疟疾疫苗研制及其存在的问题

doi:10.12140/j.issn.1000-7423.2021.03.001

摘要/Abstract

摘要：

历史上,传染病的最终控制和消除均得益于有效疫苗的接种。60多年来,研究者们一直致力于有效疟疾疫苗的研制。近年来,亚单位疟疾疫苗RTS,S和减毒子孢子疫苗的临床试验效果使研究者们看到了研制安全、有效疟疾疫苗的希望。然而,有效疟疾疫苗的最终研制成功还存在诸多的技术问题和理论瓶颈。本文从疟原虫的生物学及其感染免疫学特点角度对目前疟疾疫苗研制过程中所面临的问题进行分析,以期为有效疟疾疫苗的最终研制成功提供参考和努力的方向。

关键词: 疟疾, 疫苗, 红外期, 红内期, 蚊期

Abstract:

Historically, the ultimate control and elimination of infectious diseases were all attributed to the inoculation of vaccines. For more than 60 years, scientists have never stopped their efforts on developing effective malaria vaccines. Recently, clinical trials on subunit vaccine RTS,S and attenuated sporozoite vaccine have shedded light on production of a safe and effective malaria vaccines. However, there are still many technical and theoretical bottlenecks that hinder the final development of effective malaria vaccine. In this paper, we analyze the problems currently encountered in the malaria vaccine development process from the view point of biological and immunological characteristics ofPlasmodium spp., in the hope to provide clues and directions for the ultimate development of effective malaria vaccines.

Key words: Malaria, Vaccine, Pre-erythrocytic stage, Erythrocytic stage, Mosquito stage

中图分类号:

R531.3

陈穗林, 刘太平, 徐文岳. 疟疾疫苗研制及其存在的问题[J]. 中国寄生虫学与寄生虫病杂志, 2021, 39(3): 283-295.

CHEN Sui-lin, LIU Tai-ping, XU Wen-yue. Development of malaria vaccines and the challenges[J]. Chinese Journal of Parasitology and Parasitic Diseases, 2021, 39(3): 283-295.

