Correspondence
A Cluster-Randomized Effectiveness Trial of Vi Typhoid Vaccine in India
N Engl J Med 2009; 361:2191-2193November 26, 2009
- Article
To the Editor:
In their article on a trial of Vi polysaccharide vaccine in Kolkata, India, Sur et al. (July 23 issue)1 report that typhoid fever was diagnosed in 34 subjects who received the Vi vaccine, as compared with 96 subjects in a control group that received a hepatitis A vaccine. Bacterial isolates from these 34 patients should be evaluated for a phenotypic expression of Vi antigen and the presence of genotypic components responsible for Vi antigen since Vi-negative strains might have been responsible for the vaccine failures.
Vi-negative strains cause a clinical picture resembling that caused by Vi-positive strains. The oral administration of 107 colony-forming units of Vi-positive or Vi-negative strains in volunteers caused disease in 25% of volunteers, and the disease pattern was indistinguishable among recipients of Vi-positive or Vi-negative strains.2 Such isolates were reported in Calcutta during a typhoid outbreak.3 Recently, in Faisalabad, Pakistan, among 42 blood samples that were analyzed with the use of multiplex polymerase-chain-reaction (PCR) assay, 26 were Vi-positive Salmonella enterica serotype Typhi (S. Typhi), 9 were Vi-negative S. Typhi, and 2 were S. Paratyphi A; 5 patients were found to have mixed infection.4 The circulation of Vi-negative strains would probably reduce the efficacy of Vi-based vaccines. The administration of a vaccine containing attenuated live S. enterica serotype Typhi (Ty21a) might protect recipients who are infected with Vi-negative S. Typhi.
4 ReferencesSubhash C. Arya, M.B., B.S., Ph.D.
Nirmala Agarwal, F.R.C.O.G.
Sant Parmanand Hospital, Delhi, India
subhashbhapaji@gmail.com 1
Sur D ,Ochiai RL ,Bhattacharya SK , et al. A cluster-randomized effectiveness trial of Vi typhoid vaccine in India. N Engl J Med 2009;361:335-344
Full Text | Web of Science | Medline2
Hornick RB ,Greisman SE ,Woodward TE ,DuPont HL ,Dawkins AT ,Snyder MJ . Typhoid fever: pathogenesis and immunologic control. N Engl J Med 1970;283:686-691
Full Text | Web of Science | Medline3
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;13:164-164
Web of Science | Medline4
Ali A ,Haque A ,Haque A , et al. Multiplex PCR for differential diagnosis of emerging typhoidal pathogens directly from blood samples. Epidemiol Infect 2009;137:102-107
CrossRef | Web of Science | Medline
To the Editor:
Sur et al. deliver the important message that Vi vaccine provided substantial indirect protection against typhoid fever among unvaccinated subjects in the community, with a level of protective effectiveness of 44%. The accompanying editorial by Levine1 suggests the implementation of mass vaccination to control this disease. However, since investigators isolated S. Typhi in 130 subjects and S. Paratyphi in 103 subjects, 44.2% of the cases of enteric fever were caused by paratyphoid infection. This is an increase from a rate of 24% reported in Kolkata in 2003 and 2004.2 Similarly, in a 5-year study that was conducted in Delhi from 1994 through 1998, there was an increase from 6.5% to 44.9% in the rate of S. Paratyphi isolates.3 This trend has been reported in several other Asian countries in recent years.2 Since Vi vaccine does not confer protection against paratyphoid fever, the increasing rate of S. Paratyphi infection is a concern. The implementation of a mass vaccination campaign with S. Typhi vaccine before a vaccine against paratyphoid is available would be premature and might prove to be a futile endeavor.
Eli Schwartz, M.D.
Sheba Medical Center at Tel Hashomer, Ramat Gan, Israel
elischwa@post.tau. ac. il Dr. Schwartz reports receiving lecture fees from Sanofi Pasteur. No other potential conflict of interest relevant to this letter was reported.
3 References1
Levine MM . Typhoid vaccines ready for implementation. N Engl J Med 2009;361:403-405
Full Text | Web of Science | Medline2
Ochiai RL ,Wang X ,von Seidlein L , et al. Salmonella paratyphi A rates, Asia. Emerg Infect Dis 2005;11:1764-1766
Web of Science | Medline3
Sood S ,Kapil A ,Dash N ,Das BK ,Goel V ,Seth P . Paratyphoid fever in India: an emerging problem. Emerg Infect Dis 1999;5:483-484
CrossRef | Web of Science | Medline
Author/Editor Response
In response to the comments made by Arya and Agarwal: among samples obtained from subjects in our trial, none of the typhoid isolates were Vi-negative, which suggests that such strains were not epidemiologically important in the area we were studying. It also indicates that the levels of protection observed for Vi vaccine refer to protection against strains expressing the Vi capsule.
