Malaria

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History of malaria

• 2700BCのNei Ching（內經＝黃帝內經）に記述あり
• ヒポクラテスも記述
• mal=bad, aria=air　「悪い気」

• 1880年 Laveran が初めて患者の血液を顕微鏡で観察してスケッチ
• 1897年 Ronald Ross が初めてハマダラカの中腸で発見
• 1948年 P.C.C. Graham が初めてヒト肝細胞への感染を発見

Malaria in Yaeyama, Okinawa, Japan

• Malaria History in Yaeyama War Malaria & Malaria Elimination (in 4 languages)
• マラリア撲滅への挑戦者たち (やいま文庫13)　南風原 英育

Pathogen and life cycle

• YouTube: Malaria Lifecycle Part 1
• YouTube: Malaria Lifecycle Part 2

etymology

• sporo-
• mero-
  • [Gr] part
• tropho-
• hypno-
• -zoite, -zont
• gameto-
• oo-
• -kinate
• -cyst

• sporozoite
• merozoite
• trophozoite
• schizont
• hypnozoite
• gametocyte
• ookinate
• oocyst

Human liver stage

1. sprozoite→schizont
   1. hypnozoite only by P. vivax and P. ovale

Human blood stage

1. merozoite
2. trophozoite
   1. schizont
   2. gametocyte
      1. male/female

Mosquito stage

1. gametocyte
2. macrogametocyte
3. ookinete
4. oocyst
5. sporozoite

1. Re-infection
2. Recrudescence
   1. insufficient treatment
   2. drug resistant
   3. antigenic drift of Plasmodium inside human during one single infection
      1. RBCに感染したP.fが発現する赤血球接着分子は14あるP.染色体中に分散してコードされており，機序不明だが感染後の一定日数はその一部のみが発現して接着分子をRBC表面に構築する．それに対してヒトが免疫を獲得しても，数日後には別のコードが発現して異なる形の接着分子を発現し，免疫からescapeしてしまう．
      2. 繰り返し感染することで重症化リスクが下がっていくのは，多様な接着分子への免疫を漸次獲得していくため
3. Relapse

• Duffy antigen on human RBC
  • P. vivax recognizes and utilizes as ligand Duffy antigen on human RBC surface
    • Duffy-binding protein (DBP) in P. vivax
  • Genetically sub-Saharan people highly lack Duffy antigen, which consists the reason why P. vivax is not endemic in sub-Sahara

Epidemiology

in 2017

• 219mil. per year ←500mil. in 2005
• 435,000 death per year ←1mil. in 2005
  • most sub-Saharan Africa
  • most in children under 5y/o

during 1934-1939 in Japan

• 殆どが琵琶湖周辺の5県に集中していた
  • 琵琶湖南岸の水田と湖へ注ぐ小川でハマダラカが繁殖
• 最後の患者は1961年沖縄

China is certified as malaria-free by WHO in 2021

• From 30 million cases to zero: China is certified malaria-free by WHO

Control

Ross-MacDonald equation

[math]\displaystyle{ R_0 = \frac{m a^2 b_1 b_2 e^{-μT}}{r μ} }[/math]

[math]\displaystyle{ m }[/math] = no. of mosquito per person

• larval control
  • breeding site destruction
  • chemical larviciding
  • biological control
• increase human population!
  • 奇妙に思えるが人口を増やすことで蚊にとっての原虫reservoirが薄まるために結果的にtransmissionが減る
  • 実際にurbanizationでマラリアが減ることが実証されている

[math]\displaystyle{ a }[/math] = biting rate of mosquitos；1人刺して2人目を刺すから二乗する

• bed net
• repellent

[math]\displaystyle{ b_1 }[/math] = susceptibility of mosquito

• 蚊を遺伝子操作/生殖腺に放射線照射して地域に放つ
  • 地域住民の理解を得るのが難しい
• 蚊の体内で生殖が起きないようにするワクチンをヒトに接種する

[math]\displaystyle{ b_2 }[/math] = susceptibility of human

• 感染を防ぐワクチンをヒトに接種する
• 予防内服

[math]\displaystyle{ e }[/math] = 自然対数（ネイピア数）

[math]\displaystyle{ μ }[/math] = mortality rate of mosquitoes

• insecticide
  • spray insecticide on walls
    • インドで大成功 malaria eradication programme in India 1958
      • DDT

[math]\displaystyle{ T }[/math] = incubation time of malaria parasites

• 気温が下がるほど潜伏期間は長くなる
  • 温暖化対策

[math]\displaystyle{ e^{-μT} }[/math] = fraction of infected mosquitoes that survive to become infectious

[math]\displaystyle{ r }[/math] = recovery rate of human

• 迅速診断迅速治療開始
• 適切な治療
• 無症候性感染者の発見と治療

【整理すると】

• anti-mosquite
• drugs
• diagnostic
• treatment
• economical development

Prophylaxis

• ABCD of malaria prophylaxis
  • Awareness
  • Bite protection
  • Chemoprophylaxis
  • Diagnosis and treatment

