Establishment of an evaluation model for <italic style="font-style: italic">Plasmodium falciparum</italic> circumsporozoite protein  vaccines  using   MHC-Ⅰ   humanized  mice  and  transgenic  plasmodium: Effective antibody responses but limited CD8⁺ T-cell responses

LI Teyang; JIAO Shiming; TAN Nie; DING Yan; LIU Taiping; XU Wenyue

doi:10.16016/j.2097-0927.202512046

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Establishment of an evaluation model for Plasmodium falciparum circumsporozoite protein vaccines using MHC-Ⅰ humanized mice and transgenic plasmodium: Effective antibody responses but limited CD8⁺ T-cell responses

Basic Medicine | 更新时间：2026-02-23

- Establishment of an evaluation model for Plasmodium falciparum circumsporozoite protein vaccines using MHC-Ⅰ humanized mice and transgenic plasmodium: Effective antibody responses but limited CD8⁺ T-cell responses
- Journal of Army Medical University Vol. 48, Issue 3, Pages: 283-293(2026)
- 作者机构：
  
  陆军军医大学（第三军医大学）基础医学院病原生物学教研室，重庆
- 作者简介：
  
  XU Wenyue， E-mail：xuwenyue@tmmu.edu.cn
- 基金信息：
  
  the National Key Research and Development Program of China(2024YFC2309700)
- DOI：10.16016/j.2097-0927.202512046
  CLC： R-332;R392.7;R531.3
- Received：09 December 2025，
  
  Revised：2026-01-12，
  
  Accepted：14 January 2026，
  
  Published：15 February 2026
- 稿件说明：
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李特阳，焦世铭，谭涅，等.利用MHC-Ⅰ人源化小鼠与转基因疟原虫建立恶性疟原虫环子孢子蛋白疫苗评价模型：抗体应答有效而CD8⁺ T细胞应答受限［J］.陆军军医大学学报，2026，48（03）：283-293.DOI：10.16016/j.2097-0927.202512046.

LI T Y，JIAO S M，TAN N，et al.Establishment of an evaluation model for Plasmodium falciparum circumsporozoite protein vaccines using MHC-Ⅰ humanized mice and transgenic plasmodium： Effective antibody responses but limited CD8⁺ T-cell responses［J］.J Army Med Univ，2026，48（03）：283-293.DOI：10.16016/j.2097-0927.202512046.
李特阳，焦世铭，谭涅，等.利用MHC-Ⅰ人源化小鼠与转基因疟原虫建立恶性疟原虫环子孢子蛋白疫苗评价模型：抗体应答有效而CD8⁺ T细胞应答受限［J］.陆军军医大学学报，2026，48（03）：283-293.DOI：10.16016/j.2097-0927.202512046. DOI：

LI T Y，JIAO S M，TAN N，et al.Establishment of an evaluation model for Plasmodium falciparum circumsporozoite protein vaccines using MHC-Ⅰ humanized mice and transgenic plasmodium： Effective antibody responses but limited CD8⁺ T-cell responses［J］.J Army Med Univ，2026，48（03）：283-293.DOI：10.16016/j.2097-0927.202512046. DOI：

摘要

目的

探究利用MHC-I类分子人源化小鼠（AAD小鼠）和表达恶性疟原虫（

Plasmodium falciparum

，

）环子孢子蛋白（circumsporozoite protein， CSP）的转基因伯氏疟原虫虫株（

CSP）建立并评估

CSP疫苗效果评价模型。

方法

采用尾静脉定量攻击不同剂量（200、500、1 000条）

Pb-Pf

CSP子孢子与野生疟原虫（

P.berghei

，

）子孢子，观察其能否感染两种不同小鼠（C57BL/6J和AAD小鼠，6~8周龄，体质量为20~35 g），每组4只。同时通过检测AAD与C57BL/6J小鼠原虫血症出现时间及原虫率变化情况，比较两种小鼠分别对

和

CSP的易感性。采用流式细胞术比较分析两种小鼠肝脏的主要免疫细胞频率与数量，初步探讨两种小鼠对不同疟原虫易感性差异的可能机制。采用硝喹（CI-679）减毒

CSP子孢子疫苗和自主设计的

CSP@LNP mRNA疫苗各免疫AAD小鼠作为免疫组小鼠（每组4只），并以未免疫的AAD小鼠作为对照组（每组4只），免疫完成后使用

CSP子孢子攻击免疫小鼠，观察免疫保护效果，并通过流式细胞术检测CSP特异性组织驻留记忆性T细胞（tissue resident memory T cell， Trm）的频率与数量，采用ELISA

