WHO estimates that more than one million new infections with the four curable sexually transmitted diseases—chlamydia, gonorrhoea, syphilis, and trichomoniasis—are acquired each day. With around 131 million annual incident infections, chlamydia remains the most common sexually transmitted bacterial disease.1 The prevalence of chlamydia is age-dependent, with highest incidence of laboratory-confirmed Chlamydia trachomatis infections observed in adolescents and young adults. However, since three in four infections remain asymptomatic, the actual incidence is likely to be underestimated.1
Untreated or repeated infections are the main drivers of chlamydia-associated morbidity,2 which is estimated to cause 370 000 disability-adjusted life years annually.3 One in every six infected women develops ascending infection and pelvic inflammatory disease, which contributes to chronic pelvic pain and is a leading cause of tubal factor infertility and ectopic pregnancy, especially in the developing world.4 C trachomatis infection is strongly associated with increased susceptibility to, and co-infection with, other sexually transmitted diseases, particularly gonorrhoea and HIV.5 Infection during pregnancy poses a risk of adverse outcomes such as miscarriage, stillbirth, and preterm birth by either direct fetal infection, placental damage, or severe maternal illness.6 More than half of infants born to infected mothers become infected during birth, of whom one in six will develop pneumonia and around half will develop conjunctivitis.7 In men, C trachomatis mainly causes epididymitis, and in both men and women C trachomatis infection can trigger reactive arthritis in a minority of cases.
Research in context
Evidence before this study
We searched PubMed using the terms “chlamydia vaccine” and “clinical trial”, with no restrictions on publication dates (from Jan 1, 1966, to Jan 31, 2019) or language, and identified no reported studies. This study is, to the best of our knowledge, the first clinical trial of a genital chlamydia vaccine, and the first of a vaccine against Chlamydia trachomatis since the 1960s, when various studies assessed the efficacy of live attenuated bacteria against ocular chlamydia infection (trachoma).
Added value of this study
In this phase 1, first-in-human, double-blind, parallel, randomised, placebo-controlled trial, we found that intramuscular administration of CTH522 adjuvanted with either CAF01 or aluminium hydroxide, as well as intranasal administration of unadjuvanted CTH522, was well tolerated and immunogenic in healthy adult women. The vaccines induced high titres of serum antibodies and cell-mediated immune responses, measured as interferon-γ release. The antibodies were neutralising and were detectable in both the nasal cavity and genital tract. Notably, the CAF01 adjuvant induced higher antibody titres and cell-mediated immune responses than aluminium hydroxide. Intranasal booster vaccination tended to increase IgA titres in both the nasal and genital tract secretions.
Implications of all the available evidence
The promising safety and immunogenicity profile of CTH522 adjuvanted with CAF01 encourages continued clinical development of this vaccine against genital chlamydia. A phase 2 dose optimisation study is planned to start in autumn 2019.
Despite the availability of both sensitive non-invasive tests and effective treatment, targeted screening and treatment programmes have, to a large degree, failed to curb the epidemic.8, 9 Thus, an effective preventive vaccine might be the best solution. Nevertheless, no vaccine against C trachomatis has entered clinical trials since a series of trials done against ocular chlamydia in the 1960s.
Studies of natural immunity suggest that infection can lead to partial and transient immunity to C trachomatis characterised by both local humoral and cellular responses.10 Data from animal models point to a key role, preferably combined, for interferon-γ-secreting T-helper-1 cells and functional antibodies.11 However, it remains incompletely understood which mechanisms are necessary to target for a vaccine to confer protective immunity against C trachomatis.
The vaccine antigen CTH522 is a recombinant, engineered version of the C trachomatis major outer membrane protein (MOMP), comprising heterologous immunorepeats from four genital C trachomatis serovars (D, E, F, and G).12 Preclinical research on this vaccine led to selection of the cationic liposomal adjuvant CAF01, which has been designed for the induction of a strong cell-mediated immune response combined with antibody induction. The vaccine has been evaluated in mice, pigs, and non-human primates, where T-cell responses and high titres of broadly neutralising antibodies were induced. Protection following genital C trachomatis challenge was found in both mice12 and guinea pigs (unpublished).
Since the genital mucosa does not have immune inductive sites, other mucosal sites have been explored for induction of local genital immunity, especially intranasal immunisation, which has been shown to induce mucosal immunity in both the respiratory and genital tract. Immunisation schedules with the adjuvant CAF01 have also highlighted how systemic priming followed by mucosal boost is highly efficacious in inducing mucosal immunity and induction of IgA.13, 14, 15
The aim of this trial was to assess the safety and immunogenicity of three intramuscular doses of CTH522 adjuvanted with CAF01 liposomes (CTH522:CAF01) or aluminium hydroxide (CTH522:AH), followed by two intranasal boosts with unadjuvanted CTH522.