Advances in Plasmodium vivax Malaria Research

Agenda

* Presentation times are subject to change.

Abstracts

Day 1: May 28, 2013

The Need for a Global Strategic Plan for Plasmodium vivax Control & Elimination
Robert D. Newman, MD, MPH, World Health Organization

While Plasmodium falciparum is responsible for the vast majority of cases and deaths from malaria worldwide, P. vivax, the most geographically widespread species, is responsible for a large number of cases; it is increasingly recognized as a cause of severe malaria and even death. There are an estimated 2.6 billion people at risk of P. vivax; and the World Malaria Report 2011 estimated 19.4 million P. vivax cases (range 13.4 to 24.6 million) in 2010, with the greatest number in Asia and Latin America. Many countries have exclusively P. vivax transmission. Abundant data show that transmission of P. falciparum is more responsive to control measures. The scale up of integrated malaria control measures generally results in a shift in balance between the two species such that P. vivax becomes dominant. P. vivax is increasingly becoming resistant to chloroquine, the primary drug used for treatment.
 
The prevention of P. vivax, especially in settings where vectors are exophilic and/or exophagic, has received inadequate attention. Although control strategies such as seasonal mass drug administration (MDA) with primaquine have been used successfully in some settings in Central Europe and Asia, inadequate documentation of safety and efficacy has prevented the wider uptake of such interventions. Parasitological diagnosis of P. vivax has been hampered by late development and slow roll out of highly sensitive and specific bivalent Rapid Diagnostic Tests.
 
Despite a WHO recommendation that confirmed P. vivax infection be radically treated with primaquine, it is not policy in all transmission areas; where it is policy, such treatment is sometimes not prescribed by health workers due to fears of primaquine-induced haemolytic anaemia among patients with G6PD deficiency, for which reliable field tests are still not available. Globally, there remains confusion and disagreement over dosages and treatment duration. While many WHO technical and strategy documents makes reference to P. vivax, there has never been a specific global strategy with time-bound objectives that articulates how to approach the problem of P. vivax at global, regional, and country levels. Such a strategy has now been called for by the WHO Malaria Policy Advisory Committee as a first step in developing a Global Technical Strategy for Malaria Control and Elimination 2016–2025. This P. vivax strategy will be based on: 1) a review of the most recent evidence on programmatic effectiveness of different prevention, control and surveillance interventions of vivax malaria; 2) a review of the current policy and practice on P. vivax service delivery at country and regional level; 3) a review of P. vivax-specific recommendations that are dispersed across various WHO guidance documents; 4) an analysis of on-going research with regard to P. vivax, and how results emerging from such work are likely to influence control and elimination strategies over the next decade, and what research gaps remain; and 5) an economic analysis of the requirements for P. vivax control and elimination.

Global P. vivax Diversity: From Genome to Populations
Jane M. Carlton, PhD, New York University

Recent Advances in Vector Genomic Resources
Daniel E. Neafsey, PhD, Broad Institute

For more than 10 years, the only publicly available, high quality, annotated reference genome assembly for a malaria vector mosquito has been that of Anopheles gambiae. Given the effectively disjoint geographic ranges of this vector species and Plasmodium vivax, investigators in the P. vivax research community have had limited opportunity to take advantage of vector genomic resources to better understand transmission biology.
 
This situation is poised to change. The Broad Institute, in collaboration with VectorBase, the MR4, and many members of the Anopheles research community, has begun releasing draft de novo assemblies of 16 species of Anopheles, including several important vectors of P. vivax. Several years of research and development were invested in devising an optimal strategy for sequencing and assembling these repetitive and highly heterozygous genomes using short-read Illumina next generation sequencing, and the end result will be a collection of assemblies that will rival the original Sanger sequencing-based An. gambiae assembly in quality. It is hoped that these new vector genomic resources will enable a better understanding of vectorial capacity, and facilitate investigations into the transmission biology of all malaria parasites in a range of geographic contexts outside of sub-Saharan Africa.

