Malaria. Edwin J. Asturias, MD

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1 Malaria Edwin J. Asturias, MD Associate Professor of Pediatrics and Epidemiology Director for Latin America Center for Global Health, Colorado School of Public Health Global Health and Disasters Course University of Colorado AMC, November 2015

2 Despite 47% reduction since 2000, a child dies every minute in Africa from malaria 198 million malaria cases in ,000 deaths in 2013, 90% in Africa Three biggest risks Financing fragility Artemisinin resistance Insecticide resistance WHO World Malaria Report 2013

3 Discovery of Plasmodium Charles Louise Alphonse Laveran Military physician in Algeria 1907 Nobel prize in physiology

4 Types of Malaria Affecting Humans Plasmodium falciparum most virulent P. vivax P. ovale P. malariae Rare cases of P. knowlesi

5 Incubation and natural history After acquiring Plasmodium, the incubation period ranges from 7 to 30 days. Shorter incubation periods usually associated with P. falciparum, while longer ones can be P. malariae. Prophylactic anti-malarial drugs may delay symptoms for weeks to months. May result in missed or delayed diagnosis. Patients should let health care professionals know if they have traveled to malaria endemic regions during the last 12 months.

6 Malaria life cycle: mosquito-human

7 Malaria life cycle: transgenic bioluminescent stages

8 Uncomplicated Malaria Symptoms Classic attack (rare lasts 6-10 hours) Cold stage (patient feels cold, shivering) Hot stage (fever, headache, vomiting, seizures in young children) Sweating stage (sweat, then return to normal temp) Common symptoms Fever, chills, sweats, headache, nausea & vomiting, body aches, and general malaise

9 Malaria fever induction

10 Episodes of tertiary fever during primary P. falciparum infection

11 Malaria fever patterns

12 Malaria natural history and complications Acute Disease Chronic Disease Non-severe Acute Febrile disease Cerebral Malaria Death Chronic or Recurrent Asymptomatic Infection Anemia Developmental Disorders Transfusions Death Infection During Pregnancy Placental Malaria & Anemia Low Birth weight Increased Infant Mortality

13 Naturally acquired immunity to different presentations of malaria in Kenya Marsh & Kinyanjui. Parasite Immunology, 2006, 28, 51 60

14 Malaria diagnosis Thick film considered gold standard for detection of parasites (10µl of blood) Thin film for species identification Exam under oil immersion Negatives should not be reported until 200 fields have been examined Additional specimens at 12- hour intervals for 36 hours.

15 Thick and thin smears Thick smear Parasite Thin smear species

16 Thin smear species differentiation using Plasmodium trophozoites

17 Gametocytes

18 Is it possible to eliminate malaria?

WHO 2015 All cases of suspected malaria should have a parasitological test (microscopy or RDT) Thick and thin smears by competent microscopist (quality-assured 3 every 6-12 h) or

19 WHO 2015 All cases of suspected malaria should have a parasitological test (microscopy or RDT) Thick and thin smears by competent microscopist (quality-assured 3 every 6-12 h) or RDT (pfhrp2) when no QA mc or partial therapy Severe malaria in high-risk or malaria in immune deficient (HIV/AIDS) absence of parasitological test should not delay empiric therapy

BinaxNOW Malaria Test Detects circulating malaria antigens in whole blood. 15 minute test The only FDA cleared rapid malaria test. Plasmodium falciparum: Sensitivity 95.

20 BinaxNOW Malaria Test Detects circulating malaria antigens in whole blood. 15 minute test The only FDA cleared rapid malaria test. Plasmodium falciparum: Sensitivity 95.3% Specificity 94.2% Plasmodium vivax: Sensitivity 68.9% Specificity 99.8% * For parasitemia levels >5,000 (parasites/µl). Refer to product insert for additional information.

21 Spread of chloroquine and sulphadoxinepyrimethamine resistance Chloroquine Supha-pyr

22 Treatment efficacy First at Thai-Burmese demonstration project border in Thailand Cured (%) Mefloquine + artesunate 60 Mefloquine 15 Mefloquine Year

23 Current antimalarial armamentarium Youyou TU Antimalarial medicines Chinese government project Based on traditional herbal medicines

24 Treating uncomplicated P. falciparum Treatment of uncomplicated malaria falciparum malaria Artemisinin-based combination therapies (ACT) are the treatments recommended for all cases of uncomplicated falciparum malaria including: in infants, in people living with HIV/AIDS for home-based management of malaria pregnant women in the 2 nd and 3 rd trimesters Exception: 1 st trimester of pregnancy

