Overview of the impact of Typhoid and Paratyphoid fever. Utility of Ty21a vaccine (Vivotif®).


Typhoid Fever
enteric fever
ty21a vaccine
S. typhi
S. paratyphi.


Cases of diarrhoeal disease number from 1.7 to 5 billion per year worldwide. One of the main causes of diarrhoeal disease is typhoid fever, which is a potentially life-threatening multi-systemic illness. According to the most recent estimates, a total of 26.9 million typhoid fever episodes occurred in 2010. The geographical distribution of the disease differs widely; in developed countries, the incidence rate per 100,000 per year varies from <0.1 to 0.3, and the disease mainly affects people who travel to endemic areas located in low- and middle-income countries. Low- and middle-income countries are mainly affected owing to the lack of clean water and proper sanitation. In the fight against this plague, prevention is fundamental, and vaccination against typhoid is an effective measure.

Vivotif® is an oral live attenuated vaccine which contains a mutated strain of Salmonella (Ty21a) and reproduces the natural infection. The vaccine was first licensed in Europe in 1983 and in the US in 1989, and over the years it has proved efficacious and safe. It is indicated for adults and children from 5 years of age upwards. Specifically, in the most developed countries, vaccination is suggested for high-risk population groups and particularly for international travellers to destinations where the risk of contracting typhoid fever is high. It must also be borne in mind that international travel is increasing. Indeed, international tourist arrivals totalled 1,184 million in 2015 and, on the basis of current trends, international travel is expected to grow by 3% - 4% in 2017.

Vivotif® appears to be a powerful means of disease prevention, the importance of which is highlighted by the spread of antibiotic-resistant strains of S. Typhi.



CDC. Newton Ae, Routh JA, Mahon BE. Infectious Diseases Related Travel. Chapter 3. Typhoid & Paratyphoid fever. Available at https://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/typhoid-paratyphoid-fever [Accessed on 20 January 2017]

Popoff MY, Bockemühl J, Gheesling LL.Supplement 2002 (no. 46) to the Kauffmann-White scheme. Res Microbiol. 2004;155(7):568-70.

World Health Organization (WHO). Diarrhoeal disease. Available at: http://www.who.int/mediacentre/factsheets/fs330/en/

GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385(9963):117-71. doi: 10.1016/S0140-6736(14)61682-2. [Accessed on 20 January 2017]

World Health Organization (WHO). Sanitation. Available at http://www.who.int/mediacentre/factsheets/fs392/en/ [Accessed on 20 January 2017]

Prüss-Ustün A(1), Bartram J, Clasen T, Colford JM Jr, Cumming O, Curtis V, Bonjour S, Dangour AD, De France J, Fewtrell L, Freeman MC, Gordon B, Hunter PR, Johnston RB, Mathers C, Mäusezahl D, Medlicott K, Neira M, Stocks M, Wolf J, Cairncross S.Burden of disease from inadequate water, sanitation and hygiene in low- and middle-income settings: a retrospective analysis of data from 145 countries. Trop Med Int Health. 2014;19(8):894-905. doi: 10.1111/tmi.12329.

World Health Organization (WHO). WHO estimates of the global burden of foodborne diseases. Available at: http://apps.who.int/iris/bitstream/10665/199350/1/9789241565165_eng.pdf?ua=1 [Accessed on 23 December 2016]

Franco-Paredes C, Khan MI, Gonzalez-Diaz E, Santos-Preciado JI, Rodriguez-Morales AJ, Gotuzzo E.Enteric Fever: A Slow Response to an Old Plague. PLoS Negl Trop Dis. 2016;10(5):e0004597. doi: 10.1371/journal.pntd.0004597.

World Health Organization (WHO). Guidelines on the quality, safety and efficacy of typhoid conjugate vaccines. Available at: http://www.who.int/biologicals/areas/vaccines/TYPHOID_BS2215_doc_v1.14_WEB_VERSION.pdf?ua=1&ua=1 [Accessed on 23 December 2016]

Steele AD, Hay Burgess DC, Diaz Z, Carey ME, Zaidi AK. Challenges and Opportunities for Typhoid Fever Control: A Call for Coordinated Action. Clin Infect Dis. 2016;62 Suppl 1:S4-8. doi: 10.1093/cid/civ976.

Buckle GC, Walker CL, Black RE. Typhoid fever and paratyphoid fever: Systematic review to estimate global morbidity and mortality for 2010. J Glob Health. 2012;2(1):010401. doi: 10.7189/jogh.02.010401.

