Final Report Summary - PREGVAX (Plasmodium Vivax infection in pregnancy)
Executive summary:
Plasmodium vivax (p. vivax) is the most common and widely distributed human malaria parasite and causes up to 80 million cases annually, with the majority occurring in Asia and the western Pacific, central and south America and the Middle East. It has been estimated that globally 93 million pregnancies occurred in areas endemic for p. vivax in 2007.
While the effects of plasmodium falciparum (p. falciparum) malaria in pregnancy have been well characterised and are responsible for considerable maternal and infant morbidity and mortality, surprisingly little is known about the burden and impact of p. vivax infection on maternal and foetal health. Some studies indicate adverse effects of p. vivax malaria in pregnancy; yet, they all provide only partial information on the epidemiological and clinical aspects of the infection in pregnancy and none on the mechanisms involved. This gives us a disconcerting and incomplete picture of the true burden and impact of p. vivax in pregnancy.
The PREGVAX consortium started back in 2008 to address those knowledge gaps in p. vivax infection during pregnancy. It has brought together 11 research institutions and some of the best multidisciplinary scientists and experts on p. vivax malaria from a variety of countries and regions across the world. Under the umbrella of this consortium a cohort observational study of pregnant women from five p. vivax endemic countries (Brazil, Colombia, Guatemala, India and Papua New Guinea), broadly representing most of the world's p. vivax infections, has been conducted. This study describes the epidemiological and clinical features of p. vivax malaria in pregnancy following standardised methods for data collection. In addition, the PREGVAX consortium has been working to determine whether there are pregnancy specific p. vivax immune responses and characterise genotypically and phenotypically the parasites of the placenta.
In an unprecedented effort, almost 10 000 pregnant women have been enrolled at the different project sites during their routine antenatal care visits and followed up at the health facility until delivery. Recruited women have been 1 696 in Brazil, 2 039 in Colombia, 2 009 in Guatemala, 2 050 in India and 1 679 at Papua New Guinea. Deliveries attended and included in the study have been 905 in Brazil, 783 in Colombia, 1 025 in Guatemala, 1 332 in India and 935 at Papua New Guinea. This means that about 53 % of the women participants in the study were followed up until delivery showing a low rate of loss to follow up during the study. In the context of this large cohort of pregnant women, almost 98 000 study visits have occurred. A database has been built up that includes information from near 98 000 questionnaires and almost 77 000 biological samples have been collected.
Although p. falciparum is the most deadly species and the subject of most malaria related research and literature, more attention should be given to p. vivax. So far, with PREGVAX study, some progress has been made and further evidence is becoming available. This recent evidence suggests that p. vivax malaria can have deleterious effects on the health of the mother and the neonate. More accurate data of vivax malaria during gestation are essential to improve its clinical management and to guide control policies. Furthermore, elucidating the mechanisms involved in the pathology of p. vivax in pregnancy will help to develop specific control tools such as more effective drugs and vaccines.
Project context and objectives:
Despite the reality that p. vivax is the most widely distributed human malaria parasite, it has been the focus of surprisingly little research. Vivax malaria accounts for approximately 70 to 80 million cases worldwide per year and for more than half of the malaria cases reported in Latin America, the Middle East and Asia. Of the total p. vivax cases, 65 % occur in southern Asia and the western Pacific, 12.5 % in south America and 4.5 % in central America. While p. falciparum in Africa, the region with the highest concentration of falciparum malaria cases, affects primarily children, p. vivax affects all age groups. Very little is known about the burden of p. vivax in pregnancy and its impact on maternal and foetal health. Furthermore, the health and economic impact associated with p. vivax malaria has not been established, but it is likely to be considerable.
PREGVAX was devised in order to respond to all these knowledge gaps on p. vivax from an epidemiological perspective, including evaluation of burden and impact, pregnancy specific immunological responses and histopathological changes in the placenta. Furthermore, ancillary studies have been conducted to assess the economic impact of p. vivax infection during pregnancy.
