|Year : 2012 | Volume
| Issue : 2 | Page : 161-169
Typhoid fever & vaccine development: A partially answered question
Sandhya A Marathe, Amit Lahiri, Vidya Devi Negi, Dipshikha Chakravortty
Department of Microbiology & Cell Biology, Indian Institute of Science, Bangalore, India
|Date of Acceptance||03-May-2010|
|Date of Web Publication||22-Mar-2012|
Centre for Infectious Disease Research & Biosafety Laboratories, Department of Microbiology & Cell Biology, Indian Institute of Science, Bangalore 560 012
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Typhoid fever is a systemic disease caused by the human specific Gram-negative pathogen Salmonella enterica serovar Typhi (S. Typhi). The extra-intestinal infections caused by Salmonella are very fatal. The incidence of typhoid fever remains very high in impoverished areas and the emergence of multidrug resistance has made the situation worse. To combat and to reduce the morbidity and mortality caused by typhoid fever, many preventive measures and strategies have been employed, the most important being vaccination. In recent years, many Salmonella vaccines have been developed including live attenuated as well as DNA vaccines and their clinical trials have shown encouraging results. But with the increasing antibiotic resistance, the development of potent vaccine candidate for typhoid fever is a need of the hour. This review discusses the latest trends in the typhoid vaccine development and the clinical trials which are underway.
Keywords: DNA vaccine - immunity - Salmonella - typhoid fever - vaccination
|How to cite this article:|
Marathe SA, Lahiri A, Negi VD, Chakravortty D. Typhoid fever & vaccine development: A partially answered question. Indian J Med Res 2012;135:161-9
|How to cite this URL:|
Marathe SA, Lahiri A, Negi VD, Chakravortty D. Typhoid fever & vaccine development: A partially answered question. Indian J Med Res [serial online] 2012 [cited 2019 Oct 23];135:161-9. Available from: http://www.ijmr.org.in/text.asp?2012/135/2/161/94205
| Introduction|| |
Infectious diseases are caused by pathogenic microorganisms such as bacteria, viruses, multicellular parasites or fungi, protozoa and aberrant proteins namely prions. These diseases are known to be contagious. Evidence of infective diseases has been reported in history  . There are many infectious diseases which are more geographically localized, but still create worldwide concern, e.g., haemorrhagic fever, Nipah virus, monkeypox, etc. Today, in spite of having increased knowledge about causative agents of many infectious diseases, we are far behind from controlling many of these and in the development of an efficient vaccine. Typhoid fever is one such disease, which is caused by Salmonella More Details enterica serovar Typhi. Though Salmonellosis More Details is rare in developed and industrialized countries, it still remains a serious problem in most of the developing countries especially Southeast Asian countries, Africa and Latin America.
S. enterica is a Gram-negative intracellular pathogenic bacterium which infects humans and many warm blooded animals. S. enterica includes 2500 serovars most of which have been described as human pathogens but only a few are of public health importance , . Salmonella can infect a wide range of host including reptiles, birds and mammals. However, some serovars are highly specific viz. S. Typhi or S. Paratyphi  .
| Disease impact of typhoid fever|| |
Some of the Salmonella serovars are known to cause osteomyelitis, splenic abscess and septicemia  . S. Typhi or S. Paratyphi infect human and cause typhoid and paratyphoid fever, respectively. Transmission of the disease occurs through faecal-oral route, upon ingestion of contaminated water and food and inadequate sanitation, consuming raw milk products, flavored drinks and ice-creams. This disease can also spread through consumption of raw fruits and vegetables grown in fields irrigated with sewage water and fertilizer , . The incubation period of the disease is usually 10-14 days and varies considerably from 8-15 days, but may be as short as 5 days and as long as 30 or 35 days depending upon the inoculum size and the state of host defenses. Occurrence of the disease has to be confirmed by the presence of the pathogen either S. Typhi or S. Paratyphi in patient, which requires isolation of the bacteria from blood, stool or bone marrow. The sensitivity of the test decreases with increased duration of fever. Another method is Widal test, which identifies the presence of antibodies against Salmonella specific O (somatic) and H (flagellar) antigens in the serum which appear only in the 2 nd week after the disease onset. One of the recent diagnostic techniques developed in our laboratory is a PCR based method which utilizes specific primer designed against a region unique to S. Typhi and S. Paratyphi A. This method can detect very small number of bacteria within 4-5 days of onset of infection  . This method is more sensitive than Widal test and can also differentiate between S. Typhi CT18, S. Typhi Ty2 and S. Paratyphi A.
