Elsevier

Vaccine

Volume 30, Issue 31, 29 June 2012, Pages 4638-4643
Vaccine

Cross-protective immunity against o‘nyong-nyong virus afforded by a novel recombinant chikungunya vaccine

https://doi.org/10.1016/j.vaccine.2012.04.099Get rights and content

Abstract

Emerging mosquito-borne alphavirus infections caused by chikungunya virus (CHIKV) or o‘nyong-nyong virus (ONNV) are responsible for sporadic and sometimes explosive urban outbreaks. Currently, there is no licensed vaccine against either virus. We have developed a highly attenuated recombinant CHIKV candidate vaccine (CHIKV/IRES) that in preclinical studies was demonstrated to be safe, immunogenic and efficacious. In this study we investigated the potential of this vaccine to induce cross-protective immunity against the antigenically related ONNV. Our studies demonstrated that a single dose of CHIKV/IRES elicited a strong cross-neutralizing antibody response and conferred protection against ONNV challenge in the A129 mouse model. Moreover, CHIKV/IRES immune A129 dams transferred antibodies to their offspring that were protective, and passively transferred anti-CHIKV/IRES immune serum protected AG129 mice, independently of a functional IFN response. These findings highlight the potential of the CHIKV/IRES vaccine to protect humans against not only CHIKV but also against ONNV-induced disease.

Highlights

► The CHIKV/IRES vaccine elicits cross-neutralizing antibody responses against ONNV. ► CHIKV/IRES immune animals are protected against ONNV challenge. ► Protection is mediated by antibodies as evident by passive transfer studies. ► CHIKV/IRES immune dams transfer protective anti-ONNV antibodies to their off springs.

Introduction

Emerging mosquito-borne alphavirus infections caused by chikungunya virus (CHIKV) or o‘nyong-nyong virus (ONNV) are responsible for sporadic and sometimes explosive epidemics characterized by debilitating pain and inflammation of musculoskeletal tissue. In particular, ONNV which is transmitted by Anopheles mosquitoes, was the cause of a major epidemic of debilitating joint pain that began in Uganda and spread over Eastern Africa, affecting at least two million people between 1959 and 1962 [1]. More recently, ONNV was the cause of another epidemic in southern Uganda [2]. A vertebrate reservoir has yet to be identified for this virus. CHIKV has for decades been an important etiologic agent of human disease in Africa and Asia. The virus recently reemerged into the Indian Ocean islands, India and Southeast Asia to cause several million cases of severe and often chronic arthralgia [3], [4]. In addition, reports of autochthonous transmission in southern France [5], and Italy [6] highlight the potential of this virus for worldwide dissemination and impact on public health. Unlike ONNV, CHIKV in Africa appears to be maintained in a sylvatic cycle that involves non-human primates and numerous species of Aedes mosquitoes [3], [4]. In Asia the virus circulates between A. aegypti and A. albopictus mosquitoes and naïve human hosts [3], [4].

Both ONNV and CHIKV belong to the family Togaviridae, genus Alphavirus. They are enveloped viruses with single-stranded, positive-sense RNA genomes and are grouped under the Semliki Forest Virus antigenic complex on the basis of serological cross-reactivity of their envelope proteins [7]. Typically, infection by these viruses is manifested by rash, headache, fever, viremia (which is short-lived), arthritis, myositis, arthralgia and myalgia. Serological tests have shown strong cross-reactivity of anti-CHIKV antibodies with ONNV whereas the reciprocal cross-reaction is weaker [8], [9]. Despite the close antigenic relationship between CHIKV and ONNV, genetic studies and phylogenetic analyses have clearly demonstrated that these two viruses are genetically distinct [2], [4].

Because humans appear to be the only amplification host during epidemic transmission of CHIKV and ONNV, the best means of controlling their spread is by vaccination. Currently, there is no licensed vaccine available for either. Several attempts to develop a vaccine against CHIKV have been described, including alphavirus chimeras [10], live attenuated virus [11], formalin-killed vaccines [12], [13], consensus-based DNA vaccines [14], a virus-like particle vaccine [15], and an adenovirus vectored vaccine [16]. We recently developed a candidate CHIKV vaccine by employing an attenuation mechanism that also prevents the infection of potential mosquito vectors [17]. The internal ribosome entry site (IRES) from encephalomyocarditis virus was used to replace the subgenomic promoter in a cDNA CHIKV clone, thus altering the level and host-specific mechanism of structural protein gene expression [18]. The testing of the vaccine in both normal outbred mice and interferon response-defective mice demonstrated; (i) that it is highly attenuated, immunogenic and efficacious after a single dose, and (ii) is incapable of replicating in mosquito cells or infecting mosquitoes in vivo, an important safety feature for use in non-endemic locations [18].