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参考文献 122

[1]	O’Meara WP, Mangeni JN, Steketee R, et al. Changes in the burden of malaria in sub-Saharan Africa[J]. Lancet Infect Dis, 2010,10(8):545-555.
[2]	Phyo AP, Nkhoma S, Stepniewska K, et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study[J]. Lancet, 2012,379(9830):1960-1966.
[3]	Uwimana A, Legrand E, Stokes BH, et al. Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda[J]. Nat Med, 2020,26(10):1602-1608.
[4]	Ranson H, N’Guessan R, Lines J, et al. Pyrethroid resistance in African anopheline mosquitoes: what are the implications for malaria control?[J]Trends Parasitol, 2011,27(2):91-98.
[5]	Dai LP, Gao GF. Viral targets for vaccines against COVID-19[J]. Nat Rev Immunol, 2021,21(2):73-82.
[6]	Nussenzweig RS, Vanderberg J, Most H, et al. Protective immunity produced by the injection of X-irradiated sporozoites of Plasmodium berghei[J]. Nature, 1967,216(5111):160-162.
[7]	Duffy PE, Patrick Gorres J. Malaria vaccines since 2000: progress, priorities, products[J]. NPJ Vaccines, 2020,5(1):48.
[8]	Epstein JE, Tewari K, Lyke KE, et al. Live attenuated malaria vaccine designed to protect through hepatic CD8 T cell immunity[J]. Science, 2011,334(6055):475-480.
[9]	Seder RA, Chang LJ, Enama ME, et al. Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine[J]. Science, 2013,341(6152):1359-1365.
[10]	Lyke KE, Ishizuka AS, Berry AA, et al. Attenuated PfSPZ vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection[J]. Proc Natl Acad Sci USA, 2017,114(10):2711-2716.
[11]	Ishizuka AS, Lyke KE, DeZure A, et al. Protection against malaria at 1 year and immune correlates following PfSPZ vaccination[J]. Nat Med, 2016,22(6):614-623.
[12]	Sissoko MS, Healy SA, Katile A, et al. Safety and efficacy of PfSPZ Vaccine against Plasmodium falciparum via direct venous inoculation in healthy malaria-exposed adults in Mali: a randomised, double-blind phase 1 trial[J]. Lancet Infect Dis, 2017,17(5):498-509.
[13]	WHO. Malaria vaccine technology roadmap[R]. Geneva: WHO, 2013.
[14]	Gordon DM, McGovern TW, Krzych U, et al. Safety, immunogenicity, and efficacy of a recombinantly produced Plasmodium falciparum circumsporozoite protein-hepatitis B surface antigen subunit vaccine[J]. J Infect Dis, 1995,171(6):1576-1585.
[15]	Bejon P, White MT, Olotu A, et al. Efficacy of RTS,S malaria vaccines: individual-participant pooled analysis of phase 2 data[J]. Lancet Infect Dis, 2013,13(4):319-327.
[16]	RTS, S Clinical Trials Partnership, Agnandji ST, Lell B, et al. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children[J]. N Engl J Med, 2011,365(20):1863-1875.
[17]	RTS, S Clinical Trials Partnership, Agnandji ST, Lell B, et al. A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants[J]. N Engl J Med, 2012,367(24):2284-2295.
[18]	TS, S Clinical Trials Partnership. Efficacy and safety of the RTS,S/AS01 malaria vaccine during 18 months after vaccination: a phase 3 randomized, controlled trial in children and young infants at 11 African sites[J]. PLoS Med, 2014,11(7):e1001685.
[19]	TS, S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial[J]. Lancet, 2015,386(9988):31-45.
[20]	Keating C. The history of the RTS, S/AS01 malaria vaccine trial[J]. Lancet, 2020,395(10233):1336-1337.
[21]	Collins KA, Snaith R, Cottingham MG, et al. Enhancing protective immunity to malaria with a highly immunogenic virus-like particle vaccine[J]. Sci Rep, 2017,7:46621.
[22]	Ewer KJ, O’Hara GA, Duncan CJ, et al. Protective CD8⁺ T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation[J]. Nat Commun, 2013,4:2836.
