• 1.

    Mendis K, Sina BJ, Marchesini P, Carter R, 2001. The neglected burden of Plasmodium vivax malaria. Am J Trop Med Hyg 64: 97106.

  • 2.

    Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, Anstey NM, 2007. Vivax malaria: neglected and not benign. Am J Trop Med Hyg 77: 7987.

  • 3.

    2006. Malaria Vaccine Technology Roadmap. Available at: http://www.malariavaccine.org/files/Malaria_Vaccine_TRM_Final.pdf.

  • 4.

    Herrera S, Corradin G, Arévalo-Herrera M, 2007. An update on the search for a Plasmodium vivax vaccine. Trends Parasitol 23: 122128.

  • 5.

    Guerra CA, Snow RW, Hay SI, 2006. Mapping the global extent of malaria in 2005. Trends Parasitol 22: 353358.

  • 6.

    Yeom JS, Kim TS, Oh S, Sim JB, Barn JS, Kim HJ, Kim YA, Ahn SY, Shin MY, Yoo JA, Park JW, 2007. Plasmodium vivax malaria in the Republic of Korea during 2004–2005: changing patterns of infection. Am J Trop Med Hyg 76: 865868.

    • Search Google Scholar
    • Export Citation
  • 7.

    Faulde MK, Hoffmann R, Fazilat KM, Hoerauf A, 2007. Malaria reemergence in northern Afghanistan. Emerg Infect Dis 13: 14021404.

  • 8.

    Aramburu Guarda J, Ramal Asayag C, Witzig R, 1999. Malaria reemergence in the Peruvian Amazon region. Emerg Infect Dis 5: 209215.

  • 9.

    PAHO, 2003. Informe de la situación de los programas de malaria en las Américas. Available at: http://www.paho.org/Spanish/AD/DPC/CD/programas-nacionales.pdf.

    • Search Google Scholar
    • Export Citation
  • 10.

    Joshi H, Prajapati SK, Verma A, Kang'a S, Carlton JM, 2008. Plasmodium vivax in India. Trends Parasitol 24: 228235.

  • 11.

    Karunaweera ND, Wijesekera SK, Wanasekera D, Mendis KN, Carter R, 2003. The paroxysm of Plasmodium vivax malaria. Trends Parasitol 19: 188193.

  • 12.

    Ozen M, Gungor S, Atambay M, Daldal N, 2006. Cerebral malaria owing to Plasmodium vivax: case report. Ann Trop Paediatr 26: 141144.

  • 13.

    Kochar DK, Saxena V, Singh N, Kochar SK, Kumar SV, Das A, 2005. Plasmodium vivax malaria. Emerg Infect Dis 11: 132134.

  • 14.

    Tjitra E, Anstey NM, Sugiarto P, Warikar N, Kenangalem E, Karyana M, Lampah DA, Price RN, 2008. Multidrug-resistant Plasmodium vivax associated with severe and fatal malaria: a prospective study in Papua, Indonesia. PLoS Med 5: e128.

    • Search Google Scholar
    • Export Citation
  • 15.

    Price L, Planche T, Rayner C, Krishna S, 2007. Acute respiratory distress syndrome in Plasmodium vivax malaria: case report and review of the literature. Trans R Soc Trop Med Hyg 101: 655659.

    • Search Google Scholar
    • Export Citation
  • 16.

    Poespoprodjo JR, Fobia W, Kenangalem E, Lampah DA, Warikar N, Seal A, McGready R, Sugiarto P, Tjitra E, Anstey NM, Price RN, 2008. Adverse pregnancy outcomes in an area where multidrug-resistant Plasmodium vivax and Plasmodium falciparum infections are endemic. Clin Infect Dis 46: 13741381.

    • Search Google Scholar
    • Export Citation
  • 17.

