Chikungunya: vaccines and therapeutics

Background

Chikungunya virus (CHIKV) is an arthritogenic alphavirus of the Togaviridae family transmitted to humans by female Aedes mosquito vectors. Chikungunya viral disease (CHIKVD) affects all age groups, and symptoms present as fever, rash and severe, debilitating polyarthralgia that often progresses to a chronic stage^1,2. A significant manifestation is the loss of function of tarsal joints (hands, fingers and elbows), rendering simple activities extremely painful. In rare cases, CHIKVD can be fatal, particularly in the elderly, neonates and individuals with pre-existing conditions such as diabetes and cardiovascular disorders^3–5.

Unlike other alphaviruses, CHIKV sustains urban transmission between humans and mosquitoes causing large, sporadic epidemics such as those seen during the 2004–2006 outbreaks in Lamu Island⁶, La Reunion⁷ and Southern India⁸. From localised outbreaks in Southern and Southeast Asia, the epidemic has disseminated—potentially enhanced by international travel—and caused small outbreaks in Europe^9,10 and North America^11,12 while severely affecting territories in South and Central America and the Caribbean^13,14, and more than a million cases are reported annually. With elevating global temperatures facilitating the spread of Aedes mosquito, the strong potential for other mosquito species to carry CHIKV, poor vector controls and a lack of licensed vaccines or therapeutics, the risk for future epidemics stretching beyond the geographical confines of tropical, developing areas is increasing significantly. In this article, we explore recent findings and progress in the development of therapeutics and vaccines against CHIKV.

Current treatments

Current therapies for CHIKV-infected patients with arthritis/arthralgia mainly involve management of pain and inflammation using non-steroid anti-inflammatory drugs (NSAIDs), along with fluid intake to prevent dehydration. NSAIDs remain the primary approach for disease management as the use of aspirin may pose a risk of bleeding and potentially developing Reye’s syndrome, and the administration of corticosteroids is likely to cause immunosuppression and exacerbate the disease. In patients who exhibit limited response to NSAIDs or those with chronic CHIKVD, disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate, hydroxychloroquine and sulfasalazine have been reported to alleviate pain and joint swelling^15,16. As there are no licensed antivirals or vaccines available for CHIKVD, there is an imperative need for the development of novel and potent drugs and vaccines.

Therapeutics

Vaccines

Like all vaccines under development, CHIKV vaccine candidates developed via various technologies - such as live-attenuated virus vaccines, inactivated viral vaccine, recombinant viral vaccines, chimeric-alphavirus candidates, DNA vaccines and virus-like particles (VLPs) - require an optimal balance between immunogenicity and safety. Of the various vaccine candidates that are in pre-clinical studies, two (MV-CHIK and VRC-CHKVLP059-00-VP) have successfully completed phase I clinical trials^40–42.

The MV-CHIK vaccine is a recombinant measles virus (MV) that expresses CHIKV surface proteins from the La Reunion ECSA CHIKV strain⁴⁰. In pre-clinical studies, this vaccine protected mice from lethal CHIKV challenge after one or two immunizations⁴⁰. In a phase I trial (Vienna)⁴¹, 42 healthy adults (18–45 years) were evaluated with three different immunization doses. MV-CHIK elicited a strong neutralizing antibody response in all subjects following the first dose, which was further boosted after a second immunization with no reports of adverse events. Importantly, MV-CHIK showed no significant immunogenic response to pre-existing MV exposure. Phase II trials, where dosage levels are compared by assessing immunogenicity, safety and tolerability, began in August 2016⁴³ and are expected to be completed in June 2018.

In addition, a VLP vaccine, VRC-CHKVLP059-00-VP, the first VLP candidate to reach phase I trials, induced a strong immune response and protected against CHIKV infection in mice and non-human primates^44–46. The vaccine is composed of VLPs expressed on host cell–derived membrane transfected with a plasmid encoding CHIKV structural E1, E2 and capsid (C) proteins. The phase I study tested 25 healthy adults at three intramuscular immunization doses (10, 20 and 30 µg) administered at weeks 0, 4 and 24⁴⁷. The vaccine was well tolerated and produced high antibody titers against the eastern, central and southern African OPY1 CHIKV outbreak strains. Neutralizing antibody titers achieved after the third dose were reported to be comparable to titers found in recovering CHIKV-infected patient sera. A multi-centre phase II trial commenced in September 2015⁴⁸ with an estimated completion date in December 2017.

The VLP-based vaccines lack a live and replicating virus; instead, they consist of structural proteins of the virus which, alone or in combination, can elicit a protective immune response. It must be noted that a potential shortcoming of the VLP-based vaccines is that multiple immunizations or the use of adjuvants may be required to provide sufficient long-term immunity; this could enhance reactogenicity, impair the vaccine’s tolerability and increase the manufacturing cost of the vaccine.

Recently, vaccines based on mutation-attenuated virus have been the focus of pre-clinical studies. A study by Taylor et al. revealed that site-directed mutations in the nuclear localisation sequence (NoLS) of the N-terminal region of CHIKV capsid protein impaired viral replication in vitro and protected adult mice 30 days post-immunization from wild-type CHIKV infection⁴⁹. This attenuated CHIKV-NoLS vaccine also proved to be cross-protective by reducing peak viremia in immunized mice challenged with a related arthritogenic alphavirus, Ross River virus. Although traditional attenuated live viral vaccines are highly efficient, new approaches using chimeric virus vaccines are proving to be useful. A chimeric viral vaccine combining Eilat virus—an insect-specific alphavirus—and CHIKV structural proteins induced a rapid, long-lasting neutralizing antibody response in C57BL/6 and immunocompromised IFNα/βR^−/− mice after a single dose⁵⁰. This single-dose efficacy of the vaccine also stimulated similar immunogenicity and protected against CHIKV infection in cynomolgus macaques.

Conclusions

CHIKV outbreaks are sporadic and episodic, and the dissemination of CHIKV to the Caribbean and South and Central America is a strong reminder of the importance and urgency of effective treatments and vaccines. Vaccines are the most cost-effective method to prevent disease. While VLP- and MV-based vaccines have higher safety profiles, the cost of production and the potential requirement for additional boosters may discourage widespread use in resource-poor countries where CHIKV is endemic, such as India, Bangladesh and southern Indian Ocean islands. Various promising antiviral inhibitory drugs have been reported to be effective against CHIKV replication in vitro, and some studies have shown efficacy using in vivo alphavirus infection models. Similarly, the administration of neutralizing antibodies may prove to be highly efficient, although high manufacturing costs and the potential risks of hypersensitivity, immunosuppression and infections constitute significant shortcomings. The effectiveness of therapeutics and vaccine candidates from current research is dependent on capital investment, product stability and the long-term public health measures and preventative strategies in endemic regions. Moreover, substantial gaps in our understanding of the underlying mechanism of viral replication and acute/chronic disease clearly indicate that more research is needed to develop effective therapeutic and preventative strategies.