Next generation designer virus-like particle vaccines for dengue

ABSTRACT

Introduction: A safe and efficacious vaccine for dengue continues to be an unmet public health need. The recent licensing of a dengue vaccine (Dengvaxia) developed by Sanofi has brought to the fore the safety issue of vaccine-induced infection enhancement.

Areas covered: This article focuses on two new yeast-produced tetravalent dengue envelope domain III-displaying virus-like particulate vaccine candidates reported in early 2018 and reviews the rationale underlying their design, and pre-clinical data which suggest that these may offer promising alternate options.

Expert commentary: These are the only vaccine candidates so far to have demonstrated the induction of primarily serotype-specific neutralizing antibodies to all dengue virus serotypes in experimental animals. Interestingly, these antibodies lack infection-enhancing potential when evaluated using the AG129 mouse model.

KEYWORDS:

• Dengue vaccine
• virus-like particle
• Pichia pastoris
• envelope domain III
• live attenuated vaccine

Article highlights

• A safe and efficacious dengue vaccine for all continues to be elusive: A tetravalent LAV, CYD-TDV, has been licensed recently for individuals aged 9-45 years in endemic areas. However, this LAV tends to simulate a primary infection in dengue seronegative individuals, sensitizing recipients to severe dengue during a subsequent natural infection. Thus, a dengue vaccine for target populations of all age groups continues to be elusive. An ideal dengue vaccine must elicit predominantly protective antibodies, in the absence of pathogenic antibodies.

• Two VLP vaccine candidates have emerged: DENV EDIII has emerged as a preferable target for dengue vaccine development, as anti-EDIII antibodies possess not only superior serotype-specific virus neutralization capacity, but also lower ADE potential. Two alternate tetravalent VLP dengue vaccine candidates, DSV4 and T-mVLPs, both capable of displaying EDIIIs of all four DENV serotypes, produced using the yeast P. pastoris, have been developed recently.

• Encouraging pre-clinical data: Both these dengue VLP vaccine candidates elicit nAbs specific to the EDIIIs of the four DENV serotypes in mice. One of them (DSV4) has also been demonstrated to be effective at neutralizing multiple genotypes of each DENV serotype. This candidate is also immunogenic in monkeys eliciting tetravalent nAb response. Both the VLP vaccine candidates lack discernible infection enhancement capacity, demonstrated using the dengue-sensitive AG129 mouse model.

• Safety: The vaccines are made using a GRAS organism. Both are non-replicating vaccines, eliminating safety concerns associated with whole virus-based vaccines. The vaccines, which are structurally stable and lack detrimental epitopes, are based on eliciting immune response against the serotype-specific EDIIIs, reducing the risk of inducing cross-reactive infection-enhancing antibodies and the associated ADE risk.

• Efficacy: The use of a VLP display platform augments the immunogenicity of EDIII. This also helps focus the immune response to EDIII, which is involved in host receptor recognition and contains serotype-specific potent neutralizing epitopes. As a result, EDIII-directed antibodies are potent blockers of virus infectivity.

• Affordability: Both vaccine candidates are tetravalent, based on unique ‘4-in-1’ designs. This obviates the need for developing four monovalent vaccines to be mixed into a tetravalent formulation. Instead of four fermentations and four downstream processing protocols, these ‘4-in-1’ vaccine candidates can be produced in one fermentation followed by a single purification. Further cost-affordability is provided by the high expression potential of the P. pastoris host system.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest or conflict of interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was in part supported by the Department of Biotechnology, Government of India: ND/DBT/14/015; Sun Pharmaceuticals India Limited: ND/SPI/16/027; and The Wellcome Trust, UK: ND/WTL/14/012.