Vaccines licensed and in clinical trials for the prevention of dengue

Abstract

Dengue has become a major global public health threat with almost half of the world's population living in at-risk areas. Vaccination would likely represent an effective strategy for the management of dengue disease in endemic regions, however to date there is only one licensed preventative vaccine for dengue infection. The development of a vaccine against dengue virus (DENV) has been hampered by an incomplete understanding of protective immune responses against DENV. The most clinically advanced dengue vaccine is the chimeric yellow fever-dengue vaccine (CYD) that employs the yellow fever virus 17D strain as the replication backbone (Chimerivax-DEN; CYD-TDV). This vaccine had an overall pooled protective efficacy of 65.6% but was substantially more effective against severe dengue and dengue hemorrhagic fever. Several other vaccine approaches have been developed including live attenuated chimeric dengue vaccines (DENVax and LAV Delta 30), DEN protein subunit V180 vaccine (DEN1-80E) and DENV DNA vaccines. These vaccines have been shown to be immunogenic in animals and also safe and immunogenic in humans. However, these vaccines are yet to progress to phase III trials to determine their protective efficacy against dengue. This review will summarize the details of vaccines that have progressed to clinical trials in humans.

Keywords: dengue; dengue vaccines; immune response; neutralising antibody; preventative vaccination.

Figure 1.

CYD TDV is recombinant live-attenuated chimeric yellow-fever-dengue virus tetravalent vaccine that was produced by replacing the prM and E of the 17D yellow fever vaccine virus with the prM and E proteins of DEN-1, -2, -3 or -4 viruses.

Figure 2.

DENVax TDV consists of a live attenuated DENV-2 strain (TDV-2) and three chimeric viruses that contain the prM and E proteins of DENV-1, 3 and 4 on the attenuated DENV-2 genome backbone (TDV-1, -3 and -4).

Figure 3.

LAV Delta 30 consists of live attenuated viral vaccines that carry nucleotide deletions or that have been chimerized. The DEN-1 and -4 viruses carry a 30 nucleotide deletion in the 3’ untranslated region (UTR) of the genome (rDEN1-delta30 and rDEN4-delta30). The DEN-3 virus carries a 30 and 31 nucleotide deletion in to the 3’UTR of DEN3 (rDEN3 delta30/31). The DEN-2 virus was produced by replacing the prM and E proteins of the rDEN4delta30 virus with those of DEN-2 to produce a chimeric attenuated virus (rDEN2/4delta30).

Figure 4.

DEN protein subunit V180 vaccine (DEN-80E) is a recombinant envelope glycoprotein subunit vaccine that consists of a recombinant E truncated protein containing 80% of the N-terminal DENV E protein (DEN-80E). The truncated dengue envelope proteins (DEN-80E) for all four dengue virus types are expressed in the Drosophila S2 expression system to produce a tetravalent vaccine.

Figure 5.

The D1ME100 vaccine is a monovalent DNA plasmid vaccine containing the pre-membrane (prM) and envelope (E) genes of DENV-1 virus. The plasmid contains regulatory elements including a CMV promoter, and CMV intron A, a BGH terminator and kanamycin resistance gene. Coding sequences of the DENV prM/E, genes and their orientation in the plasmid are indicated by arrows. Adapted from ref. .