Multi-OMICS Approaches for Dissecting vivax-vector Interactions
Rhoel R. Dinglasan, PhD, MPH, Johns Hopkins University

Although the molecular (genomics) information for Plasmodium vivax is growing steadily, the same cannot be said for the mosquito vectors of P. vivax malaria. Despite the inclusion of a few relevant anopheline vectors from P. vivax-endemic regions into the genome sequencing pipeline, the information for these vectors remains remarkably deficient. While the genome of the "model" African P. falciparum vector, Anopheles gambiae, has been sequenced, substantial evolutionary divergence limits its utility as a reference across anophelines, especially with respect to several non-sequenced P. vivax vectors. This critical gap in knowledge was highlighted in papers resulting from the malaria eradication research agenda (malERA) effort that were published in PLoS Medicine in 2011. To help fill this gap, we recently reported on the development and application of a hybrid bioinformatic approach that provided not only whole midgut transcriptomic data for the non-sequenced P. vivax vector (Anopheles albimanus), but also mosquito midgut microvilli (MMV) proteomic information. This allowed us to perform a direct comparison of A. gambiae and A. albimanus MMV proteomes with the aim of identifying conserved, mosquito-based transmission-blocking vaccine targets. We envision that this analytical platform can be applied to other P. vivax-vectors across the globe, even for those species which are difficult to colonize. Applying this approach to Anopheles dirus in particular, can hopefully provide comparative insight into the complement of MMV proteins involved in P. vivax vs. P. falciparum invasion of the A. dirus midgut; especially having observed that antibodies against a novel secreted MMV molecule found in both A. gambiae and A. dirus, only blocks P. falciparum oocyst development.

Systems Biology Approaches to P. vivax Research
Mary R. Galinski, PhD, Emory University

We are at an unimaginable point at the cutting edge of science, where breakthroughs may be possible that were unthinkable even a few short years ago. New ways forward are important to study Plasmodium vivax; New World Monkey infections and P. cynomolgi-rhesus monkey model systems hold much promise. The lack of robust in vitro culture systems for blood and liver-stage forms has been a hindrance, but much can be done regardless—and with the benefit of in vivo and ex vivo samples. The in vivo environment matters. Studying the parasite in the context of its host is important and arguably the only true way to research and understand "the disease." Basic ongoing research to understand the liver-stage forms including hypnozoites and relapses, merozoites and invasion of reticulocytes, the infected erythrocyte’s caveolae vesicle complexes, and virulence resulting from P. vivax infections will be presented. The Malaria Host-Pathogen Interaction Center (MaHPIC) will also be introduced. The MaHPIC was created to take a systems biology approach to studying malaria infections caused by P. vivax, P. cynomolgi and other species (mahpic.emory.edu or www.systemsbiology.emory.edu). The central unifying hypothesis of this project is: "Non-Human Primate host interactions with Plasmodium pathogens as model systems will provide insights into mechanisms as well as indicators for human malarial disease conditions."

From Host-Parasite Biology to Antigen Discovery
Hernando del Portillo, PhD, ICREA at Barcelona Institute for Global Health (ISGLOBAL) / Barcelona Centre for International Health Research (CRESIB)

Our goal is to discover new antigens to advance vaccine development against Plasmodium vivax. We have used a systems approach to identify coding-genes whose expression is dependent on an intact spleen as we hypothesize that such genes will encode proteins that are the targets of protective immune responses in natural infections. To look for associations with clinical protections we have used the sera from children 1 to 5 years of age from a prospective longitudinal study in Papua New Guinea. In addition, to look for mechanistics insights of protection, we have developed functional cytoadherence assays on human spleen and lung fibroblasts and tested whether P. vivax-infected reticulocyte cytoadhere to such fibroblasts. This is the first report on the discovery of novel antigens involved in acquisition of natural protective immunity in P. vivax and in challenging the dogma that human Plasmodium-infected cells avoid passage through the spleen.

Mechanisms of Naturally Acquired Immunity to P. vivax Malaria
Christopher L. King, MD, PhD, MPH, Center for Global Health and Diseases, Case Western Reserve University

Naturally acquired immunity to Plasmodium vivax malaria differs in fundamental respects compared to that of the much better studied P. falciparum. For example, individuals acquire immunity to P. vivax more quickly than P. falciparum irrespective of overall transmission intensity resulting in the peak burden of P. vivax malaria in younger age groups. Similarly, actively induced P. vivax infections in malaria therapy patients resulted in faster and generally more strain transcending acquisition of immunity than P. falciparum infections. Potential mechanisms behind the more rapid acquisition of immunity to P. vivax are poorly understood. Natural acquired immune responses to P. vivax target both pre-erythrocytic and blood-stage antigens and include humoral and cellular components. To date, only a few studies have investigated the association of these immune responses with protection, with most studies focusing on a few merozoite antigens [such as the Duffy binding protein (PvDBP), the reticulocyte binding proteins (PvRBPs), or merozoite surface proteins (PvMSP1, 3, and 9)] or the circumsporozoite protein (PvCSP). Naturally acquired transmission blocking immunity was also found in several populations. Though limited, these data support the development of a multi-stage P. vivax vaccine may be feasible.