Most commonly used antibiotics for the treatment of typhoid fever are fluoroquinolone such as ciprofloxacin, ofloxacin and pefloxacin and third-generation cephalosporins such as ceftriaxone or cefotaxime. Antibiotic treatments are often ineffective in carriers with gallstones. In these carriers, Salmonella are resistant to bile  forming biofilm on the gallbladder conferring antimicrobial resistance to bacteria  . Emergence of multidrug resistance (MDR) in Salmonella has made treatment of the disease more difficult and complicated. In 1948, chloramphenicol was first reported for the treatment of typhoid fever  . In 1972, chloramphenicol resistance was identified as a major problem in the treatment of disease during an outbreak in Mexico, India, Vietnam, Thailand, Korea and Peru  . The resistance to chloramphenicol was associated with high-molecular-weight, self-transferable, IncHI plasmids which encode the resistance genes; but strains of S. Typhi with such plasmid mediated MDR are not observed in Latin America , . In the 1970s and 1980s, use of antibiotics like fluoroquinolones such as ciprofloxacin and ofloxacin had become widespread especially in countries where MDR was a problem. In 2005, the existence of MDR strains of S. Typhi was noticed in patients in Lagos, Nigeria  , ciprofloxacin resistance in Karachi and in 2007 in India, MDR strains of S. Typhi were reported  . MDR strains of S. Typhimurium have become a major cause of salmonellosis worldwide e.g. MDR definitive phage type 104 (DT104), which was found to be resistant to ampicillin, chloramphenicol, streptomycin, sulphonamides and tetracycline , .
MDR is also mediated by another plasmid pHCM1, in bacteria  . The situation has further worsened because some variants of Salmonella have developed MDR as an integral part of their genome and therefore, are likely to retain their drug-resistant genes even when antimicrobial drugs are no longer used, making the pathogen more virulent and potent. One such example is the chromosomally encoded gene complex known as the Salmonella genomic island 1 in S. Typhimurium  , which can be transferred to other Salmonella serotypes  . Thus, the emergence and global spread of antimicrobial resistant Salmonella strains have necessitated to understand in depth the mechanism of pathogenesis so as to find new drug target for the MDR strains of the pathogen and develop a vaccine as a prophylactic strategy. During its intracellular life in macrophages, Salmonella induces a variety of regulatory systems which are responsible for its survival inside the host  . Salmonella has evolved different strategies to evade the host immune response. One of the strategies is modification of lipopolysaccharides (LPS) which is normally recognized by TLR-4 triggering downstream signaling cascade to evoke host immune response , . This membrane remodelling blocks recognition by host TLR-4 and also increases resistance of bacteria against host antimicrobial peptides. Salmonella also prevents the fusion of Salmonella containing vacuole with lysosome and vesicles containing reactive oxygen and nitrogen species  . Salmonella inhibits antigen presentation via dendritic cells , . There are many regulators in Salmonella like PhoP/Q, PmrA/B, OmpR/EnvZ, two component system (TCS), sigma factor RpoS and RpoE, which are responsible for regulating such phenotypes. PhoP/Q TCS is required for antimicrobial peptide (AMP) resistance, virulence and survival of Salmonella within macrophages  . PmrA/B TCS was described for the first time in 1993  and was later associated with resistance against AMPs like polymyxin B, Cationic antimicrobial protein 37 and Cationic antimicrobial protein 57 (BPI)  . Some of these regulated genes are involved in LPS modification as well as AMPs resistance. PmrA/B and PhoP/Q, regulate genes in mouse model especially in GI tract and in spleen  .
| Vaccine status for Salmonella pathogenesis/typhoid fever|| |
Typhoid fever caused by S. Typhi or S. Paratyphi is a major health problem with global incidence of 21 million cases and 200,000 (1-4% death worldwide) deaths per year  . Salmonella has become a major threat to the society due to the disease severity, recurrence of disease through carrier state, emergence of multidrug resistance and its use as a potential candidate in bioterrorism  . This demands for an effective prophylactic measures. In 2000 and 2008, WHO has explained the importance of vaccine against typhoid fever , . There have been many efforts done by different groups of scientists to develop an effective vaccine against Salmonella. But at present, only two licensed vaccine for typhoid fever - a subunit (Vi PS) and a live attenuated S. Typhi strain (Ty21a) are commercially available. Continuous efforts are being undertaken to develop typhoid vaccine with the advancement of Vi polysaccharide conjugate vaccine and live attenuated Salmonella strain to attain higher antibody titres and increased immunogenicity  . Murine model of typhoid fever (BALB/c mice infection with S. Typhimurium) is used initially to test the efficiency and potency of the vaccine. Once the vaccine is found to be safe, it will be underaken for clinical/field trial in humans.
