Recombinant envelope vaccine against flavivirus infection

Details Recombinant envelope vaccine against flavivirus infection Recombinant envelope vaccine against flavivirus infection

1999-07-13

2002-08-13

Wortman, Donna C. (Department: 1648)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Virus or component thereof

C424S186100, C424S279100, C424S283100

Reexamination Certificate

active

06432411

ABSTRACT:

TECHNICAL FIELD
The invention relates to vaccines designed to protect against flaviviral disease. More specifically, the invention concerns recombinant envelope (E) glycoprotein produced in cellular production systems and formulated with modern adjuvants that are shown to maximize 1) induction of high titer virus neutralizing antibodies believed to be important in protection against infection and 2) provide protection of immunized animals from virulent viral challenge.
BACKGROUND ART
The family Flaviviridae includes the family prototype yellow fever virus (YF), the four serotypes of dengue virus (DEN-1, DEN-2, DEN-3, and DEN-4), Japanese encephalitis virus (JE), Tick-borne encephalitis virus (TBE), and about 70 other disease causing viruses. Flaviviruses are small, enveloped viruses containing a single, positive-strand RNA genome. The envelope of flaviviruses is derived from the host cell membrane and is decorated with virally-encoded transmembrane envelope proteins. The E glycoprotein, which is the largest viral structural protein, contains functional domains responsible for cell surface attachment and intraendosomal fusion activities. It is also a major target of the host immune system, inducing virus neutralizing antibodies and protective immunity, as well as antibodies which inhibit hemagglutination.
Although flavivirus transmission and the pathology of infection are quite varied among the different viruses, Dengue viruses serve as an illustrative example of the family. Dengue viruses are transmitted to man by mosquitoes of the genus Aedes, primarily
A. aegypti
and
A. albopictus
. The viruses cause an illness manifested by high fever, headache, aching muscles and joints, and rash Some cases, typically in children, result in a more severe form of infection, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), marked by severe hemorrhage, vascular permeability, or both, leading to shock Without diagnosis and prompt medical intervention, the sudden onset and rapid progression of DHF/DSS can be fatal.
Dengue viruses are the most significant group of arthropod-transmitted viruses in terms of global morbidity and mortality with an estimated one hundred million cases of dengue fever occurring annually including 250,000 to 500,000 cases of DHF/DSS (Rigau Perez et al., 1998; Gubler, 1998). With the global increase in population, urbanization of the population especially throughout the tropics, and the lack of sustained mosquito control measures, the mosquito vectors of dengue have expanded their distribution throughout the tropics, subtropics, and some temperate areas, bringing the risk of dengue infection to over half the world's population. Modern jet travel and human emigration have facilitated global distribution of dengue serotypes, such that multiple serotypes of dengue are now endemic in many regions. Accompanying this there has been an increase in the frequency of dengue epidemics and the incidence of DHF/DSS in the last 15 years. For example, in Southeast Asia, DHF/DSS is a leading cause of hospitalization and death among children (Hayes and Gubler, 1992).
The flaviviral genome is a single, positive-strand RNA molecule, approximately 10,500 nucleotides in length containing short 5′ and 3′ untranslated regions, a single long open reading frame, a 5′ cap, and a nonpolyadenylated 3′ terminus. The complete nucleotide sequence of numerous flaviviral genomes, including all four DEN serotypes and YF virus have been reported (Fu et al., 1992; Deubel et al, 1986; Hahn et al, 1988; Osatomi et al., 1990; Zhao et al, 1986; Mackow et al., 1987; Rice et al., 1985). The ten gene products encoded by the single open reading frame are translated as a polyprotein organized in the order, capsid (C), premembrane/membrane (prM/M), envelope (E), nonstructural protein (NS) 1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5 (Chambers, et al. 1990). Processing of the polyprotein is initiated cotranslationally, and full maturation requires both host and virally-encoded proteases. The sites of proteolytic cleavage in the YF virus have been determined by comparing the nucleotide sequence and the amino terminal sequences of the viral proteins. Subsequent to initial processing of the polyprotein, prM is converted to M during viral release (Wengler, and Wengler, 1989) and anchored C is processed during virus maturation (Nowak and Wengler, 1989).
