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Infection and Immunity, January 2006, p. 313-320, Vol. 74, No. 1
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.1.313-320.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Immunogenicity and Protection of a Recombinant Human Adenovirus Serotype 35-Based Malaria Vaccine against Plasmodium yoelii in Mice

O. J. A. E. Ophorst,1,5 K. Radosevic,1 M. J. E. Havenga,1* M. G. Pau,1 L. Holterman,1 B. Berkhout,2 J. Goudsmit,1,5 and M. Tsuji3,4

Crucell Holland BV, P.O. Box 2048, 2301 CA Leiden, The Netherlands,1 Department of Human Retrovirology, Academic Medical Center, Amsterdam, The Netherlands,2 Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, New York 10010,3 Aaron Diamond AIDS Research Center, The Rockefeller University, 455 First Ave., New York, New York 10016,4 Center of Poverty-Related Communicable Diseases, Academic Medical Center, Amsterdam, The Netherlands5

Received 30 June 2005/ Returned for modification 24 August 2005/ Accepted 20 October 2005

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.

* Corresponding author. Mailing address: Crucell Holland B.V., P.O. Box 2048, 2301 CA Leiden, The Netherlands. Phone: 31 (0) 71 5248726. Fax: 31 (0) 71 5248702. E-mail: m.havenga{at}Crucell.com.

Editor: J. F. Urban, Jr.

Infection and Immunity, January 2006, p. 313-320, Vol. 74, No. 1
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.1.313-320.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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