Geographical variation in Plasmodium vivax relapse
© Battle et al.; licensee BioMed Central Ltd. 2014
Received: 7 February 2014
Accepted: 31 March 2014
Published: 15 April 2014
Plasmodium vivax has the widest geographic distribution of the human malaria parasites and nearly 2.5 billion people live at risk of infection. The control of P. vivax in individuals and populations is complicated by its ability to relapse weeks to months after initial infection. Strains of P. vivax from different geographical areas are thought to exhibit varied relapse timings. In tropical regions strains relapse quickly (three to six weeks), whereas those in temperate regions do so more slowly (six to twelve months), but no comprehensive assessment of evidence has been conducted. Here observed patterns of relapse periodicity are used to generate predictions of relapse incidence within geographic regions representative of varying parasite transmission.
A global review of reports of P. vivax relapse in patients not treated with a radical cure was conducted. Records of time to first P. vivax relapse were positioned by geographic origin relative to expert opinion regions of relapse behaviour and epidemiological zones. Mixed-effects meta-analysis was conducted to determine which geographic classification best described the data, such that a description of the pattern of relapse periodicity within each region could be described. Model outputs of incidence and mean time to relapse were mapped to illustrate the global variation in relapse.
Differences in relapse periodicity were best described by a historical geographic classification system used to describe malaria transmission zones based on areas sharing zoological and ecological features. Maps of incidence and time to relapse showed high relapse frequency to be predominant in tropical regions and prolonged relapse in temperate areas.
The results indicate that relapse periodicity varies systematically by geographic region and are categorized by nine global regions characterized by similar malaria transmission dynamics. This indicates that relapse may be an adaptation evolved to exploit seasonal changes in vector survival and therefore optimize transmission. Geographic patterns in P. vivax relapse are important to clinicians treating individual infections, epidemiologists trying to infer P. vivax burden, and public health officials trying to control and eliminate the disease in human populations.
KeywordsMalaria Plasmodium vivax Map Relapse Periodicity Recurrence Recrudescence Strain
Malaria is a significant global public health problem and the greatest burden of disease is found in the world’s poorest countries . The majority of malaria morbidity and mortality is caused by two of the five species of Plasmodium that naturally infect humans, Plasmodium falciparum and Plasmodium vivax. The broader global distribution of P. vivax relative to P. falciparum puts an estimated 2.5 billion people at risk for endemic vivax malaria [2, 3]. An increasing body of evidence has shown that P. vivax should no longer be thought of as a benign and rarely fatal disease [4–9], but instead as being capable of causing severe disease and death, particularly in pregnant women and small children [9–12].
Plasmodium vivax is epidemiologically and biologically different to P. falciparum and it is not, therefore, appropriate to assume that control methods developed for falciparum malaria are directly transferable to P. vivax[13–16]. Biological features of P. vivax that distinguish it from P. falciparum also present unique challenges to the control of the parasite [17–19]; in elimination settings, P. vivax is often the “last parasite standing” following P. falciparum elimination [20, 21]. Plasmodium vivax gametocytes are present earlier in the progression of a primary or recrudescent infection compared to P. falciparum[17, 22], such that the majority of patients have sufficient gametocytaemia to allow for transmission before diagnosis or treatment may occur [23–25]. In addition, P. vivax gametocytes are transmitted more efficiently to Anopheles mosquito vectors than those of P. falciparum and are transmissible at lower parasite densities [18, 26, 27]. Within the mosquito, P. vivax sporozoites develop faster than P. falciparum at equivalent temperatures, which contributes to its exploitation of a wider geographic range .
Glossary of terms relevant to Plasmodium vivax relapse
Presence of parasites in any of its forms of incubation, prepatency, patency, subpatency or latency.
The period between inoculation of sporozoites and release of merozoites into the blood stream (primary exo-erythrocytic cycle).
The period prior to a primary attack where asexual parasites in the blood are both not detectable and asymptomatic, though present.
The period of clinical attack with demonstration of asexual parasites in blood as the cause of illness.
The period following a primary attack where asexual parasites are both not detectable and asymptomatic, though present.
An event following sub-patency when parasites are both demonstrated to be present and the cause of another clinical attack or asymptomatic patency.
The period between a primary attack and a relapse; in some strains also the period between inoculation of sporozoites and the occurrence of a patent primary attack, typically six months or more.
Patent asexual parasitaemia originating from activation of latent hypnozoites.
Patency by asexual blood stage parasites deriving from a new inoculation of sporozoites.