Objectives and milestones have been classified in work packages (WPs), being fundamentally:
1. WP1, Epidemiology: To determine the burden (prevalence and incidence) of p. vivax malaria in pregnancy in different epidemiological settings and its impact on pregnancy outcomes (mother and newborn)
2. WP2, Immunology: To study naturally acquired antigen-specific antibody and cellular immune responses in pregnant women infected with p. vivax parasites
3. WP3, Genotyping and molecular diagnosis: To evaluate the presence of submicroscopic infections by molecular diagnosis and to characterise the genetic structure and transmission dynamics of p. vivax parasites in different epidemiological regions
4. WP4, Adhesion: To study the adhesive features of p. vivax infected red blood cells eluted from the placenta and from the peripheral blood, including resetting
5. WP5, Histopathology: To evaluate the placental histological changes associated with p. vivax infection during pregnancy and their possible impact on maternal and foetal health, to investigate whether p. vivax infected erythrocytes accumulate in the placenta and to evaluate whether there is an immune cell reaction in the placenta and to evaluate its cell composition
6. WP6, Management: To coordinate the technical activities of the project and the overall financial and administrative management, in order to accomplish the milestones of WP1 to WP5 and to disseminate knowledge within the scientific community, raise public interest on the project and public health in general and generate public awareness and participation.
Project results:
The project has been successful in defining a clearer framework of the true burden of p. vivax infection among pregnant women and its impact on maternal and foetal health. In order to accomplish this, the PREGVAX project has set up an unprecedented and unique multi-country research platform, a very large cohort of women enrolled during gestation and followed up until delivery. After five years of intensive work, the PREGVAX project has got to its last stage. Definitive results from the project will be soon available. Nevertheless, among the preliminary findings there are already key data:
1. the prevalence of p. vivax malaria detected by microscopy during pregnancy was low across sites. However, molecular diagnosis by reverse transcription polymerase chain reaction (RT-PCR) detected substantially more p. vivax and p. falciparum infections than microscopy, suggesting a high proportion of submicroscopic infections. To what extend these submicroscopic infections may have an impact on maternal and foetal health is not yet known since no study had previously attained this research question. Furthermore, they emphasise the importance of understanding the role of asymptomatic carriers on transmission. Submicroscopic infections are becoming a key issue in low endemicity settings and in a context of malaria control and elimination. The PREGVAX project is by far in the best position to respond to these knowledge gaps.
2. under the umbrella of the PREGVAX project, the first p. vivax congenital malaria case in Guatemala and the first in Latin America, with genotypical, histological and clinical characterisation has been described. The findings show that maternal p. vivax infection still occurs in areas that are in the pathway towards malaria elimination and can be associated with detrimental health effects for the neonate. It also highlights the need in very low transmission areas of not only maintaining, but increasing awareness of the problem and developing surveillance strategies to detect the infection, particularly in most vulnerable groups of the population.
3. so far, evidence of the presence of p. vivax in the placenta had been scarce and inconclusive. This information is relevant to understanding whether p. vivax affects placental function and how it may contribute to poor pregnancy outcomes. A histopathological and molecular study of placental infection with p. vivax conducted as part of PREGVAX objectives has shown that p. vivax can be associated with placental infection and might be able to sequester in the placenta. Placental inflammation was not observed in p. vivax placental malaria cases differently to what has been well described for p. falciparum infection; what suggests that other causes of poor delivery outcomes must be associated with p. vivax infection.
4. cytoadhesion phenotypes with a clinical impact in p. vivax. Cytoadhesion of infected erythrocytes (IE) may contribute to mild p. vivax sequestration although its physiological impact remains still unknown. In this study we aimed to describe clinically relevant cytoadhesive phenotypes of p. vivax IEs isolated from pregnant and non-pregnant malaria patients in the Brazilian Amazons. It was seen that rosetting and cytoadhesion to chondroitin-4-sulfate (CSA) in p. vivax infections may negatively impact the health of infected hosts.
Potential impact:
Despite global efforts, malaria continues to represent a huge health burden, particularly to most vulnerable populations, pregnant women and infants. While the effects of falciparum infection are well-known, at least in sub-Saharan Africa and specific policy recommendations have been developed, the reality is that little focus has been devoted to p. vivax, both in research, advocacy and more importantly in specific policy guidance.
This project provides accurate data on the burden and impact of vivax malaria during gestation. This is essential to improve its clinical management and to guide malaria in pregnancy control policies in low transmission settings. Besides, elucidating the mechanisms involved in the pathology of p. vivax in pregnancy, as for instance, the histopathological and molecular features of placental p. vivax infection and the cytoadhesion phenotypes with a clinical impact in p. vivax, investigated as part of this project, may help to develop specific control tools such as more effective drugs and vaccines.
