Table of Contents

Volume 6, Issue 1

  January 2010

  Pages 1 - 150

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 Issue Catalogue (MARC XML)

EDITOR'S CORNER

Open Access Article

Letter from the Editor

Ronald W. Ellis and Eva Riedmann
Page 1
http://dx.doi.org/10.4161/hv.6.1.10702
PDF

Open Access Article

Special issue on malaria vaccine development

Denise L Doolan
Page 2
http://dx.doi.org/10.4161/hv.6.1.10703
PDF




SPECIAL FOCUS REVIEWS

Open Access Article

A biologist’s perspective on malaria vaccine development

Robert Sinden
Pages 3 - 11
http://dx.doi.org/10.4161/hv.6.1.9604
Abstract | PDF

A vaccine to reduce human suffering caused by malarial parasites has been the holy grail of malaria research. Early studies in the 1940’s indicated that attenuated parasites could induce useful immunity. Since that time the genomic revolution led inevitably to the idea of cheap production of safe recombinant vaccines using either expressed protein or DNA vector technologies. It has been difficult to reflect with these ‘simple’ formulations the efficacies observed with intact parasite immunogens. With the new-found ability to attenuate the parasites by genetic manipulation, ideas have come full circle. Some of the highs and lows of this journey are described from the specific viewpoint of our growing understanding of parasite biology. The objective of many current vaccine initiatives targeting morbidity and mortality is questioned in the light of renewed calls to consider eradication as an objective. The biological rational for approaches to limit parasite transmission are highlighted and their place in future efforts to improve the lives of the 40% of the world’s population at risk of the disease is discussed.

Open Access Article

Malaria vaccine development: An endemic country perspective

Kwadwo A. Koram and Ben A. Gyan
Pages 12 - 16
http://dx.doi.org/10.4161/hv.6.1.9605
Abstract | PDF

The quest for an effective vaccine as an additional strategy in the control of malaria and to significantly impact the disease burden has progressed tremendously over the past decade and there is a very high probability that that a malaria vaccine will be available for use in the near future.  The development and deployment of an effective malaria vaccine faces several challenges and the early engagement of endemic country institutions in the entire process will be beneficial to all.  It is very likely that the initial vaccines will have to be improved upon, especially as our understanding of the disease processes improves and the number of potential vaccine antigens increase.  This will place greater demands on the currently insufficient capacity for trials.  Current strategies for testing and deployment of a malaria vaccine, for example those focusing on risk groups, will also need modifications as efforts are moved towards malaria elimination.  Also, a successful malaria vaccine development will need strengthening of the weak regulatory framework obtained in endemic countries to enable them have oversight over clinical trials. The introduction of any malaria vaccine will be confronted by some cultural issues and it is essential to understand how these factors will ultimately affect its utilization. These and other challenges related to the development and deployment of an effective malaria vaccine especially as they concern endemic countries are discussed.

Open Access Article

Vaccines against malaria: Perspectives from Papua, New Guinea

Ivo Mueller, Blaise Genton, Inoni Betuela and Michael P. Alpers
Pages 17 - 20
http://dx.doi.org/10.4161/hv.6.1.10332
Abstract | PDF

Despite its small population and isolate location Papua New Guinea (PNG) with a malaria burden comparable to sub-Saharan Africa, its intense transmission of all 4 human Plasmodium species and an unrivalled combination of environmental and human variation offers unique perspectives on malaria vaccines. Building on a long history of malaria research, in this article we review past achievements, highlight current research and outline future directions in malaria vaccine research. With intensive transmission of all four species of human malaria, a full range of malaria endemicities, well described epidemiology and a demonstrated capacity to evaluate a malaria vaccine, PNG currently has the only field site that is ready to conduct proof-of-principle studies of currently available P. vivax vaccine candidates and future combined P. falciparum / P. vivax vaccines and also offers unique opportunities for P. falciparum vaccine research. PNG is thus ready to contribute significantly in the global malaria vaccine endeavour.

Open Access Article

Guidelines and considerations for testing malaria vaccines in pregnant women

Clara Menendez and Pedro Alonso
Pages 21 - 26
http://dx.doi.org/10.4161/hv.6.1.10331
Abstract | PDF

Malaria in pregnancy continues being an important cause of maternal and infant morbidity and mortality in endemic areas, where up to 50 million pregnancies are exposed to the infection every year. Important progress has been made in the last years especially in sub-Saharan Africa, with the introduction of strategies to prevent malaria in pregnancy consisting of intermittent preventive treatment and insecticide treated nets. However, their coverage is still unacceptably low and malaria continues to demand a huge toll on pregnant women and their newborns. Thus, there is a need to explore other preventive strategies such as a vaccine against malaria, which combined with the current tools would maximise the protection efficacy. Given the specific and complex characteristics of the pregnancy status, it is important to review all the issues that would need to be considered in the evaluation of a vaccine against malaria in pregnancy while waiting for it to become available.

