ArticlesImmunogenicity, safety, and tolerability of a recombinant measles-virus-based chikungunya vaccine: a randomised, double-blind, placebo-controlled, active-comparator, first-in-man trial
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
References (45)
- et al.
Chikungunya in Europe
Lancet
(2008) - et al.
Chikungunya virus and arthritic disease
Lancet Infect Dis
(2014) - et al.
Clinical burden of chikungunya virus infection
Lancet Infect Dis
(2008) - et al.
Chikungunya virus, epidemiology, clinics and phylogenesis: a review
Asian Pac J Trop Med
(2014) - et al.
Safety and tolerability of chikungunya virus-like particle vaccine in healthy adults: a phase 1 dose-escalation trial
Lancet
(2014) - et al.
Pediatric measles vaccine expressing a dengue tetravalent antigen elicits neutralizing antibodies against all four dengue viruses
Vaccine
(2010) - et al.
A recombinant measles vaccine expressing chikungunya virus-like particles is strongly immunogenic and protects mice from lethal challenge with chikungunya virus
Vaccine
(2013) - et al.
Development of an attenuated strain of chikungunya virus for use in vaccine production
Vaccine
(1986) - et al.
Immunogenicity and safety of a novel therapeutic hepatitis C virus (HCV) peptide vaccine: a randomized, placebo controlled trial for dose optimization in 128 healthy subjects
Vaccine
(2006) - et al.
Estimating the burden of disease and the economic cost attributable to chikungunya, Andhra Pradesh, India, 2005–2006
Trans R Soc Trop Med Hyg
(2010)
Chikungunya, an epidemic arbovirosis
Lancet Infect Dis
A complex adenovirus vaccine against chikungunya virus provides complete protection against viraemia and arthritis
Vaccine
Immunogenicity of novel consensus-based DNA vaccines against chikungunya virus
Vaccine
Chikungunya virus infections among travelers—United States, 2010–2013
Am J Trop Med Hyg
Chikungunya at the door—deja vu all over again?
N Engl J Med
High level of vector competence of Aedes aegypti and Aedes albopictus from ten American countries as a crucial factor in the spread of Chikungunya virus
J Virol
High efficiency of temperate Aedes albopictus to transmit chikungunya and dengue viruses in the Southeast of France
PloS One
Morbidity and impaired quality of life 30 months after chikungunya infection: comparative cohort of infected and uninfected French military policemen in Reunion Island
Medicine
Chikungunya virus-associated long-term arthralgia: a 36-month prospective longitudinal study
PLoS Negl Trop Dis
Atypical chikungunya virus infections: clinical manifestations, mortality and risk factors for severe disease during the 2005–2006 outbreak on Reunion
Epidemiol Infect
Chikungunya virus and prospects for a vaccine
Expert Rev Vaccines
Chikungunya: a paradigm of emergence and globalization of vector-borne diseases
Med Clin North Am
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These authors contributed equally