Several vaccine strategies have been attempted for the development of dengue vaccine. These are live attenuated vaccine, inactivated vaccine, subunit vaccine, DNA vaccine, vector based vaccine and virus-like particles. Amongst these, several live attenuated vaccines have reached phase III clinical trial. The only dengue vaccine which has got the licensure so far is also a variety of live attenuated vaccine.

Live Attenuated Vaccine

The methods used for attenuation are passage in cell culture, site directed mutagenesis and chimeric vaccine. Low replication capacity in humans and mosquitoes are desirable to decrease the risk of symptomatic infection and vector borne transmission of the vaccine virus.

Cell culture passage based live attenuated vaccine: Mahidole University, Bangkok, Thailand, was the first one to develop a tetravalent dengue LAV by attenuating DEN1, DEN2 and DEN4 strains in primary dog kidney (PDK) cells and DEN3 in primary African monkey kidney cells followed by fetal rhesus monkey lung cells. However, the vaccine failed to mount a balanced immune response to all the dengue serotypes and due to occurrence of increased frequency of adverse reactions like fever, rash, myalgia and retro-orbital pain, the further development of vaccine was stopped.

Walter Reed Army Institute of Research (WRAIR), Maryland, USA developed a tetravalent LAV with GlaxoSmithKline (GSK) where all the four dengue serotypes were attenuated by passaging in PDK cell line. Several formulations of this vaccine were tried with different concentration of four dengue serotypes. However, phase II clinical trials with different formulations of tetravalent vaccine showed inconsistent result regarding DEN-4 potency.

Target mutagenesis based live attenuated vaccine: Laboratory of Infectious Disease at National Institute of Allergy and Infectious Disease (NIAID) and National Institute of Health (NIH), Maryland, USA used this strategy of site-directed mutagenesis for attenuation of dengue virus strains. Dengue virus strains (DEN 1–4) were attenuated by targeted deletion of 30 nucleotides in 3’ untranslated region (UTR) of full length complementary DNA clones. This candidate vaccine contains DENV1D30 and DENV4 D30 attenuated DEN 1 and DEN 4, respectively. DEN 2 and DEN 3 attenuated strains were prepared by using the backbone of DEN-4 D30 which is replaced with serotype specific prM and E gene. Various tetravalent preparations are under clinical trial. TV003 contains 10³ pfu of each dengue virus serotype and TV005 contains 10³ pfu of all except DEN 2 which is present at a 10-fold higher concentration (10⁴ pfu). Various vaccine manufacturers in different countries have got license from NIH for its development (Instituto Butantan in Brazil, Vabiotech in Vietnam and Panacea Biotech and Serum Research Institute in India). Presently phase III clinical trial of this vaccine is ongoing in Brazil.

Chimeric dengue vaccine: Chimeric dengue vaccines are made of two varieties: (i) Chimera with another attenuated flavivirus, and (ii) inter typic chimera with another dengue virus serotype.

i. Dengvaxia: Chimeric yellow fever dengue tetravalent dengue vaccine (CYD-TDV) is the only licensed vaccine available so far against dengue virus infection.

This is a recombinant chimeric live attenuated tetravalent vaccine. It contains the structural genes (pre-membrane and envelop proteins) of dengue virus 1, 2, 3 and 4 in the backbone of 17 D strain of yellow fever virus (genes of capsid and non-structural proteins). This is made with the concept that the structural proteins of dengue virus (prM and E gene) are responsible for production of neutralizing antibodies during natural infection, so chimeric vaccine containing these genes would mount the protective immunity in vaccine.

It induces neutralizing antibodies against the envelop protein of the virus and thus prevents the entry of virus into the host cell.

Two large scale phase III clinical trials have been conducted—one in five countries of Asia Pacific region in children of 2–14 years of age where CYD-TDV or placebo was given in 3 doses (0, 1, 6 months) and were followed up till 25 months, another phase III clinical trial was conducted in five dengue endemic Latin American countries in children of 9–16 years age.

 • The overall efficacy was found to be 56–61% against dengue infection and 67–80% against hospitalization.

• Vaccine efficacy was 67.8% in children > 9 years and 44.6% in children < 9 years age. Efficacy was further lower in children < 9 years age in dengue naïve areas (14.4%).

• Increased risk of hospitalization was observed in children < 9 after 2 years of vaccination.

• Efficacy was maximum against dengue type 4, followed by type 3, type 1 and type 2.

It is manufactured by Sanofi-Pasteur and licensed in December, 2015. In 2017, Sanofi Pasteur announced that the people who have been vaccinated with dengvaxia but not been infected previously with dengue virus may develop severe disease if infected naturally with dengue virus after vaccination. Considering this, WHO currently recommends dengvaxia only in persons who have had confirmed previous infection.

Considering the poor efficacy of vaccine in children < 9 years and population in dengue naïve areas, vaccine has been recommended for the age group of 9–45 years individuals in the dengue endemic countries with three-dose schedule in 0–1–6 months.

ii. Intertypic chimeric vaccine: DENVax is a intertypic chimeric tetravalent vaccine. It contains DEN 2 strain which is attenuated by several PDK cell passage. This attenuated DEN 2 strain is used as the backbone for construction of other three dengue virus strains by replacing its prM and E genes with the corresponding serotype specific genes. Vaccine is manufactured by Inviragen Inc., Fort Collins Co, USA. Phase I study shows the vaccine as safe and immunogenic. Currently the vaccine is under phase III trial.

Tetravalent inactivated virus vaccine, recombinant dengue E protein subunit vaccine and tetravalent DNA vaccines with prM and E gene have also been developed and currently under phase I clinical trial.

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مواضيع ذات صلة

Vaccination (Active Immunoprophylaxis)

Applications of Vaccines

Viral Vaccines

Microbiota, Chronic Infections, and Vaccines

Vaccines and the Role of Pre-existing Immunity

Examples of Protein Subunit Vaccines

Methods for Using Full-Length Antigens (Proteins) as Vaccines

Pan-Genomic Analysis

Reverse Vaccinology

Improving Vaccines over Natural Immune Responses

Selecting Vaccine Antigens

Principles of Vaccine Development