A Phase II clinical vaccine trial, sponsored by the US Government in 2000, used a live, attenuated virus, developing viral resistance in 98% of those tested after 28 days and 85% still showed resistance after one year. However, live chikungunya vaccines are still questionable as there could be a risk of a live vaccine possibly inducing chronic rheumatism.

DNA vaccination is a technique for protecting an organism against disease by injecting it with genetically engineered DNA to produce an immunological response. Nucleic acid vaccines are still experimental, and have been applied to a number of viral, bacterial and parasitic models of disease, as well as to several tumour models. DNA vaccines have a number of advantages over conventional vaccines, including the ability to induce a wider range of immune response types. A recent study supports a novel consensus-based approach to vaccine design for chikungunya virus employing a DNA vaccine strategy. The vaccine cassette was designed based on chikungunya virus Capsid and Envelope specific consensus sequences with several modifications, including codon optimization, RNA optimization, the addition of a Kozak sequence, and a substituted immunoglobulin E leader sequence. Analysis of cellular immune responses, including epitope mapping, demonstrates that these constructs induces both potent and broad cellular immunity in mice. In addition, antibody ELISAs demonstrate that these synthetic immunogens are capable of inducing high titer antibodies capable of recognizing native antigen. Taken together, these results support further study of the use of consensus CHIKV antigens in a potential vaccine cocktail.

As of 2019, no approved vaccines are available. A phase-II vaccine trial used a live, attenuated virus, to develop viral resistance in 98% of those tested after 28 days and 85% still showed resistance after one year. However, 8% of people reported transient joint pain, and attenuation was found to be due to only two mutations in the E2 glycoprotein. Alternative vaccine strategies have been developed, and show efficacy in mouse models. In August 2014 researchers at the National Institute of Allergy and Infectious Diseases in the USA were testing an experimental vaccine which uses virus-like particles (VLPs) instead of attenuated virus. All the 25 people participated in this phase 1 trial developed strong immune responses. As of 2015, a phase 2 trial was planned, using 400 adults aged 18 to 60 and to take place at 6 locations in the Caribbean. Even with a vaccine, mosquito population control and bite prevention will be necessary to control chikungunya disease.