Main results of PREGVAX project are expected to inform and guide key global recommendations for malaria control during pregnancy in low transmission settings. This is aligned with the current goal of the World Health Organisation (WHO) aimed to develop an evidence-driven global strategic plan for p. vivax control and elimination that will be an integral part of the global technical strategy for malaria control and elimination, lasting from 2016 to 2025. PREGVAX project will genuinely contribute to identify the most adequate approach in clinical management, epidemiological surveillance and preventive strategies for malaria control during pregnancy in areas where p. vivax malaria transmission occurs.
List of websites:
http://www.pregvax.net
PREGVAX project contact:
Clara Menéndez, MD, PhD, Project Coordinator and Principal Investigator
FCRB - CRESIB - Hospital Clínic - ISGlobal
Rosselló, 132 5è 1a, Barcelona 08036 - Spain
Telephone: +34-227-1851
Fax: +34-227-1850
Email: menendez@clinic.ub.es
PREGVAX consortium:
1. Barcelona Centre for International Health Research (CRESIB)-Barcelona Institute for Global Health (ISGlobal). Hospital Clínic, Barcelona, Spain (coordinating institution), http://www.fundacioclinic.org http://www.cresib.cat http://www.isglobal.org email: menendez@clinic.ub.es
2. Karolinska Institutet (KI), Stockholm, Sweden, http://www.ki.se email: mats.wahlgren@ki.se
3. Istituto Superiore di Sanità (ISS), Rome, Italy, http://www.iss.it email: carlo.severini@iss.it
4. Papua New Guinea Institute of Medical Research (PNG IMR), Madang, Papua New Guinea, http://www.pngimr.org.pg email: inoni.betuela@pngimr.org.pg
5. Sardar Patel Medical College (SPMC), Bikaner, India, http://www.spmcbkn.com email: sfalodia@yahoo.co.in
6. International Centre for Genetic Engineering and Biotechnology (ICGEB), Delhi India, http://www.icgeb.org email: cchitnis@icgeb.res.in
7. Fundação de Medicina Tropical HeitorVieira Dourado (FMT-HVD), Manaus, Brazil, http://www.fmt.am.gov.br email: florespinosa@gmail.com
8. Universidad del Valle de Guatemala (CES-UVG), Guatemala, Guatemala, http://www.uvg.edu.gt email: npadilla@ces.uvg.edu.gt
9. Centro Internacional de Vacunas (CIV), Cali, Colombia, http://www.inmuno.org email: marevalo@inmuno.org
Plasmodium vivax (p. vivax) is the most common and widely distributed human malaria parasite and causes up to 80 million cases annually, with the majority occurring in Asia and the western Pacific, central and south America and the Middle East. It has been estimated that globally 93 million pregnancies occurred in areas endemic for p. vivax in 2007.
While the effects of plasmodium falciparum (p. falciparum) malaria in pregnancy have been well characterised and are responsible for considerable maternal and infant morbidity and mortality, surprisingly little is known about the burden and impact of p. vivax infection on maternal and foetal health. Some studies indicate adverse effects of p. vivax malaria in pregnancy; yet, they all provide only partial information on the epidemiological and clinical aspects of the infection in pregnancy and none on the mechanisms involved. This gives us a disconcerting and incomplete picture of the true burden and impact of p. vivax in pregnancy.
The PREGVAX consortium started back in 2008 to address those knowledge gaps in p. vivax infection during pregnancy. It has brought together 11 research institutions and some of the best multidisciplinary scientists and experts on p. vivax malaria from a variety of countries and regions across the world. Under the umbrella of this consortium a cohort observational study of pregnant women from five p. vivax endemic countries (Brazil, Colombia, Guatemala, India and Papua New Guinea), broadly representing most of the world's p. vivax infections, has been conducted. This study describes the epidemiological and clinical features of p. vivax malaria in pregnancy following standardised methods for data collection. In addition, the PREGVAX consortium has been working to determine whether there are pregnancy specific p. vivax immune responses and characterise genotypically and phenotypically the parasites of the placenta.
In an unprecedented effort, almost 10 000 pregnant women have been enrolled at the different project sites during their routine antenatal care visits and followed up at the health facility until delivery. Recruited women have been 1 696 in Brazil, 2 039 in Colombia, 2 009 in Guatemala, 2 050 in India and 1 679 at Papua New Guinea. Deliveries attended and included in the study have been 905 in Brazil, 783 in Colombia, 1 025 in Guatemala, 1 332 in India and 935 at Papua New Guinea. This means that about 53 % of the women participants in the study were followed up until delivery showing a low rate of loss to follow up during the study. In the context of this large cohort of pregnant women, almost 98 000 study visits have occurred. A database has been built up that includes information from near 98 000 questionnaires and almost 77 000 biological samples have been collected.
