Conjugate Typhoid Vaccine Arrives!

Abstracts & Commentary

Synopsis: Each year, there are at least 16 million cases of typhoid fever worldwide, resulting in approximately 600,000 deaths. The majority of cases occur in southeast Asia, where resistance to multiple antibiotics is increasingly prevalent. A new typhoid vaccine appears ready to break the hold that typhoid fever has on children both living within and traveling to the developing world.

Sources: Guerrant RL, Kosek M. Polysaccharide conjugate typhoid vaccine. N Engl J Med. 2001;344:1322-1323. Editorial; 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.

TMA Update has recently reviewed the issue of increasing resistance of Salmonella typhi to multiple antibiotics. We now address recently published data from the New England Journal of Medicine to show evidence of a promising, well-tolerated typhoid vaccine1 that may not only help travelers but may potentially assist in the control of both endemic and epidemic disease due to S typhi.

Currently existing typhoid vaccines include a parenteral inactivated whole-cell vaccine, an oral-attenuated S typhi Ty21A vaccine and a Vi polysaccharide vaccine. At best, each may confer about 70% protection against typhoid fever in older children and adults, but these vaccines do not protect young children to the same extent. There are other limitations to current typhoid vaccines. Frequent local and systemic side effects occur upon administration of the heat- and phenol-inactivated vaccine, and it has recently been discontinued from the US market. The oral vaccine has been essentially unavailable recently; its multiple dosing regimen and refrigeration requirement makes it cumbersome to administer.

Conjugate vaccines have been developed for other organisms, such as Hemophilus influenzae and Neisseria meningitidis, to produce T-cell priming glycoconjugates that induce far better immune responses than do unconjugated polysaccharide vaccines, even in young children. The new conjugated typhoid vaccine achieves enhanced immunogenicity by binding Vi, the virulence factor and capsular polysaccharide of S typhi, to a nontoxic recombinant protein that is antigenically identical to Pseudomonas aeruginosa exotoxin-A (r-EPA). In initial trials, Vi-rEPA elicited a booster response in 2- to 4-year-old children producing antibody titers approximately 3 times higher than those elicited by Vi polysaccharide vaccine in 5- to 14-year-olds.

A double-blind, randomized, placebo-controlled vaccine trial was conducted in Vietnamese children from ages 2 to 5. In this 1998 study, 11,091 children received either the vaccine or placebo. The participating children were given 2 vaccine doses 6 weeks apart and were observed at 20 minutes, 6, 24, and 48 hours after inoculation for fever and inflammatory changes at the injection site. Children whose axillary temperatures exceeded 37.5°C were excluded. Subsequently, all received weekly visits. Axillary temperatures were measured, and, if elevated, evidence for typhoid fever was sought with blood cultures. Paired sera were obtained prior to the first, and 4 weeks after the second vaccination. No serious adverse experiences were identified in either group.

Following the first inoculation, 81 of 5525 children in the vaccine group had axillary temperatures measuring higher than 37.5°C, with 17 of these having a temperature higher than 39°C. This compares to 32 out of 5566 in the placebo group who had temperature readings higher than 37.5°C, 5 of whom had temperatures higher than 39°C. After the second injection, 109 vaccine recipients had temperatures higher than 37.5°C vs. 25 placebo recipients. Swelling at the injection site, greater than 5 cm in circumference, occurred in 20 vaccinated individuals vs. 1 in the placebo group. Erythema, greater than 5 cm, without swelling occurred in 2 vaccinated children vs. none in the placebo group. All changes occurring at the injection site resolved within 48 hours.

The efficacy of the vaccine was found to be greater than that of any existing typhoid vaccine. Four cases of typhoid fever were diagnosed by blood culture in vaccine recipients, compared with 47 cases diagnosed in those who were given placebo (possibly 48, if counting 1 subject who received a placebo injection that was deemed not properly labeled). Counting all improperly labeled recipients, there were 5 typhoid cases diagnosed in the vaccine group compared with 56 diagnosed cases in the placebo group. Twenty-one of these 61 typhoid fever patients were hospitalized; all were from the placebo group.

Antibody titers (serum IgGViAb) increased by a factor of more than 575 when measured 4 weeks after the second injection. Persistence of antibodies was documented 2 years after the 2-dose series. Titers remained approximately 19 times higher in those who were vaccinated compared with those children who received placebo injections.

Comment by Maria D. Mileno, MD

Typhoid fever is all too common and increasingly difficult to treat in developing countries with emergence of S typhi resistance to multiple antibiotics. Lin and colleagues describe a safe and highly immunogenic conjugate typhoid vaccine that provides outstanding protection to children who are between 2 and 5 years old. This vaccine should prove to be at least as protective, if not more so, in older individuals. Travelers, missionaries, and volunteers working abroad face enormous challenges finding safe food and drinking water, especially while venturing into rural areas of the developing world. A sufficient number of reports indicate that even travelers who are vaccinated with the currently available typhoid vaccines risk contracting typhoid fever. Now that the whole-cell preparation of typhoid vaccine is off the market, individuals younger than 2 years old have no alternative vaccine protection. The high antibody titers induced by the conjugate vaccine are promising in potentially conferring some protection on this age group, although further investigation is needed to show this. There is no doubt in my mind that this new vaccine will have a strong role in the protection of travelers against typhoid fever. The greatest promise it holds is for the control of typhoid fever among the youngest of those living in impoverished areas of the developing world.

Reference

1. Typhoid vaccines. Wkly Epidemiol Rec. 2000;75: 257-264.