase in anti-Vi antibodies, as measured by has traditionally been a limiting factor for use in typhoid-endemic radioimmunoassay and ELISA. Antibody levels remained elevated developing countries. Before 1999, Vi vaccines were produced at 6 and 12 months post-vaccination [56,57] . at limited scale by local and international producers. However, In addition, a randomized, double-blind study of a Vi vac- because Vi is not in the domain of intellectual property proteccine produced in China was performed in southwestern China. tion, there was an increase in the number of manufacturers of A total of 131,271 individuals aged between 3 and 50 years were Vi in developing countries, including several state producers in randomized to receive either the Vi vaccine or placebo. A majority China, Finlay Institute in Cuba, Bharat Biotech and BioMed in (92%) of the participants were school-aged children. Protective India, and the Institute of Vaccines and Biological Substances efficacy against blood culture-proven typhoid 19 months post- (IVAC) (now Vaccine Company of Dalat Pasteur [DAVAC]) in vaccination was 69% (95% CI: 28–87%). No serious adverse Vietnam. This encouraging development has made Vi vaccines events were recorded. The participants in this field trial were more affordable and accessible mainly due to reduction in prices. subsequently followed up to assess long-term protection. Although This may broaden the use of Vi vaccines in endemic settings of the diagnosis of typhoid was based on routine clinical and sero- developing countries. logical criteria, protective efficacy 3 years after vaccination was 51% (95% CI: -96–88%), which was consistent with results from Programmatic use of Vi vaccines the South Africa study [61] . Experience with the use of Vi vaccine in public Concurrently, there was a global effort by scientists and produc- health practice tion specialists to establish guidelines for the manufacturing and Vi vaccination has been introduced as a routine immunizalicensing of Vi vaccine. This led to the publication of the WHO tion program into endemic settings of China, Vietnam and Technical Report Series in 1994 by the WHO Expert Committee India [65] . Available government data from China and Vietnam on Biological Standardization [62] . Having the standardized man- suggest a significant reduction in the burden of typhoid fever ufacturing guideline in the public domain and given that Vi pro- in these settings. duction technology was not patent protected, the production of The typhoid vaccination program in China originated in the vaccine became a possibility for any vaccine manufacturers the 1980s in several endemic provinces that used both the old­ with appropriate technologies. generation WC killed vaccine and the new-generation oral live US$

820

488

Expert Rev. Vaccines 9(5), (2010)

Population impact of Vi capsular polysaccharide vaccine

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Typhoid incidence (per 100,000 population)

Vaccine coverage (% of population)

