An Immunogenic and Protective Alphavirus Replicon Particle-Based Dengue Vaccine Overcomes Maternal Antibody Interference in Weanling Mice

Abstract

Dengue viruses (DENV) are members of the family Flaviviridae and one of the most important groups of emerging viruses of global significance today (36, 66). There are four distinct antigenic serotypes (DENV1, DENV2, DENV3, and DENV4), all of which are capable of causing a spectrum of diseases in humans ranging from asymptomatic infections to debilitating classical dengue fever and severe and often fatal dengue hemorrhagic fever/dengue shock syndrome (DHF/ DSS) (36,68). DENV is transmitted to humans primarily by the mosquito Aedes aegypti. The lack of effective mosquito control, as well as demographic and economic changes, has contributed to the dramatic expansion and worldwide distribution of DENV epidemic activity in tropical and subtropical areas (36). It is estimated that up to 100 million infections and several hundred thousand cases of DHF/DSS occur each year, with more than 2.5 billion people living in areas at risk of infection in 2004 (21, 68). DHF is a leading cause of hospitalization and death among children in many countries in Southeast and South Asia, and the WHO has reported a rising trend in disease over the past decade (68). At the peak of epidemic times, as many as 70 children with severe DHF may present to a single hospital in a day, 20 of them with potentially fatal DSS (58). Although DHF/DSS in infants has not been comprehensively studied, it is estimated that more than 5% of all DHF/ DSS cases occur in infants (26,33,41,43,56,67,70).In the absence of vector control effective on a global scale, there is a clear need for a DENV vaccine. However, the development of a DENV vaccine has faced significant challenges that have resulted in the lack of a licensed vaccine after 70 years of research (17). In many areas where there is cocirculation of two or more serotypes, there is a high probability that individuals will be infected more than once in their lifetimes. Preexisting homotypic immunity protects from a secondary infection with the same serotype, and this protection seems to last for life (24,25). However, preexisting heterotypic nonneutralizing immunity to a secondary infection with a different DENV serotype is a risk factor for the development of severe DHF/DSS (23, 27, 61). These considerations suggest that a safe and efficacious DENV vaccine must be tetravalent and induce a long-term and balanced immune response to all four serotypes simultaneously in order to avoid sensitizing the vaccine recipient to a more severe outcome during a subsequent DENV infection. Additionally, primary infections during the first year of life that result in DHF/DSS have been associated with the presence of subneutralizing levels of maternal anti-DENV antibodies, which may increase the risk of enhanced infection and disease by antibody-mediated enhancement (26,33,41,56). To protect infants and children in dengue-endemic countries from severe dengue, the ideal DENV vaccine should

Dengue vaccine–induced CD8+ T cell immunity confers protection in the context of enhancing, interfering maternal antibodies

“…Our study did not find evidence of seroconversion and instead supported the occurrence of maternal antibody interference, a phenomenon that is well documented in human and veterinary medicine (29). Our observations are also consistent with an earlier study reporting the ability of maternal DENV2 antibodies to block seroconversion despite 2 injections of DENV2 New Guinea C (NGC) strain in BALB/c pups (61). Several mechanisms have been proposed to explain maternal antibody interference that may not be mutually exclusive.…”

An Alphavirus Vector-Based Tetravalent Dengue Vaccine Induces a Rapid and Protective Immune Response in Macaques That Differs Qualitatively from Immunity Induced by Live Virus Infection

“…DENV genes were cloned into the VEE replicon plasmid, pVKE (pVR21 with KanR and EcoRV) (28), as follows. Viral RNA was extracted from virus growth culture media and used as the template to generate cDNA by reverse transcription-PCR.…”

“…Two doses of DENV2 prME-VRP were immunogenic and protective in BALB/c mice (28) and, when formulated as a tetravalent VRP cocktail, induced balanced responses that lasted at least 71 weeks after the second dose (L. J. White, unpublished data).…”

“…A number of nonpropagating vaccine strategies are in development. They include (i) adjuvanted recombinant E protein expressed in Drosophila S2 cells (reviewed in reference 22), currently in phase 1 clinical testing; (ii) plasmid DNA expressing prM and E proteins, currently in phase 1 clinical testing (23); (iii) adjuvanted inactivated virus (24); (iv) modified adenovirus and alphavirus as viral vectors expressing DENV envelope protein sequences (25)(26)(27)(28); and (v) recombinant E domain III (29-32; reviewed in references 33 and 34).…”

An Alphavirus Replicon-Based Human Metapneumovirus Vaccine Is Immunogenic and Protective in Mice and Cotton Rats

“…Second, these replicons are potential vaccine vectors for use in very young infants, since they are encapsidated in a heterologous VEE coat that shields them from maternal hMPV-specific antibodies. Recently, these replicons were found to induce neutralizing antibody responses in young mice, regardless of the maternal immune status (45). In addition, these VEE replicon particles appear to induce novel aspects of mucosal immunity that other approaches do not.…”