Skip to main content
    • Aa
    • Aa

Re-assessing the relationship between sporozoite dose and incubation period in Plasmodium vivax malaria: a systematic re-analysis

  • ANDREW A. LOVER (a1) and RICHARD J. COKER (a1) (a2)

Infections with the malaria parasite Plasmodium vivax are noteworthy for potentially very long incubation periods (6–9 months), which present a major barrier to disease elimination. Increased sporozoite challenge has been reported to be associated with both shorter incubation and pre-patent periods in a range of human challenge studies. However, this evidence base has scant empirical foundation, as these historical analyses were limited by available analytic methods, and provides no quantitative estimates of effect size. Following a comprehensive literature search, we re-analysed all identified studies using survival and/or logistic models plus contingency tables. We have found very weak evidence for dose-dependence at entomologically plausible inocula levels. These results strongly suggest that sporozoite dosage is not an important driver of long-latency. Evidence presented suggests that parasite strain and vector species have quantitatively greater impacts, and the potential existence of a dose threshold for human dose-response to sporozoites. Greater consideration of the complex interplay between these aspects of vectors and parasites are important for human challenge experiments, vaccine trials, and epidemiology towards global malaria elimination.

Corresponding author
* Corresponding author. Infectious Diseases Programme, Saw Swee Hock School of Public Health, National University of Singapore, MD3, 16 Medical Drive, Singapore 117597, Singapore. E-mail: or
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

A. Animut , M. Balkew , T. Gebre-Michael and B. Lindtjørn (2013). Blood meal sources and entomological inoculation rates of anophelines along a highland altitudinal transect in south-central Ethiopia. Malaria Journal 12, 76. doi: 10.1186/1475-2875-12-76.

P. Brasil , P. de , A. Costa , R. S. Pedro , S. da , C. Bressan , S. da Silva , P. L. Tauil and C. T. Daniel-Ribeiro (2011). Unexpectedly long incubation period of Plasmodium vivax malaria, in the absence of chemoprophylaxis, in patients diagnosed outside the transmission area in Brazil. Malaria Journal 10, 122. doi: 10.1186/1475-2875-10-122.

W. E. Collins (2002). Nonhuman primate models: II. Infection of Saimiri and Aotus monkeys with Plasmodium vivax. In Malaria Methods and Protocols (ed. D. L. Doolan ), pp. 8592. Humana Press, Totowa, NJ, USA.

W. E. Collins , J. C. Skinner , M. Pappaioanou , J. R. Broderson , V. K. Filipski , H. M. McClure , E. Strobert , B. B. Sutton , P. S. Stanfill and A. Y. Huong (1988). Sporozoite-induced infections of the Salvador I strain of Plasmodium vivax in Saimiri sciureus boliviensis monkeys. Journal of Parasitology 74, 582585.

W. E. Collins , C. L. Morris , B. B. Richardson , J. S. Sullivan and G. G. Galland (1994). Further studies on the sporozoite transmission of the Salvador I strain of Plasmodium vivax. Journal of Parasitology 80, 512517.

W. E. Collins , J. A. S. Sullivan , C. L. Morris , G. G. Galland and B. B. Richardson (1996). Observations on the biological nature of Plasmodium vivax sporozoites. Journal of Parasitology 82, 216219.

F. Frischknecht , P. Baldacci , B. Martin , C. Zimmer , S. Thiberge , J.-C. Olivo-Marin , S. L. Shorte and R. Ménard (2004). Imaging movement of malaria parasites during transmission by Anopheles mosquitoes. Cellular Microbiology 6, 687694. doi: 10.1111/j.1462-5822.2004.00395.x.

M. R. Galinski and J. W. Barnwell (2008). Plasmodium vivax: who cares? Malaria Journal 7 (Suppl. 1), S9. doi: 10.1186/1475-2875-7-S1-S9.