Kirk MD, Pires SM, Black RE, Caipo M, Crump JA, Devleesschauwer B, Döpfer D, Fazil A, Fischer-Walker CL, Hald T, Hall AJ, Keddy KH, Lake RJ, Lanata CF, Torgerson PR, Havelaar AH, Angulo FJ.World Health Organization Estimates of the Global and Regional Disease Burden of 22 Foodborne Bacterial, Protozoal, and Viral Diseases, 2010: A Data Synthesis. PLoS Med. 2015 Dec 3;12(12):e1001921. doi: 10.1371/journal.pmed.1001921. eCollection 2015.

Crump JA, Mintz ED. Global trends in typhoid and paratyphoid fever. Clin Infect Dis. 2010; 50(2): 241–246. doi: 10.1086/649541

Crump JA, Sjölund-Karlsson M, Gordon MA, Parry CM. Epidemiology, Clinical Presentation, Laboratory Diagnosis, Antimicrobial Resistance, and Antimicrobial Management of Invasive Salmonella Infections. Clin Microbiol Rev. 2015;28(4):901-37. doi: 10.1128/CMR.00002-15.

Wain J, Hendriksen RS, Mikoleit ML, Keddy KH, Ochiai RL. Typhoid fever. Lancet. 2015; 385(9973):1136-45. doi: 10.1016/S0140-6736(13)62708-7.

Bhan MK, Bahl R, Bhatnagar S. Typhoid and paratyphoid fever. Lancet. 2005;366(9487):749-62.

Maskey AP, Day JN, Tuan PQ, 2 Thwaites GE, Campbell JI, Zimmerman M, Farrar J, Basnyat B. Salmonella enterica Serovar Paratyphi A and S. enterica Serovar Typhi Cause Indistinguishable Clinical Syndromes in Kathmandu, Nepal. Clinical Infectious Diseases 2006; 42:1247–53.

Anwar E, Goldberg E, Fraser A, Acosta CJ, Paul M, Leibovici L. Vaccines for preventing typhoid fever. Cochrane Database Syst Rev. 2014 Jan 2;(1):CD001261. doi: 10.1002/14651858.CD001261.pub3.

CDC. Health information for international travel. The yellow book 2016. Oxford University Press. Available at: https://wwwnc.cdc.gov/travel/page/yellowbook-home-2014/ Accessed on 20 January 2017

World Health Organization. The diagnosis, treatment and prevention of typhoid fever. WHO/V&B/03.17. Geneva, Switzerland: WHO, 2003

World Health Organization. Typhoid. Available at: http://www.who.int/immunization/diseases/typhoid/en/ Accessed on 20 January 2017

Szu SC. Development of Vi conjugate - a new generation of typhoid vaccine. Expert Rev Vaccines. 2013;12(11):1273-86. doi: 10.1586/14760584.2013.845529.

Lopalco PL, Prato R, Germinario C. Typhoid fever: from parenteral to oral vaccines. Ann Ig. 2002;14(3 Suppl 3):27-32.

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.

Ivanoff B, Levine MM, Lambert PH. Vaccination against typhoid fever: present status. Bull World Health Organ. 1994;72:957–71.

Germanier R, Furer E. Immunity in experimental salmonellosis. II. Basis for the avirulence and protective capacity of galE mutants of Salmonella Typhimurium. Infect Immun 4:663-673, 1971.

Vivotif. Available at: https://www.medicines.org.uk/emc/history/30294 Acessed on 10 January 2017

Faucher JF, Binder R, Missinou MA, Matsiegui PB, Gruss H, Neubauer R, Lell B, Que JU, Miller GB, Kremsner PG. Efficacy of atovaquone/proguanil for malaria prophylaxis in children and its effect on the immunogenicity of live oral typhoid and cholera vaccines. Clin Infect Dis 2002; 35: 1147–54].

Nisini R, Biselli R, Matricardi PM, Fattorossi A, D'Amelio R. Clinical and immunological response to typhoid vaccination with parenteral or oral vaccines in two groups of 30 recruits. Vaccine. 1993;11(5):582-6.

Cryz SJ Jr, Vanprapar N, Thisyakorn U, Olanratmanee T, Losonsky G, Levine MM, Chearskul S. Safety and immunogenicity of Salmonella typhi Ty21a vaccine in young Thai children. Infection and Immunity 1993;61(3):1149–51

Gilman RH, Hornick RB, Woodard WE, DuPont HL, Snyder MJ, Levine MM, Libonati JP. Evaluation of a UDP-glucose-4-epimeraseless mutant of Salmonella typhi as a liver oral vaccine. J Infect Dis. 1977;136(6):717-23

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.