| Inactivated whole-cell typhoid vaccine|| |
In 1896, heat killed phenol preserved and acetone killed lyophilized injectable whole cell S. Typhi vaccine was generated and used in England and Germany. The efficacy of this vaccine was assessed in a trial in 1960 in Yugoslavia, USSR, Poland, and Guyana. This vaccine is still in use in a few countries but most of the countries have withdrawn the usage of this vaccine due to the side effects. The acetone killed vaccine was more superior to heat-phenol killed vaccine. It was due to the preservation of Vi-polysaccharide in acetone killed vaccine , . However, inactivated whole-cell vaccine causes local inflammation, pain, systemic fever, malaise and disease like symptoms in 9-34 per cent of the recipients. Thus, whole cell inactivated vaccine was not considered suitable for public use and in spite of being licensed it is no longer available in the market , . Unfortunately for paratyphoid fever, there is no licensed vaccine till date. Increasing emergence of multidrug resistance strains of Salmonella has further complicated the situation of the disease and its treatment with existing antibiotics.
| Vi-polysaccharide (Vi-PS) vaccine|| |
Felix and co-workers showed the presence of serological response against Vi-polysaccharide in typhoid fever , . Considering this and the ability of acetone killed whole-cell vaccine to be more effective due to presence of Vi-polysaccharide , , it was considered as a potential candidate for vaccine development. In 1986, Robbins and Robbins at NIH developed an injectable subunit vaccine Vi-polysaccharide vaccine (sold as Typhim Vi by Sanofi Pasteur and Typherix by GlaxoSmithKline). The vaccine was licensed to Sanofi-Pasteur in 1994 (Typhim TM, Sanofi-Pasteur; TypbarTM, Bharar). Vi polysaccharide, a linear homopolymer of galacturonic acid is purified from the bacteria by treatment with detergent Cetavlon. During initial trial, this vaccine gave 75 per cent protection during 20 months surveillance in 5-44 yr age group in Nepal. In South Africa, among the age group of 5-16 yr, 64 per cent protection was observed after 21 months and after 3 yr the protection was only 55 per cent , . In China, the protection among 5-9 yr old children was 69 per cent  . This vaccine has certain drawbacks being non-immunogenic in children below 2 yr of age and unable to induce booster effect. Most importantly many of the S. Typhi strains are negative for Vi polysaccharide or lose their Vi-antigen , and in such cases Vi-PS vaccine will not be able to protect the patient. The recent data of the community vaccination in high-incidence areas of Kolkata, Karachi, and North Jakarta showed the cost effectiveness of Vi-polysaccharide vaccine in children .
| The live attenuated Ty21a vaccine|| |
Due to the side effects and low effectiveness of the killed whole cell vaccine a need for a more competent vaccine candidate emerged. With the knowledge that live attenuated strain elicits more immune response, attenuated Salmonella strains were considered for vaccine development. Ty21a was the first live oral attenuated Salmonella vaccine (sold as Vivotif by Berna Biotech, now crucell and was developed in Switzerland by chemical mutagenesis of wild-type S. Typhi strain Ty2 ,  . This strain lacks both functional galactose-epimerase (galE) gene and the Vi antigen and is highly attenuated. The Ty21a vaccine is licensed in 56 countries of Asia, Africa, USA and Europe  . This vaccine is available in both liquid as well enteric coated capsule forms. Clinical trials in Alexandria, Egypt, with the liquid form of vaccine showed 96 per cent protection for 3 yr and in Santiago, Chile, it was found to be 67 per cent for 3 yr and 62 per cent over 7 yr  . Ty21a, was also shown to provide 42-56 per cent protection against paratyphoid caused by S. Paratyphi, in Chile  . It is also hypothesized that Ty21a can give rise to herd-immunity effect  . Despite an adequate immune response and efficacy against typhoid fever, Ty21a has certain drawbacks. To obtain sufficient immunity, high numbers (10 9 ) of bacteria are required for oral dose; its use is recommended for children only above 5-6 yr of age. This vaccine is highly acid-labile and hence stomach acidity has to be either neutralized or bypassed when Ty21a is to be fed orally.
| Other non-commercialized vaccines against typhoid fever|| |
Several live attenuated S. Typhi strains have been developed for oral vaccination against typhoid fever. Many of the developed strains have been used in humans to check the efficacy and immunity against the pathogen. 541Ty (Vi+) and 543Ty (Vi-) were developed by Stocker and co-worker by transducing deletion in aroA, purA and hisG ,  . 543Ty is a spontaneous mutant of 541Ty that lacks Vi-polysaccharide antigen. These strains are unable to maintain growth in mammalian tissue. 541Ty and 543Ty induced good immune response in the Phase I clinical trial  . Another attenuated strain, CVD 908 with mutation in aroC and aroD was developed  . A further mutation in the htrA locus, gave rise to the CVD908-htrA  vaccine strain with multiple deletions in aroC/aroD/htrA. When compared with the usage of existing vaccine Ty21a, single-dose CVD 908-htrA stimulated vigorous mucosal, humoral, and cellular immune responses that equaled or surpassed those measured after multiple doses of Ty21a. In 1992, Tacket and colleagues developed vaccine candidate χ3927 which is mutated in cya and crp. Along with other two CVD 906 (ISP1820 ΔaroC Δ aroD), CVD 908 (Ty2 Δ aroC Δ aroD) mutated vaccine strains, χ3927 vaccine were able to induce LPS specific antibody response when used in the volunteers  .