With respect to Schwartz's comments: the key issue to be considered when deciding whether to deploy Vi vaccine is the absolute incidence of typhoid fever, rather than the proportion of enteric fever cases that are caused by S. Paratyphi. In this regard, it was noteworthy that among the control subjects, who received hepatitis A vaccine, there were 266 blood culture–confirmed cases of typhoid fever per 100,000 person-years, well above the incidence that is considered to demarcate populations at highest risk for typhoid.1 Since blood-culture diagnosis of typhoid is known to be insensitive, the true burden of typhoid in Kolkata may be twice this number. We therefore disagree with Schwartz's assertion that the call for mass vaccination with Vi vaccine is premature. Moreover, in his calculation of the proportion of enteric fever cases caused by S. Paratyphi in the Kolkata trial, Schwartz aggregated subjects in the group receiving Vi vaccine and the group receiving the hepatitis A vaccine. As expected, because Vi vaccine protected against typhoid fever, but not against paratyphoid fever, the proportion of enteric fever cases caused by S. Paratyphi in the Vi group was very high (61%) and did not reflect the proportion in the general unvaccinated population. The proportion for the group receiving hepatitis A vaccine (34%), which better reflects the proportion in the general unvaccinated population, was lower than that in the combined study groups. However, we agree with Schwartz that S. Paratyphi has emerged as an important cause of enteric fever in Asia and that Vi vaccine will not protect against disease caused by this pathogen. A combined typhoid–paratyphoid vaccine constitutes an important priority for the future, but we should not delay the introduction of effective vaccines against typhoid fever while awaiting the development of a combined vaccine.
1 ReferencesJohn Clemens, M.D.
International Vaccine Institute, Seoul, Korea
jclemens@ivi.int Dipika Sur, M.D.
National Institute of Cholera and Enteric Diseases, Kolkata, IndiaR. Leon Ochiai, M.Sc.
International Vaccine Institute, Seoul, Korea1
Crump JA ,Luby SP ,Mintz ED . The global burden of typhoid fever. Bull World Health Organ 2004;82:346-353
Web of Science | Medline
Author/Editor Response
Arya and Agarwal caution that Vi-negative strains of S. Typhi could be responsible for vaccine failures in recipients of Vi vaccine. The viaB locus contains genes responsible for the synthesis (tviA–E) and export to the bacterial surface (vexA–E) of Vi. Baker et al.1 showed that stable Vi-negative strains usually harbor deletions of tviA and tviB. They used PCR to detect Typhi genes in vivo in the blood of patients with typhoid fever; of 42 patients with S. Typhi, 4 had organisms with deletions of tviA and tviB.
Since Vi-negative strains are pathogenic, it is fair to ponder whether such strains will be selected under immune pressure. Immune pressure does not arise from typhoid endemicity, since most patients who have recovered from typhoid fever do not have increased levels of serum IgG Vi antibody.2,3 Nor did the large-scale use of Ty21a vaccine in Chile encourage the emergence of Vi-negative strains, since Ty21a does not express Vi or elicit anti-Vi. Only when Vi is implemented on a large scale in high-incidence areas will conditions exist for possible selection and emergence of Vi-negative S. Typhi. So far in the limited use of Vi vaccine, this finding has not been observed. Nevertheless, as Arya and Agarwal point out, large-scale use of Vi vaccine should be accompanied by microbiologic surveillance to monitor the emergence of Vi-negative strains.
Schwartz argues that because of the emergence of enteric fever caused by S. Paratyphi in Asia, it is premature to implement the use of licensed typhoid vaccines (parenteral Vi and oral Ty21a). S. Paratyphi enteric fever is indeed clinically indistinguishable from that caused by S. Typhi.4 However, this is no reason to delay the implementation of typhoid vaccines to control the S. Typhi proportion of enteric fever. It is public health practice to implement vaccines that protect against only a proportion of the pathogens that cause a clinical syndrome while awaiting vaccines against other pathogens. For example, the predominant causes of pediatric meningitis worldwide are Haemophilus influenzae type b (Hib), Streptococcus pneumoniae, and Neisseria meningitidis. However, health authorities did not delay implementing Hib conjugate vaccine while a pneumococcal conjugate vaccine was in development.
None of the S. Paratyphi vaccine candidates have entered clinical trials, and it will be years until they are available. In the meantime, much typhoid morbidity and mortality can be prevented if existing licensed typhoid vaccines are implemented programmatically, even where the burden of paratyphoid fever is also high.
4 ReferencesMyron M. Levine, M.D., D.T.P.H.
University of Maryland School of Medicine, Baltimore, MD1
Baker S ,Sarwar Y ,Aziz H , et al. Detection of Vi-negative Salmonella enterica serovar typhi in the peripheral blood of patients with typhoid fever in the Faisalabad region of Pakistan. J Clin Microbiol 2005;43:4418-4425
CrossRef | Web of Science | Medline2
Losonsky GA ,Ferreccio C ,Kotloff KL ,Kaintuck S ,Robbins JB ,Levine MM . Development and evaluation of an enzyme-linked immunosorbent assay for serum Vi antibodies for detection of chronic Salmonella typhi carriers. J Clin Microbiol 1987;25:2266-2269
Web of Science | Medline3
Lanata CF ,Levine MM ,Ristori C , et al. Vi serology in detection of chronic Salmonella typhi carriers in an endemic area. Lancet 1983;2:441-443
CrossRef | Web of Science | Medline4
Vollaard AM ,Ali S ,Widjaja S , et al. Identification of typhoid fever and paratyphoid fever cases at presentation in outpatient clinics in Jakarta, Indonesia. Trans R Soc Trop Med Hyg 2005;99:440-450
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
M Imran Khan, R Leon Ochiai, John D Clemens. (2010) Population impact of Vi capsular polysaccharide vaccine. Expert Review of Vaccines 9:5, 485-496
CrossRef
