©2013 Landes Bioscience. Do not distribute. Human Vaccines & Immunotherapeutics 9:12, 2558–2565; December 2013; © 2013 Landes Bioscience 2558 Human Vaccines & Immunotherapeutics Volume 9 Issue 12 COMMENTARY Plasmodium vivax malaria vaccines Why are we where we are? Arturo Reyes-Sandoval 1, * and Martin F Bachmann 1,2 1 The Jenner Institute; University of Oxford; Oxford, UK; 2 Dermatology; University Hospital Zurich; Zurich, Switzerland M alaria is one of the few diseases in which morbidity is still mea- sured in hundreds of millions of cases every year. Plasmodium vivax and Plas- modium falciparum are responsible for nearly all the malaria cases in the world and despite difficulties in obtaining an exact number, estimates indicate an astonishing 349–552 million clinical cases of malaria due to P. falciparum in 2007 and between 132–391 mil- lion clinical episodes due to P. vivax in 2009. It is becoming evident that eradi- cation of malaria will be an arduous task and P. vivax will be one of the most difficult species to eliminate and per- haps become the last standing malaria parasite. Indeed, in countries that suc- ceed in decreasing the disease burden, nearly all the remaining malaria cases are caused by P. vivax. Such resilience is mainly due to the sophisticated mech- anism that the parasite has evolved to remain dormant for months or years forming hypnozoites, a small structure in the liver that will be a major hurdle in the efforts toward malaria eradica- tion. Furthermore, while clinical trials of vaccines against P. falciparum are making fast progress, a very different picture is seen with P. vivax, where only few candidates are currently active in clinical trials. Introduction There is consensus that Plasmodium vivax is the most widely distributed human malaria parasite in the world and the one that presents most challenges in the route toward malaria elimination. Almost 3 billion people lived at risk of P. vivax malaria in 2010. This should not be surprising if we consider that the para- site is endemic in a third of the earth’s land mass, spanning approximately 44 million square kilometres within 95 countries. This represents an impressive geographi- cal range stretching over three continental zones and including both, hot and tem- perate climates, 1 an achievement that no other human malaria parasite has made. Despite the tremendous disease burden caused by P. vivax, most efforts in terms of research and development of preventa- tive measures have been concentrated in its sibling, P. falciparum. Figure 1 shows a comparison of disease burden (Fig. 1A) and investment in research and global malaria vaccine pipeline (Fig. 1B) for each parasite. Disease burden is comparable for both parasites with a higher proportion of number of clinical cases caused by P. fal- ciparum every year, 2,3 a similar proportion in number of people being at risk and a more widespread presence of P. vivax in the world as shown here by the number of countries where this parasite is endemic. 4,5 The picture changes and a rather uneven distribution is seen when comparing the investment on research and the number of vaccines that are currently reaching clinical trial status. Between 2007 and 2009, only 3.1% of the global funds were invested in P. vivax R&D, while 44.6% was destined to P. falciparum in a study where 52.3% of funds did not specify a particular strain. 6 The differences in the number of clinical trials seem to reflect the levels of investment for each parasite. Only two trials for a P. vivax vaccine are currently active according to WHO and Keywords: Plasmodium vivax, vaccine, clinical trials, malaria, human trials Abbreviations: PEV, pre-erythrocytic vaccines; BSV, blood-stage vaccines; TBV, transmission blocking vaccines; *Correspondence to: Arturo Reyes-Sandoval; Email: arturo.reyes@ndm.ox.ac.uk Submitted: 07/23/2013 Accepted: 08/15/2013 http://dx.doi.org/10.4161/hv.2615720