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Immunogenicity, safety, and tolerability of a recombinant measles-virus-based chikungunya vaccine: a randomised, double-blind, placebo-controlled, active-comparator, first-in-man trial

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Summary

Background

Chikungunya is an emerging arthropod-borne disease that has spread from tropical endemic areas to more temperate climates of the USA and Europe. However, no specific treatment or preventive measure is yet available. We aimed to investigate the immunogenicity and safety of a live recombinant measles-virus-based chikungunya vaccine.

Methods

We did a randomised, double-blind, placebo-controlled, active-comparator, phase 1, dose-escalation study at one centre in Vienna, Austria. Healthy men and women aged 18–45 years with no comorbidities were randomly assigned, by computer-generated block randomisation (block size of 14), to receive either one of three escalating doses of the measles-virus-based candidate vaccine (low dose [1·5 × 104 median tissue culture infection doses (TCID50) per 0·05 mL], medium dose [7·5 × 104 TCID50 per 0·25 mL], or high dose [3·0 × 105 TCID50 per 1·0 mL]), or the active comparator—Priorix. Participants were additionally block-randomised to receive a booster injection on either day 28 or day 90 after the first vaccination. Participants and study investigators were masked to group allocation. The primary endpoint was the presence of neutralising anti-chikungunya antibodies on day 28, as assessed by 50% plaque reduction neutralisation test. Analysis was by intention to treat and per protocol. This trial is registered with EudraCT, number 2013-001084-23.

Findings

Between Nov 22, 2013, and Feb 25, 2014, we randomly assigned 42 participants to receive the low dose (n=12), the medium dose (n=12), or the high dose (n=12) of the measles-virus-based candidate vaccine, or Priorix (n=6), of whom 36 participants (86%; n=9, n=12, n=10, n=5, respectively) were included in the per-protocol population. The candidate vaccine raised neutralising antibodies in all dose cohorts after one immunisation, with seroconversion rates of 44% (n=4) in the low-dose group, 92% (n=11) in the medium-dose group, and 90% (n=10) in the high-dose group. The immunogenicity of the candidate vaccine was not affected by pre-existing anti-measles immunity. The second vaccination resulted in a 100% seroconversion for all participants in the candidate vaccine groups. The candidate vaccine had an overall good safety profile, and the rate of adverse events increased with vaccine dose and volume. No vaccination-related serious adverse events were recorded.

Interpretation

The live recombinant measles-virus-based chikungunya vaccine had good immunogenicity, even in the presence of anti-vector immunity, was safe, and had a generally acceptable tolerability profile. This vaccine is the first promising measles-virus-based candidate vaccine for use in human beings.

Funding

Themis Bioscience GmBH.

Introduction

Once restricted to tropical areas with endemic self-limiting outbreaks, chikungunya virus is becoming a global threat with continuous geographical expansion from African and Asian countries to more temperate climates of the industrialised countries.1, 2, 3 Increased travelling and global warming drive the transmission of vector-borne diseases by aiding the establishment and distribution of virus-carrying arthropods. Both Aedes aegypti and Aedes albopictus—the main vectors of chikungunya virus in urban areas—are already established in the USA and Europe, emphasising the menace of autochthonous chikungunya emergence in these parts of the world.4, 5

Symptomatic patients with chikungunya virus frequently have high fever and debilitating arthritis, which can persist for years causing substantial long-term morbidity and loss in quality of life.6, 7, 8, 9 Additionally, pathological changes in the joints in a subset (up to 30%) of patients is a major driver for vaccine development. Such symptomatic patients need advanced and prolonged immunotherapy because of joint pain and associated radiographical and virological features of disease, which has a major effect on health-care costs in the affected countries. Although rare, severe complications include respiratory and cardiovascular failure, meningoencephalitis, hepatitis, renal impairment, and Guillain-Barré syndrome. Patients older than 65 years and children younger than 1 year are a high-risk population.10, 11

During an epidemic, infected people are potentially the amplifying hosts of chikungunya virus through a cycle of human–mosquito transmission.12 Thus, the size of an epidemic case load is dependent on established human herd immunity,12 which also protects individuals unsuitable for vaccination, such as pregnant women and immunocompromised patients. Ongoing epidemic outbreaks emphasise the need for an effective vaccine;13 however, no suitable drugs or preventive measure for chikungunya virus-related disease are yet available. In the past 15 years only two vaccine candidates have been investigated in human trials.14, 15 The first vaccine was assessed in several phase 1 clinical trials, in which it showed an acceptable safety profile with only a mild, very transient, arthralgia in some participants. Later sequence analysis showed two attenuating point mutations.16 The other candidate has been assessed in a small phase 1 trial15 to test the effect of high vaccine doses given without an adjuvant.

The measles-virus-based chikungunya candidate vaccine is a live attenuated recombinant viral vectored vaccine based on the Schwarz strain of measles vaccine, which was originally introduced by the Pasteur Institute in Paris.17 Recombinant measles-virus vectors provide strong and protective immunity against various arboviruses18, 19, 20 and has been shown to be immunogenic against HIV,21, 22 independent of anti-measles immunity. The immunogenicity and protective efficacy of the measles-virus-based chikungunya vaccine was shown in a measles virus-susceptible mouse model, showing that neutralising antibodies induced by the vaccine confer complete protection against a lethal challenge with chikungunya virus.23

We investigated the immunogenicity, safety, and tolerability of the recombinant measles virus-based chikungunya candidate vaccine for prevention of chikungunya virus in the presence of pre-existing anti-vector immunity in healthy adults.

Section snippets

Study design and participants

We did a randomised, double-blind, placebo-controlled, active-comparator, phase 1, dose-escalation study at the Department of Clinical Pharmacology at the Medical University of Vienna, Austria. Healthy men and women aged between 18 and 45 years with no comorbidities were eligible for inclusion. We excluded participants with a recent infection (within 1 week before their first treatment at visit one) and those vaccinated within 12 weeks before the screening visit. Other exclusion criteria were

Results

Figure 1 shows the trial profile. Between Nov 22, 2013, and Feb 25, 2014, we randomly assigned 42 participants to receive the low, medium, or high dose of the candidate vaccine, or priorix, of whom 36 participants (86%) were included in the per-protocol population. The overall study duration per participant was 4 months. Baseline characteristics were similar between groups (table 1).

The candidate vaccine induced chikungunya virus neutralising antibodies in all dose cohorts after one

Discussion

Our findings show, for the first time, the ability of a measles-vectored vaccine to induce functional, neutralising anti-chikungunya virus antibodies in healthy adults, even in the presence of pre-existing anti-vector immunity. This asset is fundamental for this vaccine platform, which is based on a replicating vector derived from one of the safest and most efficient human vaccines.

Although no specific therapy or preventive treatment for chikungunya disease is available, only two candidate

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    These authors contributed equally

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