[23]	Ogwang C, Kimani D, Edwards NJ, et al. Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults[J]. Sci Transl Med, 2015,7(286): 286re5.
[24]	Mensah VA, Gueye A, Ndiaye M, et al. Safety, immunogenicity and efficacy of prime-boost vaccination with ChAd63 and MVA encoding ME-TRAP againstPlasmodium falciparum infection in adults in Senegal[J]. PLoS One, 2016,11(12):e0167951.
[25]	Mueller AK, Labaied M, Kappe SH, et al. Genetically modified Plasmodium parasites as a protective experimental malaria vaccine[J]. Nature, 2005,433(7022):164-167.
[26]	Roestenberg M, McCall M, Hopman J, et al. Protection against a malaria challenge by sporozoite inoculation[J]. N Engl J Med, 2009,361(5):468-477.
[27]	Roestenberg M, Teirlinck AC, McCall MB, et al. Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study[J]. Lancet, 2011,377(9779):1770-1776.
[28]	Ocaña-Morgner C, Mota MM, Rodriguez A. Malaria blood stage suppression of liver stage immunity by dendritic cells[J]. J Exp Med, 2003,197(2):143-151.
[29]	Keitany GJ, Kim KS, Krishnamurty AT, et al. Blood stage malaria disrupts humoral immunity to the pre-erythrocytic stage circumsporozoite protein[J]. Cell Rep, 2016,17(12):3193-3205.
[30]	Luke TC, Hoffman SL. Rationale and plans for developing a non-replicating, metabolically active, radiation-attenuatedPlasmodium falciparum sporozoite vaccine[J]. J Exp Biol, 2003,206(Pt 21):3803-3808.
[31]	Butler NS, Schmidt NW, Vaughan AM, et al. Superior antimalarial immunity after vaccination with late liver stage-arresting genetically attenuated parasites[J]. Cell Host Microbe, 2011,9(6):451-462.
[32]	Steinhardt LC, Richie TL, Yego R, et al. Safety, tolerability, and immunogenicity of Plasmodium falciparum sporozoite vaccine administered by direct venous inoculation to infants and young children: findings from an age de-escalation, dose-escalation, double-blind, randomized controlled study in western Kenya[J]. Clin Infect Dis, 2020,71(4):1063-1071.
[33]	Cohen S, McGregor IA, Carrington S. Gamma-globulin and acquired immunity to human malaria[J]. Nature, 1961,192:733-737.
[34]	Sabchareon A, Burnouf T, Ouattara D, et al. Parasitologic and clinical human response to immunoglobulin administration in falciparum malaria[J]. Am J Trop Med Hyg, 1991,45(3):297-308.
[35]	Laurens MB. The promise of a malaria vaccine: are we closer?[J]. Annu Rev Microbiol, 2018,72:273-292.
[36]	Ogutu BR, Apollo OJ, McKinney D, et al. Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya[J]. PLoS One, 2009,4(3):e4708.
[37]	Sagara I, Dicko A, Ellis RD, et al. A randomized controlled phase 2 trial of the blood stage AMA1-C1/alhydrogel malaria vaccine in children in Mali[J]. Vaccine, 2009,27(23):3090-3098.
[38]	Sirima SB, Cousens S, Druilhe P. Protection against malaria by MSP3 candidate vaccine[J]. N Engl J Med, 2011,365(11):1062-1064.
[39]	Wright KE, Hjerrild KA, Bartlett J, et al. Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies[J]. Nature, 2014,515(7527):427-430.
[40]	Douglas AD, Baldeviano GC, Lucas CM, et al. A PfRH5-based vaccine is efficacious against heterologous strain blood-stage Plasmodium falciparum infection in Aotus monkeys[J]. Cell Host Microbe, 2015,17(1):130-139.
[41]	Pombo DJ, Lawrence G, Hirunpetcharat C, et al. Immunity to malaria after administration of ultra-low doses of red cells infected with Plasmodium falciparum[J]. Lancet, 2002,360(9333):610-617.
[42]	Elliott SR, Kuns RD, Good MF. Heterologous immunity in the absence of variant-specific antibodies after exposure to subpatent infection with blood-stage malaria[J]. Infect Immun, 2005,73(4):2478-2485.
