Usefulness of the Serial Measurement of Vi Antibodies

In a secondary analysis [1] of a published immunogenicity trial [2] comparing Vi capsular polysaccharide vaccine with a similar dose (25 μg) conjugated to tetanus toxoid, Voysey and Pollard have succeeded in not only establishing an argument that serial measurement of Vi antibodies are a marker of typhoid exposure but have also paved the way for future conjugate typhoid vaccines to be evaluated in endemic settings at a fraction of the recruitment required for traditional typhoid efficacy trials. The key to their observations came from extending the analysis of the data from the trial beyond the initial immunogenicity timepoint of 6 weeks postimmunization, to consider further time points 18 months and 2 years after the initial vaccines were administered. Antibody decay was analyzed using a Gaussian mixture model during 2 time periods (6 weeks to 18 months; and 18–24 months) that assumed quite reasonably that a single Vi immunization would lead to a decay of antibody in the first period and that anyone with higher levels of antibody at 18 months than at 6 weeks postimmunization, had had an additional exposure to Vi antigen. Further, subjects with an increase in Vi antibody, or indeed a sharp decay in Vi antibody between 18 months and 24 months had likewise been exposed to Vi antigen either in the intervening months (rise in antibody) or shortly before 18 months (rapid fall in antibody between 18 and 24 months). The authors’ posit that these Vi antigen exposures are symptomatic or asymptomatic episodes of typhoid infection. Is this reasonable? As they point out in their discussion, the Vi antigen has been found in gut commensals such as Citrobacter, so the proof of their contention may lie in studies that associate Vi antibodies specifically with Salmonella Typhi exposure in endemic areas. Chronic typhoid carriers have S. Typhi antibodies orders of magnitude greater than those reported post acute infection or postimmunization [3]; the change in antibody concentrations according to their definition, found by Voysey and Pollard to define typhoid infection in this study, across 8 trial sites in India occurred in a remarkable 21% of subjects, for whom serology was available, over 2 years. Could so many subjects have been exposed to typhoid infection in a 2-year period? If so, then the vast majority of typhoid infections are asymptomatic as typhoid clinical attack rates, measured by hospitalization, rarely exceed 1% of subjects at risk per year, even in highly endemic areas. Few long-term follow-up studies of Vi antibodies have been reported, but in the 10-year follow-up4 of schoolchildren who were enrolled in a Vi polysaccharide trial in a highly endemic area of South Africa at that time, 58% of children in the control group had acquired measurable levels of Vi antibody over the 10-year period, in keeping with the considerable exposure to the pathogen seen over 2 years in the current study in India. A further line of evidence that these changes in Vi antibody represent true infection is that the incremental 63% efficacy of the Vi conjugate compared to Vi polysaccharide identified in this study translates to 85% protection against typhoid fever using an estimate of Vi polysaccharide baseline protection of 59% [5]. This estimate of efficacy is consistent with the only efficacy study to date comparing a Vi conjugate to placebo in Vietnam (91% efficacy against blood culture proven typhoid fever [6]), which strengthens the argument that this efficacy estimate effect is protection against true S. Typhi exposures. There are more things to consider about typhoid fever that arise from this study than just Vi conjugate vaccine efficacy and the frequency of subclinical typhoid exposure in endemic areas. The asymptotic line in Figure 21 suggests that even considerable levels of Vi antibody will still not completely protect against subsequent typhoid infection. These subjects may or may not be clinically ill, but the degree to which one or more typhoid exposures defined by alterations in their Vi antibodies over time, leads to protection from infection in future time periods, could be calculated in future descriptive sero-epidemiological E D I T O R I A L C O M M E N T A R Y