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Preclinical Assessment of Viral Vectored and Protein Vaccines Targeting the Duffy-Binding Protein Region II of Plasmodium Vivax.

de Cassan SC, Shakri AR, Llewellyn D, Elias SC, Cho JS, Goodman AL, Jin J, Douglas AD, Suwanarusk R, Nosten FH, Rénia L, Russell B, Chitnis CE, Draper SJ - Front Immunol (2015)

Bottom Line: The almost complete dependence of P. vivax red blood cell invasion on the interaction of the P. vivax Duffy-binding protein region II (PvDBP_RII) with the human Duffy antigen receptor for chemokines (DARC) makes this antigen an attractive vaccine candidate against blood-stage P. vivax.We report on the antibody and T cell immunogenicity of these vaccines in mice or rabbits, either used alone in a viral vectored prime-boost regime or in "mixed-modality" adenovirus prime - protein-in--adjuvant boost regimes (using a recombinant PvDBP_RII protein antigen formulated in Montanide(®)ISA720 or Abisco(®)100 adjuvants).Antibodies induced by these regimes were found to bind to native parasite antigen from P. vivax infected Thai patients and were capable of inhibiting the binding of PvDBP_RII to its receptor DARC using an in vitro binding inhibition assay.

View Article: PubMed Central - PubMed

Affiliation: The Jenner Institute, University of Oxford , Oxford , UK.

ABSTRACT
Malaria vaccine development has largely focused on Plasmodium falciparum; however, a reawakening to the importance of Plasmodium vivax has spurred efforts to develop vaccines against this difficult to treat and at times severe form of relapsing malaria, which constitutes a significant proportion of human malaria cases worldwide. The almost complete dependence of P. vivax red blood cell invasion on the interaction of the P. vivax Duffy-binding protein region II (PvDBP_RII) with the human Duffy antigen receptor for chemokines (DARC) makes this antigen an attractive vaccine candidate against blood-stage P. vivax. Here, we generated both preclinical and clinically compatible adenoviral and poxviral vectored vaccine candidates expressing the Salvador I allele of PvDBP_RII - including human adenovirus serotype 5 (HAdV5), chimpanzee adenovirus serotype 63 (ChAd63), and modified vaccinia virus Ankara (MVA) vectors. We report on the antibody and T cell immunogenicity of these vaccines in mice or rabbits, either used alone in a viral vectored prime-boost regime or in "mixed-modality" adenovirus prime - protein-in--adjuvant boost regimes (using a recombinant PvDBP_RII protein antigen formulated in Montanide(®)ISA720 or Abisco(®)100 adjuvants). Antibodies induced by these regimes were found to bind to native parasite antigen from P. vivax infected Thai patients and were capable of inhibiting the binding of PvDBP_RII to its receptor DARC using an in vitro binding inhibition assay. In recent years, recombinant ChAd63 and MVA vectors have been quickly translated into human clinical trials for numerous antigens from P. falciparum as well as a growing number of other pathogens. The vectors reported here are immunogenic in small animals, elicit antibodies against PvDBP_RII, and have recently entered clinical trials, which will provide the first assessment of the safety and immunogenicity of the PvDBP_RII antigen in humans.

No MeSH data available.


