6  Human Immune Response

Morbidity due to P. falciparum infections can vary from mild clinical symptoms of febrile illness to severe and life-threatening disease due to vital organ dysfunction. Individuals living in malaria endemic areas, however, do acquire substantial protection against clinical and severe forms of malaria, but rarely, if ever, is sterile immunity achieved.1 Generally, immunity against severe malaria develops rapidly, followed by immunity against clinical disease and finally, more slowly, the build-up of immune tolerance to blood-stage parasites (Figure 6.1).2 While immunity to patent parasitaemia can develop by adulthood, subpatent infections that are detectable with advancements in molecular diagnostic techniques still occur. It is this immune tolerance that results in asymptomatic carrier infections among adult populations in malaria-endemic areas.34

The acquisition of immunity to malaria has been shown to be both age- and exposure-dependent leading to a high degree of variability in patterns of immunity across populations.56789 This progressive acquisition of immunity to malaria is why younger children are particularly vulnerable to episodes of severe malaria, once a period of protection provided from maternally derived antibodies wanes and before the acquisition of this effective immunity

Figure 6.1: Progression of Naturally Acquired Immunity to Malaria. The relationship between age and malaria severity in an area of moderate transmission inte nsity shows how with repeated exposure by early childhood, protection is first acquired against severe disease, then more slowly protection builds up against clinical disease and finally much more slowly develops against parasitaemia. In areas with higher transmission intensity the rate of acquisition of naturally acquired immunity can increase. Reproduced from Griffin et al 2015 doi: https://doi.org/10.1098/rspb.2014.2657.

6.1 Immune response overview

Due to the parasites multistage lifecycle, there are several points at which the immune system could respond to the invading threat. Upon first exposure to blood stage parasites, the innate immune system launches a non-specific immune response triggering a release of pro-inflammatory cytokines which help to limit parasite growth.10 These cytokine responses also allow for the effective priming of the humoral and cellular-mediated immune responses which then provide adaptive responses upon re-exposure.

Key to the adaptive immune response is the phenomenon of pattern recognition of parasite antigens by B and T cells, which enables a rapid and more effective parasite specific protective response to each lifecycle stage. However, the exact immune effector mechanisms involved in parasite regulation, control and elimination at each lifecycle stage are not fully characterised. The ability of malaria parasites to evade and interfere with effective immune responses also presents several challenges in mounting and understanding successful immune responses. 11 12 13

The key mechanisms understood to play a significant role at each parasite life-stage are shown in Figure 6.1.

Overview of the immune responses directed against each malaria parasite life stage.
Key Take-aways

Naturally occurring immune responses to sporozoite life-stages are poor and frequently inefficient at eliminating parasites and are generally considered inadequate to confer protection against clinical malaria.

The majority of naturally acquired immunity is directed against blood stage parasites – both freely circulating merozoites and infected red blood cells. However inflammatory responses associated with immune response to this stage can result in significant immunopathology.

Gametocyte specific antibodies are often poorly induced and not widely circulating in populations

6.2 Prof. Kevin Marsh - “Immunity to Malaria in Humans”

Below is a great lecture by Professor Kevin Marsh that describes how knowledge of immunity to malaria in humans has developed over the past thirty years and what impact this has for future research. This seminar was delivered at the University of Oxfords Centre for Tropical Medicine, Oxford, UK, 29th October 2013.

Watch this for a great overview to a very complex topic!

  1. Doolan DL, Dobaño C, Baird JK. Acquired immunity to malaria. Clin Microbiol Rev. 2009 Jan;22(1):13-36, https://doi.org/10.1128%2FCMR.00025-08↩︎

  2. Griffin Jamie T., Hollingsworth T. Déirdre, Reyburn Hugh, Drakeley Chris J., Riley Eleanor M. and Ghani Azra C. 2015 Gradual acquisition of immunity to severe malaria with increasing exposure. Proc. R. Soc. B.28220142657 http://doi.org/10.1098/rspb.2014.2657↩︎

  3. Bousema T, Okell L, Felger I, Drakeley C. Asymptomatic malaria infections: detectability, transmissibility and public health relevance. Nat Rev Microbiol. 2014 Dec;12(12):833-40. doi: 10.1038/nrmicro3364.↩︎

  4. Okell LC, Bousema T, Griffin JT, Ouédraogo AL, Ghani AC, Drakeley CJ. Factors determining the occurrence of submicroscopic malaria infections and their relevance for control. Nat Commun. 2012;3:1237. doi: 10.1038/ncomms2241↩︎

  5. Griffin Jamie T., Hollingsworth T. Déirdre, Reyburn Hugh, Drakeley Chris J., Riley Eleanor M. and Ghani Azra C. 2015 Gradual acquisition of immunity to severe malaria with increasing exposure. Proc. R. Soc. B.28220142657 http://doi.org/10.1098/rspb.2014.2657↩︎

  6. Rodriguez-Barraquer I, Arinaitwe E, Jagannathan P, Kamya MR, Rosenthal PJ, Rek J, Dorsey G, Nankabirwa J, Staedke SG, Kilama M, Drakeley C, Ssewanyana I, Smith DL, Greenhouse B. Quantification of anti-parasite and anti-disease immunity to malaria as a function of age and exposure. Elife. 2018 Jul 25;7:e35832. doi: 10.7554/eLife.35832.↩︎

  7. Greenwood B, Marsh K, Snow R. Why do some African children develop severe malaria? Parasitol Today. 1991 Oct;7(10):277-81. doi: 10.1016/0169-4758(91)90096-7↩︎

  8. Baird JK. Host age as a determinant of naturally acquired immunity to Plasmodium falciparum. Parasitol Today. 1995 Mar;11(3):105-11. doi: 10.1016/0169-4758(95)80167-7↩︎

  9. Reyburn H, Mbatia R, Drakeley C, Bruce J, Carneiro I, Olomi R, Cox J, Nkya WM, Lemnge M, Greenwood BM, Riley EM. Association of transmission intensity and age with clinical manifestations and case fatality of severe Plasmodium falciparum malaria. JAMA. 2005 Mar 23;293(12):1461-70. doi: 10.1001/jama.293.12.1461.↩︎

  10. Stevenson MM, Riley EM. Innate immunity to malaria. Nat Rev Immunol. 2004 Mar;4(3):169-80. doi: 10.1038/nri1311↩︎

  11. Langhorne J, Ndungu FM, Sponaas AM, Marsh K. Immunity to malaria: more questions than answers. Nat Immunol. 2008 Jul;9(7):725-32. doi: 10.1038/ni.f.205↩︎

  12. Ramasamy R. Molecular basis for evasion of host immunity and pathogenesis in malaria. Biochim Biophys Acta. 1998 Feb 27;1406(1):10-27. doi: 10.1016/s0925-4439(97)00078-1↩︎

  13. Gomes PS, Bhardwaj J, Rivera-Correa J, Freire-De-Lima CG, Morrot A. Immune Escape Strategies of Malaria Parasites. Front Microbiol. 2016 Oct 17;7:1617. doi: 10.3389/fmicb.2016.01617↩︎