Ty21a. Owing to the side effects of the former vaccine and the high cost of the latter, 16 45 Coverage of the population (%) the Ministry of Health decided to embark Typhoid incidence (per 100,000 population) 40 on a research program to develop and pro14 duce the Vi vaccine locally. In support of 35 12 this endeavor, the NIH transferred the 30 Vi vaccine production technology to the 10 Chinese Institutes of Biological Products 25 in 1990, and the Vi vaccine was developed 8 20 and subsequently licensed in China. 6 This locally produced Vi vaccine was 15 then introduced into typhoid-endemic 4 10 provinces in China (Jiangsu, Hunan, Hubei, Yunnan, Guizhou, Sichuan and 2 5 Guangxi Zhuang Autonomous Region), as 0 well as the cities, Beijing and Lanzhou, in 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 1995. Approximately 26 million doses of Year vaccine were administered to school-aged children and other high-risk groups such Figure 2. Incidence of typhoid and the use of Vi polysaccharide vaccine in highas food handlers. The most robust data endemic regions of Guangxi Zhuang Autonomous Region, China (1995–2007). on the impact of Vi vaccines on typhoid incidence comes from the city of Guilin in Guangxi Zhuang to selected high-incidence districts in approximately half of the Autonomous Region in Southwest China. Between 1995 and country’s 61 provinces. The Vi vaccine was initially procured from 2006, a million doses were administered to specific target groups Aventis Pasteur (now sanofipasteur) at a specially discounted price in Guilin, and the number of doses peaked in 2000 and 2001. by the NIP. Subsequently, from 2004, the vaccine was produced by Overall, there was vaccination coverage of 77% in students, and the National IVAC and provided to the NIP at a price of approxivaccination coverage of 23% in food handlers and residents of mately US$0.52 per dose. The typhoid vaccination program conoutbreak areas. Coverage rates varied broadly from year to year sisted of annual campaigns in which children aged 3–10 years were but averaged 60–70% for students over the 11-year period, and vaccinated with the Vi vaccine in selected districts. Selection of 80–85% for the other target groups [66] . districts was based on typhoid disease reports provided by each The reported annual incidence of typhoid fever in Guilin province during quarterly regional epidemiological meetings, and averaged 57 per 100,000 in the student population, and 42 on a list of high-incidence districts provided by these provinces. per 100,000 in the nonstudent population during 1991–1994 Districts with reported typhoid outbreaks were also targeted before Vi vaccination began. From 1995 to 2006, the annual for vaccination, and adults and children in those districts were incidence rates of typhoid fever in Guilin reported to the National vaccinated. Between 2002 and 2004, the program provided the Notifiable Infectious Disease Reporting System declined to very first dose of the Vi vaccine to more than 500,000 3–10-year-olds low levels (0.2–4.5 per 100,000) in both the student and non- in 30 or more provinces per year. Two main regions known for student populations (Figure 2) [67] . Vaccination coverage in the high incidence of typhoid fever exist in Vietnam. An analysis general population ranged between 3 and 13%; however, it conducted by the Diseases of the Most Impoverished (DOMI) ranged between 15 and 74% in the program’s targeted student Program showed a consistently high burden of typhoid in the population. During the 11-year period, approximately 3.5 mil- northwestern region bordering Lao People’s Democratic Republic lion doses of Vi vaccine were provided in Guilin. Interestingly, and in the Southern Mekong Delta region. Review of data from a dramatic increase in incidence of S. Paratyphi A was reported the NIP regarding the use of Vi vaccines in the northwestern during the same time period. S. Paratyphi A is also transmitted region showed a decline in the annual incidence rate of typhoid fecal–orally under similar circumstances of poor water quality, fever from 97 per 100,000 individuals in 1999 to less than 20 per poor sanitation and poor hygiene. As the Vi vaccine does not 100,000 individuals from 2006 onwards after the introduction of protect against S. Paratyphi A, this observation suggests that the Vi vaccine (Figure 3) . Vaccination coverage was high in the targeted decline of typhoid fever cases after Vi vaccine introduction may population (~70–90%), but in the general population it ranged be attributable to the Vi vaccine rather than to any concomitant between 0.1 and 4%. A similar decline in the incidence of typhoid improvements in water, sanitation and hygiene. fever was seen in other high typhoid-endemic regions, such as the The National Immunization Program (NIP) in Vietnam Southern Mekong Delta, as well as in other regions with medium launched its typhoid vaccination program using the Vi vaccine incidence rates of typhoid where the Vi vaccine was introduced. in 1997. This program was established as a result of the rise in the The State Government of Delhi has recently initiated a reported incidence of typhoid fever, and the rise in rates of anti- typhoid vaccination program targeting 2–5-year-old children microbial-resistant strains. The vaccination program was limited in Delhi using the Vi vaccine. The program represents the first 489

Vaccine coverage (% of population)

5.0 4.5

Khan, Ochiai & Clemens

120

Coverage of the population (%) Typhoid incidence (per 100,000 population)

100

4.0 3.5

80

3.0 2.5

60

2.0 40

1.5 1.0

20

0.5 0

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

0

Year

Figure 3. Incidence of typhoid and the use of Vi polysaccharide vaccine in the northwestern region of Vietnam (1997–2007).

