Vergelijking met vorige publicaties over Crucells malaria vaccins:
Nu, in 2010, wordt dus een vaccin met 3 componenten getest: CS protein, met Ad35 en Ad26.
Een prime/boost van 2 componenten, CS-protein met Ad35, werd in 2008 getest door Crucell (1).
Walter Reed heeft, ook in 2008, Ad5, Ad35 en RTS,S met elkaar vergeleken (2).
Ad35 alleen ,werd al in 2006 door Crucell getest (3).
Een 3-componenten vaccin blijkt nu, nog beter dan een 2-componenten systeem, de CD8+ T-cell response te verhogen. Dit is nodig omdat met GSK's RTS,S vaccins voornamelijk de B-cell en de CD4+ T-cell response triggert, wat slechts kortere-termijn immuniteit genereert, terwijl met de CD8+ response erbij een langdurigere immuniteit wordt gevormd.
Geen spetterend nieuws m.i., maar degelijk onderzoek, dat de hoop levend houdt dat Crucells Ad-vaccins het tot een daadwerkelijk vaccin gaan brengen.
(1)
Infect Immun. 2008 Apr;76(4):1709-18. Epub 2008 Jan 22.
Impact of recombinant adenovirus serotype 35 priming versus boosting of a Plasmodium falciparum protein: characterization of T- and B-cell responses to liver-stage antigen 1.
Rodríguez A, Goudsmit J, Companjen A, Mintardjo R, Gillissen G, Tax D, Sijtsma J, Weverling GJ, Holterman L, Lanar DE, Havenga MJ, Radosevic K.
Prime-boost vaccination regimens with heterologous antigen delivery systems have indicated that redirection of the immune response is feasible. We showed earlier that T-cell responses to circumsporozoite (CS) protein improved significantly when the protein is primed with recombinant adenovirus serotype 35 coding for CS (rAd35.CS). The current study was designed to answer the question whether such an effect can be extended to liver-stage antigens (LSA) of Plasmodium falciparum such as LSA-1. Studies with mice have demonstrated that the LSA-1 protein induces strong antibody response but a weak T-cell immunity. We first identified T-cell epitopes in LSA-1 by use of intracellular gamma interferon (IFN-gamma) staining and confirmed these epitopes by means of enzyme-linked immunospot assay and pentamer staining. We show that a single immunization with rAd35.LSA-1 induced a strong antigen-specific IFN-gamma CD8(+) T-cell response but no measurable antibody response. In contrast, vaccinations with the adjuvanted recombinant LSA-1 protein induced remarkably low cellular responses but strong antibody responses. Finally, both priming and boosting of the adjuvanted protein by rAd35 resulted in enhanced T-cell responses without impairing the level of antibody responses induced by the protein immunizations alone. Furthermore, the incorporation of rAd35 in the vaccination schedule led to a skewing of LSA-1-specific antibody responses toward a Th1-type immune response. Our results show the ability of rAd35 to induce potent T-cell immunity in combination with protein in a prime-boost schedule without impairing the B-cell response.
(2)
Vaccine. 2008 Jun 2;26(23):2818-23. Epub 2008 Apr 16.
Adenovirus 5 and 35 vectors expressing Plasmodium falciparum circumsporozoite surface protein elicit potent antigen-specific cellular IFN-gamma and antibody responses in mice.
Shott JP, McGrath SM, Pau MG, Custers JH, Ophorst O, Demoitié MA, Dubois MC, Komisar J, Cobb M, Kester KE, Dubois P, Cohen J, Goudsmit J, Heppner DG, Stewart VA.
Division of Malaria Vaccine Development, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. Joseph.Shott@rhsp.org
Abstract
Falciparum malaria vaccine candidates have been developed using recombinant, replication-deficient serotype 5 and 35 adenoviruses (Ad5, Ad35) encoding the Plasmodium falciparum circumsporozoite surface protein (CSP) (Ad5.CS, Ad35.CS) (Crucell Holland BV, Leiden, The Netherlands). To evaluate the immunogenicity of these constructs, BALB/cJ mice were immunized twice with either Ad5.CS, Ad35.CS, empty Ad5-vector (eAd5), empty Ad35 vector (eAd35), or saline. Another group received the CSP-based RTS,S malaria vaccine formulated in the proprietary Adjuvant System AS01B (GlaxoSmithKline Biologicals, Rixensart, Belgium). Here we report that Ad5.CS, Ad35.CS, and RTS,S/AS01B, elicited both cellular and serologic CSP antigen-specific responses in mice. These adenoviral vectors induce strong malaria-specific immunity and warrant further evaluation.
(3)
Infect Immun. 2006 Jan;74(1):313-20.
Immunogenicity and protection of a recombinant human adenovirus serotype 35-based malaria vaccine against Plasmodium yoelii in mice.
Ophorst OJ, Radosević K, Havenga MJ, Pau MG, Holterman L, Berkhout B, Goudsmit J, Tsuji M.
Crucell Holland B.V., P.O. Box 2048, 2301 CA Leiden, The Netherlands.
Abstract
Given the promise of recombinant adenovirus type 5 (rAd5) as a malaria vaccine carrier in preclinical models, we evaluated the potency of rAd35 coding for Plasmodium yoelii circumsporozoite protein (rAd35PyCS). We chose rAd35 since a survey with serum samples from African subjects demonstrated that human Ad35 has a much lower seroprevalence of 20% and a much lower geometric mean neutralizing antibody titer (GMT) of 48 compared to Ad5 (seroprevalence, 85%; GMT, 1,261) in countries with a high malaria incidence. We also demonstrated that immunization with rAd35PyCS induced a dose-dependent and potent, CS-specific CD8(+) cellular and humoral immune response and conferred significant inhibition (92 to 94%) of liver infection upon high-dose sporozoite challenge. Furthermore, we showed that in mice carrying neutralizing antibody activity against Ad5, mimicking a human situation, CS-specific T- and B-cell responses were significantly dampened after rAd5PyCS vaccination, resulting in loss of inhibition of liver infection upon sporozoite challenge. In contrast, rAd35 vaccine was as potent in naive mice as in Ad5-preimmunized mice. Finally, we showed that heterologous rAd35-rAd5 prime-boost regimens were more potent than rAd35-rAd35 because of induction of anti-Ad35 antibodies after rAd35 priming. The latter data provide a further rationale for developing rAd prime-boost regimens but indicate that priming and boosting Ad vectors must be immunologically distinct and also should be distinct from Ad5. Collectively, the data presented warrant further development of rAd35-based vaccines against human malaria.