[43]	Liu TP, Xu GL, Guo B, et al. An essential role for C5aR signaling in the optimal induction of a malaria-specific CD4⁺ T cell response by a whole-killed blood-stage vaccine[J]. J Immunol, 2013,191(1):178-186.
[44]	Good MF. A whole parasite vaccine to control the blood stages of Plasmodium: the case for lateral thinking[J]. Trends Parasitol, 2011,27(8):335-340.
[45]	Pinzon-Charry A, McPhun V, Kienzle V, et al. Low doses of killed parasite in CpG elicit vigorous CD4⁺ T cell responses against blood-stage malaria in mice[J]. J Clin Invest, 2010,120(8):2967-2978.
[46]	Aly AS, Downie MJ, Mamoun CB, et al. Subpatent infection with nucleoside transporter 1-deficient Plasmodium blood stage parasites confers sterile protection against lethal malaria in mice[J]. Cell Microbiol, 2010,12(7):930-938.
[47]	Ting LM, Gissot M, Coppi A, et al. Attenuated Plasmodium yoelii lacking purine nucleoside phosphorylase confer protective immunity[J]. Nat Med, 2008,14(9):954-958.
[48]	Demarta-Gatsi C, Smith L, Thiberge S, et al. Protection against malaria in mice is induced by blood stage-arresting histamine-releasing factor (HRF)-deficient parasites[J]. J Exp Med, 2016,213(8):1419-1428.
[49]	Good MF, Reiman JM, Rodriguez IB, et al. Cross-species malaria immunity induced by chemically attenuated parasites[J]. J Clin Invest, 2013,123(8):3353-3362.
[50]	Stanisic DI, Fink J, Mayer J, et al. Vaccination with chemically attenuated Plasmodium falciparum asexual blood-stage parasites induces parasite-specific cellular immune responses in malaria-naïve volunteers: a pilot study[J]. BMC Med, 2018,16(1):184.
[51]	Low LM, Ssemaganda A, Liu XQ, et al. Controlled infection immunization using delayed death drug treatment elicits protective immune responses to blood-stage malaria parasites[J]. Infect Immun, 2019,87(1):e00587-e00518.
[52]	Raja AI, Cai YP, Reiman JM, et al. Chemically attenuated blood-stage Plasmodium yoelii parasites induce long-lived and strain-transcending protection[J]. Infect Immun, 2016,84(8):2274-2288.
[53]	Coelho CH, Rappuoli R, Hotez PJ, et al. Transmission-blocking vaccines for malaria: time to talk about vaccine introduction[J]. Trends Parasitol, 2019,35(7):483-486.
[54]	Gardner MJ, Hall N, Fung E, et al. Genome sequence of the human malaria parasite Plasmodium falciparum[J]. Nature, 2002,419(6906):498-511.
[55]	Al-Olayan EM, Beetsma AL, Butcher GA, et al. Complete development of mosquito phases of the malaria parasite in vitro[J]. Science, 2002,295(5555):677-679.
[56]	Bao LL, Deng W, Huang BY, et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice[J]. Nature, 2020,583(7818):830-833.
[57]	Kaushansky A, Kappe SH. Selection and refinement: the malaria parasite’s infection and exploitation of host hepatocytes[J]. Curr Opin Microbiol, 2015,26:71-78.
[58]	Cowman AF, Tonkin CJ, Tham WH, et al. The molecular basis of erythrocyte invasion by malaria parasites[J]. Cell Host Microbe, 2017,22(2):232-245.
[59]	Raja AI, Stanisic DI, Good MF. Chemical attenuation in the development of a whole-organism malaria vaccine[J]. Infect Immun, 2017,85(7):e00062-17.
[60]	Tran TM, Li SP, Doumbo S, et al. An intensive longitudinal cohort study of Malian children and adults reveals no evidence of acquired immunity to Plasmodium falciparum infection[J]. Clin Infect Dis, 2013,57(1):40-47.
[61]	Sagara I, Sangaré D, Dolo G, et al. A high malaria reinfection rate in children and young adults living under a low entomological inoculation rate in a periurban area of Bamako, Mali[J]. Am J Trop Med Hyg, 2002,66(3):310-313.
[62]	Hoffman SL, Goh LM, Luke TC, et al. Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites[J]. J Infect Dis, 2002,185(8):1155-1164.