• atovaquone/proguanil
  • effective for both of liver stage and blood stage
  • needs 1 week continuation after leaving endemic area
• mefloquine, doxycycline
  • effective only in blood stage
  • needs 4 weeks continuation after leaving endemic area

Malaria immunology

Reasons why immunity against Plasmodium needs repetitive infections

• Genetic heterogeneity of Plasmodium
• Modulation of host immune responses by Plasmodium

Candidate antigens for malaria vaccine

• Radiation-attenuated sporozoite (RAS)
• Genetically-attenuated sporozoite (GAS)
  • Sap 1: early arresting
  • Fabb/f: late arresting
• Circumsporozoite protein (CSP)

IASR 2022年6月

Proteins on RBC knobs

• Surface proteins on trophozoite-infected RBC
  • PfEMP-1
    • binds adhesion molecules on brain endotherial cells = sequestration
      • ICAM-1, VCAM-1, CD36
    • only in ring form in blood
  • RIFINs
  • STAVOR

Vaccine

• Successful passive immunization
  • Injection of malaria-immune IgG
  • Cohen, Nature 12:733, 1961

• Successful live attenuated vaccine
  • Radiation-attenuated sporozoite (RAS) vaccine
  • sporozoite was deleted for propagation ability in human liver
  • Hoffman, 2002, JID 185:1155

human liver	pre-erythrocytic vaccine anti-infection	RTS, S/AS01
human RBC	asexual blood-stage vaccine anti-disease	BK-SE36 Rh5 PfRipr MSP1-withdrawn AMA1-withdrawn MSP3-withdrawn GLURP-withdrawn
mosquito mid-gut	transmission-blocking vaccine anti-transmission	Pfs25/Pvs25 Pfs230

RTS, S/AS01

• antigen: circumsporozoite protein (CSP)
• adjuvant: AS01
• 4 doses
• phase 3
  • efficacy: infant 26%, children 36%
  • Lancet. 2015;386(9988):31-45
• WHO Malaria Vaccine Implementation Programme (MVIP) is ongoing
  • Kenya, Ghana, Malawi
• efficacy wanes in time
  • anti-CSP Ab titers wane
  • White, Lancet Inf. Dis., 2015;15(12)1450-8

AMA1-withdrawn

• no efficacy for overall
• ad hoc analysis: 64.3% efficacy against a specific Plasmodium polymorphism, AMA1 3D7 DNA sequence
  • clinically meaningless because of many polymorphism

Pvs25-withdrawn

• antigen: Pvs25H expressed in S. cerevisiae
• adjuvant: alhydrogel, ISA51
  • not enough antibody induction or serious side effects at phase 1

Wheat Germ Cell-Free Protein Synthesis System (WGCFS)

• to extract ribosome, tRNA, TFs from germ （胚芽） of wheat
  • WGCFS is optimal recombinant protein synthesis system for Plasmodium proteins, much better than utilization of E. coli
• Immunoscreening against Plasmodium and recombinant target protein as antigen

Potential of transmission-blocking vaccine

• 被接種者個人の感染は予防されないため，TBV単独でのphase 3は原理的に困難．やるとしたら複数の村をincorporateしての大規模なcluster-randomizationを行い，村間に蚊が飛んでいかない程度の境界域も設けて，数年～10年単位で疫学的に観察する必要があり，およそ現実的ではない．
• よってTBVはphase 2までが現実的で，その後は他の直接的な感染防止策が確立された時点でcombine methodとして地域単位で接種してtransmissionの減少を観察するという phase 4 が必要．

Clinical feature

severe malaria

• cerebral malaria
• AKI, acute renal failure
  • "black water fever", mechanism unknown
    • treatment with quinine is associated with black water fever
• jaundice
• acidosis
• ARDS
• DIC, less common
• purpura fulminans, due to coagulation abnormality; rare condition

• mortality due to falciparum increases according to age

Diagnosis

• increase likelihood in imported cases
  • fever>39℃
  • splenomegaly
  • low platelet count
• decrease likelihood in imported cases

suspected cerebral malaria

• first check blood glucose
  • Plasmodium consume blood glucose and quinine induce insulin secretion
• there is no definitive diagnosis for cerebral malaria, only clinical diagnosis
• pathogenesis of cerebral malaria is still unknown

microscopy

• Comparison of Plasmodium Species Which Cause Malaria in Humans

Treatment

• Quinine [ku-wai-na-in]

arteminisin-based combination therapy

• to reduce parasites by rapid-acting arteminisin
• to prevent recrudescence and drug resistance by lumefantrine or others

• arteminisin resistant around Thailand-Myanmar border and Thailand-Cambodia border

• IV forumulations for severe malarial patients who have difficulty in PO administration
  • IV artesunate is more effective than IV quinine
    • IV artesunate is unavailable in Japan

clinical classification of malaria

malaria	severe
	uncomplicated	falciparum
		non-falciparum

• no specific additional treatment for cerebral malaria other than usual malaria treatment, nothing proved effective