E D I T O R I A L C O M M E N TA R Y

The Need for Another Typhoid Fever Vaccine

Lorenz von Seidlein
International Vaccine Institute, Seoul, South Korea

(See the article by Kirkpatrick et al., on pages 3606.)

In this issue of the Journal of Infectious Diseases, Kirkpatrick et al. [1] report data on the safety and immunogenicity of a new typhoid fever vaccine with the preliminary name M01ZH09. Better control of typhoid fever is urgently needed because, as noted by Crump et al. [2], an estimated 21,650,000 episodes of typhoid fever illness occurred in 2000. Worldwide, the highest incidence of typhoid fever is in the nonindustrialized countries of south-central and southeast Asia (1100 cases/100,000 persons/year). Intermediate levels in Asia and in Africa have been reported elsewhere [2]. Recent burden estimates include children !5 years old, who, in the past, were falsely thought to be at lower risk for typhoid fever. In Delhi, India, an area with a high incidence of typhoid fever (2730 cases/100,000 persons/year), typhoid fever has been documented in children !5 years old [3]. The encouraging development of declining deaths caused by typhoid fever (from an estimated 600,000 in 1984 to 216,510 in 2000) could be short-lived [2, 4] because
Received 4 April 2005; accepted 4 April 2005; electronically published 30 June 2005. Our team established a large linked database to detect adverse events associated with immunizations in Vietnam in 2001, which had to be terminated in 2004 because of the absence of funding. Potential conicts of interest: none reported. Reprints or correspondence: Dr. Lorenz von Seidlein, International Vaccine Institute, San 4-8 Bongcheon-7-dong, Kwanakgu, Seoul 151-600 (lseidlein@ivi.int) The Journal of Infectious Diseases 2005; 192:3579 2005 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2005/19203-0001$15.00

of the emergence of multidrug-resistant Salmonella typhi strainsspecically, quinolone-resistant strainsin high-incidence regions [5, 6]. Aside from human suffering, this disease causes considerable economic consequences in the form of direct treatment costs and lost productivity. Recent research in Jakarta, Indonesia, an area with a high incidence of typhoid fever, again emphasizes inadequate personal hygiene as a key risk factor for typhoid fever [7]. Sanitation and a safe water supply must be long-term goals for the control of typhoid fever and other enteric diseases. Unfortunately, because both require substantial investment and sometimes daunting technical challenges in the developing world, short and midterm approaches to control typhoid fever have to be considered. Therefore, in 2003, the World Health Organization recommended 2 strategies to reduce typhoid fever: routine immunization of school-aged children and immunization of children beginning at 2 years of age in sites where typhoid fever occurs in younger children [8]. At present, 2 internationally licensed vaccines that protect against typhoid fever are available. One of these vaccines is based on the Vi polysaccharide of S. typhi. This subunit vaccine is administered as a single parenteral dose. It is affordable in nonindustrialized countries, since the technology is in the public domain and has been transferred to local producers. At 21 months of follow-up, the vaccine was safe and conferred 77% protective ef-

cacy in children immunized at 25 years of age, compared with that in an unvaccinated group [9]. The protective efcacy of the vaccine was 55% 3 years after administration. Reimmunizations are recommended every 23 years. Like other polysaccharide vaccines, this vaccine does not elicit an adequate immune response in very young children and is recommended only for those 2 years old. In response to the requirement for reimmunization and the lack of protection conferred in young children, the Vi polysaccharide has been conjugated to the nontoxic recombinant Pseudomonas aeruginosa exotoxin A (VirEPA), following the example of the highly successful Haemophilus inuenzae type B conjugate vaccines. A Vi polysaccharide conjugate vaccine candidate was found to be highly protective (89%) 46 months after the rst of 2 injections in a group of Vietnamese children 25 years old [10]. An evaluation of the protective efcacy of the Vi polysaccharide conjugate vaccine candidate in children !2 years old has yet to be published. As for other conjugate vaccines, the production technology is more challenging for the Vi polysaccharide conjugate vaccine than it is for the unconjugated subunit vaccine, which will be reected in the price once a producer has licensed this vaccine. The other licensed typhoid fever vaccine is the live attenuated Ty21a. This vaccine strain is derived from the Ty2 wild strain. Thirty genes of the Ty2 wild strain have been mutated, resulting in the vac JID 2005:192 (1 August) 357