P. W. Gething , I. R. F. Elyazar , C. L. Moyes , D. L. Smith , K. E. Battle , C. A. Guerra , A. P. Patil , A. J. Tatem , R. E. Howes , M. F. Myers , D. B. George , P. Horby , H. F. L. Wertheim , R. N. Price , I. Mueller , J. K. Baird and S. I. Hay (2012). A long neglected world malaria map: Plasmodium vivax endemicity in 2010. PLoS Neglected Tropical Diseases 6, e1814. doi: 10.1371/journal.pntd.0001814.

D. L. Guilbride , P. D. L. Guilbride and P. Gawlinski (2012). Malaria's deadly secret: a skin stage. Trends in Parasitology 28, 142150. doi: 10.1016/

S. Herrera , O. Fernandez , M. R. Manzano , B. Murrain , J. Vergara , P. Blanco , R. Palacios , J. D. Velez , J. E. Epstein , M. Chen-Mok , Z. H. Reed and M. Arevalo-Herrera (2009). Successful sporozoite challenge model in human volunteers with Plasmodium vivax strain derived from human donors. American Journal of Tropical Medicine and Hygiene 81, 740746. doi: 10.4269/ajtmh.2009.09-0194.

S. Herrera , Y. Solarte , A. Jordan-Villegas , J. F. Echavarria , L. Rocha , R. Palacios , O. Ramirez , J. D. Velez , J. E. Epstein , T. L. Richie and M. Arevalo-Herrera (2011). Consistent safety and infectivity in sporozoite challenge model of Plasmodium vivax in malaria-naive human volunteers. American Journal of Tropical Medicine and Hygiene 84, 411. doi: 10.4269/ajtmh.2011.09-0498.

D. W. Hosmer , T. Hosmer , S. Le Cessie and S. Lemeshow (1997). A comparison of goodness-of-fit tests for the logistic regression model. Statistics in Medicine 16, 965980.

S. P. James (1931). Some general results of a study of induced malaria in England. Transactions of the Royal Society of Tropical Medicine and Hygiene 24, 477525.

Y. Jin , C. Kebaier and J. Vanderberg (2007). Direct microscopic quantification of dynamics of Plasmodium berghei sporozoite transmission from mosquitoes to mice. Infection and Immunity 75, 55325539. doi: 10.1128/IAI.00600-07.

S.-J. Kim , S.-H. Kim , S.-N. Jo , J. Gwack , S.-K. Youn and J.-Y. Jang (2013). The long and short incubation periods of Plasmodium vivax malaria in Korea: the characteristics and relating factors. Infection and Chemotherapy 45, 184193. doi: 10.3947/ic.2013.45.2.184.

J. Li , W. E. Collins , R. A. Wirtz , D. Rathore , A. Lal and T. F. McCutchan (2001). Geographic subdivision of the range of the malaria parasite Plasmodium vivax. Emerging Infectious Diseases 7, 3542.

A. A. Lover and R. J. Coker (2013). Quantifying effect of geographic location on epidemiology of Plasmodium vivax malaria. Emerging Infectious Diseases 19, 10581065. doi: 10.3201/eid1907.121674.

M. B. Markus (2012). Dormancy in mammalian malaria. Trends in Parasitology 28, 3945. doi: 10.1016/

B. Mayne (1933). The injection of mosquito sporozoites in malaria therapy. Public Health Reports 48, 909916. doi: 10.2307/4580870.

D. L. Medica and P. Sinnis (2005). Quantitative dynamics of Plasmodium yoelii sporozoite transmission by infected anopheline mosquitoes. Infection and Immunity 73, 43634369. doi: 10.1128/IAI.73.7.4363-4369.2005.

R. Ménard , J. Tavares , I. Cockburn , M. Markus , F. Zavala and R. Amino (2013). Looking under the skin: the first steps in malarial infection and immunity. Nature Reviews Microbiology 11, 701712. doi: 10.1038/nrmicro3111.