Till date there was no effective vaccine that could confer protection to 2-5 yr old children. Salmonella Typhi Vi O-Acetyl Pectin-rEPA conjugate vaccine, a modified conjugate vaccine where Vi-PS is conjugated to a non-toxic recombinant Pseudomonas aeruginosa otoxin A (rEPA) has been used in clinical trial among the children and infants of age under 2 yr  . The trial reports an efficacy of 90 per cent in 2-5 yr old children.
The live attenuated candidate vaccine Ty800, a deletion mutant of the global regulator phoP/phoQ of Ty2, is developed by AVANT Immunotherapeutics , . It has passed Phase II trials and Ty800 has been shown to stimulate vigorous IgA and anti-O serum antibody responses in volunteers. Salmonella live attenuated vaccine candidate M01ZH09/ZH09 against S. Typhimurium/Typhi was developed with the deletion in the SPI gene (Ty2 aroC and ssaV) and underwent Phase II trial  . This vaccine strain lacks SPI-2 structural protein SsaV, required for secretion of bacterial effectors proteins. The mutation will hinder the SPI-2 function and prevent the systemic spread. Another mutation in aroC, aromatic mutation deprives the bacterium of essential nutrients it must obtain from the mammalian host. This double mutation vaccine strain was shown to be immunogenic and well-tolerated when given as a single dose. The study was conducted till 6 months after vaccination and volunteers did not show any bacteremia or prolonged shedding of the vaccine strain, which is an important safety advantage of vaccination. None of the new oral vaccine candidates (such as CVD 908, CVD 908-htrA, Ty800, and MO1ZH09), were consistent in their ability to stimulate serum Vi antibody. Levine and his group proposed that, if the expression of Vi is rendered to be constitutive in CVD 908-htrA, the strain might elicit the serum and mucosal anti-Vi antibody in addition to whole cell antigen response. They replaced the highly regulated PtviA in CVD 908-htrA with the strong constitutive promoter Ptac, resulting in a strain "CVD 909" which constitutively expresses the Vi antigen , . This strain was the first vaccine candidate to elicit serum Vi antibodies and was able to significantly reduce the mortality of mice even with single immunization.
In 2007, a live attenuated vaccine against typhoid fever DV-STM-07 was developed in our laboratory, which has been shown to be potent in murine model of salmonellosis  . This is a multiple deletion mutant where the LPS modification and AMP resistance genes (pmrG, pmr HIFJKLM and pmrD) have been targeted and used as live vaccine. This vaccine was shown to provide immunity and protection at very low dose as well as with single dose, and was able to protect the pregnant mice and the foetus from lethal Salmonella infection. During the same year, CKS362, a killed but metabolically active (KBMA) S. Typhimurium strain was developed as a Salmonella vaccine. The safety profile of KBMA strain was speculated to be similar to that of killed micro-organisms. Salmonella KBMA strain was derived from ΔphoP/phoQΔaroA  . This mutant vaccine strain was further made devoid of uvrAB, genes involved in DNA repair mechanism. Photochemical treatment of bacteria mutant in DNA excision repair (ΔuvrAB) renders the organisms "killed but metabolically active". This strain will not be able to replicate after treatment with UVA light. Also, these bacteria cannot synthesize psoralen which makes adduct with DNA in the presence of UVA and will be eliminated during the DNA repair by uvrAB. KBMA CKS362 vaccine strain was markedly less reactive, and stimulated a humoral immune response equivalent to its live counterpart and was more attenuated and immunogenic than live strain.
In 2002, a Salmonella vaccine named complex vaccine (CV) was designed which constituted of flagellin and polysome purified from Salmonella Typhimurium LT2  . Flagellin can induce T cell specific immunity against Salmonella and polysome can induce mucosal immunity and act as Th1 specific mucosal adjuvant. Flagellin and polysome were combined in 1:1 ratio by fomaldehyde condensation to develop CV. Oral vaccination using CV along with cholera toxin (CT), was able to provide complete protection unlike single antigen vaccination  .
