Research Article: Extended Preclinical Safety, Efficacy and Stability Testing of a Live-attenuated Chikungunya Vaccine Candidate

Date Published: September 4, 2015

Publisher: Public Library of Science

Author(s): Kenneth S Plante, Shannan L. Rossi, Nicholas A. Bergren, Robert L. Seymour, Scott C. Weaver, David Joseph Diemert.

Abstract: We recently described a new, live-attenuated vaccine candidate for chikungunya (CHIK) fever, CHIKV/IRES. This vaccine was shown to be well attenuated, immunogenic and efficacious in protecting against CHIK virus (CHIKV) challenge of mice and nonhuman primates. To further evaluate its preclinical safety, we compared CHIKV/IRES distribution and viral loads in interferon-α/β receptor-incompetent A129 mice to another CHIK vaccine candidate, 181/clone25, which proved highly immunogenic but mildly reactive in human Phase I/II clinical trials. Compared to wild-type CHIK virus, (wt-CHIKV), both vaccines generated lower viral loads in a wide variety of tissues and organs, including the brain and leg muscle, but CHIKV/IRES exhibited marked restrictions in dissemination and viral loads compared to 181/clone25, and was never found outside the blood, spleen and muscle. Unlike wt-CHIKV, which caused disrupted splenic architecture and hepatic lesions, histopathological lesions were not observed in animals infected with either vaccine strain. To examine the stability of attenuation, both vaccines were passaged 5 times intracranially in infant A129 mice, then assessed for changes in virulence by comparing parental and passaged viruses for footpad swelling, weight stability and survival after subcutaneous infection. Whereas strain 181/clone25 p5 underwent a significant increase in virulence as measured by weight loss (from <10% to >30%) and mortality (from 0 to 100%), CHIKV/IRES underwent no detectible change in any measure of virulence (no significant weight loss and no mortality). These data indicate greater nonclinical safety of the CHIKV/IRES vaccine candidate compared to 181/clone25, further supporting its eligibility for human testing.

Partial Text: Chikungunya virus (CHIKV) is a reemerging arbovirus and the etiologic agent of chikungunya fever (CHIK). The virus belongs to the Alphavirus genus in the Togaviridae family. As an alphavirus, CHIKV particles are approximately 70 nm in diameter, and contain a single-stranded, positive-sense RNA genome of 11.8 kb [1]. The virus was discovered in Tanzania in 1952 by Robinson after responding to an isolated outbreak of febrile illness. This agent was later classified as a novel mosquito-borne virus that causes signs and symptoms similar to those associated with dengue fever [2–4]. The word chikungunya translates roughly from the African Kimakonde language to “that which bends up,” a reference to the hunched posture adopted by victims afflicted with severe arthralgia. CHIKF has a high attack rate, with only 2–25% of seropositive people remaining asymptomatic [5]. The symptoms and signs of CHIK include high fever, a maculopapular rash radiating outward from the trunk, intense arthralgia and myalgia, and in some rare cases neurological manifestations such as delirium and convulsions [5, 6].

The ideal vaccine for an explosively emerging viral disease like CHIK will cause no detectable disease after administration, will generate rapid and durable immunity after a single dose, and will prevent or greatly reduce the replication of challenge infections to reduce transmission (since humans are the only amplification hosts in the urban cycle). The vaccine will also remain stably attenuated during use in large numbers of vaccinees, especially for viruses like CHIKV that place tens-of-millions of persons at natural risk for severe and chronic arthralgia. A live-attenuated Chikungunya vaccine may be capable of meeting these goals [22].



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