Typhoid incidence (per 100,000 population)

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the five sites, resulting in a total of more than 190,000  people being vaccinated (either with the Vi vaccine or control vaccine). Vaccination coverage rates ranged from 58 to 91% [70–73] . The highest coverage rate (91%) was achieved in North Jakarta, Indonesia, while the lowest coverage rate was in Hue, Vietnam. The communitybased vaccination campaigns in China, India and Pakistan had participation rates ranging between 68 and 78%. Variations in vaccination coverage might be attributed to the different study designs. These results suggest that, despite the fact that the vaccine was provided outside of the routine infant immunization schedule, substantial typhoid vaccination coverage levels can be achieved either in schools or in communities, and even in predominantly poor slum areas, if accompanied by well-conceived social mobilization campaigns [70–73] .

public-sector typhoid vaccination program in India since 1987, when the conventional killed WC vaccine was discontinued due to Effectiveness of the Vi vaccine its reactogenicity and the perception at the time that typhoid fever In 1999, an outbreak of typhoid fever occurred among middlewas not a major cause of mortality. The impetus for Vi vaccine school students in Xing-An County, Guangxi, China. At the beginintroduction was the emergence of multidrug-resistant typhoid ning of the outbreak, Vi vaccines were provided to students who had fever among children seen at the city’s hospitals. not been vaccinated the year before when Vi vaccines were adminisThe program targets the 2–5-year-old age group since this age tered through a school-based campaign. The Vi vaccinations, given group was reported to be at higher risk [31] . The State Directorate at the beginning of the outbreak, were associated with a vaccine of Family Welfare and the Delhi Municipal Corporation, which effectiveness of 71% (95% CI: -9–92%), similar to the protective provides approximately 85% of the state’s government health ser- efficacy seen in students who had received the Vi vaccine the year vices, runs the program. The vaccines are purchased at US$0.53 before (protective effectiveness [PE]: 73%; 95% CI: 32–89%) [74] . per dose from a local producer. Since the start of the program, This study had highlighted the potential of the Vi vaccination to approximately 1 million children have been vaccinated at a rate control ongoing outbreak. of 300,000–325,000 children per year. The vaccination program has been well Table 2. Results of private demand surveys for new-generation accepted, but no systematic evaluation on typhoid vaccines conducted by the Diseases of the Most the vaccine’s impact has been conducted Impoverished Program in five Asian settings. to date. City, Typhoid Average willingness-to-pay per individual (or child) Vi vaccine demonstration projects in Asia

Vi vaccination demonstration projects were conducted in Asia to assess the effectiveness of the Vi vaccine in five countries [68] . The sites were chosen on the basis of reported high burden of typhoid fever from hospitalbased studies, absence of control programs against the disease, and willingness of the community to participate. Age groups selected for the study were based on the rationale that they would be likely targets for typhoid vaccination administered through a public health program [69] . Mass vaccinations were carried out in 2003 and 2004 at 490

country

incidence in for a typhoid vaccine with the characteristics of Vi 5–15-year- vaccine for their children (5–14-years-old) (2007US$) olds (per Poor households Nonpoor Full sample 100,000) households

Guilin, China† 29 (in Hechi)

N/A

N/A

16.00

Kolkata, India‡

494

2.00

2.70

2.60

North Jakarta, 180 Indonesia

4.20

6.00

5.60

Karachi, Pakistan

8.10

12.00

12.00

3.40

4.80

4.70

413

Hue, Vietnam 24

The surveys in China took place near Guilin in Guangxi Province and not in Hechi. ‡ Results for Tiljala (low-income area) of Kolkata only. N/A: Not applicable. †

Expert Rev. Vaccines 9(5), (2010)

Population impact of Vi capsular polysaccharide vaccine

A recent study showed the impact of vaccination with Vi vaccine beyond the vaccinees. The PE of Vi vaccine against typhoid fever in a cluster-randomized trial in Kolkata was 61% (95% CI: 41–75%) 2 years after vaccination. The trial enrolled 37,673 individuals aged 2 years or older, residing in 80 geographic clusters, which were randomized to either receive the Vi vaccine or an active control (hepatitis A vaccine). The results of the trial also showed for the first time Vi vaccine protection in children 2–5  years of age (PE:  80%, 95%  CI:  53–91%). Indirect protection, based on comparison of typhoid fever incidence between nonvaccinees in the Vi vaccine clusters and nonvaccinees in the control vaccine clusters, was 44% (95%  CI:  2–69%). Overall protection of all residents in the Vi vaccine clusters, vaccinated or not, was 57% (95%  CI: 37–71%), although Vi vaccine coverage was only 61% in these clusters [75] . As seen by this overall effect, the population-level protective impact of the Vi vaccine is significant, due to a combination of direct and indirect vaccine effects. Population demand for typhoid vaccine