检测CSP特异性抗体滴度，观察该疫苗能否有效诱导CSP特异性的抗体和Trm细胞的免疫应答。

结果

不同剂量

CSP都能成功感染AAD和C57BL/6J小鼠，与C57BL/6J小鼠相比，AAD小鼠更易感染

和

CSP，其易感性表现为红内期出现时间更早，在感染中期原虫血症更高（

0.05）；并且无论感染与否，AAD小鼠肝脏的NKT细胞频率与数量均显著少于C57BL/6J小鼠（

0.05），这可能是AAD小鼠更易感染疟原虫的原因之一。

CSP@LNP mRNA疫苗免疫AAD小鼠后，采用

CSP子孢子攻击免疫小鼠后的红内期出现时间延后于对照组小鼠，血清中能检测到较高滴度的CSP特异性抗体，但在肝脏中未能检测到

CSP特异性Trm。同样采用硝喹减毒

CSP子孢子疫苗免疫AAD小鼠，其免疫组的保护效果也只有16.6%，且未能检测到

CSP特异性Trm。

结论

AAD小鼠感染

CSP虫株模型可用于评价

CSP疫苗诱导产生

CSP特异性抗体的效果，但用于评价疫苗诱导产生

CSP特异性CD8

T细胞应答方面该小鼠模型有待于进一步优化。

Abstract

Objective

To investigate whether the MHC-Ⅰ humanized mouse model (AAD mice) combined with the Plasmodium berghei transgenic strain expressing

Plasmodium falciparum

circumsporozoite protein (

CSP

Pb-Pf

CSP) can be used to establish an evaluation model for

CSP-based vaccines.

Methods

AAD mice and C57BL/6J mice (6 to 8 weeks old

body weight 20 to 35 g

4 mice per group) were challenged with graded doses (200

500

and 1 000) of

Pb-Pf

CSP

sporozoites and wild-type

P.berghei

(

) sporozoites

via

tail vein injection. The susceptibility of the 2 mouse strains to

and

Pb-Pf

CSP infection was compared by monitoring the onset time of erythrocytic-stage parasitemia and the dynamic changes in parasitemia levels. Flow cytometry was performed to analyze the frequency and absolute number of major hepatic immune cell subsets in the 2

mouse strains

so as to preliminarily explore the potential mechanisms underlying the differential susceptibility to malaria parasites. For vaccine efficacy evaluation

4 AAD mice per group were immunized with either CI-679-attenuated

CSP sporozoite vaccine or LNP-encapsulated mRNA vaccine encoding

CSP (

CSP@LNP)

with unimmunized AAD mice as the control group. After immunization

all mice were challenged with

CSP sporozoites

and the protective efficacy was evaluated. The frequency and number of CSP-specific tissue-resident memory T cells (Trm) in the liver were detected by flow cytometry

and CSP-specific antibody titers in serum were measured by enzyme-linked immunosorbent assay (ELISA).

Results

CSP sporozoites at all tested doses successfully infected both AAD and C57BL/6J mice. Compared with C57BL/6J mice

AAD mice exhibited higher susceptibility to both

and

CSP infection

as evidenced by earlier onset of erythrocytic-stage parasitemia and significantly higher parasitemia levels in the mid-stage of infection (

0.05). Regardless of infection status

the frequency and absolute number of hepatic natural killer T (NKT) cells in AAD mice were significantly lower than those in C57BL/6J mice (

0.05)

which might be one of the reasons for the increased susceptibility of AAD mice to malaria parasite infection. After challenge with

CSP sporozoites

CSP@LNP-immunized AAD mice exhibited delayed erythrocytic-stage parasitemia onset compared with the control group

and detectable titers of CSP-specific antibodies were observed in their serum; however

CSP-specific Trm cells were not detected in the liver. Similarly

AAD mice immunized with the nitroquine-attenuated

CSP sporozoite vaccine only achieved a protective efficacy of 16.6%

and

CSP-specific Trm cells were not detected either.

Conclusion

The

CSP-infected AAD mouse model can be used for evaluating the efficacy of

CSP-based vaccines in inducing CSP-specific antibody responses. However

this model requires further optimization for assessing

CSP-specific CD8

T cell response induction.

关键词

Keywords

references

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Establishment of an evaluation model for Plasmodium falciparum circumsporozoite protein vaccines using MHC-Ⅰ humanized mice and transgenic plasmodium: Effective antibody responses but limited CD8⁺ T-cell responses

DOI：10.16016/j.2097-0927.202512046

摘要

Abstract

关键词

Keywords

references