[63]	Seder RA, Chang LJ, Enama ME, et al. Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine[J]. Science, 2013,341(6152):1359-1365.
[64]	Chakravarty S, Baldeviano GC, Overstreet MG, et al. Effector CD8⁺ T lymphocytes against liver stages of Plasmodium yoelii do not require gamma interferon for antiparasite activity[J]. Infect Immun, 2008,76(8):3628-3631.
[65]	Fernandez-Ruiz D, Ng WY, Holz LE, et al. Liver-resident memory CD8⁺ T cells form a front-line defense against malaria liver-stage infection[J]. Immunity, 2019,45(4):889-902.
[66]	Olsen TM, Stone BC, Chuenchob V, et al. Prime-and-trap malaria vaccination to generate protective CD8⁺ liver-resident memory T cells[J]. J Immunol, 2018,201(7):1984-1993.
[67]	Gola A, Silman D, Walters AA, et al. Prime and target immunization protects against liver-stage malaria in mice[J]. Sci Transl Med, 2018,10(460):eaap9128.
[68]	Foquet L, Hermsen CC, van Gemert GJ, et al. Vaccine-induced monoclonal antibodies targeting circumsporozoite protein prevent Plasmodium falciparum infection[J]. J Clin Invest, 2014,124(1):140-144.
[69]	White MT, Bejon P, Olotu A, et al. The relationship between RTS, S vaccine-induced antibodies, CD4⁺ T cell responses and protection againstPlasmodium falciparum infection[J]. PLoS One, 2013,8(4):e61395.
[70]	Aliprandini E, Tavares J, Panatieri RH, et al. Cytotoxic anti-circumsporozoite antibodies target malaria sporozoites in the host skin[J]. Nat Microbiol, 2018,3(11):1224-1233.
[71]	Wang LT, Pereira LS, Flores-Garcia Y, et al. A potent anti-malarial human monoclonal antibody targets circumsporozoite protein minor repeats and neutralizes sporozoites in the liver[J]. Immunity, 2020,53(4):733-744.
[72]	Feng GQ, Wines BD, Kurtovic L, et al. Mechanisms and targets of Fcγ-receptor mediated immunity to malaria sporozoites[J]. Nat Commun, 2021,12(1):1742.
[73]	Chakravarty S, Cockburn IA, Kuk S, et al. CD8⁺ T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes[J]. Nat Med, 2007,13(9):1035-1041.
[74]	Overstreet MG, Cockburn IA, Chen YC, et al. Protective CD8 T cells against Plasmodium liver stages: immunobiology of an ‘unnatural’ immune response[J]. Immunol Rev, 2008,225:272-283.
[75]	Kurup SP, Anthony SM, Hancox LS, et al. Monocyte-derived CD11c⁺ cells acquire Plasmodium from hepatocytes to prime CD8 T cell immunity to liver-stage malaria[J]. Cell Host Microbe, 2019,25(4):565-577.e6.
[76]	Carvalho LH, Sano G, Hafalla JC, et al. IL-4-secreting CD4⁺ T cells are crucial to the development of CD8⁺ T-cell responses against malaria liver stages[J]. Nat Med, 2002,8(2):166-170.
[77]	Overstreet MG, Chen YC, Cockburn IA, et al. CD4⁺ T cells modulate expansion and survival but not functional properties of effector and memory CD8⁺ T cells induced by malaria sporozoites[J]. PLoS One, 2011,6(1):e15948.
[78]	Zaidi I, Diallo H, Conteh S, et al. gammadelta T cells are required for the induction of sterile immunity during irradiated sporozoite vaccinations[J]. J Immunol, 2017,199(11):3781-3788.
[79]	Minkah NK, Wilder BK, Sheikh AA, et al. Innate immunity limits protective adaptive immune responses against pre-erythrocytic malaria parasites[J]. Nat Commun, 2019,10(1):3950.
[80]	Kisalu NK, Idris AH, Weidle C, et al. A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite[J]. Nat Med, 2018,24(4):408-416.
[81]	Tan J, Sack BK, Oyen D, et al. A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein[J]. Nat Med, 2018,24(4):401-407.
[82]	Cawlfield A, Genito CJ, Beck Z, et al. Safety, toxicity and immunogenicity of a malaria vaccine based on the circumsporozoite protein (FMP013) with the adjuvant army liposome formulation containing QS21 (ALFQ)[J]. Vaccine, 2019,37(29):3793-3803.