Strategic Approaches to Developing a P. vivax Vaccine
David C. Kaslow, MD, PATH Malaria Vaccine Initiative

"Malaria due to P. falciparum is the most deadly form and it predominates in Africa; P. vivax is less dangerous but more widespread (WHO Global Malaria Programme World Malaria Report 2012)." This epidemiologic difference—along with biological differences between these two species of the genus Plasmodium—calls for different strategic approaches and target product profiles for vaccines against P. falciparum and P. vivax. The epidemiologic differences highlight the need for P. vivax vaccines that can contribute to control and elimination efforts. The biologic differences present different challenges and opportunities at each of the three target stages of the lifecycle, particularly the liver stage hypnozoites, the Duffy blood group antigen invasion pathway, and the biology of the gametocyte. The latter may provide a unique opportunity in the controlled human malaria infection (CHMI) model to study the effect of immunization on parasite transmission. The strategic goals, the approaches to translational vaccine research and development, and some suggested priorities for a P. vivax malaria vaccine technology roadmap will be presented for discussion.

The Epidemiology of P. vivax
John Kevin Baird, PhD, Eijkman Oxford Clinical Research Unit

A single infectious mosquito bite does not result in a single attack of Plasmodium vivax malaria within two weeks—that bite typically provokes a primary attack followed by as many as 20 others for about two years. These secondary attacks are called relapses and stem from activated hypnozoites placed in the liver at the single infectious bite. Hypnozoites greatly amplify the complexity of the epidemiology of Plasmodium vivax, and, in turn, the prevention, control, and treatment of the infection as a public health problem. The risk, rate, and timing of relapse varies tremendously among strains and seems to hinge upon geographically defined seasonal abundance of anopheline vectors, along with the absolute numbers of sporozoites introduced (as a single bite or multiple bites). Consideration is also given to the relatively very low and self-limiting parasitemias of P. vivax malaria with respect to diagnostics limited to peripheral blood examination. These patterns and considerations are reviewed in the context of their impact upon fundamental epidemiological measures of force of infection, burdens of morbidity, and as critically important confounding factors in trials of chemotherapy against both asexual blood stages and hypnozoites. Strategies for coping with these confounders and deriving estimates of force of infection from both sporozoites and hypnozoites will be reviewed. The "hypnozoite reservoir" is explained as an important and useful concept in defining the epidemiology of P. vivax.

Relapse In Vitro/Ex Vivo: Where Are We?

Dominique Mazier, PhD, National Institute of National Health and Medical Research  (INSERM) and University of Pierre & Marie Curie

Plasmodium vivax hypnozoites, dormant liver forms that activate months to years after the initial infection to produce relapse episodes, pose a serious hurdle to the control and elimination of malaria in many of the endemic regions of the world. Toxicity concerns restrict the deployment of the only available drug (primaquine) that can eliminate hypnozoites. Thus, novel safe anti-hypnozoite drugs are urgently needed. However, screening for such drugs or investigations on hypnozoites that might guide drug discovery have been hampered by a lack of models—with molecular, biochemical, or cellular investigations being hitherto difficult to carry out in their natural hosts (humans infected with P. vivax or macaques infected with P. cynomolgi). We have recently developed a protocol for the in vitro cultivation of hypnozoites in their natural target cells, the primary hepatocyte, thereby making it possible for the first time to investigate hypnozoite biology (Dembele, Gego, et al., PLoS ONE, 2011). This model has been improved as follows: a) we have optimized the cultivation protocols such that the infected cultures can now be routinely maintained for 40 days, and b) we have obtained compelling evidence that the small non-dividing forms are activated to pursue their development, leading to mature hepatic schizonts (sumitted). This allowed the identification of a molecule which induces the activation of hypnozoite to resume maturation. In parallel, we have established new in vivo models of humanized mice engrafted with primary hepatocytes where both schizonts and hypnozoites develop. These tools will be of significant value not only for biological investigations, but also for pre-clinical validation of compounds targeting the hypnozoite. The ultimate goal is to apply this data to rationalize the search for novel drugs that will lead to the elimination of hypnozoites and their associated relapse episodes.

