Date Published: February 20, 2018
Publisher: Public Library of Science
Author(s): Benoit Callendret, Jort Vellinga, Kerstin Wunderlich, Ariane Rodriguez, Robin Steigerwald, Ulrike Dirmeier, Cedric Cheminay, Ariane Volkmann, Trevor Brasel, Ricardo Carrion, Luis D. Giavedoni, Jean L. Patterson, Chad E. Mire, Thomas W. Geisbert, Jay W. Hooper, Mo Weijtens, Jutta Hartkoorn-Pasma, Jerome Custers, Maria Grazia Pau, Hanneke Schuitemaker, Roland Zahn, Jens H. Kuhn.
The search for a universal filovirus vaccine that provides protection against multiple filovirus species has been prompted by sporadic but highly lethal outbreaks of Ebolavirus and Marburgvirus infections. A good prophylactic vaccine should be able to provide protection to all known filovirus species and as an upside potentially protect from newly emerging virus strains. We investigated the immunogenicity and protection elicited by multivalent vaccines expressing glycoproteins (GP) from Ebola virus (EBOV), Sudan virus (SUDV), Taï Forest virus (TAFV) and Marburg virus (MARV). Immune responses against filovirus GP have been associated with protection from disease. The GP antigens were expressed by adenovirus serotypes 26 and 35 (Ad26 and Ad35) and modified Vaccinia virus Ankara (MVA) vectors, all selected for their strong immunogenicity and good safety profile. Using fully lethal NHP intramuscular challenge models, we assessed different vaccination regimens for immunogenicity and protection from filovirus disease. Heterologous multivalent Ad26-Ad35 prime-boost vaccination regimens could give full protection against MARV (range 75%-100% protection) and EBOV (range 50% to 100%) challenge, and partial protection (75%) against SUDV challenge. Heterologous multivalent Ad26-MVA prime-boost immunization gave full protection against EBOV challenge in a small cohort study. The use of such multivalent vaccines did not show overt immune interference in comparison with monovalent vaccines. Multivalent vaccines induced GP-specific antibody responses and cellular IFNγ responses to each GP expressed by the vaccine, and cross-reactivity to TAFV GP was detected in a trivalent vaccine expressing GP from EBOV, SUDV and MARV. In the EBOV challenge studies, higher humoral EBOV GP-specific immune responses (p = 0.0004) were associated with survival from EBOV challenge and less so for cellular immune responses (p = 0.0320). These results demonstrate that it is feasible to generate a multivalent filovirus vaccine that can protect against lethal infection by multiple members of the filovirus family.
Filoviruses, which include the genera Ebolavirus and Marburgvirus, cause sporadic outbreaks of severe hemorrhagic disease in humans with case mortality rates between 25% and 90% . Outbreaks of filovirus infection start when humans have direct contact with infected animals or with their contaminated body fluids, spreading in the human population by human-to-human transmission . Mapping models of previous outbreaks and reservoir habitats in Africa have identified a population of 22 million people who are at potential risk from Ebolavirus transmission, and 105 million people who are at potential risk from Marburgvirus transmission [3, 4]. The lack of specific treatment, high mortality rates, and substantial social and economic impact of the disease indicate the need for vaccines to prevent infection in a cost effective manner.
This is the first report on NHP efficacy studies evaluating a multivalent filovirus vaccine candidate based on human Ad26, Ad35 and MVA vectors. All regimens tested induced a strong and durable humoral immune response against all vaccine antigens, and a cellular response against all antigens. A heterologous Ad26-Ad35 prime-boost vaccination regimen could give full protection against MARV and EBOV challenge and partial protection against SUDV challenge in stringent NHP challenge models. Full protection against EBOV challenge was also achieved when Ad26 and MVA were combined in a prime-boost vaccination regimen. Such an Ad26/MVA regimen with monovalent Ad26 priming is currently being explored in clinical trials as a potential vaccine candidate against EBOV infection.
The opinions, interpretations, conclusions, and recommendations contained here are those of the authors and are not necessarily endorsed by the US Department of Defense.