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Box 1. Low- and middle-income countries where Vi vaccine is registered†. • Angola • Argentina • Azerbaijan • Bangladesh • Benin • Bolivia • Bosnia & Herzegovina • Botswana • Brazil • Bulgaria • Cambodia • Cameroon • Central African Republic • Chad • Chile • China • Colombia • Congo • Democratic Republic of Congo • Costa Rica • Croatia • Cuba • Czech Republic • Dominican Republic • Ecuador • Egypt • El Salvador • Estonia • Gabon

• Guatemala • Gabon • Guatemala • Guinea • Honduras • Hungary • India • Indonesia • Ivory Coast • Jamaica • Jordan • Kazakhstan • Kenya • Latvia • Lebanon • Lithuania • Macao • Macedonia • Madagascar • Malaysia • Mauritius • Mexico • Morocco • Myanmar • Namibia • Nepal • Niger • Nigeria • Pakistan • Peru

• Philippines • Papua New Guinea • Paraguay • Peru • Philippines • Poland • Romania • Russian Federation • Senegal • Serbia & Montenegro • Slovakia • South Africa • Sri Lanka • Syria • Tanzania • Thailand • Togo • Trinidad & Tobago • Tunisia • Turkey • Uganda • Ukraine • Uruguay • Uzbekistan • Venezuela • Vietnam • Yemen • Zambia • Zimbabwe

One critical finding of the DOMI Program was that the introduction of typhoid vaccines in Asian countries could be further facilitated by provision of country-specific evidence of population demand for the vac- †Information as of January 2009. cines [76] . The DOMI studies measured the population demand for Vi vaccines, focusing on private prevent 456, 158 and 258 typhoid cases, and five, two and three demand, in sites in China, India and Pakistan. Formal contin- deaths over 3 years in Kolkata, North Jakarta and Karachi per gent valuation methodology was used to assess willingness to 100,000 child population, respectively. Similarly, the program pay for Vi vaccine among randomly selected households in both would avert 126, 44 and 72 disability-adjusted life years, respeclow- and middle-income areas of the DOMI sites (Table 2) [77–79] . tively. In those three settings, the program would be considered Respondents living in low-income areas said the average amount ‘very cost effective’ (i.e., costs per disability-adjusted life year they were willing to pay for the vaccine for their children ranged averted less than per capita gross national income) under a wide from US$2 in Kolkata, India to US$16 in Guilin, China. A total range of assumptions. Community-based vaccination programs of 40% or more of the respondents in the Chinese, Indian and that also targeted adults in Kolkata and Jakarta were less cost Pakistani sites were willing to pay at least US$2 for their child to effective than programs targeting only children because incidence be vaccinated. As expected, willingness to pay for the vaccine was is lower in adults than children, but they were still likely to be higher in nonpoor than poor households. These data highlight ‘very cost effective’. the high demand for typhoid vaccines among all of the study sites, and raise the possibility that the costs of providing Vi vac- Expert commentary cine by governments may be subsidized by imposing users’ fees Even though typhoid fever has been nearly eradicated in the for wealthier subpopulations. developed world, it remains a major public health problem in The DOMI Program also evaluated the cost–effectiveness of developing countries, particularly in South and Southeast Asia. the Vi vaccination program [80] . It was estimated that a Vi vac- Today, typhoid fever continues to pose a great public health cination program targeting all children (aged 2–15 years) would challenge since it is a disease complicated by factors in diagnosis www.expert-reviews.com

