4.2.4. Virus-like particles (VLPs)

VLP vaccines are virus-like particles that do not contain replicative genetic material, but permit presentation of antigen in a repetitive, ordered array similar to the virion structure, which is thought to increase immunogenicity [25]. Thus, the safety concerns of virus vaccines regarding reversion mutants and immunocompromised individuals are obviated. The recombinant of VLP allows these vaccines to be usually manufactured large-scale in a cost-effective manner, following current good manufacturing practices. They induce quick and fulminant humoral immune responses by displaying antigens in an ordered and repetitive way. Their particulate nature and dimensions allows an efficient assimilation by dendritic cells (DCs) and transportation to lymph nodes, followed by presentation and induction of optimal immune responses. VLPs are renowned for inducing rapid and strong antibody responses. This trait is attributed to their dense, highly repetitive, quasi-crystalline structures [26], see Dengue vaccine candidates in Table 1.

4.3. Vaccines under clinical trials

Sanofi Pasteur's CYD vaccine is a live-attenuated tetravalent chimeric vaccine. In this vaccine, the premembrane and envelope proteins from a wild-type dengue virus corresponding to each of the four serotypes are substituted into the yellow fever (YF) 17D vaccine backbone. A strong neutralizing antibody response to DENV2 was elicited in the first CYD clinical trial in healthy adults, which evaluated only the serotype 2 vaccine strain. Participants previously given YF vaccine seroconverted to all four dengue serotypes [28]. The first licensed dengue vaccine, a live, attenuated, tetravalent dengue vaccine (CYD-TDV; Dengvaxia), has recently been registered in 15 countries as a three-dose immunization schedule administered subcutaneously at 6 month intervals [29]. In the case of Dengvaxia, vaccination of children with no previous infection (seronegative) may mimic an initial infection during the first step in the development of ADE. Because vaccine protection is incomplete and unequal against the four serotypes, a natural infection later in life can complete the sequence of events, causing ADE and severe, life-

Current Status of Vaccines against Dengue Virus http://dx.doi.org/10.5772/intechopen.80820 155

Following CYD-TDV introduction, it should be administered as a three-dose series given on a 0-/6-/12-month schedule. However, additional evidence is required in order to determine whether equivalent or better protection may be obtained through simplified schedules. In response to a delay in a vaccine dose for any reason, the vaccine course should be resumed (not restarted), maintaining the 6-month interval between subsequent doses. Given the 12 month duration of the immunization schedule and to enable better vaccine monitoring, countries should have vaccine tracking systems implemented. CYD-TDV is not recommended for use in children under 9 years of age, consistent with current labeling, in view of the association of CYD-TDV with increased risk of hospitalized and severe dengue illness in the 2- to 5-year age group. The target age for routine vaccination should be defined by each country, intended to maximize the vaccination impact and programmatic feasibility of targeting specific age groups. For instance, some countries may present the highest incidence of dengue illness among the adult age population and may consider vaccinating people up to 45 years of age in routine programs. The implementation of a routine CYD-TDV vaccination program at 9 years of age in settings meeting the criteria mentioned above is expected to contribute to a 10–30% reduction in symptomatic and hospitalized dengue illness over 30 years [31], see Table 2. This vaccine will be reviewed further in a separate section since, differently to other vaccines in this

The Laboratory of Infectious Diseases at the U.S National Institutes of Health has evaluated numerous monovalent and tetravalent dengue candidate vaccines to identify candidates with the most acceptable safety, infectivity, and immunogenicity profile. Among these, TV003 is an admixture of four live-attenuated recombinant dengue vaccine candidate viruses (rDEN1D30, rDEN2/4D30, rDEN3D30/31, and rDEN4D30) [36]. Various monovalent candidates were initially tested in Phase 1 trials in order to optimize each of the four vaccine virus strains. Vaccine virus serotypes 1, 3, and 4 are based on complete viruses, while serotype 2 is a recombinant

4.3.1. CYD-TDV Dengvaxia

threatening dengue fever [30].

section, Dengvaxia has already been registered.

4.3.2. TV003 and TV005 Dengue vaccine


Dengue vaccine candidates; adapted from Kirsten et al. [27].

Table 1. Dengue vaccine candidates.