Viret JF, Favre D, Wegmüller B, Herzog C, Que JU, Cryz SJ Jr, Lang AB. Mucosal and systemic immune responses in humans after primary and booster immunizations with orally administered invasive and noninvasive live attenuated bacteria. Infect Immun. 1999;67(7):3680-5.

Pakkanen SH, Kantele JM, Kantele A. Cross-reactive gut-directed immune response against Salmonella enterica serovar Paratyphi A and B in typhoid fever and after oral Ty21a typhoid vaccination. Vaccine. 2012;30(42):6047-53.

Wahid R, Simon R, Zafar SJ, Levine MM, Sztein MB. Live oral typhoid vaccine Ty21a induces cross-reactive humoral immune responses against Salmonella enterica serovar Paratyphi A and S. Paratyphi B in humans. Clin. Vaccine Immunol. 2012, 19:825–834.

Wahdan MH, Serie C, Germanier R, Lackany A, Cerisier Y, Guerin N, Sallam S, Geoffroy P, el Tantawi AS, Guesry P. A controlled field trial of live oral typhoid vaccine Ty21a. Bulletin of the World Health Organization. 1980; 58:469–474.

Wahdan MH, Sérié C, Cerisier Y, Sallam S, Germanier R.. A controlled field trial of live Salmonella typhi strain Ty21a oral vaccine against typhoid: three year results. The Journal of Infectious Diseases. 1982; 145:292–296.

Levine MM, Ferreccio C, Black RE, Germanier R.Large-scale field trial of Ty21a live oral typhoid vaccine in enteric-coated capsule formulation.Lancet. 1987;1(8541):1049-52.

Levine MM, Ferreccio C, Cryz S, Ortiz E. Comparison of enteric-coated capsules and liquid formulation of Ty21a typhoid vaccine in randomised controlled field trial.Lancet. 1990;336(8720):891-4.

Simanjuntak CH, Paleologo FP, Punjabi NH, Darmowigoto R, Soeprawoto, Totosudirjo H, Haryanto P, Suprijanto E, Witham ND, Hoffman SL. Oral immunisation against typhoid fever in Indonesia with Ty21a vaccine. Lancet. 1991;338(8774):1055-9.

Fraser A, Paul M, Goldberg E, Acosta CJ, Leibovici L. Typhoid fever vaccines: systematic review and meta-analysis of randomised controlled trials. Vaccine. 2007;25(45):7848-57.

Ferreccio C, Levine MM, Rodriguez H, Contreras R. Comparative efficacy of two, three, or four doses of TY21a live oral typhoid vaccine in enteric-coated capsules: a field trial in an endemic area. J Infect Dis. 1989;159(4):766-9.

Levine MM, Black RE, Ferreccio C, et al. (1986). The efficacy of attenuated Salmonella typhi oral vaccine strain Ty 21a evaluated in controlled field trials. In Holmgren J, Lindberg A, Molly K. (eds.) Development of vaccines and drugs against diarrhea. Lund, Sweden, Studentlitteratur, 1986: 90–101.

Black RE, Levine MM, Young C, ooney J, Levine S, Clements ML, O'Donnell S, Hugues T, Germanier R. Immunogenicity of Ty21a attenuated Salmonella typhi given with bicarbonate or in enteric-coated capsules. Developments in Biological Standardization. 1983; 53: 9–14.

Simanjuntak CH, Paleologo FP, Punjabi NH, Darmowigoto R, Soeprawoto, Totosudirjo H, Haryanto P, Suprijanto E, Witham ND, Hoffman SL.Oral immunisation against typhoid fever in Indonesia with Ty21a vaccine.Lancet. 1991;338(8774):1055-9.

Black RE, Levine MM, Ferreccio C, Clements ML, Lanata C, Rooney J, Germanier R. Efficacy of one or two doses of Ty21a Salmonella typhi vaccine in enteric-coated capsules in a controlled field trial. Chilean Typhoid Committee.Vaccine. 1990;8(1):81-4.

Griot-Wenk ME, Hartmann K, Herzog C, Ackermann J, Maspes B. Excellent long-term safety data established in a recent post-marketing surveillance for the oral typhoid fever vaccine, VIVOTIF®. Ital J Trop Med 2001;6:104–5.

Begier EM, Burwen DR, Haber P, Ball R; Vaccine Adverse Event Reporting System Working Group. Postmarketing safety surveillance for typhoid fever vaccines from the Vaccine Adverse Event Reporting System, July 1990 through June 2002.Clin Infect Dis. 2004;38(6):771-9.

