A Tetravalent Dengue Vaccine Based on a Complex Adenovirus Vector Provides Significant Protection in Rhesus Monkeys against All Four Serotypes of Dengue Virus

Abstract

Nearly a third of the human population is at risk of infection with the four serotypes of dengue viruses, and it is estimated that more than 100 million infections occur each year. A licensed vaccine for dengue viruses has become a global health priority. A major challenge to developing a dengue vaccine is the necessity to produce fairly uniform protective immune responses to all four dengue virus serotypes. We have developed two bivalent dengue virus vaccines, using a complex adenovirus vector, by incorporating the genes expressing premembrane (prM) and envelope (E) proteins of dengue virus types 1 and 2 (dengue-1 and -2, respectively) (CAdVax-Den12) or dengue-3 and -4 (CAdVax-Den34). Rhesus macaques were vaccinated by intramuscular inoculation of a tetravalent dengue vaccine formulated by combining the two bivalent vaccine constructs. Vaccinated animals produced high-titer antibodies that neutralized all four serotypes of dengue viruses in vitro. The ability of the vaccine to induce rapid, as well as sustained, protective immune responses was examined with two separate live-virus challenges administered at 4 and 24 weeks after the final vaccination. For both of these virus challenge studies, significant protection from viremia was demonstrated for all four dengue virus serotypes in vaccinated animals. Viremia from dengue-1 and dengue-3 challenges was completely blocked, whereas viremia from dengue-2 and dengue-4 was significantly reduced, as well as delayed, compared to that of controlvaccinated animals. These results demonstrate that the tetravalent dengue vaccine formulation provides significant protection in rhesus macaques against challenge with all four dengue virus serotypes.

Enhanced Induction of Intestinal Cellular Immunity by Oral Priming with Enteric Adenovirus 41 Vectors

“…Intramuscular administration with low-dose vector stimulated humoral immune responses to the transgene that could be boosted further despite the presence of antivector neutralizing antibodies in the homologous prime-boost immunization. These results are in agreement with those generated in a Dengue virus vaccine model (28).…”

Mechanistic Study of Broadly Neutralizing Human Monoclonal Antibodies against Dengue Virus That Target the Fusion Loop

“…The majority, if not all, of DENV vaccine candidates approaching or in clinical trials contain full-length DENV prM and E proteins (77)(78)(79)(80)(81)(82)(83)(84)(85)(86). Full-length DENV prM and E proteins, whether expressed as part of an attenuated DENV strain or expressed in another manner, may induce a broadly reactive and primarily nonneutralizing antibody response.…”

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

“…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).…”