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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.
Subhash C. Arya, M.B., B.S., Ph.D.
Nirmala Agarwal, F.R.C.O.G.
Sant Parmanand Hospital
Delhi, India
subhashbhapaji{at}gmail.com
References
Eli Schwartz, M.D.
Sheba Medical Center at Tel Hashomer
Ramat Gan, Israel
elischwa{at}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.
References
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.
John Clemens, M.D.
International Vaccine Institute
Seoul, Korea
jclemens{at}ivi.int
Dipika Sur, M.D.
National Institute of Cholera and Enteric Diseases
Kolkata, India
R. Leon Ochiai, M.Sc.
International Vaccine Institute
Seoul, Korea
References
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.
Myron M. Levine, M.D., D.T.P.H.
University of Maryland School of Medicine
Baltimore, MD
References
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