The typhoid vaccines designed till date give best protection to children above 2 yr of age. Considering the fact that young age group (1-5 yr) is more susceptible to Salmonella infection ,,, , Novartis Vaccines Institute for Global Health developed a Vi-CRM197 vaccine to ensure improved protection to this age group. Human clinical trials have been planned with adults (18-45 yr), children (24-59 months), older infants (9-12 months) and infants (6 wk of age) in December 2010 [Table 1]. The vaccine was prepared by independent chemical conjugation of Vi-PS of S. Typhi and O polysaccharide of S. Paratyphi A to CRM197, a non-toxic mutant of diphtheria toxin  . The vaccine was well tolerated in animal model and found to induce a better antibody response compared to unconjugated Vi-PS  . It is expected that the vaccine will provide protection to infants and young children.
| DNA vaccine for typhoid fever|| |
Epitope selection based vaccine development has been tried for long. The designing of the small DNA sequence based vaccine for many infectious diseases such as typhoid fever seems to be a promising area of research. Many efforts are being carried out in this direction. In 2004, a report stated that certain antigens of Salmonella showing high expression in vivo were preferentially recognized by CD4 T cells. Five peptides (Mig-14, IicA, SseB, SsaJ, or SifB) of Salmonella were selected on the basis of maximum in vivo expression. These peptides were GFP tagged and selected out from many proteins tested for the in vivo expression profile. Vaccination and challenge studies showed that SseB and Mig-14 were exceptionally efficacious antigens providing antigen specific immunity and protection as compared to other antigens used. Other than high expression level, there are certain antigenic parameters which can influence protective efficacy and show different immune response for different antigen  . In another DNA vaccine study sopB protein of Salmonella was chosen based on its ability to induce better cell-mediated immunity. The vaccine was able to confer protection against Salmonella challenge (lethal dose). The protection and immunity was further enhanced when used in combination with live attenuated vaccine candidates  . The Table summarizes all the clinical trials which are currently in Phase 1 and II ,,,,,,,,,.
| Need for new and effective vaccine for typhoid fever|| |
The development of a new vaccine for typhoid fever is an invigorating challenge for the scientists to pursue. Several vaccines have undergone clinical trials but public acceptance is still required. The need of an efficacious and potent vaccine against typhoid fever which can be used in children below 2-5 yr of age providing strong humoral as well as cellular immunity still persists.
| Acknowledgment|| |
This work was supported by the grant, Provision (2A) Tenth Plan (191/MCB) from the Director of Indian Institute of Science, Bangalore, India, and the Department of Biotechnology (DBT 197 and DBT 172). Infrastructure support from ICMR (Center for Advanced Study in Molecular Medicine), DST (FIST) and UGC (special assistance) is also acknowledged. The first author (SM) acknowledges CSIR for the fellowship.
| References|| |
|1.||World Health Organisation. Diarrhoeal diseases. Geneva: WHO; 2009. |
|2.||Popoff MY, Bockemühl J, Gheesling LL. Supplement 2002 (no. 46) to the Kauffmann-White scheme. Res Microbiol 2004; 155 : 568-70. |
|3.||Baumler AJ, Tsolis RM, Ficht TA, Adams LG. Evolution of host adaptation in Salmonella enterica. Infect Immun 1998; 66 : 4579-87. |
|4.||Hohmann EL. Nontyphoidal salmonellosis. Clin Infect Dis 2001; 32 : 263-9. |
|5.||Black RE, Cisneros L, Levine MM, Banfi A, Lobos H, Rodriguez H. Case-control study to identify risk factors for paediatric endemic typhoid fever in Santiago, Chile. Bull World Health Organ 1985; 63 : 899-904. |
|6.||Luby SP, Faizan MK, Fisher-Hoch SP, Syed A, Mintz ED, Bhutta ZA, et al. Risk factors for typhoid fever in an endemic setting, Karachi, Pakistan. Epidemiol Infect 1998; 120 : 129-38. |