While all dengue viruses are antigenically related, antigenic distinctions exist which define the four dengue serotypes. Infection of an individual with one serotype provides long-term immunity against reinfection with that serotype but fails to protect against infection with the other serotypes. In fact, immunity acquired by infection with one serotype may potentially enhance pathogenicity by other dengue serotypes. This is particularly troubling as secondary infections with heterologous serotypes have become increasingly prevalent as the virus has spread, resulting in the co-circulation of multiple serotypes in many geographical areas and increased numbers of cases of DHF/DSS (Rigau Perez et al., 1998; Gubler, 1998). Halstead (1982) demonstrated that anti-dengue antibodies can augment virus infectivity in vitro, and proposed that serotype crossreactive, non-neutralizing antibodies to E enhance infection in vivo, resulting in DHF/DSS (Halstead, 1981). This viewpoint is not however, universally accepted (Rosen, 1989). In particular the dengue gene product which may be responsible for the enhanced pathogenesis remains the subject of some debate. For example, it has been proposed that dengue serotype-crossreactive CD4
+
CD8-cytotoxic T cells (CTLs) specific for NS3 may contribute to the pathogenesis of DHF/DSS by producing IFN-&ggr; and by lysing dengue virus-infected monocytes (Kurane et al., 1991; Okamoto et al., 1998; Mathew et al., 1998). Recent evidence demonstrating that CTLs specific for E are not serotype-crossreactive may suggest that use of E subunit vaccines would not induce the potentially harmful cross-reactive CTL response (Livingston et al., 1994). Other studies have suggested a potential role for NS1 in DHF/DSS (Falconer, 1997). Regardless of the mechanism for enhanced pathogenicity of a secondary, heterologous dengue infection, strategies employing a tetravalent vaccine should avoid such complications. Helpful reviews of the nature of the dengue disease, the history of attempts to develop suitable vaccines, structural features of flaviviruses in general, as well as the structural features of the envelope protein of flaviviruses are available (Halstead 1988; Brandt 1990; Chambers et al., 1990; Mandl et al., 1989; Henchal and Putnak, 1990; Putnak 1994; Rey et al., 1995; Rigau Perez et al., 1998; Gubler, 1998; Cardosa, 1998).
Although many approaches to dengue vaccines have been pursued, there is no acceptable vaccine currently available. While a significant amount of effort has been invested in developing candidate live-attenuated dengue vaccine strains, the strains tested to date have proven unsatisfactory (see, e.g., Eckels et al, 1984; Bancroft et al, 1984; McKee et al, 1987). Despite this limited success, live attenuated candidate vaccine strains continue to be developed and tested (Hoke et al, 1990; Bhamarapravati et al, 1987; Dharakul et al., 1994; Edelman et al., 1994; Angsubhakorn et al., 1994; Vaughn et al., 1996). The construction of several full-length infectious flavivirus clones (Rice et al., 1989; Lai et al., 1991; Sumiyoshi et al., 1992; Kapoor et al., 1995; Polo et al., 1997; Kinney et al., 1997; Gualano et al., 1998) has facilitated studies aimed at identifying the determinants of virulence in flaviviruses (Bray and Lai, 1991; Chen et al., 1995; Kawano et al., 1993; Cahour et al., 1995; Men et al., 1996; Hiramatsu et al., 1996; Pryor et al., 1998; Lai et al., 1998; Gualano et al., 1998; Valle and Falgout, 1998). While these studies remain quite preliminary and little information on virulence has been obtained, the cDNA clones derived from these studies are being used as a backbone for development of r

Affiliated with

Also associated with

Rating

Recombinant envelope vaccine against flavivirus infection does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Recombinant envelope vaccine against flavivirus infection, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Recombinant envelope vaccine against flavivirus infection will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2923047