25 Artemisinin-based combination therapies Treatment of uncomplicated falciparum malaria The following ACTs are presently recommended: artemether-lumefantrine artesunate + amodiaquine artesunate + mefloquine artesunate + sulfadoxine-pyrimethamine dihydroartemisin + piperaquine Duration of therapy is 3 days (covers 2 cycles) Dose recommendations in the guideline

26 Recurrence of malaria Recurrence is due to Treatment of uncomplicated falciparum malaria Re-infection Recrudescence (treatment failure) Ideally confirm recurrence by parasitological testing Expert microscopist LDH-based RDT (pfhrp2 may remain (+) weeks) Second-line is alternative ACT with known efficacy in the region

insecticides with low risk to humans Insecticides kill

27 Impregnated Nets Reduction of child malaria mortality by 20% Protective barrier while sleeping Pyrethroid insecticides with low risk to humans Insecticides kill mosquitos and repel them Now 11 LT ITN last for 3 years Bhatt S. nature 2015

28 Changes in infection prevalence malaria Bhatt S. nature 2015

Global malaria vaccine pipeline Phase 1a TRANSLATIONAL PROJECTS Phase 2a Phase 1b VACCINE CANDIDATES Phase 2b Phase 3

$fractional dose M3V.Ad.PfCA M3V.D/ Ad.PfCA ChAd63/MVA MSP 1 Ad35.CS EBA 175.R2 SE36 ChAd63/ MVA ME TRAP CSVAC ChAd63.$ 1 ChAd63/MVA PvDBP GMZ2 Pfs25 EPA Pfs25 VLP P. falciparum vaccines: P.

1 ChAd63/MVA PvDBP GMZ2 Pfs25 EPA Pfs25 VLP P. falciparum vaccines: P.

29 Global malaria vaccine pipeline Phase 1a TRANSLATIONAL PROJECTS Phase 2a Phase 1b VACCINE CANDIDATES Phase 2b Phase 3 ChAd63/MVA ME TRAP + Matrix M Polyepitope DNA EP 1300 PfCelTOS FMP012 RTS,S AS01/ ChAd63/MVA TRAP RTS,S AS01 delayed fractional dose M3V.Ad.PfCA M3V.D/ Ad.PfCA ChAd63/MVA MSP 1 Ad35.CS EBA 175.R2 SE36 ChAd63/ MVA ME TRAP CSVAC ChAd63.AMA/ MVA.AMA1 +Al/CPG7909 ChAd63.AMA1/ MVA.AMA1 FMP2.1 AS01B (AMA1 3D7) PfSPZ MSP3 [ ] RTS,S/ AS01 SR11.1 ChAd63/MVA PvDBP GMZ2 Pfs25 EPA Pfs25 VLP P. falciparum vaccines: P. vivax vaccines: Pre erythrocytic Blood stage Transmission blocking Pre erythrocytic Blood stage Transmission blocking Data source:

30 Vaccine efficacy against malaria in children Comparative incidence of clinical malaria over 18 months (8922 children 5 17 months and 6537 infants 6 12 weeks) Time since vaccination Comparative incidence in children [95%CI] Comparative incidence in infants [95%CI] 0 6 months 68% [64 to 72] 47% [39 to 54] 6 12 months 41% [36 to 46] 23% [15 to 31] months 26% [19 to 33] 12% [1 to 21] Vaccine efficacy over 48 mo for severe malaria and other endpoints Endpoint VE with boost [95%CI] VE no boost [95%CI] Severe Malaria 32 (14 47) 1 ( 23 to 20 5) Malaria Hospitalization 35 ( ) 17.5 (3 30) All cause Hospitalization 16 5 (7 24.5) 11.5% (2 20) Courtesy of V. Moorthy, WHO 2015

31 Global Health and Malaria Malaria remains one of the biggest infectious killers worldwide Malaria can be eliminated if reductions in parasitemia and transmission are achieved Proper diagnosis is key Adequate use of treatment is important to avoid emergence of resistance ITNs and Malaria vaccines will continue to impact malaria endemicity

Malaria. Dr. Salim Abdulla, Director Ifakara Health Institute, Dar-es-salaam, Tanzania

Malaria. Dr. Salim Abdulla, Director Ifakara Health Institute, Dar-es-salaam, Tanzania Malaria Dr. Salim Abdulla, Director Ifakara Health Institute, Dar-es-salaam, Tanzania Despite 42% reduction since 2000, a child dies every minute in Africa from malaria 207 million malaria cases in 2012,