1. Different vaccines for Dengue and their efficacy

Around 390 million Dengue viral infections occur annually and out of which 96 million people are clinically ill with sign and symptoms caused by four different serotypes of dengue viruses (Dengue virus serotype 1, DENV1, DENV2, DENV3 and DENV4).  However, there is no any specific medicine for treatment till date. The only mean of control for dengue virus infection is control of vector. Vaccines in the other way have been developed for the prevention of dengue infections. Many of vaccines are under the clinical trials while one of them has already been licensed in Asia and Latin America instead of few minor drawbacks (da Silveira et al., 2019; Deng et al., 2020).

An ideal dengue vaccine candidate should have at least target to all four serotypes of dengue viruses; DENV1 to DENV4 (tetravalent). The candidate vaccine should be low reactogenic, highly immunogenic providing lifelong immunogenicity, effective with minimal or no repeat immunizations, minimize the cost of production and finally should have high efficacy. Except few vaccines, most of the vaccines couldn’t meet these requirements because of which only a few vaccines are under the progress.

Till now, five different types of vaccines have been developed. These are live attenuated vaccines, inactivated vaccines, recombinant subunit vaccines, viral vectored vaccines and DNA vaccines. All of the vaccines act primarily by increasing immune responses against dengue virus envelope (E) protein and non-structural protein (NS-1).  Two major challenges have been faced in the course of ideal vaccine development. The first one is the antibody dependent enhancement (ADE-related complications) related complications which may lead to dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) among the seronegative children of less than 9 years. This effect is seen resulting from a second heterotypic infection (infection from different serotype) in which the preformed neutralizing antibodies against cross reactive serotype are not sufficient to neutralize the new serotype. Secondly, there is lack of conveniently accessible cheap and sensitive animal models capable of stimulating the immune response in human after infections by vaccines. Since mice are naturally resistant to DENV infections and non-human primates are good animal model but very expensive to use in the experiment. Because of which vaccines have to be tested on human cell chimeric mice and immunodeficient mice that are comparatively less convenient for vaccines evaluation (da Silveira et al., 2019; Deng et al., 2020).

The live attenuated vaccines contain antigenic substances composed of living viruses making them weak or avirulent. They will deliver a set of protective antigens. The immune responses against those antigens provide long term immune protectivity to host. Chimeric yellow fever 17D virus-tetravalent dengue vaccine (CYD-TDV) commercially known as Dengvaxia, recombinant DENV4 mutant bearing a 30-nucleotide deletion vaccine (rDEN4D30) and tetra-live attenuated virus dengue vaccine (DENVax) are examples of live attenuated vaccines. The only licensed dengue vaccine is Sanofi Pasteur’s Dengvaxia®(CYD-TDV) which is constructed by replacing prM/E RNAs of Yellow fever virus vaccine strain (YE 17D) with the structural pre-membrane (prM) and envelop (E) genes from all four serotypes of dengue virus. Recently, the vaccine has been registered in 20 dengue endemic countries, however, immunization was implemented in only two countries, Brazil and the Philippines. The vaccines are highly effective among the children older than 9 years and the immunity lasts for 4 years. The efficacy of the vaccine is however influenced by the age, virus serotypes and immune status of children (seropositive or seronegative) at the time of immunization. Due to higher risk of ADE related complication and increased hospitalization among the seronegative cases, WHO Strategic Advisory Panel-2018 updated the need of priority screening of DENV serostatus before vaccination. The problem is still unsolved because of sensitivity and specificity of rapid diagnostic kits used for prior screening of dengue infections (Deng et al., 2020; Thomas and Yoon, 2019)

