In this last three decades the Zaire Ebola virus (ZEBOV), the Sudan Ebola virus (SEBOV) and the newly discovered Bundibugyo Ebola virus (BEBOV) have caused major outbreaks with case fatality rates of 90%, (Zaire) 50% (Sudan) and 25% (Bundibugyo) (6,22). Ebola virus protection by transfusing recovering patient serum or administering anti-Ebola virus gamma globulin has proven to be a strong motivator to develop a safe and effective anti-Ebola virus vaccine (1,12,18,24).
There are at least a half a dozen different Ebola vaccines in development, but only two are currently undergoing clinical testing (3,15,20). One of these two vaccines, named cAd3-EBO, uses an adenovirus isolated from chimpanzees (serotype 3) (7,21) and engineered to express Ebola virus surface glycoprotein encoded by the Zaire and Sudan virus strains (19). The second vaccine undergoing clinical testing, named VSV-ZEBO, uses a vesicular stomatitis virus (VSV) construct engineered to express the Zaire Ebola virus glycoprotein, (8,14).

Current Ebola virus vaccines

Vaccine	Key Features	Pre-clinical	Clinical	Ref
cAd3-EBOOrigin: National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA & GlaxoSmithKline	Chimpanzee adenovirus (serotype 3) expressing Zaire and Sudan Ebola virus glycoprotein	100% protection in 16 macaques challenged with Ebola virus	Participants received a single dose of 2×1010 or 2×1011 virus particles that induced anti-Ebola virus glycoprotein antibodies in 20 of 20 participants. Participants CD4 T cell and CD8 T cells responded to Ebola virus glycoprotein in 10 of 10 and 7 of 10 participants, respectively.	13
VSV-ZEBOVOrigin: National Microbiology Laboratory, Public Health Agency Canada, & NewLink Genetics Corp/BioProtection Systems USA	VSV (Indiana strain) expressing Zaire Ebola virus glycoprotein	100% protection in 20 macaques challenged with Ebola virus	Participant solicitation and vaccine injections are underway with an expected trial completion date in 2015	11

 

Results for Current Ebola Virus Vaccines

Clinical findings for cAd3-EBO were recently been reported, while clinical testing of the VSV-ZEBOV vaccine has only just begun (13,20).

cAd3-EBO

Trials with chimpanzees vaccinated with cAd3-EBO showed 100% protection against Ebola virus challenge 5 weeks after vaccination. These same animals showed 50% resistance against Ebola virus infection after 10 months (19). Clinical findings for 20 healthy adults ranging in age from 25 to 50 and who received a single intramuscular injection of 2×10¹⁰ adenovirus particles (group 1) or 2×10¹¹ adenovirus particle (trial VRC-EBOADC069-00-VP) showed overall that cAd3-EBO vaccine was safe and with only minor adverse events (13). Reactogenicity was moderate with fevers occurring in two participants receiving the higher virus dose and were 38.1 (100.6 F) and 39.9 degrees (103.8 F). Fevers were resolved with acetaminophen or nonsteroidal anti-inflammatory drugs NSADs. Activated partial thromboplastin time (aPTT) was observed in 3 of 20 patients which suggested a clotting disorder but was later found to be due to false positive readings in the PTT test and caused by anti-phospholipid antibodies. Finally asymptomatic and transient neutropenia or leukopenia (low neutrophil and leukocyte counts) was observed 3 to 4 days after vaccination in 4 of 20 recipients.

Participant anti-Ebola antibody response four weeks after vaccination was seen in all 20 participants for at least one of the two Ebola virus glycoproteins. Anti-Ebola glycoprotein antibody for the Zaire strain was seen in 9 of 10 group 1 participants and 10 of 10 for group 2 participants. Anti-Ebola glycoprotein antibody for the Sudan strain was detected in 7 of 10 group 1 participants and in 8 of 10 group 2 participants. Vaccine-induced CD4 and CD8 T-cell responses to the Ebola virus glycoprotein when measured at 2 and 4 weeks post vaccination showed that CD8 T cells responded to at least one Ebola glycoprotein epitope (either the Zaire or Sudan glycoprotein) at week 4 in 20% of group 1 participants and 70% of group 2 participants. At four weeks CD4 T cell responses to at least one Ebola virus glycoprotein epitope was seen in 30% of group 1 participants and 100% of group 2 participants. The authors of the study viewed these levels of T-cell response comparable to that seen in earlier primate studies which showed protection upon Ebola virus challenge.

VSV-ZEBOV

The Ebola VSV vaccine platform is derived from a VSV stain isolated in 1925 during an virus outbreak that occurred in cattle in Richmond, Indiana (23). This Ebola vaccine which expresses only the Zaire strain of virus glycoprotein (11,14) was found protective in different animal models in which vaccinated animals were challenged with Ebola virus (4,5,9,10). For example Cynomolgus macaques injected with 10 million infectious VSV that expresss Zaire strain Ebola glycoprotein showed strong anti-Ebola virus antibody reactivity, even when the serum antibody was diluted 10,000 fold (17).