Travel & Lodging

Location

CosmoCaixa

Isaac Newton, 26
Barcelona, Spain
Tel. + 34 93 212 60 50
Fax: + 34 93 253 74 73

Suggested Hotel Accommodations around CosmoCaixa

ABAC Hotel
Address: Avenida Tibidabo 1, (walking distance)
Telephone: + 34 933196600
Web: http://www.abacbarcelona.com/eng
E-mail: info@abacbarcelona.com

Hotel Bertran
Address: Calle Bertran, 150 (walking distance)
Telephone: + 34 932127550 / Fax: + 34 934187103
Web: http://www.bertran-hotel.com
E-mail: info@hotelbertran.com

Hotel Alimara
Address: Calle Berruguete 126, (next to the Ronda de Dalt beltway, 20-min car ride)
Telephone: + 34 934270000 /Fax: + 34 934279292
Web: http://www.alimarahotel.com
Email: hotel.alimara@cett.es

Suggested Hotel Accommodations in Downtown Barcelona

Within walking distance of public transportation
There are not many hotels within walking distance of CosmoCaixa, and thus we recommend that participants book a hotel in downtown Barcelona around Plaza Catalunya, which is in close proximity to public transportation (Ferrocalines de Cataluña or bus # 17).

Hotel Jazz
Address: C Pelai, 3, bxs
Telephone: + 34 935529696 / Fax: + 34 935529697
Web: http://www.nnhotels.es
E-mail: jazz@nnhotels.es

Hotel Catalonia Ramblas
Address: C Pelai, 28
Telephone: + 34 933168400 / Fax: + 34 933168401
Web: http://www.hoteles-catalonia.es
E-mail: ramblas@hoteles-catalonia.es

Hotel H10 Universitat
Address: Rda Universitat 21
Telephone: + 34 933427850 / Fax: + 34 933024907
Web: http://www.h10.es
E-mail: h10.universitat@h10.es

Hotel Regina
Address: C Bergara, 2*4
Telephone: + 34 933013232 / Fax: + 34 933182326
Web: http://www.reginahotel.com
E-mail: reservas@reginahotel.com

Hotel Catalonia Duques de Bergara
Address: Bergara, 11
Telephone: + 34 933015151 / Fax: + 34 933173442
Web: http://www.hoteles-catalonia.es
E-mail: duques@hoteles-catalonia.es

Hotel Pulitzer
Address: C Bergara, 8
Telephone: + 34 934816767
Web: http://www.hotelpulitzer.es
E-mail: info@hotelpulitzer.es

Hotel Soho
Gran Vía, 543-545
Telephone: + 34 935529610 / Fax: + 34 9355296 11
Web:http://www.hotelsohobarcelona.com
E-mail: soho@nnhotels.com

Hotel Reding
Address: Gravina, 5*7
Telephone: + 34 934121097 / Fax: + 34 932683482
Web: http://www.hotelreding.com
E-mail: reding@occidental-hoteles.com

Hotel H10 Gravina
Address: Gravina, 12
Telephone: + 34 933016868 / Fax: + 34 933172838
Web: http://www.h10.es
E-mail: h10.gravina@h10.es

Hotel Inglaterra
Address: Pelai, 14
Telephone: + 34 934873939 / Fax: + 34 935051109
Web: http://www.hotel-inglaterra.com
E-mail: recepcion@hotel-inglaterra.com

Hotel Ciutat Vella
Address: C Tallers, 66
Telephone: + 34 934813799 / Fax: + 34 934813805
Web: http://www.hotelciutatvella.com
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Hotel Atlantis
Address: C Pelai, 20
Telephone: + 34 933189012 / Fax: + 34 934120914
Web: http://www.hotelatlantis-bcn.com
E-mail: info@hotelatlantis-bcn.com

Hotel Lleó
Address: C Pelai, 22
Telephone: + 34 933181039 / Fax: + 34 934122657
Web: http://www.hotel-lleo.es
E-mail: reservas@hotel-lleo.es