A Nonintegrative Lentiviral Vector-Based Vaccine Provides Long-Term Sterile Protection against Malaria

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From: PLoS ONE(Vol. 7, Issue 11)
Publisher: Public Library of Science
Document Type: Article
Length: 9,946 words
Lexile Measure: 1640L

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Author(s): Frédéric Coutant 1 , Raul Yusef Sanchez David 1 , Tristan Félix 1 , Aude Boulay 1 , Laxmee Caleechurn 1 , Philippe Souque 1 , Catherine Thouvenot 2 , Catherine Bourgouin 2 , Anne-Sophie Beignon 1 , * , Pierre Charneau 1 , *

Introduction

Plasmodium is the causative agent of malaria, a life-threatening disease affecting 216 million people worldwide and responsible for 655 000 deaths in 2010 according to the World malaria report 2011. Repeated childhood exposure to Plasmodium naturally confers specific immunity that protects against the most severe forms of malaria, but does not confer sterile protection. Children remain at risk until they have developed this partial immunity [1]. Therefore an ideal malaria vaccine should fully prevent infection from early infancy onwards.

Plasmodium sporozoites are inoculated into the host's skin by bites from infected mosquitoes. After invading skin blood vessels, they migrate to the liver where they invade hepatocytes and develop. Infected hepatocytes then produce and release merozoites into the blood circulation, which in turn invade red blood cells [2], [3], [4]. The liver-stage is asymptomatic while the erythrocytic stage is pathogenic. Immunizations with radiation-attenuated sporozoites (RAS), which interrupt their development inside hepatocytes, can confer sterile protection against malaria in humans [5] and rodents [6]. However, this strategy is not easily applicable to large-scale approaches because of major technical and logistical limitations, and was sub-optimally immunogenic and protective in a recent phase I/IIa trial following subcutaneous and intradermal injections [7]. Several other candidate vaccines, such as adenovirus or poxvirus vectorized Ag, have been or are being evaluated for safety and immunogenicity and then for protection using experimental challenges or in-field trials [8], [9], [10]. Malaria vaccine projects at advanced pre-clinical and clinical stages globally are summarized by the WHO (the WHO.28_Nov_2011 Malaria Vaccine Rainbow Tables http://www.who.int/vaccine_research/links/Rainbow/en/index.html). However, vaccine-induced immunity has so far failed to confer strong and long-lasting protection against malaria [11], [12]. The most advanced candidate vaccine is the RTS, S, a sub-unit vaccine based on a single pre-erythrocytic antigen (Ag), the Circumsporozoite protein (CSP) from Plasmodium falciparum (Pf) . It was shown to substantially reduce clinical and severe Pf malaria episodes in infants from seven countries in sub-Saharan Africa in a large phase III clinical trial yet without completely preventing infection [13]. Longer-term protection needs to be documented and higher rates of protection are likely required to achieve eradication of malaria in endemic zones [14].

Thus, there is an urgent need to develop new vaccine strategies, including new vectors. The liver stage, although clinically silent, plays a key role in the parasite life cycle. A vaccine aiming to block Plasmodium at the early steps of its cycle in the vertebrate host is likely to be more successful than a vaccine based on erythrocytic Ags only. A mosquito bite delivers about 100 sporozoites in the skin. It results in the rapid invasion of few hepatocytes [15], [16]. The liver-stage is completed in a few days, depending on the parasite and host. Then, each infected hepatocyte releases...

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Gale Document Number: GALE|A477093881