[83]	Good MF, Xu HJ, Wykes M, et al. Development and regulation of cell-mediated immune responses to the blood stages of malaria: implications for vaccine research[J]. Annu Rev Immunol, 2005,23:69-99.
[84]	Julien JP, Wardemann H. Antibodies against Plasmodium falciparum malaria at the molecular level[J]. Nat Rev Immunol, 2019,19(12):761-775.
[85]	Kurup SP, Butler NS, Harty JT. T cell-mediated immunity to malaria[J]. Nat Rev Immunol, 2019,19(7):457-471.
[86]	Zander RA, Vijay R, Pack AD, et al. Th1-like Plasmodium-specific memory CD4⁺ T cells support humoral immunity[J]. Cell Rep, 2018,23(4):1230-1237.
[87]	Junqueira C, Barbosa CRR, Costa PAC, et al. Cytotoxic CD8⁺ T cells recognize and kill Plasmodium vivax-infected reticulocytes[J]. Nat Med, 2018,24(9):1330-1336.
[88]	Voisine C, Mastelic B, Sponaas AM, et al. Classical CD11c+ dendritic cells, not plasmacytoid dendritic cells, induce T cell responses to Plasmodium chabaudi malaria[J]. Int J Parasitol, 2010,40(6):711-719.
[89]	Guermonprez P, Helft J, Claser C, et al. Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection[J]. Nat Med, 2013,19(6):730-738.
[90]	Coban C, Igari Y, Yagi M, et al. Immunogenicity of whole-parasite vaccines against Plasmodium falciparum involves malarial hemozoin and host TLR9[J]. Cell Host Microbe, 2010,7(1):50-61.
[91]	Acquah FK, Adjah J, Williamson KC, et al. Transmission-blocking vaccines: old friends and new prospects[J]. Infect Immun, 2019,87(6):e00775-e00718.
[92]	Simon N, Lasonder E, Scheuermayer M, et al. Malaria parasites co-opt human factor H to prevent complement-mediated lysis in the mosquito midgut[J]. Cell Host Microbe, 2013,13(1):29-41.
[93]	Zhu F, Liu TP, Zhao CH, et al. Whole-killed blood-stage vaccine-induced immunity suppresses the development of malaria parasites in mosquitoes[J]. J Immunol, 2017,198(1):300-307.
[94]	Noland GS, Chowdhury DR, Urban JF Jr, et al. Helminth infection impairs the immunogenicity of a Plasmodium falciparum DNA vaccine, but not irradiated sporozoites, in mice[J]. Vaccine, 2010,28(17):2917-2923.
[95]	Sokhna CS, Faye FBK, Spiegel A, et al. Rapid reappearance of Plasmodium falciparum after drug treatment among Senegalese adults exposed to moderate seasonal transmission[J]. Am J Trop Med Hyg, 2001,65(3):167-170.
[96]	Boutlis CS, Yeo TW, Anstey NM. Malaria tolerance: for whom the cell tolls?[J]. Trends Parasitol, 2006,22(8):371-377.
[97]	Wahlgren M, Goel S, Akhouri RR. Variant surface antigens of Plasmodium falciparum and their roles in severe malaria[J]. Nat Rev Microbiol, 2017,15(8):479-491.
[98]	Chookajorn T, Ponsuwanna P, Cui L. Mutually exclusive var gene expression in the malaria parasite: multiple layers of regulation[J]. Trends Parasitol, 2008,24(10):455-461.
[99]	Woodberry T, Minigo G, Piera KA, et al. Low-level Plasmodium falciparum blood-stage infection causes dendritic cell apoptosis and dysfunction in healthy volunteers[J]. J Infect Dis, 2012,206(3):333-340.
[100]	Pinzon-Charry A, Woodberry T, Kienzle V, et al. Apoptosis and dysfunction of blood dendritic cells in patients with falciparum and vivax malaria[J]. J Exp Med, 2013,210(8):1635-1646.
[101]	Wilson NS, Behrens GM, Lundie RJ, et al. Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity[J]. Nat Immunol, 2006,7(2):165-172.
[102]	Urban BC, Willcox N, Roberts DJ. A role for CD36 in the regulation of dendritic cell function[J]. Proc Natl Acad Sci USA, 2001,98(15):8750-8755.
[103]	Haque A, Best SE, Montes de Oca M, et al. Type Ⅰ IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity[J]. J Clin Invest, 2014,124(6):2483-2496.
