A Field Trial to Assess a Blood-Stage Malaria Vaccine

Malaria Research and Training Center, University of Bamako, Bamako, Mali.
New England Journal of Medicine (Impact Factor: 55.87). 09/2011; 365(11):1004-13. DOI: 10.1056/NEJMoa1008115
Source: PubMed


Blood-stage malaria vaccines are intended to prevent clinical disease. The malaria vaccine FMP2.1/AS02(A), a recombinant protein based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, has previously been shown to have immunogenicity and acceptable safety in Malian adults and children.
In a double-blind, randomized trial, we immunized 400 Malian children with either the malaria vaccine or a control (rabies) vaccine and followed them for 6 months. The primary end point was clinical malaria, defined as fever and at least 2500 parasites per cubic millimeter of blood. A secondary end point was clinical malaria caused by parasites with the AMA1 DNA sequence found in the vaccine strain.
The cumulative incidence of the primary end point was 48.4% in the malaria-vaccine group and 54.4% in the control group; efficacy against the primary end point was 17.4% (hazard ratio for the primary end point, 0.83; 95% confidence interval [CI], 0.63 to 1.09; P=0.18). Efficacy against the first and subsequent episodes of clinical malaria, as defined on the basis of various parasite-density thresholds, was approximately 20%. Efficacy against clinical malaria caused by parasites with AMA1 corresponding to that of the vaccine strain was 64.3% (hazard ratio, 0.36; 95% CI, 0.08 to 0.86; P=0.03). Local reactions and fever after vaccination were more frequent with the malaria vaccine.
On the basis of the primary end point, the malaria vaccine did not provide significant protection against clinical malaria, but on the basis of secondary results, it may have strain-specific efficacy. If this finding is confirmed, AMA1 might be useful in a multicomponent malaria vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; number, NCT00460525.).

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Available from: Ogobara K Doumbo, Oct 04, 2015
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    • "For a number of decades, merozoite surface protein 1 (MSP1) [6] and apical membrane antigen 1 (AMA1) [7] have been assessed as leading subunit vaccine candidate antigens – both are expressed by the invasive blood-stage merozoite, with evidence they are also present at the late liver-stage [8] or sporozoite stage [9] of the parasite lifecycle. These antigens, most often delivered as antibody-inducing recombinant protein formulated in adjuvant, have shown disappointing levels of efficacy in Phase IIa/b clinical trials [5], [10], [11], although one AMA1 formulation was reported to show strain-specific efficacy in a Phase IIb field trial in Malian children [12]. Consequently, a number of researchers within the field have argued that an effective blood-stage vaccine would in fact necessitate the induction of T cell responses, in conjunction with antibody responses, in order to achieve protection [13]. "
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    ABSTRACT: The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite - MSP1 and AMA1. These antigens were delivered to healthy malaria-naïve adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors - ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI) with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i) ChAd63-MVA immunization, ii) immunization and CHMI, and iii) primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i) total IgG responses before and after CHMI, ii) responses to allelic variants of MSP1 and AMA1, iii) functional growth inhibitory activity (GIA), iv) IgG avidity, and v) isotype responses (IgG1-4, IgA and IgM). These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other diseases targets, these data should help to guide further immuno-monitoring studies of vaccine-induced human antibody responses.
    PLoS ONE 09/2014; 9(9):e107903. DOI:10.1371/journal.pone.0107903 · 3.23 Impact Factor
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    • "These interventions have been routinely available in the Malian town of Bandiagara since 2007. This town has been the testing site for several malaria vaccine candidates since 2003 [4–7]. The impact of studies on the reduction of the malaria burden at other clinical trial sites has been reported [8–10]. "
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    ABSTRACT: Background The recent decline in malaria incidence in many African countries has been attributed to the provision of prompt and effective anti-malarial treatment using artemisinin-based combination therapy (ACT) and to the widespread distribution of long-lasting, insecticide-treated bed nets (LLINs). At a malaria vaccine-testing site in Bandiagara, Mali, ACT was introduced in 2004, and LLINs have been distributed free of charge since 2007 to infants after they complete the Expanded Programme of Immunization (EPI) schedule and to pregnant women receiving antenatal care. These strategies may have an impact on malaria incidence. Methods To document malaria incidence, a cohort of 400 children aged 0 to 14 years was followed for three to four years up to July 2013. Monthly cross-sectional surveys were done to measure the prevalence of malaria infection and anaemia. Clinical disease was measured both actively and passively through continuous availability of primary medical care. Measured outcomes included asymptomatic Plasmodium infection, anaemia and clinical malaria episodes. Results The incidence rate of clinical malaria varied significantly from June 2009 to July 2013 without a clear downward trend. A sharp seasonality in malaria illness incidence was observed with higher clinical malaria incidence rates during the rainy season. Parasite and anaemia point prevalence also showed seasonal variation with much higher prevalence rates during rainy seasons compared to dry seasons. Conclusions Despite the scaling up of malaria prevention and treatment, including the widespread use of bed nets, better diagnosis and wider availability of ACT, malaria incidence did not decrease in Bandiagara during the study period.
    Malaria Journal 09/2014; 13(1):374. DOI:10.1186/1475-2875-13-374 · 3.11 Impact Factor
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    • "Such variation poses significant challenges for vaccine development, since a vaccine that has high strain-specific efficacy against the antigen included in the vaccine would nonetheless be poorly effective against variant circulating strains in the field (Moorthy and Kieny, 2010). This has been demonstrated experimentally with a candidate three-component blood-stage vaccine against malaria known as Combination B (Genton et al., 2002) and subsequent field studies with recombinant merozoite surface protein 1 (MSP1) (Ogutu et al., 2009; Otsyula et al., 2013) and apical membrane antigen 1 (AMA1) vaccines (Ouattara et al., 2010, 2013; Thera et al., 2011). However, recent technological advances (see below) have allowed the development of multivalent vaccines against pathogens with multiple strains or serotype (e.g. the licensed 7-valent, 10-valent or 13-valent conjugate vaccines for Pneumococcus or the 4-valent vaccine for Meningococcus (De Gregorio and Rappuoli, 2012). "
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    ABSTRACT: Vaccines are one of the most effective interventions to improve public health, however, the generation of highly effective vaccines for many diseases has remained difficult. Three chronic diseases that characterise these difficulties include malaria, tuberculosis and HIV, and they alone account for half of the global infectious disease burden. The whole organism vaccine approach pioneered by Jenner in 1796 and refined by Pasteur in 1857 with the "isolate, inactive and inject" paradigm has proved highly successful for many viral and bacterial pathogens causing acute disease but has failed with respect to malaria, tuberculosis and HIV as well as many other diseases. A significant advance of the past decade has been the elucidation of the genomes, proteomes and transcriptomes of many pathogens. This information provides the foundation for new 21(st) Century approaches to identify target antigens for the development of vaccines, drugs and diagnostic tests. Innovative genome-based vaccine strategies have shown potential for a number of challenging pathogens, including malaria. We advocate that genome-based rational vaccine design will overcome the problem of poorly immunogenic, poorly protective vaccines that has plagued vaccine developers for many years.
    International Journal for Parasitology 09/2014; 44(12). DOI:10.1016/j.ijpara.2014.07.010 · 3.87 Impact Factor
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