Articles
Safety and immunogenicity of the chlamydia vaccine candidate CTH522 adjuvanted with CAF01 liposomes or aluminium hydroxide: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial

https://doi.org/10.1016/S1473-3099(19)30279-8Get rights and content

Summary

Background

Chlamydia is the most common sexually transmitted bacterial infection worldwide. National screening programmes and antibiotic treatment have failed to decrease incidence, and to date no vaccines against genital chlamydia have been tested in clinical trials. We aimed to assess the safety and immunogenicity, in humans, of a novel chlamydia vaccine based on a recombinant protein subunit (CTH522) in a prime–boost immunisation schedule.

Methods

This phase 1, first-in-human, double-blind, parallel, randomised, placebo-controlled trial was done at Hammersmith Hospital in London, UK, in healthy women aged 19–45 years. Participants were randomly assigned (3:3:1) to three groups: CTH522 adjuvanted with CAF01 liposomes (CTH522:CAF01), CTH522 adjuvanted with aluminium hydroxide (CTH522:AH), or placebo (saline). Participants received three intramuscular injections of 85 μg vaccine (with adjuvant) or placebo to the deltoid region of the arm at 0, 1, and 4 months, followed by two intranasal administrations of 30 μg unadjuvanted vaccine or placebo (one in each nostril) at months 4·5 and 5·0. The primary outcome was safety and the secondary outcome was humoral immunogenicity (anti-CTH522 IgG seroconversion). This study is registered with Clinicaltrials.gov, number NCT02787109.

Findings

Between Aug 15, 2016, and Feb 13, 2017, 35 women were randomly assigned (15 to CTH522:CAF01, 15 to CTH522:AH, and five to placebo). 32 (91%) received all five vaccinations and all participants were included in the intention-to-treat analyses. No related serious adverse reactions were reported, and the most frequent adverse events were mild local injection-site reactions, which were reported in all (15 [100%] of 15) participants in the two vaccine groups and in three (60%) of five participants in the placebo group (p=0·0526 for both comparisons). Intranasal vaccination was not associated with a higher frequency of related local reactions (reported in seven [47%] of 15 participants in the active treatment groups vs three [60%] of five in the placebo group; p=1·000). Both CTH522:CAF01 and CTH522:AH induced anti-CTH522 IgG seroconversion in 15 (100%) of 15 participants after five immunisations, whereas no participants in the placebo group seroconverted. CTH522:CAF01 showed accelerated seroconversion, increased IgG titres, an enhanced mucosal antibody profile, and a more consistent cell-mediated immune response profile compared with CTH522:AH.

Interpretation

CTH522 adjuvanted with either CAF01 or aluminium hydroxide appears to be safe and well tolerated. Both vaccines were immunogenic, although CTH522:CAF01 had a better immunogenicity profile, holding promise for further clinical development.

Funding

European Commission and The Innovation Fund Denmark.

Introduction

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.

Section snippets

Study design and participants

This study was a phase 1, first-in-human, double-blind, parallel, randomised, placebo-controlled trial done at the National Institute for Health Research (NIHR) Imperial Clinical Research Facility at Hammersmith Hospital in London, UK. The study protocol was approved by the London–Chelsea Research Ethics Committee, the Research and Development department at Imperial College Healthcare National Health Service (NHS) Trust, and the Medicines and Healthcare Products Regulatory Agency (EudraCT

Results

Between Aug 15, 2016, and Feb 13, 2017, 35 women were randomly assigned to receive CTH522:CAF01 (n=15), CTH522:AH (n=15), or placebo (n=5; figure 1, table 1). Of the 35 participants, 32 (91%) received all five vaccinations described in the study protocol. Because of scheduling issues, two participants in the CTH522:CAF01 group withdrew from the study (one after three vaccinations and the other after five). One participant in the CTH522:AH group withdrew after the second intramuscular

Discussion

We report the principal findings from a first-in-human clinical trial of the novel chlamydia vaccine CTH522. Results show that the CTH522 vaccine adjuvanted with CAF01 liposomes or aluminium hydroxide administered with three intramuscular vaccinations and two intranasal boosts is both safe and immunogenic. No vaccine-related serious adverse events were reported and local reactions were mild and comparable to the safety profile of licensed recombinant subunit vaccines such as the hepatitis B

References (30)

  • L Newman et al.

    Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting

    PLoS One

    (2015)
  • Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

    Lancet

    (2017)
  • CR Cohen et al.

    Pathogenesis of Chlamydia induced pelvic inflammatory disease

    Sex Transm Infect

    (1999)
  • BE Ng et al.

    Population-based biomedical sexually transmitted infection control interventions for reducing HIV infection

    Cochrane Database Syst Rev

    (2011)
  • K Adachi et al.

    Chlamydia trachomatis infection in pregnancy: the global challenge of preventing adverse pregnancy and infant outcomes in Sub-Saharan Africa and Asia

    Biomed Res Int

    (2016)
  • Cited by (122)

    View all citing articles on Scopus

    Joint first authors

    View full text