Comparison of anti-Vi IgG responses between two clinical studies of typhoid Vi conjugate vaccines (Vi-DT vs Vi-TT)

Abstract

Salmonella enterica serovar Typhi (S. Typhi) is a causative agent for typhoid fever and especially critical in developing countries. Although clinical studies for various typhoid conjugate vaccines (TCVs) have been performed, there are no comparative data on the immune responses of vaccines due to lack of harmonization of the serological assay. Recently, Typbar-TCV (Vi-TT) was prequalified by WHO and recommended for vaccination in endemic areas. Forty-eight serum samples were selected from a recent Vi-DT phase 1 study based on age cohort and anti-Vi IgG levels using an in-house ELISA. Anti-Vi IgG titers of 48 sera were also determined by Vacczyme ELISA, used in a Vi-TT phase 3 trial. A good correlation between the two assays was observed when the anti-Vi IgG titer was determined using Vacczyme ELISA based on the Vi-IgG_R1,2011, U.S. reference reagent (Pearson correlation coefficient (r) = 0.991, P < 0.001) or Vacczyme ELISA calibrator (r = 0.991, P < 0.001). Based on the correlation, multiple linear regression model was developed to convert data of 281 sera (prior to vaccination and 28 days post first-dose) in the Vi-DT phase 1 study from in-house ELISA titers to Vacczyme ELISA values and then, compared with the Vi-TT results. Similar estimates of anti-Vi IgG GMT were observed after vaccination with the Vi-DT and Vi-TT vaccines [1626 EU/ml (95% CI: 1292–2047) vs 1293 EU/ml (95% CI: 1153–1449), respectively]. The method used here can be implemented to estimate and compare anti-Vi IgG levels between different clinical studies of TCVs. This approach enables comparison of the antibody responses among TCVs under development and may help facilitate licensing of new TCVs. Typhoid fever is an infectious and life-threatening disease in developing countries. Before 2017, Ty21a and Vi polysaccharide vaccines were licensed but these are not recommended in young children under 2-year-old. Vaccine manufacturers are developing typhoid Vi conjugate vaccines (TCVs) to improve immunogenicity. Typbar-TCV (Vi-TT) demonstrated its safety and immunogenicity in infants and recently, prequalified by WHO. Serum Vi-specific IgG antibody has been used to measure the immunogenicity of TCV in many clinical trials. However, due to lack of harmonized assay, comparison of the immunogenicity among various TCVs is not possible in the absence of head-to-head clinical trials. Recently, we evaluated immunogenicity of Vi-DT using an in-house ELISA in the clinical study. In this study, 48 sera were selected from Vi-DT phase 1 study and measured anti-Vi IgG using commercial Vacczyme ELISA kit, used in the phase 3 study of Vi-TT, to compare the immunogenicity between two vaccines. Based on the correlation between two assays, anti-Vi IgG of all participants in the Vi-DT study was converted to Vacczyme antibody value using statistical model and compared with results of Vi-TT phase 3 study. The antibody levels induced by two studies were similar in pre- and post-vaccinated sera. This approach enables to compare the antibody responses among TCVs under development and would facilitate licensing of new TCVs.