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

Kenneth S. Plante, Shannan Rossi, Nicholas A. Bergren, Robert Seymour, Scott Weaver

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 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.

Original languageEnglish (US)
Article numbere0004007
JournalPLoS Neglected Tropical Diseases
Volume9
Issue number9
DOIs
StatePublished - Sep 4 2015

Fingerprint

Attenuated Vaccines
Viruses
Vaccines
Safety
Viral Load
Chikungunya virus
Virulence
Weight Loss
Interferon Receptors
Muscles
Phase II Clinical Trials
Clinical Trials, Phase I
Mortality
Primates
Leg
Spleen
Weights and Measures
Survival
Liver
Brain

ASJC Scopus subject areas

  • Infectious Diseases
  • Public Health, Environmental and Occupational Health
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Extended Preclinical Safety, Efficacy and Stability Testing of a Live-attenuated Chikungunya Vaccine Candidate. / Plante, Kenneth S.; Rossi, Shannan; Bergren, Nicholas A.; Seymour, Robert; Weaver, Scott.

In: PLoS Neglected Tropical Diseases, Vol. 9, No. 9, e0004007, 04.09.2015.

Research output: Contribution to journalArticle

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