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Sequential immunization induces strong and broad immunity against all four dengue virus serotypes.

ABSTRACT: A major challenge in dengue vaccine development is the need to induce immunity against four dengue (DENV) serotypes. Dengvaxia®, the only licensed dengue vaccine, consists of four variant dengue antigens, one for each serotype. Three doses of immunization with the tetravalent vaccine induced only suboptimal protection against DENV1 and DENV2. Furthermore, vaccination paradoxically and adversely primes dengue naïve subjects to more severe dengue. Here, we have tested whether sequential immunization induces stronger and broader immunity against four DENV serotypes than tetravalent-formulated immunization. Mice were immunized with four DNA plasmids, each encoding the pre-membrane and envelope from one DENV serotype, either sequentially or simultaneously. The sequential immunization induced significantly higher levels of interferon (IFN)γ- or tumor necrosis factor (TNF)α-expressing CD4⁺ and CD8⁺ T cells to both serotype-specific and conserved epitopes than tetravalent immunization. Moreover, sequential immunization induced higher levels of neutralizing antibodies to all four DENV serotypes than tetravalent vaccination. Consistently, sequential immunization resulted in more diversified immunoglobulin repertoire, including increased complementarity determining region 3 (CDR3) length and more robust germinal center reactions. These results show that sequential immunization offers a simple approach to potentially overcome the current challenges encountered with tetravalent-formulated dengue vaccines.

SUBMITTER: Hou J

PROVIDER: S-EPMC7382454 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Any potential dengue virus (DENV) vaccine needs to elicit protective immunity against strains from all four serotypes to avoid potential antibody-dependent enhancement (ADE). In this study, four independent DENV envelope (E) glycoproteins were generated using wild-type E sequences from viruses isolated between 1943 and 2006 using computationally optimized broadly reactive antigen (COBRA) methodology. COBRA and wild-type E antigens were expressed on the surface of subvirion viral particles (SVPs). Four separate wild-type E antigens were used for each serotype. Mice vaccinated with wild-type DENV SVPs had anti-E IgG antibodies that neutralized serotype-specific viruses. COBRA DENV SVPs elicited a broader breadth of antibodies that neutralized strains across all four serotypes. Two COBRA DENV vaccine candidates that elicited the broadest breadth of neutralizing antibodies in mice were used to vaccinate rhesus macaques (Macaca mulatta) that either were immunologically naive to any DENV serotype or had preexisting antibodies to DENV. Antibodies elicited by COBRA DENV E immunogens neutralized all 12 strains of DENV in vitro, which was comparable to antibodies elicited by a tetravalent wild-type E SVP vaccination mixture. Therefore, using a single DENV COBRA E protein can elicit neutralizing antibodies against strains representing all four serotypes of DENV in both naive and dengue virus-preimmune populations.IMPORTANCE Dengue virus infects millions of people living in tropical areas of the world. Dengue virus-induced diseases can range from mild to severe with death. An effective vaccine will need to neutralize viruses from all four serotypes of dengue virus without inducing enhanced disease. A dengue virus E vaccine candidate generated by computationally optimized broadly reactive antigen algorithms elicits broadly neutralizing protection for currently circulating strains from all four serotypes regardless of immune status. Most dengue vaccines in development formulate four separate components based on prM-E from a wild-type strain representing each serotype. Designing a monovalent vaccine that elicits protective immunity against all four serotypes is an effective and economical strategy.

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Sequential immunization induces strong and broad immunity against all four dengue virus serotypes.

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