JOURNAL OF THE LOUISIANA STATE MEDICAL SOCIETY
proguanil regimen shortened to one day fromone week requires further statistically significant confirmation in a multi-centered, randomized controlled study comparing the abridged to the standard post-travel regimen before widespread adoption of the practice. 19
falciparum malaria, malaria experts have now recommended that primaquine not be used for the primary prophylaxis of P. falciparum malaria. 21,22 In addition, effective alternatives to primaquine are already available for the primary prophylaxis of falciparum malaria, such as mefloquine, atovaquone-proguanil, and doxycycline. 22
Primaquine for Primary Prophylaxis of Malaria
The Quest for aMalaria Vaccine: The Primary Prevention of Malaria by Vaccination
Like atovaquone-proguanil, primaquine exerts dual antimalarial actions at the blood and liver stages of the malaria parasite. However, unlike any other antimalarial, primaquine is also effective against hypnozoites, the dormant liver stages of P. vivax and P. ovale , and the blood stage gametocytes of all species. As a result, the radical or terminal cure of P. vivax and P. ovale malaria will require primaquine therapy, often in combination with chloroquine that remains effective for most non- falciparum species. Primaquine is an 8-aminoquinolone related to chloroquine and mefloquine with an unknown mechanism of action probably via the generation of toxic metabolites that cause oxidative stress and damage the parasite at every stage, except the sporozoite stage. 12 Primaquine therapy offers several advantages that would support its use in the primary prophylaxis of malaria including (1) lack of parasite resistance, (2) relatively short post-travel administration schedule of two weeks, and (3) effectiveness against relapsingmalaria causedby P. vivax and P. ovale . Although primaquine chemoprophylaxis is no longer recommended for P. falciparum protection, the CDC still recommends primaquine for malaria chemoprophylaxis in areas with primarily P. vivax and/or P. ovale -endemic malaria. The use of primaquine for primary prophylaxis, however, is restricted by its ability to cause oxidative stress and hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common genetic polymorphism among Asians, Blacks, and persons of Mediterranean descent. Therefore, testing for G6PD deficiency should precede the initiation of primaquine therapy for primary prophylaxis of malaria, for presumptive anti- relapse therapy, or for curative therapy for P. vivax or P. ovale malaria. In 2013, Bennett and coinvestigators reported the failure of primaquine therapy to cure P. vivax malaria in two patients with qualitative deficiencies of the critical hepatic isoenzyme, cytochrome P450 (CYP) 2D6, responsible for the metabolism of up to 25% of all drugs in use today. 20 The investigators concluded that the active metabolites of primaquine must play important roles in the pre-erythrocytic antimalarial activity of primaquine and that normal CYP 2D6 function was required for the successful treatment of P. vivax malaria. Like G6PD deficiencies, genetic polymorphism of CYP 2D6 are relatively common with poor metabolizer phenotypes present in 5-10% of Caucasian and European populations and up to 50% of Asian populations. 19,20 Since a significant proportion of travelers might have polymorphisms limiting the function of CYP 2D6 and rendering primaquine ineffective against vivax and possibly
There is a critical need for an effective vaccine for malaria, especially for P. falciparum malaria. There are existing and highly effective vaccines for other mosquito-borne, viral infectious diseases, such as yellow fever and Japanese encephalitis. There are many other vaccines for respiratory-borne viruses and bacteria, such as influenza and pneumococcal pneumonia. Despite these existing vaccines and a quest for a malaria vaccine that began with inactivated sporozoites during World War II (1942), we still do not have a malaria vaccine. 23 Why has the quest for a malaria vaccine been so long and difficult when vaccines have nearly eradicated other viral infectious diseases like polio and smallpox? Unlike infectious diseases causedby viruses andbacteria, malaria is a parasitic disease caused by a complex organism with a huge genome and several developmental stages in its life cycle (Figure 2). Each stage of development in man from infective stage sporozoites to sexual stage gametocytes presents hundreds of antigens to the immune system. 24 Amalaria vaccine would need to be 100% effective for each stage as just one sporozoite that leaves the circulation for sequestration in the liver could cause malaria. In addition, the histological location of the parasite’s stage as either extracellular (e.g., sporozoite) or intracellular (e.g., gametocyte) will determine the necessary immune response to be elicited by vaccination as humoral or cellular respectively. 25 Because of these unique pathogen characteristics, there are still no effective vaccines for any parasitic disease including malaria in man or animals. The current candidate malaria vaccines in development and testing today share many similar characteristics and differ in others. Similar characteristics include targeting the preerythrocytic stage, specifically sporozoites; focusing on P. falciparum, even though a P.vivax vaccine is also needed; and stimulating a humoral immune response. 26 Other vaccines target intracellular erythrocytic and hepatic stages and stimulate a cellular immune response. The newest vaccine candidates block the mosquito-borne transmission of malaria in man and mosquitoes and do not prevent symptomatic malaria. 27 The vector transmission blocking or altruistic vaccines target intraerythrocytic gametocytes inman rendering them incapable of sexual reproduction in mosquitoes after human blood meals. Mass transmission-blocking vaccination programs depend on herd immunity to protect the unvaccinated and control community outbreaks of P. falciparum malaria. Similar vaccine strategies could also control community outbreaks of P. vivax malaria.
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