An evaluation of dengue type-2 inactivated, recombinant subunit, and live-attenuated vaccine candidates in the rhesus macaque model

Putnak, J. Robert; Coller, Beth-Ann; Voss, Gérald; Vaughn, David W.; Clements, David E.; Peters, Iain D.; Bignami, Gary S.; Houng, Hou-Shu; Chen, Robert C.-M.; Barvir, David A.; Seriwatana, Jitvimol; Cayphas, Sylvie; Garçon, Nathalie; Gheysen, Dirk; Kanesa-thasan, Niranjan; McDonell, Mike; Humphreys, Tom; Eckels, Kenneth H.; Prieels, Jean‐Paul; Innis, Bruce L.

doi:10.1016/j.vaccine.2005.03.042

Cited by 132 publications

(40 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Consistent with this hypothesis, recent findings indicate that EIII-specific antibodies account for a small fraction of the virus-neutralizing antibodies following DENV infections in humans (32,33,41,42) and monkeys (34), which may support the idea that EIII is not as immunodominant in primates as it is in mice. Additionally, recombinant 80E proteins, which contain all three domains, have been shown to be highly immunogenic and efficacious in NHP models when formulated in Iscomatrix, a saponin-based adjuvant (43,44). Thus, we hypothesized that limited or compromised presentation of neutralizing epitopes afforded by the EIII antigens, plus an absence of specific T helper epitopes that may be present in the EI and EII domains, might have rendered EIII-based vaccines less effective in inducing long-lasting neutralizing antibody responses.…”

Section: Discussionmentioning

confidence: 99%

“…Although this finding has important implications for vaccine design, it is worth noting that immune responses after immunization can be different from those following natural dengue infections. In fact, a subunit dengue vaccine based on adjuvanted monomeric 80E is highly immunogenic and efficacious in the NHP model (43,44). Further, a tetravalent dengue vaccine based on Iscomatrix-adjuvanted 80Es was well tolerated and immunogenic in a phase I clinical study (46).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Immunogenicity and Efficacy of Flagellin-Envelope Fusion Dengue Vaccines in Mice and Monkeys

Liu

Song

Putnak

et al. 2015

Clin. Vaccine Immunol.

View full text Add to dashboard Cite

The envelope (E) protein of flaviviruses includes three domains, EI, EII, and EIII, and is the major protective antigen. Because EIII is rich in type-specific and subcomplex-specific neutralizing epitopes and is easy to express, it is particularly attractive as a recombinant vaccine antigen. VaxInnate has developed a vaccine platform that genetically links vaccine antigens to bacterial flagellin, a Toll-like receptor 5 ligand. Here we report that tetravalent dengue vaccines (TDVs) consisting of four constructs, each containing two copies of EIII fused to flagellin (R3.2x format), elicited robust and long-lived neutralizing antibodies (geometric mean titers of 200 to 3,000), as measured with a 50% focus reduction neutralization test (FRNT 50 ). In an immunogenicity study, rhesus macaques (n ‫؍‬ 2) immunized subcutaneously with 10 g or 90 g of TDV three or four times, at 4-to 6-week intervals, developed neutralizing antibodies to four dengue virus (DENV) serotypes (mean post-dose 3 FRNT 50 titers of 102 to 601). In an efficacy study, rhesus macaques (n ‫؍‬ 4) were immunized intramuscularly with 16 g or 48 g of TDV or a placebo control three times, at 1-month intervals. The animals that received 48-g doses of TDV developed neutralizing antibodies against the four serotypes (geometric mean titers of 49 to 258) and exhibited reduced viremia after DENV-2 challenge, with a group mean viremia duration of 1.25 days and 2 of 4 animals being completely protected, compared to the placebo-treated animals, which all developed viremia, with a mean duration of 4 days. In conclusion, flagellin-EIII fusion vaccines are immunogenic and partially protective in a nonhuman primate model. Dengue disease poses a significant health threat to almost onehalf of the world's population residing in the Asian-Pacific region and Latin America, where the disease is endemic, as well as to travelers and military personnel. Currently, no licensed dengue vaccine is available. Several vaccine candidates based on live attenuated dengue viruses (DENVs) or dengue virus-flavivirus chimeras are currently being evaluated in phase II or III clinical trials (for reviews, see references 1-3). However, some of these vaccines require lengthy immunization regimens of up to 1 year for the development of immunity to all four serotypes, which seems to make them less well suited for travelers and military personnel. In a series of recently published phase IIb/III trials conducted in five Asian countries in which dengue is endemic, the Sanofi-Aventis chimeric yellow fever (YF) 17D-DENV-1 to -4 CYD tetravalent dengue vaccine (TDV) showed an acceptable safety profile and 56% overall efficacy (4); however, the vaccine failed to confer significant protection against DENV-2 (5). These findings underscore the need for the development of alternative vaccine platforms, such as those based on purified inactivated virus (6), DNA (7), and recombinant subunit truncated envelope (E) proteins (e.g., 80% envelope protein [80E]) (8). Some of these alternative vaccine candidates hav...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Immunogenicity and Efficacy of Flagellin-Envelope Fusion Dengue Vaccines in Mice and Monkeys

Liu

Song

Putnak

et al. 2015

Clin. Vaccine Immunol.