Although p. falciparum is the most deadly species and the subject of most malaria related research and literature, more attention should be given to p. vivax. So far, with PREGVAX study, some progress has been made and further evidence is becoming available. This recent evidence suggests that p. vivax malaria can have deleterious effects on the health of the mother and the neonate. More accurate data of vivax malaria during gestation are essential to improve its clinical management and to guide control policies. Furthermore, elucidating the mechanisms involved in the pathology of p. vivax in pregnancy will help to develop specific control tools such as more effective drugs and vaccines.
Project context and objectives:
Despite the reality that p. vivax is the most widely distributed human malaria parasite, it has been the focus of surprisingly little research. Vivax malaria accounts for approximately 70 to 80 million cases worldwide per year and for more than half of the malaria cases reported in Latin America, the Middle East and Asia. Of the total p. vivax cases, 65 % occur in southern Asia and the western Pacific, 12.5 % in south America and 4.5 % in central America. While p. falciparum in Africa, the region with the highest concentration of falciparum malaria cases, affects primarily children, p. vivax affects all age groups. Very little is known about the burden of p. vivax in pregnancy and its impact on maternal and foetal health. Furthermore, the health and economic impact associated with p. vivax malaria has not been established, but it is likely to be considerable.
PREGVAX was devised in order to respond to all these knowledge gaps on p. vivax from an epidemiological perspective, including evaluation of burden and impact, pregnancy specific immunological responses and histopathological changes in the placenta. Furthermore, ancillary studies have been conducted to assess the economic impact of p. vivax infection during pregnancy.
Objectives and milestones have been classified in work packages (WPs), being fundamentally:
1. WP1, Epidemiology: To determine the burden (prevalence and incidence) of p. vivax malaria in pregnancy in different epidemiological settings and its impact on pregnancy outcomes (mother and newborn)
2. WP2, Immunology: To study naturally acquired antigen-specific antibody and cellular immune responses in pregnant women infected with p. vivax parasites
3. WP3, Genotyping and molecular diagnosis: To evaluate the presence of submicroscopic infections by molecular diagnosis and to characterise the genetic structure and transmission dynamics of p. vivax parasites in different epidemiological regions
4. WP4, Adhesion: To study the adhesive features of p. vivax infected red blood cells eluted from the placenta and from the peripheral blood, including resetting
5. WP5, Histopathology: To evaluate the placental histological changes associated with p. vivax infection during pregnancy and their possible impact on maternal and foetal health, to investigate whether p. vivax infected erythrocytes accumulate in the placenta and to evaluate whether there is an immune cell reaction in the placenta and to evaluate its cell composition
6. WP6, Management: To coordinate the technical activities of the project and the overall financial and administrative management, in order to accomplish the milestones of WP1 to WP5 and to disseminate knowledge within the scientific community, raise public interest on the project and public health in general and generate public awareness and participation.
Project results:
The project has been successful in defining a clearer framework of the true burden of p. vivax infection among pregnant women and its impact on maternal and foetal health. In order to accomplish this, the PREGVAX project has set up an unprecedented and unique multi-country research platform, a very large cohort of women enrolled during gestation and followed up until delivery. After five years of intensive work, the PREGVAX project has got to its last stage. Definitive results from the project will be soon available. Nevertheless, among the preliminary findings there are already key data:
1. the prevalence of p. vivax malaria detected by microscopy during pregnancy was low across sites. However, molecular diagnosis by reverse transcription polymerase chain reaction (RT-PCR) detected substantially more p. vivax and p. falciparum infections than microscopy, suggesting a high proportion of submicroscopic infections. To what extend these submicroscopic infections may have an impact on maternal and foetal health is not yet known since no study had previously attained this research question. Furthermore, they emphasise the importance of understanding the role of asymptomatic carriers on transmission. Submicroscopic infections are becoming a key issue in low endemicity settings and in a context of malaria control and elimination. The PREGVAX project is by far in the best position to respond to these knowledge gaps.
2. under the umbrella of the PREGVAX project, the first p. vivax congenital malaria case in Guatemala and the first in Latin America, with genotypical, histological and clinical characterisation has been described. The findings show that maternal p. vivax infection still occurs in areas that are in the pathway towards malaria elimination and can be associated with detrimental health effects for the neonate. It also highlights the need in very low transmission areas of not only maintaining, but increasing awareness of the problem and developing surveillance strategies to detect the infection, particularly in most vulnerable groups of the population.
