Chapter Three - Natural Acquisition of Immunity to Plasmodium vivax: Epidemiological Observations and Potential Targets

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Abstract

Population studies show that individuals acquire immunity to Plasmodium vivax more quickly than Plasmodium falciparum irrespective of overall transmission intensity, resulting in the peak burden of P. vivax malaria in younger age groups. Similarly, actively induced P. vivax infections in malaria therapy patients resulted in faster and generally more strain-transcending acquisition of immunity than P. falciparum infections. The mechanisms behind the more rapid acquisition of immunity to P. vivax are poorly understood. Natural acquired immune responses to P. vivax target both pre-erythrocytic and blood-stage antigens and include humoral and cellular components. To date, only a few studies have investigated the association of these immune responses with protection, with most studies focussing on a few merozoite antigens (such as the Pv Duffy binding protein (PvDBP), the Pv reticulocyte binding proteins (PvRBPs), or the Pv merozoite surface proteins (PvMSP1, 3 & 9)) or the circumsporozoite protein (PvCSP). Naturally acquired transmission-blocking (TB) immunity (TBI) was also found in several populations. Although limited, these data support the premise that developing a multi-stage P. vivax vaccine may be feasible and is worth pursuing.

Section snippets

Overview of Naturally Acquired Immunity to Malaria

A major controlling force that determines the incidence and prevalence of malaria infection and disease in endemic areas is the parasitological and clinical immunity collectively referred to as naturally acquired immunity (NAI). Generally, NAI determines not only the age-specific incidence and prevalence of P. falciparum (Pf膘) and P. vivax (Pv) infections but also the expression of pathological processes that underlie the clinical manifestations of infection. Improved understanding of the

Differential Acquisition of Immunity to P. vivax and P. falciparum Under Natural Exposure

In the New Guinea island, which is highly endemic for both P. falciparum and P. vivax (Muller et al., 2003), P. vivax is the predominate source of malarial infections and disease in children younger than 2 years (Senn et al., 2012). The incidence of P. vivax malaria started to rapidly decrease from the second year of life, whereas P. falciparum incidence continued to increase until the fourth year in observational cohort studies in children aged 1–4 (Lin et al., 2010) and 5–14 years (Michon

Acquisition of Immunity in Experimental Infections – Lessons from Malaria Therapy Patients and Irradiated Sporozoites

Prior to the confirmation in 1947 that penicillin could cure syphilis, the primary treatment for neurosyphilis was fevers induced with malarial infections. Plasmodium vivax was the preferred treatment over P. falciparum because it could produce sustained fevers without requiring treatment. Because malaria therapy did not cure syphilis, but just delayed the progression of disease, individuals were often repeatedly infected. With support from the Rockefeller Foundation in the 1930s and early

Unique Biological Characteristics of P. vivax that Contribute to NAI

Individuals exposed to a comparable number of infections and clinical episodes of P. vivax and P. falciparum acquire clinical immunity to P. vivax more rapidly than P. falciparum (Lin et al., 2010; Maitland et al., 1996; Michon et al., 2007). Pv has several important differences in its biology compared to Pf, which may help to explain the differences in the acquisition of immunity to each of these species.

Effector Mechanisms for Blood-Stage Immunity

Adoptive transfer of serum from avian (Manwell and Goldstein, 1940), murine (Parashar et al., 1977), non-human primate (Coggeshall and Kumm, 1937) and human falciparum malarias with NAI (Cohen et al., 1961; McGregor, 1964) into naïve animals or humans protects against clinical malaria or significantly attenuates the severity and burden of malaria (Cohen et al., 1961; McGregor, 1964). Such experiments have established that Abs are critical for NAI to blood-stage malarial infection.

Targets of Blood-Stage Immunity

Although much can be inferred from the basic biology of Plasmodium merozoites (Fig. 3.2), there are many gaps in our knowledge of the biology of P. vivax merozoites. For example, why they selective invade host reticulocytes and details of the growth and development of the various blood-stage developmental forms (reviewed in Galinski et al., 2005). In addition, only a relatively small group of merozoite proteins have so far been identified with specific localisations and confirmed functional

Immune Responses to Malaria Pre-Erythrocytic Stages

In humans, malarial infection is initiated by the bite of an infected Anopheles mosquito that injects sporozoites into the host’s bloodstream. Although mosquitoes from highly endemic areas are estimated to carry up to 104 sporozoites in their salivary glands, it has been calculated that during a blood meal an infected mosquito inoculates a median number of only 15 parasites into the host (Rosenberg et al., 1990).

After inoculation, the sporozoites move through dermal cells and enter into the

Sexual Stage Parasites and Transmission-Blocking Immunity

The target stages of the TBI are the sexual stages of the Plasmodium life cycle. The sexual stage is initiated in the vertebrate host bloodstream as male and female gametocytes. After the ingestion of the infected blood by Anopheles mosquito, male and female gametes emerge and fertilise to form zygotes in the mosquito midgut. The zygotes transform into motile ookinetes, which traverse the epithelium of the mosquito midgut to further develop into oocysts (Tsuboi et al., 2003).

TBI has initially

Conclusions

Although we have only just begun to understand some of the major processes involved in NAI to P. vivax, the results to date support the premise that developing a multistage P. vivax vaccine may be feasible and is worth pursuing. The more rapid development of NAI to P. vivax even indicates that a highly efficacious P. vivax vaccine may be easier to achieve that a vaccine to P. falciparum. This might be especially true if there are fewer redundant pathways for erythrocyte invasion. A

Future Directions

  • 1.

    Compare Ab responses from putatively immune and susceptible individuals using protein arrays representing Pv blood-stage antigens in longitudinal cohort studies with the aim to identify new targets of blood-stage immune responses.

  • 2.

    Better characterize surface-expressed proteins on Pv-IEs and relate how these proteins are involved in stimulating NAI, and, potentially, immune evasion strategies.

  • 3.

    Study the role of host cellular immunity and protection against blood-stage Pv infection, including the

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