A Single Dose Respiratory Recombinant Adenovirus-Based Vaccine Provides Long-Term Protection for Non-Human Primates from Lethal Ebola Infection

Abstract

As the Ebola outbreak in West Africa continues and cases appear in the United States and other countries, the need for long-lasting vaccines to preserve global health is imminent. Here, we evaluate the long-term efficacy of a respiratory and sublingual (SL) adenovirus-based vaccine in non-human primates in two phases. In the first, a single respiratory dose of 1.4 × 109 infectious virus particles (ivp)/kg of Ad-CAGoptZGP induced strong Ebola glycoprotein (GP) specific CD8+ and CD4+ T cell responses and Ebola GP-specific antibodies in systemic and mucosal compartments and was partially (67%) protective from challenge 62 days after immunization. The same dose given by the SL route induced Ebola GP-specific CD8+ T cell responses similar to that of intramuscular (IM) injection, however, the Ebola GP-specific antibody response was low. All primates succumbed to infection. Three primates were then given the vaccine in a formulation that improved the immune response to Ebola in rodents. Three primates were immunized with 2.0 × 1010 ivp/kg of vaccine by the SL route. Diverse populations of polyfunctional Ebola GP-specific CD4+ and CD8+ T cells and significant anti-Ebola GP antibodies were present in samples collected 150 days after respiratory immunization. The formulated vaccine was fully protective against challenge 21 weeks after immunization. While diverse populations of Ebola GP-specific CD4+ T cells were produced after SL immunization, antibodies were not neutralizing and the vaccine was unprotective. To our knowledge, this is the first time that durable protection from a single dose respiratory adenovirus-based Ebola vaccine has been demonstrated in primates.

Post-exposure treatments for Ebola and Marburg virus infections

“…However, at the same time point in that study, complete protection against EBOV (Kikwit strain) was observed in animals that received the ChAd3-EBOV-SUDV vaccine prime followed by an MVA-EBOV-SUDV boost. A small study that used a recombinant Ad5 (rAd5) codon-optimized EBOV vaccine, delivered by the respiratory route, showed protection against homologous EBOV (Kikwit strain) challenge 21 weeks after the final vaccination, suggesting that durability may be improved by respiratory, rather than intramuscular, administration of this vaccine 266 . The rVSV-MARV vaccine completely protected cynomolgus monkeys against homologous MARV (Musoke strain) challenge if the animals were challenged 14 months after the single-injection vaccination 267 .…”

Ebola virus disease candidate vaccines under evaluation in clinical trials

“…The development of an orally or intranasally administered Ad5-vectored EVD vaccine has been pursued [67,68], and a recent study suggests that sublingual administration of an adenovirus-based vaccine may provide durable protection at least in nonhuman primates [69]. Oral administration of a live adenovirus-vectored vaccine abrogates the relevance of pre-existing vector immunity, resulting in a robust immune response to the delivered antigen [42,43,70,71].…”

Adenovirus-vectored Ebola vaccines

“…Intranasal immunization with Ad5-vectored Zaire GP has been tested in guinea pigs [48] and macaques [49]. The macaque study also evaluated combined intranasal and intratracheal, or sublingual immunization.…”