|7.||Nagarajan AG, Karnam G, Lahiri A, Allam US, Chakravortty D. Reliable means of diagnosis and serovar determination of blood-borne Salmonella strains: quick PCR amplification of unique genomic loci by novel primer sets. J Clin Microbiol 2009; 47 : 2435-41. |
|8.||Prouty AM, Van Velkinburgh JC, Gunn JS. Salmonella enterica serovar Typhimurium resistance to bile: identification and characterization of the tolQRA cluster. J Bacteriol 2002; 184 : 1270-6. |
|9.||Prouty AM, Schwesinger WH, Gunn JS. Biofilm formation and interaction with the surfaces of gallstones by Salmonella spp. Infect Immun 2002; 70 : 2640-9. |
|10.||Woodward TE, Smadel JE, Ley HL Jr, Green R, Mankikar DS. Preliminary report on the beneficial effect of chloromycetin in the treatment of typhoid fever. Ann Intern Med 1948; 29 : 131-4. |
|11.||Mirza SH, Beeching NJ, Hart CA. Multi-drug resistant typhoid: a global problem. J Med Microbiol 1996; 44 : 317-9. |
|12.||Kumar S, Rizvi M, Berry N. Rising prevalence of enteric fever due to multidrug-resistant Salmonella: an epidemiological study. J Med Microbiol 2008; 57 : 1247-50. |
|13.||Parry CM, Threlfall EJ. Antimicrobial resistance in typhoidal and nontyphoidal Salmonellae. Curr Opin Infect Dis 2008; 21 : 531-8. |
|14.||Akinyemi KO, Smith SI, Oyefolu AO, Coker AO. Multidrug resistance in Salmonella enterica serovar Typhi isolated from patients with typhoid fever complications in Lagos, Nigeria. Public Health 2005; 119 : 321-7. |
|15.||Chau TT, Campbell JI, Galindo CM, Van Minh Hoang N, Diep TS, Nga TT, et al. Antimicrobial drug resistance of Salmonella enterica serovar Typhi in asia and molecular mechanism of reduced susceptibility to the fluoroquinolones. Antimicrob Agents Chemother 2007; 51 : 4315-23. |
|16.||Helms M, Ethelberg S, Molbak K. International Salmonella Typhimurium DT104 infections, 1992-2001. Emerg Infect Dis 2005; 11 : 859-67. |
|17.||Poppe C, Smart N, Khakhria R, Johnson W, Spika J, Prescott J. Salmonella Typhimurium DT104: a virulent and drug-resistant pathogen. Can Vet J 1998; 39 : 559-65. |
|18.||Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ. Typhoid fever. N Engl J Med 2002; 347 : 1770-82. |
|19.||Mulvey MR, Boyd DA, Olson AB, Doublet B, Cloeckaert A. The genetics of Salmonella genomic island 1. Microbes Infect 2006; 8 : 1915-22. |
|20.||Ribot EM, Wierzba RK, Angulo FJ, Barrett TJ. Salmonella enterica serotype Typhimurium DT104 isolated from humans, United States, 1985, 1990, and 1995. Emerg Infect Dis 2002; 8 : 387-91. |
|21.||Groisman EA, Mouslim C. Sensing by bacterial regulatory systems in host and non-host environments. Nat Rev Microbiol 2006; 4 : 705-9. |
|22.||Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998; 282 : 2085-8. |
|23.||Chow JC, Young DW, Golenbock DT, Christ WJ, Gusovsky F. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem 1999; 274 : 10689-92. |
|24.||Chakravortty D, Hansen-Wester I, Hensel M. Salmonella pathogenicity island 2 mediates protection of intracellular Salmonella from reactive nitrogen intermediates. J Exp Med 2002; 195 : 1155-66. |
|25.||Tobar JA, Carreno LJ, Bueno SM, Gonzalez PA, Mora JE, Quezada SA, et al. Virulent Salmonella enterica serovar Typhimurium evades adaptive immunity by preventing dendritic cells from activating T cells. Infect Immun 2006; 74 : 6438-48. |
|26.||Bueno SM, Gonzalez PA, Schwebach JR, Kalergis AM. T cell immunity evasion by virulent Salmonella enterica. Immunol Lett 2007; 111 : 14-20. |
|27.||Groisman EA. The pleiotropic two-component regulatory system PhoP-PhoQ. J Bacteriol 2001; 183 : 1835-42. |
|28.||Roland KL, Martin LE, Esther CR, Spitznagel JK. Spontaneous pmrA mutants of Salmonella Typhimurium LT2 define a new two-component regulatory system with a possible role in virulence. J Bacteriol 1993; 175 : 4154-64. |
|29.||Shafer WM, Casey SG, Spitznagel JK. Lipid A and resistance of Salmonella Typhimurium to antimicrobial granule proteins of human neutrophil granulocytes. Infect Immun 1984; 43 : 834-8. |
|30.||Merighi M, Ellermeier CD, Slauch JM, Gunn JS. Resolvase-in vivo expression technology analysis of the Salmonella enterica serovar Typhimurium PhoP and PmrA regulons in BALB/c mice. J Bacteriol 2005; 187 : 7407-16. |
