Preclinical screen for protection efficacy of chlamydial antigens that are immunogenic in humans

Abstract

AbstractTo search for subunit vaccine candidates, immunogenic chlamydial antigens identified in humans were evaluated for protection against both infection and pathology in a mouse genital tract infection model under three different immunization regimens. The intramuscular immunization regimen was first used to evaluate 106 chlamydial antigens, which revealed that two antigens significantly reduced while 11 increased genital chlamydial burden. The two infection-reducing antigens failed to prevent pathology and 23 additional antigens even exacerbated pathology. Thus, intranasal mucosal immunization was tested next since intranasal inoculation with liveC. muridarumprevented both genital infection and pathology. Two of 29 chlamydial antigens evaluated were found to prevent genital infection but not pathology and three exacerbate pathology. To further improve protection efficacy, a combinational regimen (intranasal priming + intramuscular boosting + a 3rdintraperitoneal/subcutaneous boost) was tested. This regimen identified 4 infection-reducing antigens but only one of them prevented pathology. Unfortunately, this protective antigen was not advanced further due to its amino acid sequence homology with several human molecules. Two pathology-exacerbating antigens were also found. Nevertheless, intranasal mucosal priming with viableC. muridarumin control groups consistently prevented both genital infection and pathology regardless of the subsequent boosters. Thus, screening 140 different chlamydial antigens with 21 repeated multiple times in 17 independent experiments failed to identify a subunit vaccine candidate but the efforts have revealed pathogenic antigens and demonstrated the superiority of viable chlamydial organisms in inducing immunity against both genital infection and pathology, laying the foundation for developing an attenuated live Chlamydia vaccine.ImportanceThis manuscript describes a systematical effort in searching for a chlamydial subunit vaccine by taking advantage of both the immunogenic chlamydial antigens identified in humans and a robust mouse genital tract infection model for simultaneously evaluating protection against both genital infection and pathology. Screening 140 different chlamydial antigens (21 repeated multiple times) using three different immunization regimens in 17 independent experiments identified no subunit vaccine candidate. Nevertheless, the efforts revealed multiple pathogenic chlamydial antigens and demonstrated the superiority of mucosal inoculation with viable chlamydial organisms for inducing immunity against both genital infection and pathology, suggesting that a live attenuated Chlamydia vaccine strategy should be considered.