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. 2014 Feb:450-451:243-9.
doi: 10.1016/j.virol.2013.12.029. Epub 2014 Jan 9.

Protection of non-human primates against rabies with an adenovirus recombinant vaccine

Z Q Xiang  1 , L Greenberg  2 , H C Ertl  3 , C E Rupprecht  4
Affiliations

Protection of non-human primates against rabies with an adenovirus recombinant vaccine

Z Q Xiang et al. Virology. 2014 Feb.

Abstract

Rabies remains a major neglected global zoonosis. New vaccine strategies are needed for human rabies prophylaxis. A single intramuscular immunization with a moderate dose of an experimental chimpanzee adenovirus (Ad) vector serotype SAd-V24, also termed AdC68, expressing the rabies virus glycoprotein, resulted in sustained titers of rabies virus neutralizing antibodies and protection against a lethal rabies virus challenge infection in a non-human primate model. Taken together, these data demonstrate the safety, immunogenicity, and efficacy of the recombinant Ad-rabies vector for further consideration in human clinical trials.

Keywords: Adenoviral vaccine; NHP; Rabies virus; VNA.

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Figures

Figure 1
Figure 1. Induction of rabies VNA upon sequential immunizations with Ad vectors
Two rhesus macaques, shown individually in circles or cross-filled squares, were primed with AdC7rab.gp, and then boosted with AdC6rab.gp, with AdHu5rab.gp administered at the time points indicated by the arrows. The rabies VNA titers were measured from sera at various time points. Titers are shown as international units (IU) according to a reference serum tested in parallel. Control animals immunized with the same vectors, but expressing an antigen of HIV-1, were tested as well, and their sera showed titers consistently below 0.2 IU (not shown).
Figure 2
Figure 2. Vaccine Efficacy in Pre-exposure and Post-exposure Regimens
[A] Dose Escalation: Cynomologous monkeys were vaccinated once with various doses (109–1011 vp) of the AdC68rab.gp vector, a control AdC68 vector given at 1011 vp, or three doses of commercial human raies vaccine, HDCV. Additional control animals received PBS only. Animals were challenged with canine rabies vius at 18 weeks after AdC68 vaccination. [B] Effect of pre-existing HAd-V5 neutralizing antibodies: Groups of monkeys were injected with 1012 vp of an AdHu5 vector expressing a reporter protein, or they were left untreated.. Four weeks later, pre-treated, as well as untreated animals, were vaccinated with 1010 vp of AdC68rab.gp. A positive control group received commercial human rabies vaccine, HDCV given 3 times, a negative control group received PBS. Animals were challenged with canine rabies virus 18 weeks after AdC vaccination and survival was recorded. [C] Post-exposure prophylaxis: Nonhuman primates were infected with canine rabies virus. Six hours later, one group was vaccinated with 1010 vp of AdC68rab.gp and received commercial HRIG infiltrated at the rabies virus inoculation site. An additional group was vaccinated with AdC68rab.gp, but without HRIG. A positive control group was treated with the traditional vaccine regimen, i.e., HRIG combined with 4 doses of commercial PCEC human rabies vaccine, the latter given on days 1, 8, 15 and 29 relative to challenge. Additional control groups only received HRIG, a control AdC68 vector or PBS. Survival was recorded. [NB: need to change the vaccine in @C from HDCV to PCEC. Graphs A–C show percent of animals that survived without developing signs of rabies. Numbers of animals per group are shown within each graph above the bars.
Figure 3
Figure 3. Vaccine immunogenicity and efficacy in a long-term study
[A] VNA titers after immunization: Groups of 6 animals were vaccinated with 109 vp of AdC68rab.gp. The rabies VNA titers were tested periodically from sera for a period of 21 months. The graph shows rabies VNA titers of individual animals. [B] Vaccine efficacy: The vaccinated animals shown in [A] were challenged with canine rabies virus at 22 months after immunization. An additional 5 unvaccinated animals were challenged as well. Survival was recorded. [C] VNA titers after challenge. Sera from the vaccinated animals in [A] were tested the day of challenge and then at the indicated time points after challenge for VNA titers to rabies virus. The graph shows rabies VNA titers of individual animals. [NB: need to change the number of controls in B from 6 to 5.
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