**7. Challenges and recommendations**

**6. Vaccination**

84 Towards Malaria Elimination - A Leap Forward

and epidemics [69].

izing protection [72].

A vaccine that prevents the seeding of human livers by both active schizonts and dormant hypnozoites of *P. vivax* would provide a conspicuously useful tool in eliminating this species. Mass or routine vaccination now seems impractical with non-sterilizing vaccines of short-lived immunity needing 3 or 4 doses. These may improve in the future, but even now a malaria vaccine could be applied in geographically or demographically narrowed settings to potentially great impacts. For example, high-risk and hard-to-reach populations like migrant workers or soldiers having sterile immunity to malaria (even if for just a season or two) may not only protect those people from harm but also greatly slow importation of malaria into receptive areas where transmission has been interrupted. Likewise, people living in areas prone to reintroduction of endemic malaria by high volumes of immigration from high-risk areas may be immunized and protected against very dangerous outbreaks

Today, there is no vaccine available that can prevent infection by *P. vivax* with high levels of sterilizing immune protection. That is also true for all other plasmodial species. The half-century-long efforts to develop a vaccine against *P. falciparum*—greatly aided by the ability to cultivate this species in continuous laboratory cultures since the late 1970s culminated in the molecular subunit vaccine called RTS,S ASO1 (mimicking a proteincoating infectious sporozoites) [70] with the registered trademark name Mosquirix™ (GlaxoSmithKline). The vaccine did not prevent infection in the African infants and young children vaccinated but had the modest effects against higher parasitemias and signs of illness [67]. The modest efficacy combined with worrying and puzzling signals like increased risk of pneumococcal meningitis and significantly higher all-cause mortality among vaccinated females apparently explains the WHO position to withhold a favorable opinion on the vaccine until further studies involving targeted and limited rollout in several African nations are completed [71]. Molecular subunit vaccines targeting *P. vivax* molecules have not progressed beyond Phase 2a and show similar inability to achieve high levels of steril-

Over the past decade, investigators applying live-attenuated sporozoites of *P. falciparum* have shown high levels of durable (~12 months) sterilizing protection in malaria-naïve adult volunteers in controlled human malaria infection (CHMI) experiments using a challenge strain homologous to the vaccine strain [73]. This approach relies on laboratory harvest of infectious sporozoites from laboratory-reared aseptic anopheline mosquitoes infected by *P. falciparum* maintained in the laboratory. Deriving live-attenuated sporozoites of *P. vivax* is possible [74] but exceedingly difficult, not strain-specific, and not sustainable as a source of vaccine. Nonetheless, immunization by irradiated sporozoites of the murine species *Plasmodium berghei* cross-protected against the murine species *Plasmodium yoelii* and *vice versa* in murine challenge models [75]. The possibility of sporozoites of *P. falciparum* cross-protecting against *P. vivax* challenge has not been examined directly, but proteomic analyses showed that these two human plasmodia species shared substantially more common probable T-cell epitopes than that between *P. berghei* and *P. yoelii*. A vaccine derived from laboratory-kept *P. falciparum*

The greatest challenge in eliminating vivax malaria—the hypnozoite reservoir—may also be the greatest opportunity to accomplish the task. If >80% of incident malaria cases indeed derive from hypnozoites, then surely attacking and shrinking that reservoir would deliver substantial reductions in the burden of morbidity and mortality. Despite the availability of PQ for over 65 years, sustained and systematic assault on that reservoir has not been accomplished in the endemic tropics—largely due to the unsolved clinical problem of its hemolytic toxicity in G6PD-deficient patients.

Eliminating *P. vivax* malaria will require accepting the inadequacy of conventional falciparum malaria-focused control strategy, tactics, and tools and committing to the optimizing and validating of interventions suited to this stubborn parasite. This effectively means striving to solve the wrenchingly difficult problem of the hemolytic toxicity of PQ in G6PD-deficient patients by almost any means. The obstacles presented in managing populations and individual patients carrying this infection emphasize the great advantage of preventing it in the first place with an effective vector control strategy. In this context, species sanitation has proven highly effective against endemic Asian malarias a century ago [54] and would probably do so again.

Taking all these factors into considerations, we recommend the following measures for eliminating endemic vivax malaria:


**5.** Examine the possibility of sterilizing immune protection against *P. vivax* provided by attenuated *P. falciparum* sporozoite vaccines providing an immediately highly relevant tool for eliminating endemic *P. vivax*.

**Author details**

\*, Din Syafruddin1,2 and John Kevin Baird3,4

2 Hasanuddin University Medical Research Centre, Makassar, Indonesia

4 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine,

[1] Gething PW, Elyazar IR, Moyes CL, Smith DL, Battle KE, Guerra CA, Patil AP, Tatem AJ, Howes RE, Myers MF, George DB, Horby P, Wertheim HF, Price RN, Müeller I, Baird JK, Hay SI. A long-neglected world malaria map: *Plasmodium vivax* endemicity in 2010. PLoS

Challenges in the Control and Elimination of *Plasmodium vivax* Malaria

http://dx.doi.org/10.5772/intechopen.77082

87

[2] Battle KE, Gething PW, Elyazar IR, Moyes CL, Sinka ME, Howes RE, Guerra CA, Price RN, Baird KJ, Hay SI. The global public health significance of *Plasmodium vivax*. Advances

[3] Rosalind EH, Katherine EB, Kamini NM, David LS, Richard EC, Kevin Baird J, Hay SI. Global epidemiology of *Plasmodium vivax*. The American Journal of Tropical Medicine

[4] Price RN, von Seidlein L, Valecha N, Nosten F, Baird JK, White NJ. Global extent of chloroquine-resistant *Plasmodium vivax*: A systematic review and meta-analysis. The Lancet

[5] Baird JK. Resistance to therapies to infection by *Plasmodium vivax*. Clinical Microbiology

[6] White NJ, Imwong M. Relapse. Advances in Parasitology. 2012;**80**:113-150. DOI: 10.1016/

[7] Baird JK, Leksana B, Masbar S, Fryauff DJ, Sutanihardja MA, Suradi, Wignall FS, Hoffman SL. Diagnosis of resistance to chloroquine by *Plasmodium vivax*: Timing of recurrence and whole blood chloroquine levels. The American Journal of Tropical Medicine and

[8] Asih PB, Syafruddin D, Leake J, Sorontou Y, Sadikin M, Sauerwein RW, Vinetz J, Baird JK. Phenotyping clinical resistance to chloroquine in *Plasmodium vivax* in northeastern

Infectious Diseases. 2014;**14**(10):982-991. DOI: 10.1016/S1473-3099(14)70855-2

Neglected Tropical Diseases. 2012;**6**(9):1814. DOI: 10.1371/journal.pntd.0001814

in Parasitology. 2012;**80**:1-111. DOI: 10.1016/B978-0-12-397900-1.00001-3

and Hygiene. 2016;**95**(6):15-34. DOI: 10.4269/ajtmh.16-0141

Reviews. 2009;**22**:508-534. DOI: 10.1128/CMR.00008-09

B978-0-12-397900-1.00002-5

Hygiene. 1997;**56**:618-620. PMID: 9230792

\*Address all correspondence to: puji@eijkman.go.id

University of Oxford, Oxford, United Kingdom

1 Eijkman Institute of Molecular Biology, Jakarta, Indonesia

3 Eijkman Oxford Clinical Research Unit, Jakarta, Indonesia

Puji BS Asih<sup>1</sup>

**References**