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and treatment, such as nonspecific clinical presentations, emerging patterns of antimicrobial resistance and high costs of treatment  [2,17,81] . In particular, the occurrence of antimicrobial resistance in endemic settings has increased in recent years. In more affluent nations, the control of typhoid fever has been the combined result of a comprehensive prevention package, which includes improvements in water, sanitation and hygienic conditions, and increased economic development at the household level. Consequently, the improvement of environmental factors in such settings has reduced the population exposure to factors that contribute to the spread of typhoid. It has been recognized that long-term interventions, such as the provision of safe drinking water and improvement in hygienic conditions, are the ultimate solutions to typhoid control in developing countries. However, previous experiences in developing countries suggest that such solutions require strong political motivation and a major financial commitment from country leadership. Thus, vaccination as a short-term health intervention represents a comparatively cost-effective and feasible strategy for the control of typhoid in endemic resource-poor settings. A review of the literature shows that there is sufficient evidence on the safety, immunogenicity and protective efficacy of Vi vaccine to warrant its use in the population control of typhoid in endemic settings. Estimates are consistent among numerous studies, and Vi vaccination programs have been conducted in Vietnam, India and China, covering a wide range of settings and ethnicities. There is a growing concern surrounding the Vi vaccine’s impact against Vi-negative S. Typhi strains [82,83] . Though there have been reports on isolation of Vi-negative S. Typhi strains from typhoid fever patients in Pakistan [84,85] , such cases still appear to be a rare isolated incidences and overall population impact of the Vi vaccine would likely be unaffected. Furthermore, it is important to note that typhoid carriers play a significant role in the transmission of the disease. Vaccination with the Vi vaccine prevents infection and, hence, contributes to reducing the incidence of the chronic carriers. However, vaccination with the Vi vaccine does not treat carriage; thus, typhoid-endemic countries and regions must ensure surveillance for carriage and treat them appropriately. Such a mechanism for screening and treatment of typhoid carriers in endemic settings can significantly complement mass vaccination in reducing the burden of the disease. The Strategic Advisory Group of Experts of the WHO recommend the use of typhoid vaccine in areas where typhoid fever is endemic [86] . This further led to the publication of a new position paper by the WHO [28] . Efforts from the public and private sectors have brought forward the issues on typhoid fever and the potential the vaccines have for control of the disease. The position paper states that “countries should consider the programmatic use of typhoid vaccines for controlling endemic disease.” Generally, vaccination costs have limited the use of vaccines in developing countries, and typhoid vaccines are no different. However, the transfer of the manufacturing technology of Vi vaccine to manufacturers in developing countries has helped reduce its price significantly, making it more feasible for governments to 492

finance a typhoid vaccination program. Various studies, which include the empirical measurement of the cost-of-illness of typhoid fever, and cost–effectiveness analyses using epidemiological and economic data, have shown that immunization programs using the Vi vaccine are a ‘very cost-effective’ option in areas with a high burden of typhoid [80] . Furthermore, it should be noted that nearly 50% of cases occur in school-aged children in India, Pakistan and Bangladesh, and, thus, a school-based immunization program would yield many socio-economic benefits for society. The willingness-to-pay studies conducted through the DOMI Program in China, India, Pakistan and Vietnam highlighted public awareness of the disease and the need for a vaccine, and indicated the potential for public acceptance and participation in typhoid vaccination campaigns, as well as a willingness to pay for private vaccination costs [87] . Current estimates of the cost–effectiveness of the Vi vaccine have not taken into account the herd protective effects of using this vaccine. However, an effectiveness trial of the Vi vaccine in Kolkata recently demonstrated the impact of herd protection, indicating that the Vi vaccine can exert a major public health impact through direct and indirect protection. Consideration of these herd protective effects would improve estimates of Vi vaccine cost–effectiveness and would strengthen the case for using this vaccine in public health practice. The significant decline of mortality due to typhoid fever in the post-antimicrobial era has had an effect on the perceived risk of typhoid fever in the general population, and in many typhoidendemic settings, healthcare is provided in an environment where there is easy access to antimicrobials. These factors have contributed to the over-use of antimicrobials and the development of antimicrobial-resistant strains, which has resulted in an escalating costs-of-illness for typhoid. It was demonstrated in Delhi that severe typhoid cases requiring hospitalization, which were probably antimicrobial resistant, required an approximately fivefold increase in out-of-pocket costs [42] . Therefore, it is imperative to advocate for vaccination to not only reduce the disease burden, but to also the economic burden at the household, community and country levels. Furthermore, country experiences on the use of Vi vaccine in China, Vietnam and India provide convincing evidence that Vi vaccine can be feasibly introduced with public funding, and that vaccine introduction can have a significant impact on typhoid morbidity. As there is no animal reservoir for S. Typhi, the disease may be eliminated if control measures are effectively implemented. These lessons should be drawn upon in deliberations by decision makers as they consider the introduction of Vi vaccine in typhoid-endemic regions. Five-year view

