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*===Human blood stage===
*===Mosquito stage===
<math>a</math> =
*
<math>b_1</math> = ==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
<math>b_2</math> ===microscopy=== *[https://www.mcdinternational.org/trainings/malaria/english/DPDx5/HTML/Frames/M-R/Malaria/body_Malariadiagfind2 Comparison of Plasmodium Species Which Cause Malaria in Humans]
<math>e</math> ==Treatment== *Quinine [ku-'''wai'''-na-in]
<math>μ</math> = ==arteminisin-based combination therapy===*to reduce parasites by rapid-acting arteminisin*to prevent recrudescence and drug resistance by lumefantrine or others
<math>T</math> =
*
<math>r</math> = *arteminisin resistant around Thailand-Myanmar border and Thailand-Cambodia border
==症状==*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
==治療==*no specific additional treatment for cerebral malaria other than usual malaria treatment, nothing proved effective
→Vaccine
{{TM menu}} ==歴史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
*1948年 P.C.C. Graham が初めてヒト肝細胞への感染を発見
==病原体=Malaria in Yaeyama, Okinawa, Japan===*[https://storymaps.arcgis.com/collections/b8f0dcc7c52746e8837e9aecb1833db0 Malaria History in Yaeyama War Malaria & Malaria Elimination (in 4 languages)]*[https://www.amazon.co.jp/gp/product/4901427261/ 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==*[https://www.youtube.com/watch?v=1v55yg0RfoY YouTube: Malaria Lifecycle Part 1]*[https://www.youtube.com/watch?v=MxiWp8vkRFI 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===#sprozoite→schizont#schizont#hypnozoite only by ''P. vivax'' and ''P. ovale''
#merozoite
#trophozoite
##gametocyte
###male/female
#gametocyte
#macrogametocyte
#sporozoite
#Re-infection#Recrudescence##insufficient treatment##drug resistant##antigenic drift of ''Plasmodium'' inside human during one single infection###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．###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#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 ==疫学Epidemiology==
in 2017
*219mil. per year ←500mil. 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===
*[https://www.who.int/news/item/30-06-2021-from-30-million-cases-to-zero-china-is-certified-malaria-free-by-who From 30 million cases to zero: China is certified malaria-free by WHO]
==Vector==
**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>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>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>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>e</math> = 自然対数（ネイピア数）
<math>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>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>e^{-μT}</math> = fraction of infected mosquitoes that survive to become infectious
<math>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)
[https://www.niid.go.jp/niid/ja/typhi-m/iasr-reference/2566-related-articles/related-articles-508/11207-508r08.html 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
{|class="wikitable"
|-
!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
==='''W'''heat '''G'''erm '''C'''ell-'''F'''ree Protein Synthesis '''S'''ystem (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
**
==検査=clinical classification of malaria==={|class="wikitable"|-!rowspan="3"|malaria|colspan="2"|severe|-|rowspan="2"|uncomplicated|falciparum|-|non-falciparum|}
==予後Prognosis==