Guzman CA, Borsutzky S, Griot-Wenk M, Metcalfe IC, Pearman J, Collioud A, Favre D, Dietrich G.Vaccines against typhoid fever.Vaccine. 2006;24(18):3804-11.

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.

Tagliabue A, Villa L, De Magistris MT, Romano M, Silvestri S, Boraschi D, Nencioni L.IgA-driven T cell-mediated anti-bacterial immunity in man after live oral Ty 21a vaccine.J Immunol. 1986;137(5):1504-10.

Wahid R, Fresnay S, Levine MM, Sztein MB. Immunization with Ty21a live oral typhoid vaccine elicits crossreactive multifunctional CD8+ T-cell responses against Salmonella enterica serovar Typhi, S.Paratyphi A, and S.Paratyphi B in humans. Nature. 2015, 8: 1349-1359.

Wahid R, Zafar SJ, McArthur MA, Pasetti MF, Levine MM, Sztein MB. Live oral Salmonella enterica serovar Typhi vaccines Ty21a and CVD 909 induce opsonophagocytic functional antibodies in humans that cross-react with S. Paratyphi A and S. Paratyphi B. Clin Vaccine Immunol. 2014;21(3):427-3).

Wahid R, Fresnay S, Levine MM, Sztein MB. Cross-reactive multifunctional CD4+ T cell responses against Salmonella enterica serovars Typhi, Paratyphi A and Paratyphi B in humans following immunization with live oral typhoid vaccine Ty21a. Clin Immunol. 2016;173:87-95. doi: 10.1016/j.clim.2016.09.006.

Holt KE, Thomson NR, Wain J, Langridge GC, Hasan R, Bhutta ZA, Quail MA, Norbertczak H, Walker D, Simmonds M, White B, Bason N, Mungall K, Dougan G, Parkhill J. 2009. Pseudogene accumulation in the evolutionary histories of Salmonella enterica serovars Paratyphi A and Typhi. BMC Genomics. 2009;10:36. doi: 10.1186/1471-2164-10-36.

McClelland M, Sanderson KE, Clifton SW, Latreille P, Porwollik S, Sabo A, Meyer R, Bieri T, Ozersky P, McLellan M, Harkins CR, Wang C, Nguyen C, Berghoff A, Elliott G, Kohlberg S, Strong C, Du F, Carter J, Kremizki C, Layman D, Leonard S, Sun H, Fulton L, Nash W, Miner T, Minx P, Delehaunty K, Fronick C, Magrini V, Nhan M, Warren W, Florea L, Spieth J, Wilson RK. 2004. Comparison of genome degradation in Paratyphi A and Typhi, human-restricted serovars of Salmonella enterica that cause typhoid. Nat. Genet. 36:1268–1274.

Parkhill J, Dougan G, James KD, Thomson NR, Pickard D, Wain J, Churcher C, Mungall KL, Bentley SD, Holden MT, Sebaihia M, Baker S, Basham D, Brooks K, Chillingworth T, Connerton P, Cronin A, Davis P, Davies RM, Dowd L, White N, Farrar J, Feltwell T, Hamlin N, Haque A, Hien TT, Holroyd S, Jagels K, Krogh A, Larsen TS, Leather S, Moule S, O'Gaora P, Parry C, Quail M, Rutherford K,

Simmonds M, Skelton J, Stevens K, Whitehead S, Barrell BG.Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18.Nature. 2001;413(6858):848-52.

Baltazar M, Ngandjio A, Holt KE, Lepillet E, Pardos de la Gandara M, Collard JM, Bercion R, Nzouankeu A, Le Hello S, Dougan G, Fonkoua MC, Weill FX. Multidrug-resistant Salmonella enterica serotype Typhi, Gulf of Guinea Region, Africa. Emerg Infect Dis. 2015;21(4):655-9.

Roumagnac P, Weill FX, Dolecek C, Baker S, Brisse S, Chinh NT, Evolutionary history of Salmonella Typhi. Science. 2006;314:1301–4.

WHO. Typhoid vaccines: WHO position paper. Wkly Epidemiol Rec. 2008;83(6):49-59.

Watson CH, Edmunds WJ. A review of typhoid fever transmission dynamic models and economic evaluations of vaccination. Vaccine. 2015 Jun 19;33 Suppl 3:C42-54. doi: 10.1016/j.vaccine.2015.04.013.

World Tourism Organization Tourism Market Trends UNWTO. UNWTO World Tourism Barometer Available at: http://mkt.unwto.org/barometer Accessed on 20 January 2017.