In the next 5 years, it is anticipated that the Vi vaccine will be made more accessible and available to typhoid fever-endemic countries. This will be achieved in part through the likely prequalification of the Vi vaccine by the WHO, and its subsequent availability through the United Nations Children’s Fund (UNICEF) procurement system. In its review of vaccines Expert Rev. Vaccines 9(5), (2010)

Population impact of Vi capsular polysaccharide vaccine

to be considered for future investment, the Global Alliance for Vaccines and Immunization shortlisted typhoid fever vaccines in 2008 [101] . Together, with the acknowledgement by the WHO that typhoid fever is a high-priority disease [86] , more attention will be focused on the prevention and control of typhoid fever through vaccination. Easier access to Vi vaccine will enable more typhoid feverendemic countries and local governments to introduce the vaccine. Concurrent with the WHO’s efforts to expand the platform for immunization beyond the infant immunization schedule [102] , many countries may opt for school-based vaccination programs with the Vi polysaccharide vaccine. A Vi polysaccharide–protein conjugate vaccine is also likely to be available in the next 5 years. Unlike the Vi polysaccharide vaccine, which is not effective in children less than 2 years of age, the Vi conjugate vaccine could be used in infants and, thus, could be introduced into the infant immunization schedule. The Vi conjugate vaccine has been shown to be more efficacious than Vi polysaccharide vaccine [88] and, additionally, the Vi conjugate vaccine will provide longer duration of protection against the

Review

disease [89] , hence, eliminating the requirements for revaccination. These improved characteristics would provide countries and local governments an excellent opportunity to make the typhoid vaccine part of existing public health programs. The Vi poly­ saccharide vaccine will probably still be used in countries with medium typhoid incidence and where the disease burden mainly affects school-aged children. However, it is likely to be replaced by the Vi conjugate vaccine in areas with high incidence, where the burden affects younger age groups, including children less than 2 years of age. Therefore, it is anticipated that both vaccines will have an integral role in the efforts to control typhoid fever. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • The existing evidence shows that the Vi vaccine is safe and effective, and can be effectively used for the population control of typhoid fever. • Typhoid fever continues to be a public health problem in developing countries. • The WHO recommends immunization of school-aged children using new-generation typhoid fever vaccines in areas with high typhoid incidence and/or antimicrobial resistance. • Typhoid carriers play a significant role in the transmission of the disease. A mechanism for screening and treatment of typhoid carriers in endemic settings can significantly complement mass vaccination in reducing the burden of the disease. • The Vi vaccine has been evaluated in a series of efficacy and effectiveness trials, and it has shown consistent protective efficacy/effectiveness at approximately 60% for 3 years following vaccination. It has also been shown to be safe and immunogenic in various settings. • Evidence from China and Vietnam suggests that the programmatic use of Vi vaccines in selected areas largely controlled the disease within a 4–5-year period, reducing incidence to very low levels. • Experience in China also showed that Vi vaccination is effective in controlling typhoid outbreaks. • A cluster-randomized Vi vaccine field trial conducted in the slums of Kolkata, India demonstrated that the vaccine confers substantial protection when administered under programmatic public health conditions, as well as high-grade protection to children aged 2–5 years, and its overall protective impact is greatly magnified by its ability to confer herd protection. • Cost–effectiveness analyses found school-based Vi vaccination programs targeting children in high-risk areas to be ‘very cost effective’. Community-based programs targeting both children and adults are also considered to be ‘very cost effective’ in high disease burden areas.

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Expert Rev. Vaccines 9(5), (2010)