Open Access Article

The past decade in malaria synthetic peptide vaccine clinical trials

Elizabeth Nardin
Pages 27 - 38
http://dx.doi.org/10.4161/hv.6.1.9601
Abstract | PDF

Over the past  decade (2000 – 2009),  there have been nine clinical trials of synthetic malaria peptide vaccines designed to target the pre-erythrocytic and erythrocytic stages of the Plasmodium falciparum parasite.  Recent advances in parasite immunology and cell biology have been utilized to improve peptide design and adjuvant formulations.  The clinical trials demonstrated the potential of second generation peptide vaccines to elicit antibodies that can neutralize sporozoite infectivity and cooperate with monocytes in ADCI to inhibit blood stage parasites.  In addition, the peptide-induced malaria-specific human CD4⁺ and CD8⁺ T cells were shown in vitro  to have similar fine specificity and function as parasite-induced T cells. The results of these clinical trials, while encouraging, have emphasized the critical roles of immunological assays, in particular functional assays, for the evaluation of potential vaccine candidates.  Additional challenges include the need for potent adjuvants for the development of synthetic peptide vaccines that can effectively target multiple stages of the Plasmodium parasite.

Open Access Article

Recombinant protein vaccines against the asexual blood-stages of Plasmodium falciparum

Robin F. Anders, Christopher G. Adda, Michael Foley and Raymond S. Norton
Pages 39 - 53
http://dx.doi.org/10.4161/hv.6.1.10712
Abstract | PDF

It is now more than 25 years since asexual blood-stage antigens of Plasmodium falciparum were first expressed as recombinant proteins. Although many asexual blood-stage vaccine candidates have been identified none have yet been fully evaluated in clinical trials. The results of studies in animal models, and from in vitro studies with P. falciparum, indicate that antibody responses induced by many of these recombinant proteins can inhibit parasite development but so far the evidence that protection can be achieved in exposed human populations is limited. Recombinant forms of MSP2 and AMA1 expressed in E. coli have had significant effects in Phase II trials, although for both antigens the effect was against a subset of parasites expressing a form of these polymorphic antigens related to that in the vaccine. More knowledge of the antigenic structure of the native parasite antigens is required so that the recombinant protein constructs can be optimized to induce the correct antibody fine specificity. The very different structural characteristics of MSP2 and AMA1 are discussed, as are some approaches being taken to overcoming the problem of diversity in these antigens.

Open Access Article

Molecular vaccines for malaria

Joseph T. Bruder, Evelina Ango, Keith J. Limbach and Thomas L. Richie
Pages 54 - 77
http://dx.doi.org/10.4161/hv.6.1.10463
Abstract | PDF

The basic premise of vaccination is the triggering of host immune responses leading to the induction of adaptive immunity having sufficient magnitude and duration to provide long term protection. This has been achieved by many licensed vaccines, the majority based on attenuated or inactivated organisms, although often the protective antigens and underlying molecular mechanisms have not been identified. However, this traditional approach has not led to the development of a licensed vaccine for malaria or for several other devastating infectious diseases. Recently, substantial efforts have been focused on applying rational molecular design principles toward the development of novel vaccines for these refractory pathogens. In this review, we discuss the molecular aspects of antigen design, adjuvant advancement and the development of vaccine delivery systems as they are being applied to malaria vaccines.

Open Access Article

Prime-boost vectored malaria vaccines: Progress and prospects

Adrian V. S. Hill, Arturo Reyes-Sandoval, Geraldine O’Hara, Katie Ewer, Alison Lawrie, Anna Goodman, Alfredo Nicosia, Antonella Folgori, Stefano Colloca, Riccardo Cortese, Sarah C. Gilbert and Simon Draper
Pages 78 - 83
http://dx.doi.org/10.4161/hv.6.1.10116
Abstract | PDF

The difficulty of inducing protective immunity through antibodies against sporozoites led to efforts to assess vectored vaccines as a means of inducing protective T cell immunity against the malaria liver-stage parasite. Although DNA vectored vaccines used alone were poorly immunogenic and not protective, high levels of parasite clearance in the liver has been achieved with viral vectored vaccines used in heterologous prime-boost regimes. Such vectored vaccination regimes represent one of only two approaches that have induced repeatable partial efficacy in human P. falciparum subunit vaccine trials. Interestingly, vectors expressing the TRAP antigen have been consistently been more immunogenic and protective than vectors expressing the circumsporozoite protein in human trials. However, sterile protection requires induction of very potent T cell responses that are currently only achievable with heterologous prime-boost regimes. Recently, simian adenoviruses have been assessed as priming agents in Adenovirus-MVA regimes in both phase I and phase IIa trials in the UK, based on very promising pre-clinical results showing better immunogenicity and efficacy than previous prime-boost regimes. The same vectors are also being assessed clinically expressing blood-stage antigens, attempting to induce both protective antibodies and T cells as recently demonstrated in murine efficacy studies. These viral vectors now provide a major option for inclusion in a high efficacy multi-stage malaria vaccine that should achieve deployable levels of efficacy in endemic settings.