In this study we sought to investigate further the capacity of CHIKV/IRES vaccine to cross-protect against the antigenically related ONNV. Our results demonstrated that the vaccine elicited strong cross-neutralizing antibodies against ONNV and conferred protection against challenge with this virus after a single administration. Moreover, the protective role of antibodies was demonstrated in two models: (i) CHIKV/IRES immune A129 dams (which lack functional interferon type I receptor; IFN-α/β R−/−) transferred antibodies to their offspring that protected against ONNV challenge, and ii) anti-CHIKV/IRES antibodies conferred protection against ONNV challenge of AG129 mice (which lack functional interferon type I and type II receptors; IFN-α/β and -γ) independently of a functional IFN response.

Section snippets

Viruses

The virus strains used for plaque reduction neutralization assays were the CHIKV/181-25 passage Vero3, and ONNV strain SG650 passage Vero3BHK1. Each virus was diluted in 2 ml Dulbecco's Minimum Essential Medium-supplemented with 10% FBS, 100 U/ml of penicillin, and 100 mg/ml of streptomycin (DMEM Complete Media) to yield a multiplicity of infection (MOI) of 0.1 PFU/cell. Flasks (75 cm2) with confluent Vero cells were seeded with the diluted virus, and were incubated at 37 °C for 1 h with rocking every

Immunization with CHIKV/IRES candidate vaccine elicits cross protective immunity in IFN-type-I deficient A129 mice

A129 mice, which are susceptible to alphavirus infection [19], were selected to test the cross-protective efficacy of CHIKV/IRES vaccine against ONNV challenge. Intradermal administration of a single dose of CHIKV/IRES vaccine elicited an antibody response that neutralized the homologous virus and cross-neutralized ONNV (neutralizing titer of pool serum for both viruses was >320) 5 weeks post-priming. Challenge of CHIKV/IRES immune animals with 104 PFU ONNV produced no detectable viremia or any

Discussion

CHIKV and ONNV are the causes of several widespread epidemics of debilitating arthritis in Africa and Asia. There is still no licensed vaccine available to prevent disease induced by these viruses. To address this public health concern, an IRES-dependent replication of CHIKV strategy was developed that resulted in a highly attenuated profile of the virus and rendered it incapable of replicating in mosquito cells [18]. This candidate CHIKV/IRES vaccine was safe and immunogenic in mice and

Acknowledgments

We gratefully thank Dr Jill Livengood and Laszlo Varga for providing the CHIKV/IRES vaccine. PLS was supported by NIH grant 5T32AI007536, and this research was supported by NIH grant AI082202.

References (29)

  • R.S. Levinson et al.

    Complete sequence of the genomic RNA of o‘nyong-nyong virus and its use in the construction of alphavirus phylogenetic trees

    Virology

    (1990)
  • A.M. Powers et al.

    Changing patterns of chikungunya virus: re-emergence of a zoonotic arbovirus

    Journal of General Virology

    (2007)
  • A.M. Powers et al.

    Re-emergence of chikungunya and o‘nyong-nyong viruses: evidence for distinct geographical lineages and distant evolutionary relationships

    Journal of General Virology

    (2000)
  • M. Grandadam et al.

    Chikungunya virus, southeastern France

    Emerging Infectious Diseases

    (2011)
  • Cited by (76)

    • Arboviruses (Alphavirus) related to autoimmune rheumatic diseases: Triggers and possible therapeutic interventions

      2023, Translational Autoimmunity: Volume 6: Advances in Autoimmune Rheumatic Diseases
    • PCP consensus protein/peptide alphavirus antigens stimulate broad spectrum neutralizing antibodies

      2022, Peptides
      Citation Excerpt :

      Despite their potential for rapid spread, as has been illustrated by worldwide CHIKV outbreaks [7,8], there are currently no approved vaccines or specific treatments for human use against any alphavirus. However, there are many experimental vaccines against individual alphaviruses in various stages of preclinical and clinical testing [9–24]. There are also ongoing efforts to generate a trivalent vaccine by combining antigens of EEEV, VEEV and WEEV [25].

    View all citing articles on Scopus
    View full text