    Valderrama-Aguirre A, Quintero G, Gomez A, Castellanos A, Perez Y, Mendez F, Arévalo-Herrera M, Herrera S, 2005. Antigenicity, immunogenicity, and protective efficacy of Plasmodium vivax MSP1 Pv200L: a potential malaria vaccine subunit. Am J Trop Med Hyg 73: 1624.

    • Search Google Scholar
    • Export Citation
  • 18.

    Herrera SB, Perlaza BL, Fernández OL, Victoria L, Lenis AM, Soto L, Hurtado H, Acuña LM, Vélez JD, Palacios R, Chen-Mok M, Corradin G, Arévalo-Herrera M, 2005. Safety and elicitation of humoral and cellular responses in Colombian malaria-naive volunteers by a Plasmodium vivax circumsporozoite protein-derived synthetic vaccine. Am J Trop Med Hyg 73 (Suppl): 39.

    • Search Google Scholar
    • Export Citation
Past two years Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 143 62 11
PDF Downloads 25 3 1
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

 

 

Plasmodium vivax Vaccine Research: Insights from Colombian Studies

Falgunee K. ParekhPATH-Malaria Vaccine Initiative, Bethesda, Maryland; Initiative for Vaccine Research, World Health Organization, Geneva, Switzerland; Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

Search for other papers by Falgunee K. Parekh in
Current site
Google Scholar
PubMed
Close
and
Vasee S. MoorthyPATH-Malaria Vaccine Initiative, Bethesda, Maryland; Initiative for Vaccine Research, World Health Organization, Geneva, Switzerland; Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

Search for other papers by Vasee S. Moorthy in
Current site
Google Scholar
PubMed
Close

In recent years, heightened awareness of the heavy public health, economic, and social burdens attributable to malaria, has led to increased interest and support by both public and private sectors for malaria-related research and control. This interest, accompanied by some remarkable successes in achieving control in selected areas, has led to a renewed optimism about the long-term feasibility of achieving elimination and, ultimately, eradication of malaria throughout the world, if new tools can be developed to enable eradication efforts. Most of this renewed interest has focused on Plasmodium falciparum infections, which cause the greatest morbidity and mortality, most of it in sub-Saharan Africa. Approximately 40% of the world's population, however, lives at risk of malaria caused by Plasmodium vivax, which is responsible for significant morbidity, particularly in South and Central America, Asia, and the eastern Mediterranean.1 To successfully expand malaria elimination efforts and ultimately to achieve eradication, it is crucial to concurrently develop strategies that target other major species infecting humans, particularly P. vivax, which has a widespread distribution and a demonstrable public health and socioeconomic impact on a range of populations throughout the world.1,2

The majority of malaria vaccine development efforts today are concentrated on P. falciparum, with a goal of having a highly efficacious vaccine by 2025.3 Although there has been good progress on P. falciparum-focused vaccines, a single species approach to malaria vaccine development is unlikely to achieve malaria elimination and eradication. Currently, more than 70 P. falciparum vaccine research projects have been initiated, over 30 have been tested in humans, and one (RTS,S) is currently in Phase 3 trials. In contrast, only two P. vivax vaccine candidates have undergone clinical testing.4 Because of the co-endemicity of P. vivax and P. falciparum in many regions, the eventual development of a multi-species vaccine regimen that can be used in a variety of high-risk populations would be most appropriate. However, because P. vivax vaccine development lags behind that of P. falciparum, increased efforts are required to identify and test potential P. vivax vaccine candidates. In addition, it will be critical to expand our understanding of the biology and epidemiology of P. vivax to effectively design appropriate vaccines and evaluate them in clinical and field settings.

A few research groups have focused on P. vivax. One such group—the Malaria Vaccine and Drug Development Center (MVDC) in Cali, Colombia—has developed a multi-disciplinary, cross-functional research program on P. vivax. Results of their P. vivax-related investigations, presented in this supplement, provide important insights into key aspects of P. vivax biology, immunology, and transmission dynamics that will be informative for those interested in development of vaccines against vivax malaria as well as for those with an interest in malaria elimination and eradication.