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cine strain Ty21a, but the precise mechanism of attenuation is not understood. The protective efcacy varies with the formulation and dosing of the vaccine. When given as a suspension on alternate days, Ty21a had a protective efcacy of 79% 4 years after the administration of the rst dose [11]. The vaccine is safe and administered orally, and revaccination is required only every 5 years, which makes Ty21a a popular choice for travelers from industrialized countries to regions with a high incidence of typhoid fever. The stringent cold-chain requirements and the need for precise dosing intervals are no handicap for travelers but add logistic challenges to the widespread use of this vaccine in resource-poor countries. The production of a live attenuated bacterial vaccine is complex, which is reected in the price and the absence of Ty21a production in countries with high incidence of typhoid fever. Neither vaccine (Vi nor Ty21a) is ideal for use in wide-scale vaccination programs. Thus, the early report by Kirkpatrick et al. [1], described in this issue of the Journal, on the new typhoid fever vaccine candidate M01ZH09 is highly welcome. M01ZH09 is a live attenuated oral vaccine that is distributed as a lyophilized preparation and is immunogenic as a single dose. The 2 mutations in aroC and ssaV that distinguish the vaccine candidate M01ZH09 from the original Ty2 strain have been precisely described; such precise description is essential for present licensing requirements. In earlier dose-escalation studies, M01ZH09 was found to be safe and immunogenic [12]. In these earlier studies, volunteers had drunk a bicarbonate preparation before vaccination, to neutralize gastric acidity, which may be lethal for the live vaccine strain. Such administration of buffer would add a logistic hurdle to the use of the vaccine in mass immunization programs. In the study by Kirkpatrick et al. [1], the vaccine remained immunogenic when provided in a buffered solution, even when administered without a prior dose of buffer. The authors also point out that chlo-

rinated tap water can be safely used for the preparation of the vaccine, eliminating the need for bottled water for vaccine reconstitution. This is a theoretical advantage, but even chlorinated tap water may not always be available in areas where the vaccine is most needed. Unfortunately, because the study lacked a control group that received a biologically inactive agent, it is difcult to interpret the safety data on medical adverse events after administration of the vaccine candidate. We may wish to think that a similar number of adverse events would have been observed in a group of volunteers receiving a biologically inactive agent, but only the evaluation of a control group would allow such a conclusion. What lies ahead? The next step for this vaccine candidate is probably evaluation of its safety and immunogenicity in the target population, which will include children in areas with a high incidence of typhoid fever. This step is crucial, since it has been shown time and again that the immunogenicity of a vaccine candidate can be much lower in populations with a high level of preexposure than in populations that are naive to the vaccine antigens. A frequently cited example is the nding that 3 doses of oral polio vaccine, as formerly used in the United States, resulted in sustained, probably lifelong immunity, whereas children in developing countries require 13 doses for adequate seroconversion [13, 14]. Similarly, a live oral Shigella vaccine (SC602) and a live oral cholera vaccine (CVD-106HgR) shown to be immunogenic in North American volunteers were subsequently found to perform poorly in Bangladeshi and Indonesian volunteers, respectively. Colonization competition may be one of the factors responsible for this observation. Whether preexposure or colonization competition will be important factors when the live oral typhoid candidate described by Kirkpatrick et al. is tested in areas where typhoid fever is endemic has yet to be determined. The evaluation of the safety of vaccine

candidates and, in particular, of live vaccine candidates is complicated by the HIV pandemic. National regulatory agencies may be inclined to ask for data on the safety of a live vaccine candidate in HIVinfected persons, in whom the vaccine candidate could be less immunogenic or could trigger a transient increase in viremia followed by a redistribution of gut-associated virus strains. The vaccine strain was not detected in the stool of healthy volunteers, but persistent shedding in HIV-infected persons remains a concern. Such safety issues can only be resolved through vigorous safety studies in HIV-infected persons. Once safety and immunogenicity have been demonstrated, the last round before licensing will be provision of evidence that the vaccine can indeed confer protection against the disease. This will require large, expensive clinical trials in areas with a high incidence of typhoid fever. Unanticipated rare adverse events are usually detected only after licensing, once a vaccine is used widely. For example, in July 1999, a live attenuated tetravalent rhesus rotavirus vaccine was withdrawn from the US market after the Vaccine Adverse Event Reporting System detected intussusception in 15 infants who had received this vaccine in the United States [15]. Accurate, complete reporting systems and large, linked databases like those that have been used in industrialized countries to evaluate associations between adverse events and vaccinations are needed but are absent in the resource-poor regions where a new typhoid vaccine is most needed [16]. Thus, associations between rare adverse events and a new vaccine predominantly used in resourcepoor regions may go undetected. The creation of reporting systems and large, linked databases that allow the evaluation of the safety of new vaccines in resource-poor settings would help to build the condence of consumers, policymakers, and donors needed for the widespread use of new vaccines. Meanwhile, the pathogens are not at rest. Medical textbooks state that 10% of

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enteric fevers are caused by S. paratyphi, a percentage that was recently increased to 25% [2, 17]. Recent eldwork in southeast China detected more S. paratyphi A than S. typhi in blood cultures from patients with enteric fever [18]. Should this nding be reproduced in other areas, it may again become necessary to combine S. typhi vaccines with S. paratyphi vaccines to prevent enteric fever.

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References
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