Related in: MedlinePlus

Humoral responses induced by viral vectored and protein vaccines targeting PvDBP_RII. (A) BALB/c mice (n = 5) were immunized with 1010 vp of a recombinant HAdV5 expressing PvDBP_RII, and boosted 8 weeks later with 107 pfu of a recombinant MVA expressing PvDBP_RII and the selectable marker GFP. (B) BALB/c mice (n = 6/group) were immunized with 1.5 × 108 ifu of either HAdV5 or ChAd63 expressing PvDBP_RII, and 8 weeks later, mice were boosted with 107 pfu MVA-PvDBP_RII either expressing the selectable marker GFP or no marker (ML). (C) BALB/c mice (n = 4–6/group) were immunized with the regime outlined in (A) (AM), or immunized three times i.m. 3 weeks apart with 10 μg of PvDBP_RII protein formulated with the specified adjuvant (PPP), or primed i.m. with 1010 vp of HAdV5-PvDBP_RII and boosted 8 weeks later i.m. with 10 μg of PvDBP_RII protein formulated with adjuvant (AP). In all panels, serum IgG titers were measured in arbitrary units (AU) against PvDBP_RII protein by ELISA 2 weeks after each immunization (day 14 and 70) and before the boost (day 55) in (A,B), and 2 weeks after the second immunization (PP) or final immunization (PPP, AP, AM) in (C). In (C), responses following two immunizations are shown with open symbols (PP, AP, AM) and after three immunizations with closed symbols (PPP). ND, not done. Median and individual data points are shown. The dotted line indicates the threshold for responses above background in (B) determined using serum taken from the mice prior to any immunization. The same cut-off would apply in (A) but is not indicated.
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Figure 1: Humoral responses induced by viral vectored and protein vaccines targeting PvDBP_RII. (A) BALB/c mice (n = 5) were immunized with 1010 vp of a recombinant HAdV5 expressing PvDBP_RII, and boosted 8 weeks later with 107 pfu of a recombinant MVA expressing PvDBP_RII and the selectable marker GFP. (B) BALB/c mice (n = 6/group) were immunized with 1.5 × 108 ifu of either HAdV5 or ChAd63 expressing PvDBP_RII, and 8 weeks later, mice were boosted with 107 pfu MVA-PvDBP_RII either expressing the selectable marker GFP or no marker (ML). (C) BALB/c mice (n = 4–6/group) were immunized with the regime outlined in (A) (AM), or immunized three times i.m. 3 weeks apart with 10 μg of PvDBP_RII protein formulated with the specified adjuvant (PPP), or primed i.m. with 1010 vp of HAdV5-PvDBP_RII and boosted 8 weeks later i.m. with 10 μg of PvDBP_RII protein formulated with adjuvant (AP). In all panels, serum IgG titers were measured in arbitrary units (AU) against PvDBP_RII protein by ELISA 2 weeks after each immunization (day 14 and 70) and before the boost (day 55) in (A,B), and 2 weeks after the second immunization (PP) or final immunization (PPP, AP, AM) in (C). In (C), responses following two immunizations are shown with open symbols (PP, AP, AM) and after three immunizations with closed symbols (PPP). ND, not done. Median and individual data points are shown. The dotted line indicates the threshold for responses above background in (B) determined using serum taken from the mice prior to any immunization. The same cut-off would apply in (A) but is not indicated.

Mentions: BALB/c mice were immunized with 1010 viral particles (vp) HAdV5-PvDBP_RII and boosted 8 weeks later with 107 plaque forming units (pfu) MVA-PvDBP_RII (GFP). Total IgG titers were assayed against rDBP by ELISA in serum 2 weeks after each immunization and before the boost. Antigen-specific antibody responses were detected 14 days post-HAdV5 immunization (Figure 1A). These responses continued to increase by day 55 and were boosted by MVA vaccine administration on day 56. These responses confirmed the ability of viral vectored vaccines to induce anti-PvDBP_RII IgG.


Preclinical Assessment of Viral Vectored and Protein Vaccines Targeting the Duffy-Binding Protein Region II of Plasmodium Vivax.

de Cassan SC, Shakri AR, Llewellyn D, Elias SC, Cho JS, Goodman AL, Jin J, Douglas AD, Suwanarusk R, Nosten FH, Rénia L, Russell B, Chitnis CE, Draper SJ - Front Immunol (2015)

Humoral responses induced by viral vectored and protein vaccines targeting PvDBP_RII. (A) BALB/c mice (n = 5) were immunized with 1010 vp of a recombinant HAdV5 expressing PvDBP_RII, and boosted 8 weeks later with 107 pfu of a recombinant MVA expressing PvDBP_RII and the selectable marker GFP. (B) BALB/c mice (n = 6/group) were immunized with 1.5 × 108 ifu of either HAdV5 or ChAd63 expressing PvDBP_RII, and 8 weeks later, mice were boosted with 107 pfu MVA-PvDBP_RII either expressing the selectable marker GFP or no marker (ML). (C) BALB/c mice (n = 4–6/group) were immunized with the regime outlined in (A) (AM), or immunized three times i.m. 3 weeks apart with 10 μg of PvDBP_RII protein formulated with the specified adjuvant (PPP), or primed i.m. with 1010 vp of HAdV5-PvDBP_RII and boosted 8 weeks later i.m. with 10 μg of PvDBP_RII protein formulated with adjuvant (AP). In all panels, serum IgG titers were measured in arbitrary units (AU) against PvDBP_RII protein by ELISA 2 weeks after each immunization (day 14 and 70) and before the boost (day 55) in (A,B), and 2 weeks after the second immunization (PP) or final immunization (PPP, AP, AM) in (C). In (C), responses following two immunizations are shown with open symbols (PP, AP, AM) and after three immunizations with closed symbols (PPP). ND, not done. Median and individual data points are shown. The dotted line indicates the threshold for responses above background in (B) determined using serum taken from the mice prior to any immunization. The same cut-off would apply in (A) but is not indicated.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495344&req=5