3. so far, evidence of the presence of p. vivax in the placenta had been scarce and inconclusive. This information is relevant to understanding whether p. vivax affects placental function and how it may contribute to poor pregnancy outcomes. A histopathological and molecular study of placental infection with p. vivax conducted as part of PREGVAX objectives has shown that p. vivax can be associated with placental infection and might be able to sequester in the placenta. Placental inflammation was not observed in p. vivax placental malaria cases differently to what has been well described for p. falciparum infection; what suggests that other causes of poor delivery outcomes must be associated with p. vivax infection.
4. cytoadhesion phenotypes with a clinical impact in p. vivax. Cytoadhesion of infected erythrocytes (IE) may contribute to mild p. vivax sequestration although its physiological impact remains still unknown. In this study we aimed to describe clinically relevant cytoadhesive phenotypes of p. vivax IEs isolated from pregnant and non-pregnant malaria patients in the Brazilian Amazons. It was seen that rosetting and cytoadhesion to chondroitin-4-sulfate (CSA) in p. vivax infections may negatively impact the health of infected hosts.
Potential impact:
Despite global efforts, malaria continues to represent a huge health burden, particularly to most vulnerable populations, pregnant women and infants. While the effects of falciparum infection are well-known, at least in sub-Saharan Africa and specific policy recommendations have been developed, the reality is that little focus has been devoted to p. vivax, both in research, advocacy and more importantly in specific policy guidance.
This project provides accurate data on the burden and impact of vivax malaria during gestation. This is essential to improve its clinical management and to guide malaria in pregnancy control policies in low transmission settings. Besides, elucidating the mechanisms involved in the pathology of p. vivax in pregnancy, as for instance, the histopathological and molecular features of placental p. vivax infection and the cytoadhesion phenotypes with a clinical impact in p. vivax, investigated as part of this project, may help to develop specific control tools such as more effective drugs and vaccines.
Main results of PREGVAX project are expected to inform and guide key global recommendations for malaria control during pregnancy in low transmission settings. This is aligned with the current goal of the World Health Organisation (WHO) aimed to develop an evidence-driven global strategic plan for p. vivax control and elimination that will be an integral part of the global technical strategy for malaria control and elimination, lasting from 2016 to 2025. PREGVAX project will genuinely contribute to identify the most adequate approach in clinical management, epidemiological surveillance and preventive strategies for malaria control during pregnancy in areas where p. vivax malaria transmission occurs.
List of websites:
http://www.pregvax.net
PREGVAX project contact:
Clara Menéndez, MD, PhD, Project Coordinator and Principal Investigator
FCRB - CRESIB - Hospital Clínic - ISGlobal
Rosselló, 132 5è 1a, Barcelona 08036 - Spain
Telephone: +34-227-1851
Fax: +34-227-1850
Email: menendez@clinic.ub.es
PREGVAX consortium:
1. Barcelona Centre for International Health Research (CRESIB)-Barcelona Institute for Global Health (ISGlobal). Hospital Clínic, Barcelona, Spain (coordinating institution), http://www.fundacioclinic.org http://www.cresib.cat http://www.isglobal.org email: menendez@clinic.ub.es
2. Karolinska Institutet (KI), Stockholm, Sweden, http://www.ki.se email: mats.wahlgren@ki.se
3. Istituto Superiore di Sanità (ISS), Rome, Italy, http://www.iss.it email: carlo.severini@iss.it
4. Papua New Guinea Institute of Medical Research (PNG IMR), Madang, Papua New Guinea, http://www.pngimr.org.pg email: inoni.betuela@pngimr.org.pg
5. Sardar Patel Medical College (SPMC), Bikaner, India, http://www.spmcbkn.com email: sfalodia@yahoo.co.in
6. International Centre for Genetic Engineering and Biotechnology (ICGEB), Delhi India, http://www.icgeb.org email: cchitnis@icgeb.res.in
7. Fundação de Medicina Tropical HeitorVieira Dourado (FMT-HVD), Manaus, Brazil, http://www.fmt.am.gov.br email: florespinosa@gmail.com
8. Universidad del Valle de Guatemala (CES-UVG), Guatemala, Guatemala, http://www.uvg.edu.gt email: npadilla@ces.uvg.edu.gt
9. Centro Internacional de Vacunas (CIV), Cali, Colombia, http://www.inmuno.org email: marevalo@inmuno.org
