Does structurally-mature dengue virion matter in vaccine preparation in post-Dengvaxia era?

Abstract

The unexpectedly low vaccine efficacy of Dengvaxia®, developed by Sanofi Pasteur, and a higher risk of severe diseases after vaccination among dengue-naive children or children younger than 6 years old, have cast skepticism about the safety of dengue vaccination resulting in the suspension of school-based immunization programs in the Philippines. The absence of immune correlates of protection from dengue virus (DENV) infection hampers the development of other potential DENV vaccines. While tetravalent live-attenuated tetravalent vaccines (LATVs), which mimic natural infection by inducing both cellular and humoral immune responses, are still currently favored, developing a vaccine that provides a balanced immunity to all four DENV serotypes remains a challenge. With the recently advanced understanding of virion structure and B cell immune responses from naturally infected DENV patients, two points of view in developing a next-generation dengue vaccine emerged: one is to induce potent, type-specific neutralizing antibodies (NtAbs) recognizing quaternary structure-dependent epitopes by having four components of vaccine strains replicate equivalently; the other is to induce protective and broadly NtAbs against the four serotypes of DENV with a universal vaccine. This article reviews the studies related to these issues and the current knowledge gap that needs to be filled in.

Chimeric flavivirus enables evaluation of antibodies against dengue virus envelope protein in vitro and in vivo

“…In terms of maturation, DV2ChimV may produce mature virions at a higher rate than DENV-2 in IFN-α/βR–γR dKO mice. However, it is still unclear whether virion particle heterogeneity influences DENV serotypes, genotypes, or strains 38 . So far, there has been no report about the degree of maturity of DENV in mice.…”

The Dengue Vaccines: Assessment of Future Prospects, Treatment, and Vaccine Challenges

“…In the initiative of developing a DENV vaccine, Sanofi Pasteur is the furthest one currently [48][49][50][51][52][53][54][55]. The centers for prevention and disease control in the United States have also developed a chimeric dengue vaccine, DENV-axe, which has been licensed to Inviragen, Inc.…”

Challenges and solutions in the development of vaccines against emerging and neglected infectious diseases

“…17 In this study, administration of immune serum from vaccinated subjects protected 92% of immunosuppressed IFNAR mice against lethal ZIKV challenge infection independent of the presence (or absence) of neutralizing antibodies as defined by Vero cell assay, whereas neutralization was 95% against infection of U87MG neuroblastoma cells, paralleling the in vivo infection studies. 17 Galula et al 18 further discusses the dengue vaccine landscape and the effect of maturation of envelope dimers that coat and protect the virion. The authors note that antibodies against E dimer epitopes present on fully formed virions are highly neutralizing at picomolar concentrations, whereas antibodies against the fusion loop (FL) region of domain II of the envelope that is exposed prior to full maturation are highly immunogenic but poorly protective, especially for serotype 2.…”