Open Access Article

The role of Plasmodium falciparum variant surface antigens in protective immunity and vaccine development

Lars Hviid
Pages 84 - 89
http://dx.doi.org/10.4161/hv.6.1.9602
Abstract | PDF

There is substantial immuno-epidemiological evidence that the parasite-encoded, so-called variant surface antigens (VSAs) such as PfEMP1 on the surface of infected erythrocytes (IEs) are important – in some cases probably decisive – determinants of clinical outcome of P. falciparum malaria. The evidence is increasingly being underpinned by specific molecular understanding of the pathogenic processes involved. Pregnancy-associated malaria (PAM) caused by placenta-sequestering IEs expressing the PfEMP1 variant VAR2CSA is a particularly striking example of this. These findings have raised hopes that development of PfEMP1-based vaccines to protect specifically against severe malaria syndromes – in particular PAM – is feasible. This review summarizes the evidence that VSAs are important targets of NAI, discusses why VSA-based vaccines might be feasible despite the extensive intra- and interclonal variation of VSAs, and how vaccines based on this type of antigens fit into the current global strategy to reduce, eliminate, and eventually eradicate the burden of malaria.

Open Access Article

From the circumsporozoite protein to the RTS,S/AS candidate vaccine

Joe Cohen, Victor Nussenzweig, Johan Vekemans and Amanda Leach
Pages 90 - 96
http://dx.doi.org/10.4161/hv.6.1.9677
Abstract | PDF

The RTS,S/AS01E malaria vaccine candidate has recently entered phase 3 testing. Reaching this important milestone is the culmination of more than 20 years of research and development by GlaxoSmithKline and partners and collaborators. The vaccine has been developed to protect young children and infants living in sub-Saharan Africa against clinical and severe disease caused by Plasmodium falciparum infection.
Over the past 9 years, RTS,S/AS candidate vaccine has been evaluated in multiple Phase 2 studies. The vaccine was shown to have a favourable safety profile and to be well tolerated in all age groups in which it was tested, including the intended target population of infants and young children in Sub-Saharan Africa.
Data obtained so far suggest that RTS,S/AS can be co-administered with other vaccines included in the routine Expanded Program of Immunization (EPI). In Phase 2 testing, the vaccine candidate was shown to confer significant protection against P. falciparum infection and clinical disease, including severe malaria. Furthermore, a trend towards an indirect beneficial effect of the vaccine on non-malarial morbidities has been observed in several trials.
In this paper, we will describe the genesis of the RTS,S/AS concept, including the rationale for selecting the circumsporozoite protein (CSP) as the target antigen. Early development history of the vaccine will be briefly described. We will present the most salient results from recent Phase 2 studies conducted in the target pediatric population, which have led to the decision to progress RTS,S/AS to Phase 3 testing.
If the Phase 3 results confirm the observations made during Phase 2 testing, the RTS,S/AS vaccine, when broadly implemented and judiciously integrated with other malaria-prevention measures, would have a major public-health impact in Sub-Saharan Africa.


Open Access Article

Development of a metabolically active, non-replicating sporozoite vaccine to prevent Plasmodium falciparum malaria

Stephen L. Hoffman and 20 others
Pages 97 - 106
http://dx.doi.org/10.4161/hv.6.1.10396
PDF

Open Access Article

Genetically engineered, attenuated whole-cell vaccine approaches for malaria

Ashley Vaughan, Ruobing Wang and Stefan H.I. Kappe
Pages 107 - 113
http://dx.doi.org/10.4161/hv.6.1.9654
Abstract | PDF

The quest for an efficacious malaria vaccine has been ongoing for nearly a century with limited success. Malaria remains one of the most significant infectious diseases affecting human populations in developing countries.  The identification of a number of major malaria parasite antigens focused efforts on the development of subunit vaccines but has so far yielded only one partially efficacious vaccine candidate, RTS/S.  The lack of high vaccine efficacy observed with subunit vaccine candidates raises principal doubts that the development of a single antigen- or even a multi-antigen malaria subunit vaccine is possible. Fortunately, it has been demonstrated in animal studies and experimental clinical studies that immunizations with live-attenuated sporozoite stages of the malaria parasite confer long lasting, sterile protection against infection, providing a benchmark for vaccine development. These early successful vaccinations with live-attenuated malaria parasites did not however, promote a developmental path forward for such a vaccine approach.  The discovery of genetically engineered parasite strains that are fully attenuated during the early asymptomatic liver infection and confer complete sterile protection in animal malaria models support the development of a live attenuated sporozoite vaccine for Plasmodium falciparum and its accelerated safety and efficacy testing in malaria challenge models and in malaria endemic areas.

