By Leonard A. Haas and Philip R. Fischer, MD

Dr. Fischer is professor of pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN. Leonard A. Haas is a student at Mayo Medical School.

Dr. Fischer and Mr. Haas have no financial relationships relevant to this field of study.

SYNOPSIS: A phase-1 clinical trial of a virus-like particle (VLP)-based vaccine demonstrates safety, tolerability, and immunogenicity against rapidly spreading Chikungunya virus.

SOURCE: Chang L-J, Dowd K, Mendoza F, Saunders J, Sitar S, Plummer S, et al. Safety and tolerability of chikungunya virus-like particle vaccine in healthy adults: A phase 1 dose escalation trial. Lancet 2014;384(9959):2046-2052.

In this phase-1, dose-escalation trial conducted by Chang and colleagues, 25 healthy adult participants were divided into three dosage groups in order to test the safety, tolerability, and immunogenicity of a new candidate vaccine for Chikungunya virus. The vaccine is based on a virus-like particle (VLP), which is highly immunogenic, safe, and capable of eliciting high titer neutralizing antibodies in non-human primates. VLP vaccines are also relatively easy to manage since live virus production is not needed. These virus-like particles included the E1, E2, and capsid proteins from the West African virus strain. The vaccine was given to participants in three sets of injections at weeks 0, 4, and 20, with three different dosages: 10 ?g (n = 5), 20 ?g (n = 10), and 40 ?g (n = 10).

Immunogenicity was measured by determining the Chikungunya virus-specified humoral immune responses by ELISA and by neutralization antibody assays, measured at several time points. Additionally, green fluorescent protein (GFP)-expressing chimeric Chikungunya virus and a flow-based cytometry assay were used to measure neutralization titers.

The vaccine was well tolerated by the participants, with no major problems reported. Nine out of 25 participants (36%) reported mild localized symptoms after injection (pain/tenderness) and 10 of 25 participants (40%) reported mild systemic symptoms (malaise, myalgia, headache, and nausea). There were no reports of arthralgia after vaccination. Seven mild to moderate adverse reactions (transient alanine aminotransferase increases and transient neutropenia) were thought to be related to the vaccine because they occurred within 2-4 weeks after vaccination and resolved without problem. Further, antibodies to Chikungunya antigens were detected by ELISA in 100% of participants in the 10 ?g and 40 ?g groups and in 80% of the 20 ?g group after the first injection and were substantially boosted by 4 weeks after the second and third injections, respectively. The geometric mean titers were not significantly different between the three dose groups and there was no significant difference between the group geometric mean titers 4 weeks after the second and third vaccinations. Neutralizing antibodies were also found against the east, central, and south African outbreak strain (OPY1) in all participants 4 weeks after the second vaccination and remained detectable six months after the third vaccination.

COMMENTARY

Since its initial recognition in the 1950s, Chikungunya has been rapidly spreading to new places across the world. Originally found in Tanzania during a large epidemic of polyarthralgia and myalgia, it later spread from Africa to Thailand.1 Since these initial outbreaks, there have been a myriad of epidemics in Africa and Asia. Chikungunya has many clinical similarities to dengue virus, and Chikungunya is often misdiagnosed. In April 2005, a severe epidemic of Chikungunya occurred on the Comoros Islands and spread across the southwestern Indian Ocean region with attack rates as high as 35% to 75%.2 Once Chikungunya began to spread to non-endemic areas like Italy and France by viremic travelers, the CDC and PAHO got involved to prepare for potential epidemics in Americas.2 In July 2014, Chikungunya was found locally in the Caribbean. A few months later in December 2014, locally transmitted cases of Chikungunya were found in Mexico and the United States, which represents a further move northward.3 Specifically, Florida has seen a significant number of Chikungunya cases, with a total of 272 imported cases, compared with a total of 1,110 cases in all of the other 47 contiguous states combined. As of December 29, 2014, 11 locally acquired Chikungunya cases have been identified, signifying that Chikungunya virus has not only been imported into the United States, but also competent Aedes mosquitoes exist within the United States locally spreading the disease.4 Overall, PAHO reports that over one million suspected autochthonous transmission cases of Chikungunya have occurred in the Americas as of December 29, 2014.5

Previous attempts at creating a vaccine began in the 1960s with formalin-killed virus-based vaccines and live-attenuated viruses had adverse effects.1 In a phase 2 trial of a live-attenuated virus, immunogenicity was lower than that achieved in the VLP vaccine phase 1 trial and 8% of participants displayed arthralgia as a side-effect. Many groups are currently working on creating vaccines through different approaches, such as single recombinant antigens, VLPs, chimeric alphaviruses, and codon re-encoding. For those already infected, several antiviral therapies, including interferon, ribavirin, chloroquine, arbidol, furin inhibitors, and other inhibitors of viral replication have been shown effective in vitro, yet none are currently a recognized treatment.1

This VLP vaccine trial is an important step in determining the viability of this vaccine in order to combat this rapidly spreading virus. The vaccine needs further clinical trials to determine its safety and immunogenicity in larger populations, including diverse and at-risk populations. The VLP vaccine was created based on the West African strain of Chikungunya, and this strain has the greatest genotypic differences from the east, central, and south African (OPY1) strain. The VLP vaccine effectively produced neutralizing antibodies against the OPY1 strain, which suggests that cross-reactive neutralizing activity against the other Chikungunya strains could be achieved as well. Until an effective vaccine can be created, it is critical for travelers to Chikungunya-endemic locations to use preventive measures against mosquitoes. ?

REFERENCES

  1. Thiberville SD, et al. Chikungunya fever: Epidemiology, clinical syndrome, pathogenesis, and therapy. Antiviral Research, 2013;99:345-370.
  2. Morrison TE. Reemergence of Chikungunya virus. J Virology 2014;88:11644-11647.
  3. Centers for Disease Control and Prevention. Chikungunya in the Americas. December 17, 2014. http://www.cdc.gov/chikungunya/geo/americas.html.
  4. Kendrick K, Stanek D, Blackmore C. Notes from the Field: Transmission of Chikungunya Virus in the Continental United States — Florida, 2014. Morbidity and Mortality Weekly Report 2014 December 5;63(48):1137.
  5. Pan American Health Organization. Number of Reported Cases of Chikungunya Fever in the Americas, by Country or Territory 2013-2014. December 29, 2014. http://www.paho.org/hq/index.php?Itemid=40931.