|31.||Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever. Bull World Health Organ 2004; 82 : 346-53. |
|32.||World Health Organisation. Public health response to biological and chemical weapons. Geneva: WHO; 2004. |
|33.||Typhoid vaccines. Wkly Epidemiol Rec 2000; 75 : 257-64. |
|34.||Typhoid vaccines: WHO position paper. Wkly Epidemiol Rec 2008; 83 : 49-58. |
|35.||Garmory HS, Griffin KF, Leary SE, Perkins SD, Brown KA, Titball RW. The effect of recombinant plasmids on in vivo colonisation of Salmonella enterica serovar Typhimurium strains is not reflected by in vitro cellular invasion assays. Vaccine 2002; 20 : 3239-43. |
|36.||Wong KH, Feeley JC, Northrup RS, Forlines ME. Vi antigen from Salmonella typhosa and immunity against typhoid fever. I. Isolation and immunologic properties in animals. Infect Immun 1974; 9 : 348-53. |
|37.||Wong KH, Feeley JC. Isolation of Vi antigen and a simple method for its measurement. Appl Microbiol 1972; 24 : 628-33. |
|38.||Levine MM, Ferreccio C, Black RE, Tacket CO, Germanier R. Progress in vaccines against typhoid fever. Rev Infect Dis 1989; 11 (Suppl 3) : S552-67. |
|39.||Garmory HS, Brown KA, Titball RW. Salmonella vaccines for use in humans: present and future perspectives. FEMS Microbiol Rev 2002; 26 : 339-53. |
|40.||Felix A, Krikorian KS, Reitler R. The Occurrence of typhoid bacilli containing Vi antigen in cases of typhoid fever and of Vi antibody in their sera. J Hyg 1935; 35 : 421-7. |
|41.||Felix A. Detection of chronic typhoid carriers by agglutination tests. Lancet 1938; 232 : 738-41. |
|42.||Klugman KP, Koornhof HJ, Robbins JB, Le Cam NN. Immunogenicity, efficacy and serological correlate of protection of Salmonella Typhi Vi capsular polysaccharide vaccine three years after immunization. Vaccine 1996; 14 : 435-8. |
|43.||Hessel L, Debois H, Fletcher M, Dumas R. Experience with Salmonella Typhi Vi capsular polysaccharide vaccine. Eur J Clin Microbiol Infect Dis 1999; 18 : 609-20. |
|44.||Yang HH, Wu CG, Xie GZ, Gu QW, Wang BR, Wang LY, et al. Efficacy trial of Vi polysaccharide vaccine against typhoid fever in south-western China. Bull World Health Organ 2001; 79 : 625-31. |
|45.||Saha MR, Ramamurthy T, Dutta P, Mitra U. Emergence of Salmonella Typhi Vi antigen-negative strains in an epidemic of multidrug-resistant typhoid fever cases in Calcutta, India. Natl Med J India 2000; 13 : 164. |
|46.||Mehta G, Arya SC. Capsular Vi polysaccharide antigen in Salmonella enterica serovar Typhi isolates. J Clin Microbiol 2002; 40 : 1127-8. |
|47.||Cook J, Jeuland M, Whittington D, Poulos C, Clemens J, Sur D, et al. The cost-effectiveness of typhoid Vi vaccination programs: calculations for four urban sites in four Asian countries. Vaccine 2008; 26 : 6305-16. |
|48.||Ivanoff B, Levine MM, Lambert PH. Vaccination against typhoid fever: present status. Bull World Health Organ 1994; 72 : 957-71. |
|49.||Levine MM, Ferreccio C, Abrego P, Martin OS, Ortiz E, Cryz S. Duration of efficacy of Ty21a, attenuated Salmonella Typhi live oral vaccine. Vaccine 1999; 17 (Suppl 2) : S22-7. |
|50.||Levine MM, Ferreccio C, Black RE, Lagos R, San Martin O, Blackwelder WC. Ty21a live oral typhoid vaccine and prevention of paratyphoid fever caused by Salmonella enterica serovar Paratyphi B. Clin Infect Dis 2007; 45 (Suppl 1) : S24-8. |
|51.||Stocker BA, Hoiseth SK, Smith BP. Aromatic-dependent "Salmonella sp." as live vaccine in mice and calves. Dev Biol Stand 1983; 53 : 47-54. |
|52.||Hoiseth SK, Stocker BA. Aromatic-dependent Salmonella Typhimurium are non-virulent and effective as live vaccines. Nature 1981; 291 : 238-9. |
|53.||Levine MM, Herrington D, Murphy JR, Morris JG, Losonsky G, Tall B, et al. Safety, infectivity, immunogenicity, and in vivo stability of two attenuated auxotrophic mutant strains of Salmonella Typhi, 541Ty and 543Ty, as live oral vaccines in humans. J Clin Invest 1987; 79 : 888-902. |
|54.||Hone DM, Harris AM, Chatfield S, Dougan G, Levine MM. Construction of genetically defined double aro mutants of Salmonella Typhi. Vaccine 1991; 9 : 810-6. |
