Vi Typhoid Vaccine Provides Both Protection in Young Children and Herd Immunity
Abstract & Commentary
By Brian Blackburn, MD, Clinical Assistant Professor of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Source: Sur D, et al. A Cluster-randomized effectiveness trial of Vi typhoid vaccine in India. N Engl J Med. 2009;361:335-344.
Synopsis: The protective effectiveness of the Vi typhoid vaccine was 61% during a two-year follow-up period in Kolkata, India. Importantly, for children between two and five years of age, the protective effectiveness was 80%, and the level of protection among unvaccinated members of clusters, which were assigned to receive the vaccine, was 44%. These findings suggest that a larger role for the Vi vaccine should be considered in public health programs of developing countries.
Typhoid fever sickens more than 16 million people worldwide and causes up to 600,000 deaths annually, mostly in developing countries.1 Caused by Salmonella enterica serotype Typhi, the disease is acquired via the ingestion of contaminated food or water. Two vaccines are currently available and in widespread use for prevention of this disease. The Ty21a vaccine is a live attenuated strain of S. typhi; this is taken orally over several days and requires refrigeration. The Vi vaccine is a capsular polysaccharide derived from S. typhi, which is given intramuscularly as a single dose. Both have been shown to offer 50%-80% protective efficacy in various trials, although some advantages exist for the Ty21a vaccine, including a longer revaccination interval and some protection against paratyphoid fever.2,3
However, these advantages are outweighed in some settings by the logistical difficulties inherent to the Ty21a vaccine. The multiple-dose regimen and refrigeration requirement limit the usefulness of this vaccine in many developing countries. Additionally, it is not recommended for young children or the immunocompromised, and cannot be given to persons taking antimicrobials. Therefore, the Vi vaccine has wider appeal in the developing world, where most cases of typhoid fever occur.
Aside from the relatively low level of protection offered by both typhoid vaccines to the general population, other questions regarding the efficacy of the Vi vaccine have included whether the immune response in young children is robust and whether herd immunity can result from mass vaccination campaigns (both inherent limitations of polysaccharide vaccines). Sur et al, therefore, undertook a clinical trial to evaluate the effectiveness of the Vi vaccine in Kolkata, India, a highly endemic locale for typhoid fever.
After performing a census, 80 geographically contiguous clusters were defined from two wards (population about 60,000) in the slums of eastern Kolkata, India; each cluster contained a mean population of just under 800 people. Clusters were then randomized to receive either Vi typhoid vaccine or, in the control clusters, hepatitis A vaccine. Within each cluster, all persons two years of age or older were offered the vaccine appropriate for his/her study group, except for those who had an active febrile illness, were pregnant, or were lactating. Overall, 37,673 participants were vaccinated; the vaccine coverage was 61% in the Vi vaccine clusters and 60% in the hepatitis A vaccine clusters. No deaths or severe complications from typhoid were identified in either group.
Persons in the Vi vaccine clusters were significantly less likely to acquire typhoid fever (34 cases) over the two-year follow-up interval than persons in the hepatitis A vaccine clusters (96 cases), with a protective effectiveness of 61% (95% CI 41-75), p < 0.001. Protective effectiveness among children aged 2-5 years was 80% (95% CI 53-91). Among unvaccinated members of clusters that were assigned to receive the Vi vaccine, the protective effectiveness was 44% (95% CI 2-69, p =0.04), compared to unvaccinated persons in the clusters assigned to receive the hepatitis A vaccine. The overall level of protection for a person in the clusters assigned to the Vi vaccine was 57% (95% CI 37-71), whether they had been vaccinated or not. Rates of paratyphoid fever in both study groups were nearly identical, and adverse events in the two groups did not significantly differ and were minimal.
Commentary
Sur et al demonstrated a significant protective effect of the Vi typhoid vaccine in an area highly endemic for typhoid in this well-designed trial. The protective effectiveness of 61% is in the range of multiple previous studies examining typhoid vaccines;1-4 such data demonstrate that while imperfect, this vaccine offers the potential to significantly decrease the burden of typhoid fever in a developing setting like Kolkata if used widely.
On its own, this is not new or groundbreaking information. However, a weakness of polysaccharide vaccines is that they are generally poor at evoking immune responses in the very young, and are poor at inducing herd immunity. It has, thus, been unclear whether the Vi vaccine would be effective in these roles, which usually are better served by conjugate vaccines. Although a Vi conjugate typhoid vaccine has looked promising in clinical trials, it is not yet widely available.5 Therefore, an important finding of this study is that children 2-5 years old enjoyed a high level of protective effectiveness. Furthermore, the trial demonstrated that use of this vaccine on a large scale can result in herd immunity. Although the absolute level of protection for the entire population was only about 60%, even unvaccinated persons enjoyed significant protection if they were in a Vi vaccine cluster, most likely because their vaccinated neighbors were less likely to contract typhoid and subsequently transmit it to them. If anything, this trial probably underestimated this herd-immunity effect, because it is likely that persons freely moved between clusters (given their close geographic proximity). Therefore, persons from the control group could have acquired typhoid in their unvaccinated cluster and then imported it into a Vi vaccine cluster, blunting the measured protective effect in the Vi clusters.
These findings have important programmatic implications. Despite WHO recommendations, typhoid vaccines are not widely used in the developing world.6 This study demonstrates that in a highly endemic setting in which Sur et al achieved about 60% vaccine coverage, all persons in Vi vaccine clusters were afforded almost 60% protective effectiveness, regardless of whether they were vaccinated. Used on a large scale, this means typhoid vaccination programs could drastically decrease the number of cases of typhoid in the developing world. Furthermore, this study indicates that such programs should include all persons aged two years and above, given that there is clearly benefit among 2-5-year-olds (a group at high risk for acquiring typhoid in many settings). Typhoid vaccines are becoming even more important in this era of multidrug-resistant (MDR) S. typhi, which are becoming increasingly difficult to treat. In settings where the prevalence of these MDR strains of S. typhi is high (such as India), prevention of S. typhi through vaccination and other means is of paramount importance. In conjunction with the data from the current study, these points would seem to indicate that the time for large-scale typhoid vaccination programs in the developing world has come.
References
- Parry CM, et al. Typhoid fever. N Engl J Med. 2002;347:1770-1782.
- Fraser A, et al. Typhoid fever vaccines: Systematic review and meta-analysis of randomised controlled trials. Vaccine. 2007;25:7848-7857.
- Guzman CA., et al. Vaccines against typhoid fever. Vaccine. 2006;24:3804-3811.
- Bhan MK, et al. Typhoid and paratyphoid fever. Lancet. 2005;366:749-762.
- Lin FYC, et al. The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five-year-old children. N Engl J Med. 2001;344:1263-1269.
- World Health Organization. WHO position paper: Typhoid vaccines. Weekly Epidemiological Record 2000;75:257-64. September 13, 2009.
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