Considerations for the Present Ebola Virus Vaccines

cAd3-EBO

Anti-adenovirus immunity, that is common in the human population will significantly dampen adenovirus-based vaccine effectiveness (2). Although prior exposure to the chimpanzee adenovirus used to create cAd3-EBO vaccine is considered rare for most humans. this is largely based on testing in North American and European populations. Prior encounters with wild chimpanzees, or chimpanzee adenovirus exposure from uncooked chimpanzee bushmeat  is a possibility in rural West Africa. If found true this will create unanticipated negative outcomes during West Africa field testing or at vaccine “rollout”.  Underlying immunity to chimp adenovirus will prime the individual to respond more to the adenovirus vector and not to the Ebola glycoprotein (16). Since re-vaccinating rural West African populations will be difficult and animals vaccinated with cAd3-EBOV showed only 50% resistance after 10 months (19), we must ensure our present vaccine elicits sufficient life-long immunity to prevent future outbreaks.

VSV-EBOV

Although VSV outbreaks in Africa stemming from importation of infected animals are reported, outbreaks of VSV (Indiana strain) appear largely restricted to North and Central America. It is therefore less likely that the West African population has exposure and  immunity to the current VSV vector (23). If the West African population shows evidence of chimp adenovirus immunity, the lack of VSV exposure may prove advantagous. The VSV-EBOV vaccine would be useful not only if a vaccine boost proves necessary in a future outbreaks, it will also be useful for those populations that already have anti-chimpanzee adenovirus antibodies.

Source References

1. Begley, S. Nov. 2014. Scientists tell U.S. – find recipe for Ebola cure in survivors’ blood.http://www.reuters.com/article/2014/11/07/us-health-ebola-usa-antibodies-exclusive-idUSKBN0IR1I520141107

2. Capone, S, Meola, A, Ercole, BB, Vitelli, A, Pezzanera, M, Ruggeri, L, Davies, ME, Tafi, R, Santini, C, Luzzago, A, Fu, TM, Bett, A, Colloca, S, Cortese, R, Nicosia, A,Folgori, A. 2006. A novel adenovirus type 6 (Ad6)-based hepatitis C virus vector that overcomes preexisting anti-ad5 immunity and induces potent and broad cellular immune responses in rhesus macaques. J Virol 80:1688-1699.

3. ClinicalTrials.gov. <[05] Pub Date>. Safety, tolerability,and immunogenicity of the Ebola chimpanzee adenovirus vector vaccine (cAd3-EBO), VRC-EBOADC069-00-VP, in healthy adults.

4. Daddario-DiCaprio, KM, Geisbert, TW, Stroher, U, Geisbert, JB, Grolla, A, Fritz, EA, Fernando, L, Kagan, E, Jahrling, PB, Hensley, LE, Jones, SM,Feldmann, H. 2006. Postexposure protection against Marburg haemorrhagic fever with recombinant vesicular stomatitis virus vectors in non-human primates: an efficacy assessment. Lancet 367:1399-1404.

5. Feldmann, H, Jones, SM, Daddario-DiCaprio, KM, Geisbert, JB, Stroher, U, Grolla, A, Bray, M, Fritz, EA, Fernando, L, Feldmann, F, Hensley, LE,Geisbert, TW. 2007. Effective post-exposure treatment of Ebola infection. PLoS.Pathog. 3:e2.

6. Feldmann, H., A. Sanchez, and T. W. Geisbert. 2013. Filoviridae, p. 923-956. In: P. M. Howley and D. M. Knipe (eds.), Fields Virology. 6th ed. Lippincott Williams & Wilkins.

7. Folgori, A, Capone, S, Ruggeri, L, Meola, A, Sporeno, E, Ercole, BB, Pezzanera, M, Tafi, R, Arcuri, M, Fattori, E, Lahm, A, Luzzago, A, Vitelli, A, Colloca, S, Cortese, R,Nicosia, A. 2006. A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees. Nat.Med. 12:190-197.

8. Garbutt, M, Liebscher, R, Wahl-Jensen, V, Jones, S, Moller, P, Wagner, R, Volchkov, V, Klenk, HD, Feldmann, H,Stroher, U. 2004. Properties of replication-competent vesicular stomatitis virus vectors expressing glycoproteins of filoviruses and arenaviruses. J Virol 78:5458-5465.

9. Geisbert, TW, Daddario-DiCaprio, KM, Lewis, MG, Geisbert, JB, Grolla, A, Leung, A, Paragas, J, Matthias, L, Smith, MA, Jones, SM, Hensley, LE, Feldmann, H,Jahrling, PB. 2008. Vesicular stomatitis virus-based ebola vaccine is well-tolerated and protects immunocompromised nonhuman primates. PLoS.Pathog. 4:e1000225.

10. Geisbert, TW, Daddario-DiCaprio, KM, Williams, KJ, Geisbert, JB, Leung, A, Feldmann, F, Hensley, LE, Feldmann, H,Jones, SM. 2008. Recombinant vesicular stomatitis virus vector mediates postexposure protection against Sudan Ebola hemorrhagic fever in nonhuman primates. J Virol 82:5664-5668.