[104]	Montes de Oca M, Kumar R, Rivera FL, et al. Type Ⅰ interferons regulate immune responses in humans with blood-stage Plasmodium falciparum infection[J]. Cell Rep, 2016,17(2):399-412.
[105]	Kimura D, Miyakoda M, Kimura K, et al. Interleukin-27-producing CD4⁺ T cells regulate protective immunity during malaria parasite infection[J]. Immunity, 2016,44(3):672-682.
[106]	Walther M, Tongren JE, Andrews L, et al. Upregulation of TGF-beta, FOXP3, and CD4⁺CD25⁺ regulatory T cells correlates with more rapid parasite growth in human malaria infection[J]. Immunity, 2005,23(3):287-296.
[107]	Kurup SP, Obeng-Adjei N, Anthony SM, et al. Regulatory T cells impede acute and long-term immunity to blood-stage malaria through CTLA-4[J]. Nat Med, 2017,23(10):1220-1225.
[108]	Illingworth J, Butler NS, Roetynck S, et al. Chronic exposure to Plasmodium falciparum is associated with phenotypic evidence of B and T cell exhaustion[J]. J Immunol, 2013,190(3):1038-1047.
[109]	Horne-Debets JM, Faleiro R, Karunarathne DS, et al. PD-1 dependent exhaustion of CD8⁺ T cells drives chronic malaria[J]. Cell Rep, 2013,5(5):1204-1213.
[110]	Cai JJ, Chen SL, Zhu F, et al. Whole-killed blood-stage vaccine: is it worthwhile to further develop it to control malaria?[J]. Front Microbiol, 2021,12:670775.
[111]	Weiss GE, Crompton PD, Li SP, et al. Atypical memory B cells are greatly expanded in individuals living in a malaria-endemic area[J]. J Immunol, 2009,183(3):2176-2182.
[112]	Muellenbeck MF, Ueberheide B, Amulic B, et al. Atypical and classical memory B cells produce Plasmodium falciparumneutralizing antibodies[J]. J Exp Med, 2013,210(2):389-399.
[113]	Portugal S, Tipton CM, Sohn H, et al. Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function[J]. Elife, 2015,4:e07218.
[114]	Sullivan RT, Kim CC, Fontana MF, et al. FCRL5 delineates functionally impaired memory B cells associated with Plasmodium falciparum exposure[J]. PLoS Pathog, 2015,11(5):e1004894.
[115]	Obeng-Adjei N, Portugal S, Holla P, et al. Malaria-induced interferon-γ drives the expansion of Tbethi atypical memory B cells[J]. PLoS Pathog, 2017,13(9):e1006576.
[116]	Rodda LB, Pepper M. Metabolic constraints on the B cell response to malaria[J]. Nat Immunol, 2020,21(7):722-724.
[117]	Vijay R, Guthmiller JJ, Sturtz AJ, et al. Infection-induced plasmablasts are a nutrient sink that impairs humoral immunity to malaria[J]. Nat Immunol, 2020,21(7):790-801.
[118]	Hirunpetcharat C, Good MF. Deletion of Plasmodium berghei-specific CD4⁺ T cells adoptively transferred into recipient mice after challenge with homologous parasite[J]. Proc Natl Acad Sci USA, 1998,95(4):1715-1720.
[119]	Wipasa J, Xu H, Stowers A, et al. Apoptotic deletion of Th cells specific for the 19-kDa carboxyl-terminal fragment of merozoite surface protein 1 during malaria infection[J]. J Immunol, 2001,167(7):3903-3909.
[120]	Xu HJ, Wipasa J, Yan HR, et al. The mechanism and significance of deletion of parasite-specific CD4⁺ T cells in malaria infection[J]. J Exp Med, 2002,195(7):881-892.
[121]	Wykes MN, Zhou YH, Liu XQ, et al. Plasmodium yoelii can ablate vaccine-induced long-term protection in mice[J]. J Immunol, 2005,175(4):2510-2516.
[122]	Pardi N, Hogan MJ, Weissman D. Recent advances in mRNA vaccine technology[J]. Curr Opin Immunol, 2020,65:14-20.

候选疫苗	免疫原类型	当前状态	作用原理	临床试验结果（人体）
红外期疫苗
RTS,S	亚单位	Ⅲ期临床试验	特异性抗体	30%~50%保护效率
R21	亚单位	Ⅱ期临床试验	特异性抗体	74%~77%保护效率
CSP全长	亚单位	Ⅰ期临床试验	特异性抗体	-
辐照减毒子孢子	全虫	Ⅱ期临床试验	特异性抗体和CD4/CD8⁺ T细胞	-
化学减毒子孢子	全虫	Ⅱ期临床试验	特异性抗体和CD4/CD8⁺ T细胞	55%保护效率
遗传减毒子孢子	全虫	Ⅰ期临床试验	特异性抗体和CD4/CD8⁺ T细胞	-
红内期疫苗
PfRH5	亚单位	Ⅰ期临床试验	特异性抗体	-
化学减毒红内期全虫疫苗	全虫	Ⅰ期临床试验	CD3⁺ T细胞	-
蚊期
Pfs25	亚单位	Ⅰ期临床试验	特异性抗体	-
Pfs230	亚单位	Ⅱ期临床试验	特异性抗体	-