Protection of outbred mice against a vaginal challenge by a Chlamydia trachomatis serovar E recombinant major outer membrane protein vaccine is dependent on phosphate substitution in the adjuvant

Abstract

Chlamydia trachomatis is the most common bacterial sexually-transmitted pathogen for which there is no vaccine. We previously demonstrated that the degree of phosphate substitution in an aluminum hydroxide adjuvant in a TLR-4-based C. trachomatis serovar E (Ser E) recombinant major outer membrane protein (rMOMP) formulation had an impact on the induced antibody titers and IFN-γ levels. Here, we have extended these observations using outbreed CD-1 mice immunized with C. trachomatis Ser E rMOMP formulations to evaluate the impact on bacterial challenge. The results confirmed that the rMOMP vaccine containing the adjuvant with the highest phosphate substitution induced the highest neutralizing antibody titers while the formulation with the lowest phosphate substitution induced the highest IFN-γ production. The most robust protection was observed in mice vaccinated with the formulation containing the adjuvant with the lowest phosphate substitution, as shown by the number of mice with positive vaginal cultures, number of positive cultures and number of C. trachomatis inclusion forming units recovered. This is the first report showing that vaccination of an outbred strain of mice with rMOMP induces protection against a vaginal challenge with C. trachomatis.

Evaluation of Four Adjuvant Combinations, IVAX-1, IVAX-2, CpG-1826+Montanide ISA 720 VG and CpG-1018+Montanide ISA 720 VG, for Safety and for Their Ability to Elicit Protective Immune Responses in Mice against a Respiratory Challenge with Chlamydia muridarum

“…A comparison of the results obtained between the IVAX-1 and IVAX-2 versus the two combinations of Montanide ISA 720 VG confirms previous results indicating that cellular immune responses, specifically the secretion by T-cells of IFN-γ, are better indicators of protection than levels of neutralizing antibodies. For example, Pal et al [ 77 ] tested in CD-1 outbreed mice a vaccine formulated with the C. trachomatis serovar E MOMP and SPA08, an adjuvant combination containing Alum plus a TLR4 agonist. SPA08 was prepared with buffers containing different amounts of phosphate.…”

“…The most robust protection against a vaginal challenge with C. trachomatis serovar E was observed in mice vaccinated with the formulation containing the lowest phosphate substitution. This effect is thought to result from an increase in the phosphorylated adjuvant that allows the formation of a water layer between the components of the vaccine and therefore, a more rapid release of the antigen after immunization [ 77 ].…”

Effects of prime-boost strategies on the protective efficacy and immunogenicity of a PLGA (85:15)-encapsulated Chlamydia recombinant MOMP nanovaccine

“…Chlamydia major outer membrane protein (MOMP) has been studied for years and is a prime subunit vaccine target because it is immunogenic and elicits cellular and humoral immune responses that are requisites for protective immunity against genital Chlamydia (O’Meara et al 2013 , de la Maza et al 2017 , Poston et al 2019 ). Recombinant MOMP adjuvanted with DDA/MPL and chlamydial Pmps (Yu et al 2014 ), CAF01, and CAF09 (Pal et al 2017 ), TLR agonists (Cheng et al 2011 , 2014 , Pal et al 2020 , Tifrea et al 2020 ) or cholera toxin subunits (Singh et al 2006 , Ekong et al 2009 ) have all protected mice against genital Chlamydia . Nonetheless, the protection afforded by the MOMP vaccine candidates is short-term and does not induce sterilizing or long-lasting protective immunity, probably because of ineffective adjuvants to bolster mucosal immune responses (Singh et al 2006 , Stary et al 2015 ), efficient delivery systems (Dixit et al 2018 ), or inadequate routes of administration (Fiorino et al 2013 , Lorenzen et al 2015 , Pais et al 2019 ).…”

Baicalin relievesMycoplasma pneumoniaeinfection‑induced lung injury through regulating microRNA‑221 to inhibit the TLR4/NF‑κB signaling pathway

“…TLR4 could promote the sensitivity of the body to the endotoxin inducing the release of inflammatory factors and stimulating the immune response, indicating that TLR4 may have an important role in the pathogenesis of MP. It has been reported that mice overexpressing TLR4 and TLR2 genes are easily infected by chlamydia bacteria ( 31 ). Gram-positive cocci can synergistically interact with TLR2, upregulate TLR4 protein expression, activate the TLR4 signaling pathway and release the inflammatory factor IL-6, which can mediate inflammation by regulating NF-κB signaling pathways ( 32 , 33 ).…”