Although only CYD-TDV vaccine has been licensed till date, many more vaccines are on the way of progressing at different phases in clinical trials.  Inactivated virus vaccines are safer to use but less immunogenic. They are prepared from inactivated materials; capsid (C), membrane (M), envelop (E) and NS1 proteins from the viruses which can stimulate the immune response. The protectivity of such vaccines are poor. DEN2 inactivated vaccines S16803 prepared from formalin inactivation fails to arise stable antibody titers in rhesus monkey. The other inactivated vaccines; tetravalent purified formalin inactivated virus vaccine (TPIV) containing inactivated dengue serotypes or tetravalent DNA vaccine enhance the humoral immunity when given with live attenuated vaccines. Likewise, recombinant subunit vaccines are composed of antigenic proteins which are expressed by prokaryotic and eukaryotic cells. The expression of antigens in E. coli is easy but there is a problem of endotoxin contamination or misfolding of proteins in different organisms. These proteins are quite protective in mice. Tetravalent recombinant subunit vaccines when given with alum adjuvant elicit DENV2 antibodies in macaques. EDIII-P64K contains P64K antigens expressed in Neisseria meningitidis and EDIII of different dengue serotypes. The vaccines induce high tires of DENV1-DENV3 antibodies but low titre of DENV4 antibodies. The viral vectored vaccines use Vaccinia, Adeno and Alphavirus as vectors to express DENV antigens prM, E, NS1 and NS2A proteins. The non-attenuated (WR) cidofobir resistant vaccinia strain is used as safe vector but induce low level of specific antibodies against the E protein in mice. Among the virus vectors, Adeno virus is easier in gene manipulation and high level of protein expression while Alphavirus has high potential and high level of antigen expression in a single round of vaccination. The last one is DNA vaccine which is composed of a plasmid containing one or more genes encoding specific antigens of viruses. The plasmid is used to expressed prM and E proteins of virus. E80 vaccine expressing 80% E protein shows less immunogenic than EM100 which expresses prM protein and 100% E protein. In human test, D1ME100 showed safe and well tolerated. DNA vaccine alone induced a moderate level of neutralizing antibodies while it combined with recombinant proteins induced higher titers of antibodies. Despite of its stability, easy in preparation and low cost, DNA vaccines lack high immunogenicity (Deng et al., 2020; Thomas and Yoon, 2019).

As described above, there are five types of vaccines against DENV each type has its own pros and cons. Among the dengue vaccine candidates, live attenuated tetravalent dengue vaccine (CYD-TDV) can stimulate neutralizing antibodies in humans, but response to DENV2 virus is low. Many studies also reported ADE related hospitalization among immunized children. The other live attenuated vaccine, DENV monovalent vaccines with live attenuated tetravalent vaccines (LATV); rDEN4D30 and Live attenuated chimeric tetra Dengue vaccines; DENV2 PDK-53 (DENVax) have attempted to overcome the problem of adverse effects and high level of induced immune balance. They are somehow succeeded as well but they need to be evaluated more. These vaccines are under phase III clinical trials and not on the way of pilot survey. Despite of few drawbacks of Dengvaxia vaccine, it is succeeded to reduce mortality and morbidity by dengue infection in endemic regions. Hence, WHO also approved this vaccine but with updated strategic plan for screening of serostatus of vaccinees. On the basis of the results from clinical trials, the vaccine is no doubt in superiority with other vaccines. Regarding the safety and immunogenicity studies, Dengvaxia’s® acute safety profile was found to be similar to licensed Yellow fever vaccine and not affected by pre-existing Yellow fever immunity. In three clinical endpoint studies, Dengvaxia® maintained the positive acute safety and reactogenicity profile established in early clinical studies. In conclusion, the vaccine is safe, highly immunogenic and low reactogenic with satisfactory efficacy. The vaccine contains no adjuvant or preservatives or material of porcin origin, highly stable and available in powder form with separate solvent (Rosa et al., 2019; Thomas and Yoon, 2019). Till now there is no any other vaccines which can meet such criteria to be an ideal vaccine, therefore in current scenario, CYD-TDV (Dengvaxia) is the best vaccines for control of dengue infections.

 

References:

1.      da Silveira LTC, Tura B, and Santos M.  Systematic review of dengue vaccine efficacy. BMC Infectious Diseases. 2019; 19: 750.

2.      Deng S, Yang X, Wei Y, Chen J, Wang X, and Peng H. A Review on Dengue Vaccine Development. Vaccines. 2020; 8: 63. doi:10.3390/vaccines8010063.

3.      Rosa BR, Cunha AJLA, and Medronho RA. Efficacy, immunogenicity and safety of a recombinant tetravalent dengue vaccine (CYD-TDV) in children aged 2–17 years: systematic review and meta-analysis. BMJ Open. 2019; 9: e019368. doi:10.1136/bmjopen-2017-019368.

Thomas SJ and Yoon I. A review of Dengvaxia®: development to deployment. Human Vaccines & Immunotherapeutics. 2019; 15 (10): 2295–2314.