View full text Add to dashboard Cite

show abstract

“…Glycosylated antigens were produced at high levels using the Drosophila S2 cell expression system. The DEN2-80E subunit candidate induced neutralizing antibodies and partially protected rhesus macaques aft er two doses administered with fi ve diff erent adjuvants (AS04-OH, AS04-PO, AS05, AS08 or alum) (Putnak et al, 2005). When formulated with the saponin-based adjuvant ISCOMATRIX™, DEN2-80E elicited a potent neutralizing antibody response in mice that persisted for at least 6 months (Clements et al, 2010).…”

Section: Truncated E Proteinmentioning

confidence: 99%

“…Th e study will compare the safety and immunogenicity of three doses of V180 (at 1-month intervals) formulated with low or mid dose ISCOMATRIX™ adjuvant, alum or without adjuvants. [Clements et al, 2010;Manoff et al, 2015;Putnak et al, 2005] Virus-like particles prM/E VLP expressed in Pichia pastoris and 293T cells…”

Section: Truncated E Proteinmentioning

confidence: 99%

Dengue vaccine: an update on recombinant subunit strategies

Martín¹,

Hermida²

2016

View full text Add to dashboard Cite

Summary. -Dengue is an increasing public health problem worldwide, with the four serotypes of the virus infecting over 390 million people annually. Th ere is no specifi c treatment or antiviral drug for dengue, and prevention is largely limited to controlling the mosquito vectors or disrupting the human-vector contact. Despite the considerable progress made in recent years, an eff ective vaccine against the virus is not yet available. Th e development of a dengue vaccine has been hampered by many unique challenges, including the need to ensure the absence of vaccine-induced enhanced severity of disease. Recombinant protein subunit vaccines off er a safer alternative to other vaccine approaches. Several subunit vaccine candidates are presently under development, based on diff erent structural and non-structural proteins of the virus. Novel adjuvants or immunopotentiating strategies are also being tested to improve their immunogenicity. Th is review summarizes the current status and development trends of subunit dengue vaccines.

show abstract

“…These include live-attenuated virus vaccines (LAV) attenuated by chimerization with yellow fever virus (8–15), by 3′ non-coding region (NCR) mutations (16–22), by chimerization with attenuated DENV (23–26), by serial passages in cell culture (27–29), by host range mutations (30, 31), or by mutations of a viral enzyme (32). Other vaccine platforms tested in NHP are DNA vaccines (33–39), inactivated virus vaccines (40–42), viral vectored vaccines (43–46), subunit protein vaccines (47–55), and prime/boost platforms (42, 43, 56, 57). A number of vaccine candidates tested in NHP have now been evaluated in humans, and data are available for safety and immunogenicity in phase I/II clinical trials (4, 19, 58–79), and efficacy for the leading vaccine candidate, Sanofi’s CYD1–4 (80, 81) (Table 1).…”

Section: Current State Of the Nhp Model To Evaluate Dengue Vaccine Camentioning

confidence: 99%

Utility, Limitations, and Future of Non-Human Primates for Dengue Research and Vaccine Development

Sariol

White²

2014

Front. Immunol.

View full text Add to dashboard Cite

Dengue is considered the most important emerging, human arboviruses, with worldwide distribution in the tropics. Unfortunately, there are no licensed dengue vaccines available or specific anti-viral drugs. The development of a dengue vaccine faces unique challenges. The four serotypes co-circulate in endemic areas, and pre-existing immunity to one serotype does not protect against infection with other serotypes, and actually may enhance severity of disease. One foremost constraint to test the efficacy of a dengue vaccine is the lack of an animal model that adequately recapitulates the clinical manifestations of a dengue infection in humans. In spite of this limitation, non-human primates (NHP) are considered the best available animal model to evaluate dengue vaccine candidates due to their genetic relatedness to humans and their ability to develop a viremia upon infection and a robust immune response similar to that in humans. Therefore, most dengue vaccines candidates are tested in primates before going into clinical trials. In this article, we present a comprehensive review of published studies on dengue vaccine evaluations using the NHP model, and discuss critical parameters affecting the usefulness of the model. In the light of recent clinical data, we assess the ability of the NHP model to predict immunological parameters of vaccine performances in humans and discuss parameters that should be further examined as potential correlates of protection. Finally, we propose some guidelines toward a more standardized use of the model to maximize its usefulness and to better compare the performance of vaccine candidates from different research groups.

show abstract

An evaluation of dengue type-2 inactivated, recombinant subunit, and live-attenuated vaccine candidates in the rhesus macaque model

Cited by 132 publications

References 33 publications

Immunogenicity and Efficacy of Flagellin-Envelope Fusion Dengue Vaccines in Mice and Monkeys

Immunogenicity and Efficacy of Flagellin-Envelope Fusion Dengue Vaccines in Mice and Monkeys

Dengue vaccine: an update on recombinant subunit strategies

Utility, Limitations, and Future of Non-Human Primates for Dengue Research and Vaccine Development

Contact Info

Product

Resources

About