Safety and immunogenicity of tetravalent live-attenuated dengue vaccines in Thai adult volunteers: role of serotype concentration, ratio, and multiple doses.

Abstract

Abstract. Dengue fever, caused by four serotypes of a mosquito-borne virus, is a growing problem in tropical countries. Currently, there is no treatment or vaccine. We evaluated safety and immunogenicity of two doses, given six months apart, of seven formulations of dengue tetravalent live-attenuated vaccine (containing different concentrations of the component viruses) versus placebo in 59 flavivirus-seronegative Thai adults. The first dose was the more reactogenic. Most volunteers experienced clinically moderate fever, headache, myalgia, eye pain or rash 7-11 days after injection, generally lasting three days or less. Modest decreases in platelets and neutrophils were observed. After one dose, 58% of dengue recipients seroconverted (neutralizing antibody level Ն 1:10) against Ն 3 serotypes; 35% seroconverted against all four. After the second dose, seroconversion was 76% and 71%, respectively. All subjects seroconverted to serotype 3 after one dose. Serotype 4 elicited the lowest primary response but the highest increase in seroconversion after the second dose.

Dengue virus type 3 vaccine candidates generated by introduction of deletions in the 3′ untranslated region (3′-UTR) or by exchange of the DENV-3 3′-UTR with that of DENV-4

“…Unfortunately, previous attempts to develop a tetravalent, live attenuated vaccine against the DENV have found that one or more vaccine components exhibited either under-or over-attenuation resulting in unacceptable reactogenicity or poor immunogenicity, respectively [10,11]. Modification of the concentration of one of the serotypes in a tetravalent vaccine has not been able to reliably correct problems of reactogenicity or over-attenuation [12][13][14]. Therefore, it appears that the path towards generation of an efficacious, live attenuated tetravalent DENV vaccine will include the development and evaluation of multiple vaccine candidates for each serotype to identify four individual viruses that can be combined into a formulation that successfully balances attenuation and immunogenicity.…”

Development of DENVax: A chimeric dengue-2 PDK-53-based tetravalent vaccine for protection against dengue fever

“…Due to the predominance of DEN-3 virus replication, and increased clinical symptoms with formulations that included the DEN-3 vaccine, several formulations with higher concentrations of the DEN-1, DEN-2 and DEN-4 components and a lower dose of the DEN-3 component were tested in adults (N = 59 total for seven formulations [37]) and children (N = 40 and N = 42 for each of two different formulations [38]). In these studies, the DEN-3 virus was still the dominant replicating vaccine virus and still dominated the immune responses.…”

Immunogenicity of a Candidate DNA Vaccine Based on the <i>prM/E</i> Genes of a Dengue Type 2 Virus Cosmopolitan Genotype Strain

“…Vaccination is a preventative method that may prove successful, as it has with other infectious diseases (3). Several dengue vaccine candidates are being developed using different approaches, such as live attenuated (4)(5)(6)(7)(8), chimeric (8)(9)(10), recombinant subunit (8,(11)(12)(13)(14), and DNA vaccines (8,(15)(16)(17)(18)(19).…”