Although the disease burden of P. vivax varies regionally, its widespread distribution in many tropical, sub-tropical, and temperate regions places an estimated 2.6 billion people at risk of P. vivax malaria each year, greater than that of P. falciparum.2,5 In addition, many regions, such as Korea, the Amazon region, and Afghanistan have witnessed a re-emergence of malaria, predominantly caused by P. vivax, over the past several decades.68 Outside of Africa, P. vivax accounts for more than 50% of all malaria cases.1 In Colombia, P. vivax causes 65% of reported clinical malaria cases.9 In Africa P. vivax malaria accounts for between 5% and 20% of all malaria in eastern and southern Africa, and Madagascar, making up 6–15 million cases of malaria in Africa alone.1 Taken together, these data indicate that P. vivax malaria has a significant presence both outside and within Africa.

With an estimated 70–391 million cases annually, it is not surprising that P. vivax imposes a significant disease burden across the world.2,5 Although not associated with high mortality rates as is P. falciparum, P. vivax infection unleashes its own distinctive pathobiology in the human host that can result in severe disease. Acute P. vivax infection, consisting of repeated episodes of fever, malaise, chills, and pronounced paroxysms, causes serious and incapacitating illness, that can often be more agonizing than uncomplicated P. falciparum infection.10 High fever and rigors are more common in P. vivax compared with P. falciparum, possibly because of the greater synchronicity of schizont rupture in P. vivax infections or its ability to elicit a strong host inflammatory response, including TNF-α, at a lower parasitemia level.2,11 Unlike P. falciparum malaria, this pathobiology affects individuals of all ages because most areas affected with P. vivax tend to have low transmission and thus a flat age-incidence curve.1 Moreover, the ability of P. vivax hypnozoites to remain dormant in the liver and relapse at varying intervals can lead to repeated debilitating malaria episodes. This also makes P. vivax more difficult to eliminate from an afflicted individual and from a population.

Though commonly believed to be a “benign” malaria, several studies and case reports have shown that P. vivax infections do cause severe malaria, similar to P. falciparum malaria. In fact, since 1920 there have been at least 45 reports of cerebral malaria caused by P. vivax infection.12 Recent studies conducted in India, Indonesia, and Papua New Guinea have shown that P. vivax does cause severe malaria—albeit at lower rates than P. falciparum malaria. A report from Rajasthan, India reviewed 11 cases of severe malaria caused by P. vivax infection in 2003 including cerebral malaria, coma, acute respiratory distress syndrome, severe anemia, jaundice, circulatory collapse, and renal failure.13 In one recently published prospective study conducted in Indonesian Papua, it was reported that those admitted to the hospital with P. vivax infection (mostly children) experienced an increased risk for severe malaria compared with those admitted with P. falciparum infections; severe anemia (Hb < 5g/dL), respiratory distress, coma, and death comprised the severe complications seen in P. vivax-infected patients.14 Similarly, a study conducted in Papua New Guinea reported that P. vivax caused 21% of all severe malaria cases (mostly children < 5 years of age), and of these, 26% presented with neurological complications.15 Respiratory distress was more commonly present in P. vivax associated severe malaria, especially in children < 5 years of age, supporting previous evidence that P. vivax may sequester within the pulmonary microvasculature.15 Plasmodium vivax infection during pregnancy is also associated with an increased risk of anemia in the mother and a reduction in mean birth weight.16

