Recombinant polymorphic membrane protein D in combination with a novel, second-generation lipid adjuvant protects against intra-vaginal Chlamydia trachomatis infection in mice

TY - JOUR

T1 - Recombinant polymorphic membrane protein D in combination with a novel, second-generation lipid adjuvant protects against intra-vaginal Chlamydia trachomatis infection in mice

AU - Kaye, Paul

AU - Lacey, Charles John Nash

AU - Paes, William Neville Wayne

AU - Brzozowski, Andrzej Marek

AU - Bland, John Martin

AU - Brown, Najmeeyah

AU - Reed, Steve

AU - Carter, Darrick

AU - Cole, Rhea

PY - 2016/7/29

Y1 - 2016/7/29

N2 - The development of a chlamydial vaccine that elicits protective mucosal immunity is of paramount importance in combatting the global spread of sexually transmitted Chlamydia trachomatis (Ct) infections. While the identification and prioritization of chlamydial antigens is a crucial prerequisite for efficacious vaccine design, it is likely that novel adjuvant development and selection will also play a pivotal role in the translational potential of preclinical Ct vaccines. Although the molecular nature of the immuno-modulatory component is of primary importance, adjuvant formulation and delivery systems may also govern vaccine efficacy and potency. Our study provides the first preclinical evaluation of recombinant Ct polymorphic membrane protein D (rPmpD) in combination with three different formulations of a novel second-generation lipid adjuvant (SLA). SLA was rationally designed in silico by modification of glucopyranosyl lipid adjuvant (GLA), a TLR4 agonistic precursor molecule currently in Phase II clinical development. We demonstrate robust protection against intra-vaginal Ct challenge in mice, evidenced by significantly enhanced resistance to infection and reduction in mean bacterial load. Strikingly, protection was found to correlate with the presence of robust anti-rPmpD serum and cervico-vaginal IgG titres, even in the absence of adjuvant-induced Th1-type cellular immune responses elicited by each SLA formulation, and we further show that anti-rPmpD antibodies recognize Ct EBs. These findings highlight the utility of SLA and rational molecular design of adjuvants in preclinical Ct vaccine development, but also suggest an important role for anti-rPmpD antibodies in protection against urogenital Ct infection.

AB - The development of a chlamydial vaccine that elicits protective mucosal immunity is of paramount importance in combatting the global spread of sexually transmitted Chlamydia trachomatis (Ct) infections. While the identification and prioritization of chlamydial antigens is a crucial prerequisite for efficacious vaccine design, it is likely that novel adjuvant development and selection will also play a pivotal role in the translational potential of preclinical Ct vaccines. Although the molecular nature of the immuno-modulatory component is of primary importance, adjuvant formulation and delivery systems may also govern vaccine efficacy and potency. Our study provides the first preclinical evaluation of recombinant Ct polymorphic membrane protein D (rPmpD) in combination with three different formulations of a novel second-generation lipid adjuvant (SLA). SLA was rationally designed in silico by modification of glucopyranosyl lipid adjuvant (GLA), a TLR4 agonistic precursor molecule currently in Phase II clinical development. We demonstrate robust protection against intra-vaginal Ct challenge in mice, evidenced by significantly enhanced resistance to infection and reduction in mean bacterial load. Strikingly, protection was found to correlate with the presence of robust anti-rPmpD serum and cervico-vaginal IgG titres, even in the absence of adjuvant-induced Th1-type cellular immune responses elicited by each SLA formulation, and we further show that anti-rPmpD antibodies recognize Ct EBs. These findings highlight the utility of SLA and rational molecular design of adjuvants in preclinical Ct vaccine development, but also suggest an important role for anti-rPmpD antibodies in protection against urogenital Ct infection.

KW - Chlamydia trachomatis

KW - Pmps

KW - TLR4 adjuvant

KW - Vaccine

UR - http://www.scopus.com/inward/record.url?scp=84977139178&partnerID=8YFLogxK

U2 - 10.1016/j.vaccine.2016.06.081

DO - 10.1016/j.vaccine.2016.06.081

M3 - Article

VL - 34

SP - 4123

EP - 4131

JO - Vaccine

JF - Vaccine

SN - 0264-410X

IS - 35

ER -