A newly patent parasitaemia occurring at any point after clearance of sub-patency of a primary parasitaemia where the origin is not known with certainty as being a reinfection, recrudescence or relapse.
The hypnozoite stage in the life cycle of P. vivax and the potential for relapse makes chemical therapies that target only the blood stage of infection ineffective as a radical cure. The 8-aminoquinolines are the only class of drugs known to have activity on the hypnozoite parasite [32–34]. Primaquine therapy, the only currently licensed radical cure, comes with caveats that add to the challenge of controlling the parasite to the point of elimination. Primaquine is associated with potentially fatal haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency [32, 35, 36] and is contra-indicated in pregnant women because of the risk of acute haemolytic anaemia in the foetus of unknown G6PD status . The hypnozoite stage and the paucity of therapy for safe and effective treatment render vivax malaria an exceedingly difficult challenge for clinicians and those responsible for the control of endemic malaria. Relapse also has critical implications for understanding epidemiological metrics such as the basic reproduction number and force of infection, obtained from prevalence rates derived from malariometric surveys and cartographic studies that form a central part in elimination scenario planning [38, 39].
It has long been known that there is significant geographical variation in the rate at which a “strain” of P. vivax relapses [40–42]. Temperate and subtropical strains often exhibit either a long incubation or latent period (Figure 1) of around eight to ten months. Tropical strains are characterized by short incubation times and short latency (approximately three to six weeks) . Incubation period refers to the time from sporozoite inoculation (the mosquito bite) to the primary blood-stage infection. The latent period describes the time from the primary attack to relapse. How hypnozoite relapse is triggered, and the source of this phenotypic variation, is unresolved . One theory is that the mechanism is an adaptive trait of the parasite to sequester or “hibernate” during times when climatic conditions would be inhospitable to the parasite’s anopheline mosquito vectors [45–47]. Another is that latent hypnozoites are activated by a systemic febrile illness, explaining the large number of P. vivax relapses that follow P. falciparum infections [47–49]. These hypotheses need not be mutually exclusive.
Regardless of the triggering mechanism and aetiology of relapse, evidence from both controlled experimental and natural settings indicate considerable geographical variation in the timing of relapse. Although the historical perception has been that frequent relapsing strains originate from the tropics and long-latency strains from temperate regions , it does not sufficiently describe the observed variation in relapsing phenotypes. This binary classification conflicts with evidence of long-latency strains in tropical regions in the Americas, for instance. Coatney et al.  described in 1971 that there were three patterns of relapse. These included the Chesson strain of New Guinea-South Pacific which exhibits a short incubation period (seven to fourteen days), followed by regular re-invasions of the bloodstream within approximately three weeks after the primary infection and may continue to relapse for more than 18 months without a radical cure of the hypnozoite stage. The St Elizabeth strain from southern USA has a similar incubation period to the Chesson strain, but hypnozoites remain quiescent for several months following the primary infection before relapsing at regular intervals of three to four weeks for up to two years . A third variety, such as the strain once found in the Netherlands , has a long period of incubation (around eight months) before the primary clinical episode followed by frequent relapses (the lower arm of Figure 1). This three-type classification likely oversimplifies the degree of variation in P. vivax relapse periodicity and offers limited information regarding the geographic origin of the described phenotypes. Furthermore, the majority of P. vivax strains have short incubation periods and the greatest difference lies in the latency period from primary attack to first relapse.
A systematic review of P. vivax relapse events was conducted with the aim of revealing systematic geographical patterns of relapse frequency and a quantitative description of the potential time to relapse in different regions of the P. vivax-endemic world.
A formal literature search for data was conducted on PubMed  with the keywords: “vivax AND relapse” on 15 November, 2012 and updated on 24 October, 2013. The search returned 449 references. This list was augmented with the reports of P. vivax relapse cited by Baird and Hoffman  and from the reference list of two recent reviews of variation in relapse periodicity [47, 51]. Additional studies were obtained by correspondence with colleagues active in this research area. Malaria in the military was also examined using references from the US Army and medical records from British soldiers who contracted malaria during duty in World War II. Medical records were obtained from contacts and the Malaria Research Library, now the Malaria Reference Library, kept at the London School of Hygiene and Tropical Medicine. The aim was to obtain as much data as possible regarding P. vivax recurrence in all regions where vivax malaria is or has been endemic. The literature sources ostensibly refer to the recurrence events as relapses; however treatment trials and studies conducted in endemic areas may include recrudescences and reinfections in measures of relapse. Because much of the data on P. vivax relapse in patients not treated with primaquine originated before use of the drug became common following World War II , no restrictions were applied on study dates.
