Probing the attenuation and protective efficacy of a candidate chikungunya virus vaccine in mice with compromised interferon (IFN) signaling

Abstract

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes explosive outbreaks of febrile illness associated with rash, and painful arthralgia. The CHIK vaccine strain 181/clone25 (181/25) developed by the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) was shown to be well-tolerated and highly immunogenic in phase I and II clinical trials although it induced transient arthralgia in some healthy adult volunteers. In an attempt to better understand the host factors that are involved in the attenuating phenotype of CHIK 181/25 vaccine virus we conducted studies in interferon (IFN)-compromised mice and also evaluated its immunogenic potential and protective capacity. Infection of AG129 mice (defective in IFN-α/β and IFN-γ receptor signaling) with CHIK 181/25 resulted in rapid mortality within 3-4 days. In contrast, all infected A129 mice (defective in IFN-α/β receptor signaling) survived with temporary morbidity characterized by ruffled appearance and body weight loss. A129 heterozygote mice that retain partial IFN-α/β receptor signaling activity remained healthy. Infection of A129 mice with CHIK 181/25 induced significant levels of IFN-γ and IL-12 while the inflammatory cytokines, TNFα and IL-6 remained low. A single administration of the CHIK 181/25 vaccine provided both short-term and long-term protection (38 days and 247 days post-prime, respectively) against challenge with wt CHIKV-La Reunion (CHIKV-LR). This protection was at least partially mediated by antibodies since passively transferred immune serum protected both A129 and AG129 mice from wt CHIKV-LR and 181/25 virus challenge. Overall, these data highlight the importance of IFNs in controlling CHIK 181/25 vaccine and demonstrate the ability of this vaccine to elicit neutralizing antibody responses that confer short-and long-term protection against wt CHIKV-LR challenge.

A Novel Poxvirus-Based Vaccine, MVA-CHIKV, Is Highly Immunogenic and Protects Mice against Chikungunya Infection

“…In addition, natural antibodies present in the sera of uninfected C57BL/6 mice were able to partially inhibit CHIKV (75). Furthermore, therapies based on passively transferred anti-CHIKV neutralizing antibodies conferred protection to A129 mice (42,44,45,70,71,73,(76)(77)(78) and nonhuman primates (37) against CHIKV and protection to mice against more distantly related arthrogenic alphaviruses (43,93,96), establishing the key role of humoral immunity in the control of CHIKV replication. Interestingly, complete protection from CHIKV challenge can be obtained using adoptive transfer of antibodies induced by immunization with a CHIKV/IRES vaccine candidate and occurs in the absence of CD4 ϩ /CD8 ϩ T cells (42); a titer of 35 for neutralizing antibodies was sufficient to protect mice from a challenge with 100 PFU of CHIKV (42).…”

“…Moreover, IFN-␣/␤ knockout mice (A129 mice) exhibited severe CHIKV disease (62-64, 66, 92), confirming the key role of type I IFNs in the control of CHIKV infection, by restricting virus replication early in the infection, although their effects are not enough to eliminate CHIKV from infected hosts. In fact, it has been reported that in the absence of an IFN-␣/␤ response, IFN-␥ partially controls CHIKV replication (77). Therefore, our results showing that MVA-CHIKV promotes a strong innate immune response in human macrophages and moDCs, upregulating the expression of IFN-␤, IFN-inducible genes (IFIT1 and IFIT2), and some key cytosolic sensors that lead to antiviral IFN production (RIG-I and MDA-5), could be relevant to promoting the recruitment of leukocytes to sites of infection and therefore be an efficient antiviral defense in the control of CHIKV infection after challenge.…”

“…Modified A129 mice, lacking the IFN-␣/␤ receptor, are susceptible to lethal CHIKV infection (62), and some CHIKV vaccine candidates have been tested in this animal model to assess immune protection after challenge with CHIKV (34,(42)(43)(44)(45)77). However, adult C57BL/6 mice can be used as a model of CHIKV disease when CHIKV challenge is administered to the footpad (93,98).…”

“…Antibodies against CHIKV are crucial to control CHIKV infection (37,42,44,45,(70)(71)(72)(73)(74)(75)(76)(77)(78). Thus, to study the ability of MVA-CHIKV to elicit humoral immune responses against CHIKV, we analyzed the levels of CHIKV envelope-specific antibodies present in the sera of C57BL/6 mice immunized with one or two doses of MVA-CHIKV (see Materials and Methods).…”

The Role of Innate versus Adaptive Immune Responses in a Mouse Model of O'Nyong-Nyong Virus Infection

“…Sections for hematoxylin and eosin (H&E) staining were prepared as previously described. 19,20 Statistics. Differences in animal weights were analyzed using two-way analysis of variance with a Tukey-Kramer posthoc test.…”