I. Mueller , M. R. Galinski , J. K. Baird , J. M. Carlton , D. K. Kochar , P. L. Alonso and H. A. del Portillo (2009). Key gaps in the knowledge of Plasmodium vivax, a neglected human malaria parasite. Lancet Infectious Diseases 9, 555566. doi: 10.1016/S1473-3099(09)70177-X.

R. E. Paul , M. Diallo and P. T. Brey (2004). Mosquitoes and transmission of malaria parasites – not just vectors. Malaria Journal 3, 39. doi: 10.1186/1475-2875-3-39.

R. Rosenberg (2008). Malaria: some considerations regarding parasite productivity. Trends in Parasitology 24, 487491. doi: 10.1016/

E. Schwartz , M. Parise , P. Kozarsky and M. Cetron (2003). Delayed onset of malaria – implications for chemoprophylaxis in travelers. New England Journal of Medicine 349, 15101516.

D. G. Shanks (2012). Control and elimination of Plasmodium vivax. In Advances in Parasitology, Vol. 80 (ed. S. I. Hay , R. N. Price and J. K. Baird ), pp. 301341. Academic Press, London, UK.

S. H. Sheehy , A. J. Spencer , A. D. Douglas , B. K. L. Sim , R. J. Longley , N. J. Edwards , I. D. Poulton , D. Kimani , A. R. Williams , N. A. Anagnostou , R. Roberts , S. Kerridge , M. Voysey , E. R. James , P. F. Billingsley , A. Gunasekera , A. M. Lawrie , S. L. Hoffman and A. V. S. Hill (2013). Optimising controlled human malaria infection studies using cryopreserved P. falciparum parasites administered by needle and syringe. PLoS ONE 8, e65960. doi: 10.1371/journal.pone.0065960.

P. G. Shute , G. H. Lupascu , P. Branzei , M. Maryon , P. Constantinescu , L. J. Bruce-Chwatt , C. C. Draper , R. Killick-Kendrick and P. C. C. Garnham (1976). A strain of Plasmodium vivax characterized by prolonged incubation: the effect of numbers of sporozoites on the length of the prepatent period. Transactions of the Royal Society of Tropical Medicine and Hygiene 70, 474481.

G. A. T. Targett , V. S. Moorthy and G. V. Brown (2013). Malaria vaccine research and development: the role of the WHO MALVAC committee. Malaria Journal 12, 362. doi: 10.1186/1475-2875-12-362.

E. Ungureanu , R. Killick-Kendrick , P. C. C. Garnham , P. Branzei , C. Romanescu and P. G. Shute (1976). Prepatent periods of a tropical strain of Plasmodium vivax after inoculations of tenfold dilutions of sporozoites. Transactions of the Royal Society of Tropical Medicine and Hygiene 70, 482483.

J. P. Vanderberg (2014). Imaging mosquito transmission of Plasmodium sporozoites into the mammalian host: immunological implications. Parasitology International. in press. doi: 10.1016/j.parint.2013.09.010.

J. P. Verhave (2013). Experimental, therapeutic and natural transmission of Plasmodium vivax tertian malaria: scientific and anecdotal data on the history of Dutch malaria studies. Parasites and Vectors 6, 19. doi: 10.1186/1756-3305-6-19.

N. J. White (2011). Determinants of relapse periodicity in Plasmodium vivax malaria. Malaria Journal 10, 297.

C. M. Whorton , W. Kirschbaum , T. N. Pullman , R. Jones , B. Craige and A. S. Alving (1947). The Chesson strain of Plasmodium vivax malaria I. Factors influencing the incubation period. Journal of Infectious Diseases 80, 223227.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

  • ISSN: 0031-1820
  • EISSN: 1469-8161
  • URL: /core/journals/parasitology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 3
Total number of PDF views: 17 *
Loading metrics...

Abstract views

Total abstract views: 175 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 21st September 2017. This data will be updated every 24 hours.