The exclusion criteria for the studies were minimal. Data were not used from patients who had been treated with a sufficient dose (15 mg per kg for 7 or 14 days) of primaquine, or any 8-aminoquinoline drug (pamaquine, plasmochin or pentaquine), due to the effect of the drug on hypnozoites, and therefore patterns of relapse. For example, a series of clinical trials demonstrated that 8-aminoquinoline drug failures (relapses) occurred 60–90 days post-patency, whereas untreated relapses almost always occurred between day 17 and day 35 post-patency . Studies that had treated patients with a five-day course of 15 mg base of primaquine or less, which was shown to be ineffective in preventing relapse , were permitted. Relapse in patients treated with a seven-day course of primaquine in South America, where the treatment schedule has been shown to be inadequate , were also considered. Blood-stage treatments were not exclusion criteria, but were noted for analysis purposes. Mefloquine prophylaxis and treatments such as mepacrine (quinacrine, atabrine) or chloroquine may cause a delay in relapse because the drugs retain suppressive levels in the patient for long periods after treatment [61, 62], making it difficult to distinguish the observed relapse as a first or second relapse. A 14-day cut-off was applied to data abstracted from drug treatment trials. Any re-appearance of infection before the 14th day was categorized as a treatment failure, while infection after day 14 was listed as a relapse. This conservative cut-off was applied to maximize sensitivity. A primary relapse is unlikely to occur before two weeks, even in fast relapsing strains . However, a 14-day cut-off may result in some recrudescence events being classed as a relapse.
When possible, data on time to recurrence from the start of treatment of the primary infection were abstracted to the individual level. Start of treatment was almost invariably the first day of patency, and we considered it most probable that the vast majority of recurrences represented relapses. The majority of studies reported by the day, but those that reported the week or month of relapse were also included (with the last day of the month or week given as the time to relapse). Studies that aggregated months together were excluded. The period of follow-up was recorded for all individuals in each study, including those that did not experience a relapse. Data on the type of patient (prison volunteer, malaria therapy patients, soldiers, etc.) were also collected as it is likely that this would have influenced the time to first relapse. Data on duration of prepatent period from studies performed in experimental settings were recorded where this information was available.
Geopositioning of relapse studies was implemented using established methods  for those references that did not provide specific coordinates for the study site. The latitude and longitude of entries that provided cities or towns were located as points (<10 sq km) using Google Maps . The centroid of small and large polygons (>25 to <100 sq km and >100 sq km, respectively), such as islands, regions or countries were obtained using ArcMAP 10.0  to determine the latitude and longitude of those areas. The latitude and longitude values recorded corresponded to the origin of infection. Therefore, infections in returning travellers were geopositioned to the place of travel and malaria therapy or experimental trials were positioned to the origin of the strain used.
The number of cases, total person time observed, and mean and standard deviation of time to first relapse were calculated among individuals who experienced at least one relapse in each study. The incidence rate of relapse was calculated from the number of relapse events and total person time. The factors affecting this rate were modelled using mixed-effects meta-analysis in the package metafor [67, 68] within the statistical programming language R . As data must be normalized for use in metafor, how to best accomplish this was tested by applying different transformations to the data from each study and assessing deviation from normality by the Shapiro-Wilk test.
Comparison of geographic classification systems
To visualize geographic variation in relapse, maps were generated by plotting points of median time to relapse in individuals who experienced a relapse from each study included in the final dataset. Regional maps were produced to illustrate the relapse incidence and mean time to relapse modelled within the geographic system chosen in the meta-analysis.
Relapse rate data were available from 29 different countries and regions. The vast majority of the data were from India (78%, 23537/30049); although of the patients to experience a relapse, only one third (34%, 1931/5731) originated from the subcontinent (Additional file 1). There were data from 23 known strains in experimental infections, but the majority of individuals contracted wild P. vivax (94%, 28149/30049). Many of the subjects were not residents of endemic areas. For example, over one third of the patients to relapse (37%, 2731/5731) were military personnel deployed from non-endemic regions. A summary of key aspects of the dataset, such as treatment and patient type, is available in Additional file 1.