11. Geisbert, TW, Geisbert, JB, Leung, A, Daddario-DiCaprio, KM, Hensley, LE, Grolla, A,Feldmann, H. 2009. Single-injection vaccine protects nonhuman primates against infection with marburg virus and three species of ebola virus. J Virol 83:7296-7304.

12. Guimard, Y, Bwaka, MA, Colebunders, R, Calain, P, Massamba, M, De, RA, Mupapa, KD, Kibadi, K, Kuvula, KJ, Ndaberey, DE, Katwiki, KR, Mapanda, BB, Nkuku, OB, Fleerackers, Y, Van den Enden, E,Kipasa, MA. 1999. Organization of patient care during the Ebola hemorrhagic fever epidemic in Kikwit, Democratic Republic of the Congo, 1995. J Infect.Dis. 179 Suppl 1:S268-S273.

13. Ledgerwood, JE, DeZure, AD, Stanley, DA, Novik, L, Enama, ME, Berkowitz, NM, Hu, Z, Joshi, G, Ploquin, A, Sitar, S, Gordon, IJ, Plummer, SA, Holman, LA, Hendel, CS, Yamshchikov, G, Roman, F, Nicosia, A, Colloca, S, Cortese, R, Bailer, RT, Schwartz, RM, Roederer, M, Mascola, JR, Koup, RA, Sullivan, NJ,Graham, BS. 2014. Chimpanzee Adenovirus Vector Ebola Vaccine – Preliminary Report. N.Engl.J Med.

14. Marzi, A, Ebihara, H, Callison, J, Groseth, A, Williams, KJ, Geisbert, TW,Feldmann, H. 2011. Vesicular stomatitis virus-based Ebola vaccines with improved cross-protective efficacy. J Infect.Dis. 204 Suppl 3:S1066-S1074.

15. Marzi, A,Feldmann, H. 2014. Ebola virus vaccines: an overview of current approaches. Expert.Rev.Vaccines. 13:521-531.

16. McCoy, K, Tatsis, N, Korioth-Schmitz, B, Lasaro, MO, Hensley, SE, Lin, SW, Li, Y, Giles-Davis, W, Cun, A, Zhou, D, Xiang, Z, Letvin, NL,Ertl, HC. 2007. Effect of preexisting immunity to adenovirus human serotype 5 antigens on the immune responses of nonhuman primates to vaccine regimens based on human- or chimpanzee-derived adenovirus vectors. J Virol 81:6594-6604.

17. Mire, CE, Geisbert, JB, Marzi, A, Agans, KN, Feldmann, H,Geisbert, TW. 2013. Vesicular stomatitis virus-based vaccines protect nonhuman primates against Bundibugyo ebolavirus. PLoS.Negl.Trop.Dis. 7:e2600.

18. Mupapa, K, Massamba, M, Kibadi, K, Kuvula, K, Bwaka, A, Kipasa, M, Colebunders, R,Muyembe-Tamfum, JJ. 1999. Treatment of Ebola hemorrhagic fever with blood transfusions from convalescent patients. International Scientific and Technical Committee. J Infect.Dis. 179 Suppl 1:S18-S23.

19. Stanley, DA, Honko, AN, Asiedu, C, Trefry, JC, Lau-Kilby, AW, Johnson, JC, Hensley, L, Ammendola, V, Abbate, A, Grazioli, F, Foulds, KE, Cheng, C, Wang, L, Donaldson, MM, Colloca, S, Folgori, A, Roederer, M, Nabel, GJ, Mascola, J, Nicosia, A, Cortese, R, Koup, RA,Sullivan, NJ. 2014. Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge. Nat.Med. 20:1126-1129.

20. Stover, K. Oct 2014 NIH begins early human clinical trial of VSV Ebola vaccine. http://www.nih.gov/news/health/oct2014/niaid-22.htm

21. Tatsis, N, Tesema, L, Robinson, ER, Giles-Davis, W, McCoy, K, Gao, GP, Wilson, JM,Ertl, HC. 2006. Chimpanzee-origin adenovirus vectors as vaccine carriers. Gene Ther. 13:421-429.

22. Towner, JS, Sealy, TK, Khristova, ML, Albarino, CG, Conlan, S, Reeder, SA, Quan, PL, Lipkin, WI, Downing, R, Tappero, JW, Okware, S, Lutwama, J, Bakamutumaho, B, Kayiwa, J, Comer, JA, Rollin, PE, Ksiazek, TG,Nichol, ST. 2008. Newly discovered ebola virus associated with hemorrhagic fever outbreak in Uganda. PLoS.Pathog. 4:e1000212.

23. Whelan, S. P. J. 2008. Vesicular Stomatitis Virus, p. 291-299. In: B. W. J. Mahy and M. H. V. Van Regenmortel (eds.), Encyclopedia of Virology. 3rd ed. Elsvier.

24. Wong, G, Richardson, JS, Pillet, S, Patel, A, Qiu, X, Alimonti, J, Hogan, J, Zhang, Y, Takada, A, Feldmann, H,Kobinger, GP. 2012. Immune parameters correlate with protection against ebola virus infection in rodents and nonhuman primates. Sci.Transl.Med. 4:158ra146.

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