Figure 1: Humoral responses induced by viral vectored and protein vaccines targeting PvDBP_RII. (A) BALB/c mice (n = 5) were immunized with 1010 vp of a recombinant HAdV5 expressing PvDBP_RII, and boosted 8 weeks later with 107 pfu of a recombinant MVA expressing PvDBP_RII and the selectable marker GFP. (B) BALB/c mice (n = 6/group) were immunized with 1.5 × 108 ifu of either HAdV5 or ChAd63 expressing PvDBP_RII, and 8 weeks later, mice were boosted with 107 pfu MVA-PvDBP_RII either expressing the selectable marker GFP or no marker (ML). (C) BALB/c mice (n = 4–6/group) were immunized with the regime outlined in (A) (AM), or immunized three times i.m. 3 weeks apart with 10 μg of PvDBP_RII protein formulated with the specified adjuvant (PPP), or primed i.m. with 1010 vp of HAdV5-PvDBP_RII and boosted 8 weeks later i.m. with 10 μg of PvDBP_RII protein formulated with adjuvant (AP). In all panels, serum IgG titers were measured in arbitrary units (AU) against PvDBP_RII protein by ELISA 2 weeks after each immunization (day 14 and 70) and before the boost (day 55) in (A,B), and 2 weeks after the second immunization (PP) or final immunization (PPP, AP, AM) in (C). In (C), responses following two immunizations are shown with open symbols (PP, AP, AM) and after three immunizations with closed symbols (PPP). ND, not done. Median and individual data points are shown. The dotted line indicates the threshold for responses above background in (B) determined using serum taken from the mice prior to any immunization. The same cut-off would apply in (A) but is not indicated.
Mentions: BALB/c mice were immunized with 1010 viral particles (vp) HAdV5-PvDBP_RII and boosted 8 weeks later with 107 plaque forming units (pfu) MVA-PvDBP_RII (GFP). Total IgG titers were assayed against rDBP by ELISA in serum 2 weeks after each immunization and before the boost. Antigen-specific antibody responses were detected 14 days post-HAdV5 immunization (Figure 1A). These responses continued to increase by day 55 and were boosted by MVA vaccine administration on day 56. These responses confirmed the ability of viral vectored vaccines to induce anti-PvDBP_RII IgG.

Bottom Line: The almost complete dependence of P. vivax red blood cell invasion on the interaction of the P. vivax Duffy-binding protein region II (PvDBP_RII) with the human Duffy antigen receptor for chemokines (DARC) makes this antigen an attractive vaccine candidate against blood-stage P. vivax.We report on the antibody and T cell immunogenicity of these vaccines in mice or rabbits, either used alone in a viral vectored prime-boost regime or in "mixed-modality" adenovirus prime - protein-in--adjuvant boost regimes (using a recombinant PvDBP_RII protein antigen formulated in Montanide(®)ISA720 or Abisco(®)100 adjuvants).Antibodies induced by these regimes were found to bind to native parasite antigen from P. vivax infected Thai patients and were capable of inhibiting the binding of PvDBP_RII to its receptor DARC using an in vitro binding inhibition assay.

View Article: PubMed Central - PubMed

Affiliation: The Jenner Institute, University of Oxford , Oxford , UK.

ABSTRACT
Malaria vaccine development has largely focused on Plasmodium falciparum; however, a reawakening to the importance of Plasmodium vivax has spurred efforts to develop vaccines against this difficult to treat and at times severe form of relapsing malaria, which constitutes a significant proportion of human malaria cases worldwide. The almost complete dependence of P. vivax red blood cell invasion on the interaction of the P. vivax Duffy-binding protein region II (PvDBP_RII) with the human Duffy antigen receptor for chemokines (DARC) makes this antigen an attractive vaccine candidate against blood-stage P. vivax. Here, we generated both preclinical and clinically compatible adenoviral and poxviral vectored vaccine candidates expressing the Salvador I allele of PvDBP_RII - including human adenovirus serotype 5 (HAdV5), chimpanzee adenovirus serotype 63 (ChAd63), and modified vaccinia virus Ankara (MVA) vectors. We report on the antibody and T cell immunogenicity of these vaccines in mice or rabbits, either used alone in a viral vectored prime-boost regime or in "mixed-modality" adenovirus prime - protein-in--adjuvant boost regimes (using a recombinant PvDBP_RII protein antigen formulated in Montanide(®)ISA720 or Abisco(®)100 adjuvants). Antibodies induced by these regimes were found to bind to native parasite antigen from P. vivax infected Thai patients and were capable of inhibiting the binding of PvDBP_RII to its receptor DARC using an in vitro binding inhibition assay. In recent years, recombinant ChAd63 and MVA vectors have been quickly translated into human clinical trials for numerous antigens from P. falciparum as well as a growing number of other pathogens. The vectors reported here are immunogenic in small animals, elicit antibodies against PvDBP_RII, and have recently entered clinical trials, which will provide the first assessment of the safety and immunogenicity of the PvDBP_RII antigen in humans.

No MeSH data available.


Related in: MedlinePlus