Relapse incidence rates for the modified Macdonald system
Based on raw data, ML with 95% CI
Model-based, REML with 95% CI
357 (CI: 318–400)
455 (CI: 313–662)
217 (CI: 198–238)
259 (CI: 120–557)
419 (CI: 328–528)
1093 (CI: 535–2,233)
5 + 6
214 (CI: 186–245)
262 (CI: 82–839)
221 (CI: 191–255)
213 (CI: 95–477)
25 (CI: 24–26)
62 (CI: 33–116)
9 + 10
975 (CI: 811–1163)
836 (CI: 351–1,995)
11 + 4
138 (CI: 120–159)
134 (CI: 64–278)
1023 (CI: 981–1,067)
1224 (CI: 689–2,174)
Mean time to relapse among geographic zones
Based on raw data, ML with 95% CI
Model-based, REML with 95% CI
100 (CI: 99–101)
185 (CI: 162–208)
239 (CI: 239–240)
164 (CI: 117–212)
53 (CI: 53–53)
65 (CI: 18–113)
5 + 6
153 (CI: 153–153)
151 (CI: 80–221)
31 (CI: 30–31)
107 (CI: 57–158)
181 (CI: 180–181)
120 (CI: 82–159)
9 + 10
289 (CI: 288–290)
41 (CI: -11–92)
11 + 4
89 (CI: 87–90)
299 (CI: 254–345)
122 (CI: 121–123)
47 (CI: 12–81)
The aims of this paper were to review the timing and frequency of P. vivax relapse of known origin in patients not treated with a hypnozoitocide to characterize variance in these patterns within geographic dimension, to identify a system to classify the variation in relapse observed and to describe the pattern of relapse in each area. A modified classification of the zoogeographical zones of malaria transmission outlined by Macdonald  was found to best describe the observed variation in relapse incidence. The rate of relapse and mean time from primary infection to relapse was predicted in each of the nine zones. These quantitative estimates of the contribution of relapses to P. vivax case incidence are crucial in informing estimates of disease burden and the origin of acute attack, i.e., from biting mosquitoes or emergent hypnozoites. This understanding, in turn, informs critical decision-making in control strategies that effectively weigh the benefit of anti-mosquito versus hypnozoitocidal interventions. They also help identify regions in which strains have long-term latency and are therefore undetectable to standard diagnostic methods (rapid diagnostic tests and microscopy) for long periods of time.
The results presented here further refine historical interpretations and recent analyses of the geographic variation in relapse periodicity. As shown in Figure 2, tropical strains relapse more rapidly than temperate strains and New World strains vary from those in the Old World. White’s illustration of the variation in relapse phenotype shown in Figure 2A shows that Southeast Asia and Asia-Pacific is the only region having exclusively frequent relapse behaviour. The results also showed infections from this region to relapse quickly, with a few rare exceptions. White showed that both frequent relapsing and long-latency strains are present in India and South America. The data from India appear to affirm this, with relapse patterns from the subcontinent and surrounding areas so heterogeneous that it was impossible to generate logical model predictions of relapse incidence for the region. The low incidence in region 8 shown in Table 3 is not believed to be a reflection of the presence of long relapsing strains, but rather a result of natural infections that either did not result in a relapse or the resulting parasitaemia was too low to be detected by the study. There is not presently an explanation for the lack of relapses, but this phenomenon has also been observed in recent tafenoquine trials in India . The variation in relapse timing in the raw data observed in India (Figure 5B) is likely a result of the wide variation in transmission settings found within this zone. There are tropical forest areas, similar to zone 12, dry habitats like those in zone 5 and highland areas that border zone 11. In addition, the presence of Anopheles stephensi, adapted to breeding in artificial water collections [76, 77], has extended transmission into urban areas. Therefore, in addition to issues of data availability and study design, the range of ecological settings in the zone, and likely some of the other zones, may also contribute to the variance in relapse behaviours observed.
The results presented for South America were different from what was shown in White’s phenotype map (Figure 2A). South America was predicted to have a high relapse incidence, comparable to Southeast Asia, and a two-month mean time from primary attack to relapse. The data available from this region were limited and determining the cause for the observed difference is therefore difficult. There has been renewed interest in the origin of the American strains of P. vivax, whether they originate from somewhere in Asia or were sent west from Africa by migration and the slave trade, as has been proposed for P. falciparum. This could influence the nature of the relapse periodicity observed. Improved understanding of the phylogeny of P. vivax may reveal information about the pattern of relapse in this region.