|55.||Tacket CO, Sztein MB, Losonsky GA, Wasserman SS, Nataro JP, Edelman R, et al. Safety of live oral Salmonella Typhi vaccine strains with deletions in htrA and aroC aroD and immune response in humans. Infect Immun 1997; 65 : 452-6. |
|56.||Tacket CO, Hone DM, Curtiss R, 3rd, Kelly SM, Losonsky G, Guers L, et al. Comparison of the safety and immunogenicity of ÄaroC, ÄaroD and Ä cya Ä crp Salmonella Typhi strains in adult volunteers. Infect Immun 1992; 60 : 536-41. |
|57.||Hohmann EL, Oletta CA, Miller SI. Evaluation of a phoP/phoQ-deleted, aroA-deleted live oral Salmonella Typhi vaccine strain in human volunteers. Vaccine 1996; 14 : 19-24. |
|58.||Hohmann EL, Oletta CA, Killeen KP, Miller SI. phoP/phoQ-deleted Salmonella Typhi (Ty800) is a safe and immunogenic single-dose typhoid fever vaccine in volunteers. J Infect Dis 1996; 173 : 1408-14. |
|59.||Kirkpatrick BD, Tenney KM, Larsson CJ, O'Neill JP, Ventrone C, Bentley M, et al. The novel oral typhoid vaccine M01ZH09 is well tolerated and highly immunogenic in 2 vaccine presentations. J Infect Dis 2005; 192 : 360-6. |
|60.||Wang JY, Noriega FR, Galen JE, Barry E, Levine MM. Constitutive expression of the Vi polysaccharide capsular antigen in attenuated Salmonella enterica serovar Typhi oral vaccine strain CVD 909. Infect Immun 2000; 68 : 4647-52. |
|61.||Tacket CO, Levine MM. CVD 908, CVD 908-htrA, and CVD 909 live oral typhoid vaccines: a logical progression. Clin Infect Dis 2007; 45 (Suppl 1) : S20-3. |
|62.||Negi VD, Singhamahapatra S, Chakravortty D. Salmonella enterica serovar Typhimurium strain lacking pmrG-HM-D provides excellent protection against salmonellosis in murine typhoid model. Vaccine 2007; 25 : 5315-23. |
|63.||Lankowski AJ, Hohmann EL. Killed but metabolically active Salmonella Typhimurium: application of a new technology to an old vector. J Infect Dis 2007; 195 : 1203-11. |
|64.||Harada H, Nishikawa F, Higashi N, Kita E. Development of a mucosal complex vaccine against oral Salmonella infection in mice. Microbiol Immunol 2002; 46 : 891-905. |
|65.||Sinha A, Sazawal S, Kumar R, Sood S, Reddaiah VP, Singh B, et al. Typhoid fever in children aged less than 5 years. Lancet 1999; 354 : 734-7. |
|66.||Saha SK, Baqui AH, Hanif M, Darmstadt GL, Ruhulamin M, Nagatake T, et al. Typhoid fever in Bangladesh: implications for vaccination policy. Pediatr Infect Dis J 2001; 20 : 521-4. |
|67.||Lin FY, Vo AH, Phan VB, Nguyen TT, Bryla D, Tran CT, et al. The epidemiology of typhoid fever in the Dong Thap Province, Mekong Delta region of Vietnam. Am J Trop Med Hyg 2000; 62 : 644-8. |
|68.||Brooks WA, Hossain A, Goswami D, Nahar K, Alam K, Ahmed N, et al. Bacteremic typhoid fever in children in an urban slum, Bangladesh. Emerg Infect Dis 2005; 11 : 326-9. |
|69.||Micoli F, Rondini S, Pisoni I, Proietti D, Berti F, Costantino P, et al. Vi-CRM 197 as a new conjugate vaccine against Salmonella Typhi. Vaccine 2011; 29 : 712-20. |
|70.||Rollenhagen C, Sorensen M, Rizos K, Hurvitz R, Bumann D. Antigen selection based on expression levels during infection facilitates vaccine development for an intracellular pathogen. Proc Natl Acad Sci USA 2004; 101 : 8739-44. |
|71.||Tran TH, Nguyen TD, Nguyen TT, Ninh TT, Tran NB, Nguyen VM, et al. A randomised trial evaluating the safety and immunogenicity of the novel single oral dose typhoid vaccine M01ZH09 in healthy Vietnamese children. PLoS One 2010; 5 : e11778. |
|72.||Tacket CO, Sztein MB, Wasserman SS, Losonsky G, Kotloff KL, Wyant TL, et al. Phase 2 clinical trial of attenuated Salmonella enterica serovar typhi oral live vector vaccine CVD 908-htrA in U.S. volunteers. Infect Immun 2000; 68 : 1196-201. |
|73.||Lin FY, Ho VA, Khiem HB, Trach DD, Bay PV, Thanh TC, et al. The efficacy of a Salmonella Typhi Vi conjugate vaccine in two-to-five-year-old children. N Engl J Med 2001; 344 : 1263-9. |
|74.||Hone DM, Tacket CO, Harris AM, Kay B, Losonsky G, Levine MM. Evaluation in volunteers of a candidate live oral attenuated Salmonella Typhi vector vaccine. J Clin Invest 1992; 90 : 412-20. |
|75.||Azze RF, Rodriguez JC, Iniesta MG, Marchena XR, Alfonso VM, Padron FT. Immunogenicity of a new Salmonella Typhi Vi polysaccharide vaccine--vax-TyVi--in Cuban school children and teenagers. Vaccine 2003; 21 : 2758-60. |