Because the pathogenic mechanisms are not clearly understood, it is apparent that P. vivax causes severe malaria with a wide range of clinical manifestations, and is a significant global public health problem. Although currently available tools for control have shown some significant efficacy against P. falciparum, it is likely that they will not have the same impact on P. vivax because of the distinct biology and survival mechanisms of this parasite species. Interrupting transmission of P. vivax is challenging, in part because gametocytes usually appear in the circulation at about the same time as the asexual blood-stage parasites and before onset of clinical symptoms or disease. Transmission of P. vivax thus can occur before drug treatment is clinically indicated and initiated. Additionally, the ability of the dormant phase to relapse months to years after the initial infection enhances the parasite's long-term survivability and transmission capabilities. Day-biting mosquitoes that transmit P. vivax render bednets less effective for P. vivax control than for control of P. falciparum. Therefore, it is likely that the proportion of disease related to P. vivax will increase in many co-endemic areas as P. falciparum control measures take effect. Previous evidence from the island of Vanuatu has shown that P. vivax is more difficult to eliminate from a population than P. falciparum using currently available control methods. In the 1990s a combination of malaria control methods, including mass drug administration, insecticide-treated bed nets, and larvae eating fish was implemented in Vanuatu, an island with a greater prevalence of P. falciparum infections than P. vivax.1 Within one year of initiating these control methods, P. falciparum was eliminated; however, it took five years to eliminate P. vivax.1 The Vanuatu experience thus illustrates that P. vivax is less susceptible to current control methods, and argues for the need to develop more targeted approaches—notably the development of a highly efficacious vaccine against P. vivax—to reduce the burden of vivax malaria globally.

As described in this supplement, investigators at the MVDC in Cali have developed a translational research program focused on addressing the multiple aspects of P. vivax vaccine development. The Center has effectively used the resources of its regions, including the availability of Aotus monkeys, accessibility to endemic regions with varying transmission levels, and populations of both malaria-naive and malaria-exposed individuals. These capabilities have allowed the center to conduct pre-clinical and clinical testing of potential vaccine antigens,17,18 maintain an insectary of Anopheles albimanus mosquitoes that can be infected with naturally occurring P. vivax parasites, and develop the P. vivax sporozoite challenge model for humans. In addition, scientists at the MVDC have the ability to regularly assess P. vivax epidemiology and examine the transmission dynamics in areas of co-endemicity of P. vivax and P. falciparum, which will be useful for determining the future impact of a potential vaccine in this type of endemic region. Understanding these various aspects of P. vivax, and conducting these types of cross-functional studies allow for a stepwise approach in moving P. vivax vaccine development forward. Results from these investigations are presented in this supplement, and provide critical data that can be used in designing the next steps for vaccine development.

ACKNOWLEDGMENTS:

We acknowledge the helpful discussions and critical comments by B. Fenton Hall during the preparation of this manuscript.

  • 1.

    Mendis K, Sina BJ, Marchesini P, Carter R, 2001. The neglected burden of Plasmodium vivax malaria. Am J Trop Med Hyg 64: 97106.

  • 2.

    Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, Anstey NM, 2007. Vivax malaria: neglected and not benign. Am J Trop Med Hyg 77: 7987.

  • 3.

    2006. Malaria Vaccine Technology Roadmap. Available at: http://www.malariavaccine.org/files/Malaria_Vaccine_TRM_Final.pdf.

  • 4.

    Herrera S, Corradin G, Arévalo-Herrera M, 2007. An update on the search for a Plasmodium vivax vaccine. Trends Parasitol 23: 122128.

  • 5.

    Guerra CA, Snow RW, Hay SI, 2006. Mapping the global extent of malaria in 2005. Trends Parasitol 22: 353358.

  • 6.

    Yeom JS, Kim TS, Oh S, Sim JB, Barn JS, Kim HJ, Kim YA, Ahn SY, Shin MY, Yoo JA, Park JW, 2007. Plasmodium vivax malaria in the Republic of Korea during 2004–2005: changing patterns of infection. Am J Trop Med Hyg 76: 865868.

    • Search Google Scholar
    • Export Citation
  • 7.

    Faulde MK, Hoffmann R, Fazilat KM, Hoerauf A, 2007. Malaria reemergence in northern Afghanistan. Emerg Infect Dis 13: 14021404.