The analysis by Lover and Coker  revealed that tropical regions relapse more quickly than temperate strains. However, Central America and sub-Saharan Africa had relapse patterns similar to the Mediterranean with moderate relapse incidence (around 250 relapses per 100,000 person days) and five to six months between primary infection and relapse. These regions seem to be better described as an “intermediate” relapsing phenotype between the frequent relapsing strains in Southeast Asia and South America and the long-latency temperate strains in North America and Europe/Asia.
The results of the northern temperate regions concur with the findings of Lover and Coker . The authors noted that while in general, temperate strains relapse more slowly than tropical strains and that New World tropical strains were slower than Old World strains, the opposite was true of the temperate strains. Based on this analysis, the New World temperate strains relapsed more rapidly than the Old World temperate strains (Figure 7). The modelled results showed that the relapse incidence was 455 per 100,000 person days and mean time to relapse was six months in North America. However, again, this high incidence compared to that in northern Asia and Europe (134 relapses per 100,000 person days) could be due to a few exceptional experimental subjects who received large sporozoite inoculations [79–81].
The utility of the predictions made is limited by the nature of the data available. There are few contemporary data on P. vivax infections in patients not treated with a hypnozoitocide. Therefore, much of the data used were from drug trials on adult workers, military personnel and prison “volunteers”, as well as data from when malaria was used to treat neurosyphilis patients. The age and immunity of the patients would perhaps not be representative of relapse as it would occur among residents of the strain region of origin. This could be important because the children in many endemic settings likely carry the greatest burden of relapsing infections . Some experimental challenge subjects were inoculated with relatively heavy sporozoite dosages, a factor that greatly influences the time from primary attack to relapse  and is likely to differ from relapses following more modest numbers of sporozoites acquired from wild anophelines. It is straightforward to attribute an infection as a relapse or re-infection in experimental settings, but this could not be distinguished for P. vivax infections acquired in the wild. Effort was made to obtain studies where the follow-up period was conducted in a non-endemic area (for example, in a hospital in a city). Of the 5731 records of relapse 88% (n = 5030) were obtained from experimental or non-local populations (such as military personnel). Lastly, the strains used in therapy and drug trials in the first half of the twentieth century were of “known” origin and infections were geopositioned to those sites. However, it is not certain if the strains used were of their named origin. For example, the “Madagascar” strain was obtained from an Indian seaman whose last port of call was in Madagascar  and may conceivably, therefore, originate from elsewhere.
A principal limitation of this work is the inability to conclusively identify a recurrent infection as a relapse, recrudesence or reinfection. This is particularly an issue given the rising rate of resistance to standard treatments such as chloroquine . In cases of chloroquine failure, recurrence can occur one to two months after initial treatment , making differentiation between relapse and recrudescence a challenge. Chloroquine and chloroquine-combination therapies were by far the most common treatment regimens (82%, 24787/30049). Of those patients to receive chloroquine, 2519 patients experienced a relapse or recurrence, 523 of which occurred before 60 days. This is equivalent to 9% (523/5731) of the relapse records. In addition, the effect of resistance on recurrence is likely abated by the historical nature of the dataset. The first cases of chloroquine-resistant P. vivax were reported in 1989 . Of the 5731 records of relapse, 2080 occurred before 60 days and 82% of those (n = 1701) were observed before 1989. Therefore, increased resistance is unlikely to have a large effect on the results and instances of recrudesence being classed as a relapse would have been rare. While the relapse signal represented in these data certainly contains some noise due to reinfection or recrudescence, we considered these other sources of recurrences improbable relative to relapse. Figures 5C and 6 seem consistent with this assumption because recurrence due to reinfection or recrudescence would have been far more stochastic than relapse, obscuring or effacing the patterns shown by the randomness of timing of those events relative to primary parasitaemia.
There are aspects of the data that were not incorporated into the analysis performed here that could be addressed in future work. First, it was difficult to account for strains with long incubation periods before primary infection (information only available for a subset of data from experimental settings) followed by relatively short time to relapse. This was occasionally exhibited by the North American St Elizabeth strain and P. vivax multinucleatum from China (see Additional file 3). The link between the sporozoite dose and latency, mentioned above, was shown in the literature to be an important factor in determining relapse patterns [46, 86, 87], but was not incorporated into the analysis as it cannot be known for wild infections. This may be a possible explanation why the incidence of relapse in North America was greater than that predicted for Central America. However, this was likely not a common problem with the experimental studies used. The majority of studies aimed to induce patency and the sporozoite inoculations were large, but not extreme. There were only a handful of studies included that used particularly large inoculations in order to study the effect of dosage on relapse pattern [79–81].
