Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model

Abstract

Effective vaccines against Salmonella Typhi, a major cause of febrile illness in tropical regions, can have a significant effect as a disease control measure. Earlier work has shown that immunization with either of two Salmonella Typhi vaccines, licensed Ty21a or candidate M01ZH09, did not provide full immunity in a controlled human infection model. Here, we describe the human humoral immune responses to these oral vaccines and their functional role in protection after challenge with S. Typhi. Serum, obtained from healthy volunteers before and after vaccination with Ty21a or M01ZH09 or placebo and before and after oral challenge with wild-type S. Typhi, was assessed for bactericidal activity. Single-dose vaccination with M01ZH09 induced an increase in serum bactericidal antibodies (p = 0.001) while three doses of Ty21a did not. No association between bactericidal activity and protection against typhoid after challenge was seen in either vaccine arm. Bactericidal activity after vaccination correlated significantly with delayed disease onset (p = 0.013), lower bacterial burden (p = 0.006), and decreased disease severity scores (p = 0.021). Depletion of antibodies directed against lipopolysaccharide significantly reduced bactericidal activity (p = 0.009). We conclude that antibodies induced after ingestion of oral live-attenuated typhoid vaccines or after challenge with wild-type S. Typhi exhibit bactericidal activity. This bactericidal activity is mediated by anti-O:LPS antibodies and significantly reduces clinical symptoms but does not provide sterile immunity. This directs future vaccine studies toward other antigens or mechanisms of protection against typhoid.

Safety and immunogenicity of a Vi-DT typhoid conjugate vaccine: Phase I trial in Healthy Filipino adults and children

“…Some studies suggest that anti-Vi IgG contributed to reduce disease symptoms and prevention of infection in some individuals [34] , [35] . However, recently, it was shown that bactericidal antibody reduced typhoid severity but not protection against disease in a human challenge model [36] .…”

Antibodies and Protection in SystemicSalmonellaInfections: Do We Still Have More Questions than Answers?

“…This would indicate that opsono-phagocytosis is likely to be the prevailing antimicrobial mechanism mediated by anti-Salmonella antibodies. Furthermore, no correlation was found between protection afforded by live vaccination and SBA in a controlled human typhoid challenge model (111).…”

Human challenge trials in vaccine development, Rockville, MD, USA, September 28–30, 2017

“…Bactericidal activity is induced by vaccination, important for controlling the infection, leading to fewer symptoms, but not preventing infection [35]. A model has also been developed to look at Salmonella paratyphi A infection and, furthermore, in a heterologous re-challenge study: individuals with previous S. typhi exposure were not protected against rechallenge with S. paratyphi, but did show reduced overall attack rates, and a delayed time to diagnosis.…”