Open Access Article

Whole parasite blood stage malaria vaccines: A convergence of evidence

James S McCarthy and Michael F. Good
Pages 114 - 123
http://dx.doi.org/10.4161/hv.6.1.10394
Abstract | PDF

There is a growing realization of the limitations of recombinant protein-based malaria vaccines. This, coupled with a better understanding of the protective immunity to malaria, both in animal models and in naturally exposed human populations and experimentally infected volunteers, as well as the increased capacity to manipulate parasites provides new impetus to evaluate whole blood stage parasite approaches to malaria vaccine development. In this review previous studies in rodents and primates of whole killed and attenuated blood stage vaccines, and recent work on the effect of genetically attenuated parasites on immunity in rodent models of blood stage immunity are discussed. The relationship between these findings and what is now known about protective immunity in human populations, specifically against the blood stages of the parasite lifecycle is discussed and recent findings from human experimental infection are be reviewed. Finally, the prospect for and impediments to the development whole blood stage parasites are reviewed.

Open Access Article

Current status of Plasmodium vivax vaccine

Myriam Arévalo-Herrera, Chetan Chitnis and Sócrates Herrera
Pages 124 - 132
http://dx.doi.org/10.4161/hv.6.1.9931
Abstract | PDF

From a total of 2.6 billion people at permanent risk of suffering malaria infection worldwide, 80-300 million experience Plasmodium vivax infections every year, with clinical manifestations ranging from asymptomatic to mild and chronic infection that in some cases lead to severe disease and death. The increasing P. vivax drug resistance and reports of severe and lethal cases, the relapsing parasite behavior and the existence of Plasmodium spp co-infections must prompt more investment and greater efforts for the development of P. vivax vaccine. Currently there are only two P. vivax vaccine candidates being tested in clinical trials and few others are being assessed in preclinical studies which contrast with the numerous P. falciparum vaccines candidates under evaluation. The recent availability of the P. vivax genome and ongoing proteomic analysis are likely to accelerate P. vivax vaccine development. Recent development of human sporozoite-challenge models would contribute to move clinical development forward and to identify mechanisms of immunity.

Open Access Article

Alternative approaches to vaccine delivery

Lina Wang, Charles Ma and Ross L. Coppel
Pages 133 - 138
http://dx.doi.org/10.4161/hv.6.1.9878
Abstract | PDF

Subunit vaccines under development for malaria utilise a limited number of approaches to delivery. The majority of these deliver recombinant proteins by parenteral injection either alone or as fusions assembling into particles and several are now in clinical trial with varying results. If and when an effective or partially-effective vaccine formulation becomes available in the future, the challenge of producing with an affordable cost of goods and delivering it to a large target population many of who live in remote areas will remain. In addition, the significant safety concerns of appropriate reuse and disposal of needles from the vaccination process will need to be addressed. Therefore, along with the efforts to advance the most promising vaccine formulations through the development pipeline, research is taking place into alternative methods for cheaper vaccine production and easy administration. This chapter will discuss some of these approaches, including transgenic plants and mammals as bioreactors for low cost vaccine production and alternative routes of vaccine delivery such as mucosal immunization.

Open Access Article

PATH Malaria Vaccine Initiative (MVI): Perspectives on the status of malaria vaccine development

Ashley J. Birkett
Pages 139 - 145
http://dx.doi.org/10.4161/hv.6.1.10462
PDF

Open Access Article

European malaria vaccine initiative: Portfolio and perspectives for the future

Egeruan Babatunde Imoukhuede, Roland Ventura, Nathalie Imbault, Harry van Schooten and Odile Leroy
Pages 146 - 150
http://dx.doi.org/10.4161/hv.6.1.9603
Abstract | PDF

Over the past ten years, EMVI has continually strived to maintain its main goal of accelerating the development of candidate malaria vaccines by facilitating the translational gap between promising experimental malaria vaccines and subsequent clinical trials in Europe and in Africa. To date, EMVI has funded approximately ten vaccine formulations and subsequent human clinical trials. In recent years EMVI’s role has expanded into harmonisation activities relevant to malaria vaccine development as well as making contributions to global coordination efforts in the field of malaria vaccine research and development (R&D). In the next five years, EMVI will be coordinating the European Network of Vaccine Research and Development (TRANSVAC), an EC-supported action implementing a vaccine development infrastructure for Europe. By stimulating collaboration, cooperation, networking and joint integrated activities across various fields of research and diseases, and by facilitating the federation of research infrastructures, EMVI is acting today as a catalyst for tomorrow’s vaccines.