The type of patient varied among studies (prison volunteers, military personnel, malaria therapy patients, outpatients in an endemic area, etc.) and the drug type and dosage varied within and among studies. In some studies, primary attacks were treated with insufficient doses of 8-aminoquinolines or drugs that have long half-lives. Mepacrine has a half-life of up to a month and can delay relapses by about 30 days [88, 89] and chloroquine, the most common drug in the dataset, can delay parasite re-appearance by anywhere from two to six weeks . Inclusion of the subject-type and treatment as explanatory variables was tested; however, the results were similar to the simpler model used (see Additional file 1). Finally, the analysis only addressed the periodicity between primary attack and first observed recurrence (relapse). The modelled estimates of incidence do not account for multiple relapses. Both the frequency and number of relapses will vary based on a variety of factors including inoculums, age of patient and origin of infection. While many studies did not follow patients long enough to report multiple relapses, further work in this area will be essential to obtain measures of the P. vivax force of infection.
Strategies for modelling survival data obtained from many dissimilar sources
Accounts for individual-level variation
Accounts for between-study variation
No; operates on summary statistics
Many software packages, e.g., meta and metafor
No; operates on summary statistics
Many packages, e.g., meta and metafor; also general-purpose software such as lme4 may be used
Survival analysis for pooled data
A number of packages, e.g., survival, eha and flexsurv
Survival analysis with mixed effects
Most notably R/coxme; flexible software seems to be hard to find
The mechanism of hypnozoite activation to cause an acute attack (relapse) remains unknown. There is clearly variation in relapse “phenotype”. Based on the results presented here, timing of relapse appears to vary geographically in conjunction with areas of similar ecology and malaria transmission patterns. However, it is difficult to determine whether long latency occurs in regions of frequent relapse (tropical areas such as zones 9 + 10 and 12). A long-latency relapse may be thought to be another short-term relapse in a succession of rapid relapses, and the genotype cannot reveal if it is in fact a separate relapse “event” . Nonetheless, understanding broad patterns of relapse is of use epidemiologically. There tends to be fewer overall relapses in the long-latency strains because hepatocytes that host the hypnozoites may die before the relapse event occurs. The resulting burden of hypnozoites from different strains or regions has implications for sensitivity to primaquine and therefore the dosage of primaquine that should be used . This was observed in treatment of soldiers returning from Korea (fewer hypnozoites)  relative to those returning from the Pacific (high hypnozoite burden)  and will have implications for future control strategies.
Frequency of relapse varies geographically. The association between relapse rate and the geographic regions does not clarify causation. Geographic variation does not directly imply environmental cues as triggers for relapse, even if the revised Macdonald system resembles the distribution of transmission suitability. Relapse frequency may result from evolved responses to average transmission season duration or arise from proximate cues, such as triggers from other infections, correlated with P. vivax transmission and/or vector suitability periods. There is likely an interaction between activation of latent hypnozoites from infection and an evolved trait for strains from areas of seasonal transmission to remain dormant during periods of low mosquito abundance. Regardless of the cause, these patterns are important for the treatment of individual infections, measures of P. vivax burden and the prospects for control and eventual elimination of the disease from endemic areas.
- 95% CI:
95% confidence interval
Akaike information criterion
Corrected Akaike information criterion
Bayesian information criterion
Papua New Guinea
Restricted maximum likelihood.
We would like to thank Nick White, David Warhust, Ellis McKenzie, Wallace Peters, Bill Collins, Andrei Beljaev, John Barnwell and David Bradley for their input and suggestions at the early stages of this work. We acknowledge the contribution of references from Ric Price, Socrates Herrera, unpublished data contribution from François Nosten and Cindy Chu and data support from Lilia Gonazalez-Ceron and Manjoit Roy. We also thank David Pigott for proofreading.
This work was supported by a Wellcome Trust Senior Research Fellowship (#095066) held by SIH, which also supports KEB, MSK and REH. PWG is a Medical Research Council Career Development Fellow (#K00669X) and receives support from the Bill and Melinda Gates Foundation (#OPP1068048) that also supports SB. NG is funded by a grant from the Bill & Melinda Gates Foundation (#OPP1053338). JPM is funded by the International Research Consortium on Dengue Risk Assessment Management and Surveillance (IDAMS, European Commission 7th Framework Programme (#21803)). TPVB was funded by a grant from the Belgian Fond National pour la Recherche Scientifique and the Fondation Wiener-Anspach. DLS and SIH acknowledge funding support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. JKB is supported by Wellcome Trust grant #B9RJIXO.
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