  • 8.

    Aramburu Guarda J, Ramal Asayag C, Witzig R, 1999. Malaria reemergence in the Peruvian Amazon region. Emerg Infect Dis 5: 209215.

  • 9.

    PAHO, 2003. Informe de la situación de los programas de malaria en las Américas. Available at: http://www.paho.org/Spanish/AD/DPC/CD/programas-nacionales.pdf.

    • Search Google Scholar
    • Export Citation
  • 10.

    Joshi H, Prajapati SK, Verma A, Kang'a S, Carlton JM, 2008. Plasmodium vivax in India. Trends Parasitol 24: 228235.

  • 11.

    Karunaweera ND, Wijesekera SK, Wanasekera D, Mendis KN, Carter R, 2003. The paroxysm of Plasmodium vivax malaria. Trends Parasitol 19: 188193.

  • 12.

    Ozen M, Gungor S, Atambay M, Daldal N, 2006. Cerebral malaria owing to Plasmodium vivax: case report. Ann Trop Paediatr 26: 141144.

  • 13.

    Kochar DK, Saxena V, Singh N, Kochar SK, Kumar SV, Das A, 2005. Plasmodium vivax malaria. Emerg Infect Dis 11: 132134.

  • 14.

    Tjitra E, Anstey NM, Sugiarto P, Warikar N, Kenangalem E, Karyana M, Lampah DA, Price RN, 2008. Multidrug-resistant Plasmodium vivax associated with severe and fatal malaria: a prospective study in Papua, Indonesia. PLoS Med 5: e128.

    • Search Google Scholar
    • Export Citation
  • 15.

    Price L, Planche T, Rayner C, Krishna S, 2007. Acute respiratory distress syndrome in Plasmodium vivax malaria: case report and review of the literature. Trans R Soc Trop Med Hyg 101: 655659.

    • Search Google Scholar
    • Export Citation
  • 16.

    Poespoprodjo JR, Fobia W, Kenangalem E, Lampah DA, Warikar N, Seal A, McGready R, Sugiarto P, Tjitra E, Anstey NM, Price RN, 2008. Adverse pregnancy outcomes in an area where multidrug-resistant Plasmodium vivax and Plasmodium falciparum infections are endemic. Clin Infect Dis 46: 13741381.

    • Search Google Scholar
    • Export Citation
  • 17.

    Valderrama-Aguirre A, Quintero G, Gomez A, Castellanos A, Perez Y, Mendez F, Arévalo-Herrera M, Herrera S, 2005. Antigenicity, immunogenicity, and protective efficacy of Plasmodium vivax MSP1 Pv200L: a potential malaria vaccine subunit. Am J Trop Med Hyg 73: 1624.

    • Search Google Scholar
    • Export Citation
  • 18.

    Herrera SB, Perlaza BL, Fernández OL, Victoria L, Lenis AM, Soto L, Hurtado H, Acuña LM, Vélez JD, Palacios R, Chen-Mok M, Corradin G, Arévalo-Herrera M, 2005. Safety and elicitation of humoral and cellular responses in Colombian malaria-naive volunteers by a Plasmodium vivax circumsporozoite protein-derived synthetic vaccine. Am J Trop Med Hyg 73 (Suppl): 39.

    • Search Google Scholar
    • Export Citation

Author Notes

*Address correspondence to Falgunee K. Parekh, CAMRIS International, 6931 Arlington Road, Suite 575, Bethesda, MD 20814. E-mail: falgunee_parekh@yahoo.com

Authors' addresses: Falgunee Parekh, CAMRIS International, 6931 Arlington Road, Suite 575, Bethesda, MD 20814, E-mail: falgunee_parekh@yahoo.com. Vasee S. Moorthy, Initiative for Vaccine Research, World Health Organization, Geneva, Switzerland, E-mail: moorthyv@who.int.

Save