Protective Effect of Vaccine Promoted Neutralizing Antibodies against the Intracellular Pathogen Chlamydia trachomatis

Abstract

There is an unmet need for a vaccine to control <i>Chlamydia trachomatis</i> (<i>C.t</i>.) infections. We have recently designed a multivalent heterologous immuno-repeat 1 (Hirep1) vaccine construct based on major outer membrane protein variable domain (VD) 4 regions from <i>C.t</i>. serovars (Svs) D-F. Hirep1 administered in the Cationic Adjuvant Formulation no. 1 (CAF01) promoted neutralizing antibodies in concert with CD4⁺ T cells and protected against genital infection. In the current study, we examined the protective role of the antibody (Ab) response in detail. Mice were vaccinated with either Hirep1 or a vaccine construct based on a homologous multivalent construct of extended VD4's from SvF (extVD4^F*4), adjuvanted in CAF01. Hirep1 and extVD4^F*4 induced similar levels of Ab and cell-mediated immune responses but differed in the fine specificity of the B cell epitopes targeted in the VD4 region. Hirep1 induced a strong response toward a neutralizing epitope (LNPTIAG) and the importance of this epitope for neutralization was demonstrated by competitive inhibition with the corresponding peptide. Immunization with extVD4^F*4 skewed the response to a non-neutralizing epitope slightly upstream in the sequence. Vaccination with Hirep1 as opposed to extVD4^F*4 induced significant protection against infection in mice both in short- and long-term vaccination experiments, signifying a key role for Hirep1 neutralizing antibodies during protection against <i>C.t</i>. Finally, we show that passive immunization of Rag1 knockout mice with Hirep1 antibodies completely prevented the establishment of infection in 48% of the mice, demonstrating an isolated role for neutralizing antibodies in controlling infection. Our data emphasize the role of antibodies in early protection against <i>C.t</i>. and support the inclusion of neutralizing targets in chlamydia vaccines.