Abstract
Infection treatment vaccine (ITV) can lead to sterile protection against malaria infection in mice and humans. However, parasite breakthrough is frequently observed post-challenge. The mechanism of rapid decline in protection after the last immunization is unclear. Herein, C57BL/6 mice were immunized with 103, 105, or 107 ITV thice at 14-day intervals. Mice were challenged with 103 parasites at 1, 3, and 6 months after last immunization and the protection was checked using blood smear. The phenotypes of B cells were analyzed by flow cytometry. The levels of serum cytokines were quantified using cytometric bead array. The 103 ITV vaccination group exhibited 100% protection at 1 month after last immunization, and the 105 group showed sterile protection at 3 months after last immunization. However, the 107 group showed only partial protection. Further, the protection declined to 16.7% at 6 months after last immunization in 105 and 107 groups, whereas it maintained for more than 60% in 103 group. The number of memory B cells (MBC) decreased along with the decline in protection. However, programmed cell death protein 1 (PD-1) expressed on MBCs did not show significant variation among the three groups. Interestingly, CD19+CD1dhiCD5hi B cells, defined as B10 cells, exhibited negative regulation with respect to protection. The numbers of CD19+CD1dhiCD5hi B cells in the 103 group at 1 months and in the 105 group at 3 months post-immunization were the lowest compared to those in the other groups. Moreover, the serum levels of interleukin 10 (IL-10) in these two groups were also significantly lower than those in other groups. We conclude that higher immunization dose may not lead to better protection with the malaria vaccine as CD19+CD1dhiCD5hi B cells can downregulate ITV protection against malaria via IL-10 secretion. These results could facilitate the design of an effective long-lasting malaria vaccine with the aim of maintaining MBC function.
Highlights
Malaria is still one of the three most important infectious diseases worldwide, resulting in 228 million clinical cases and 405,000 deaths in 2018, mostly in Africa in children under 5 years of age [1]
We mainly explored the role of memory B cell (MBC) and B10 cells in immune dose-mediated long-term protection decline of malaria blood stage Infection treatment vaccine (ITV), and clarified the role of PD-1 in MBC and B10-related cytokines in this process
The goal of blood stage malaria vaccines is to inhibit the proliferation of intraerythrocytic malaria parasites so as to control the symptoms of malaria and prevent the disease
Summary
Malaria is still one of the three most important infectious diseases worldwide, resulting in 228 million clinical cases and 405,000 deaths in 2018, mostly in Africa in children under 5 years of age [1]. An effective and long-lasting malaria vaccine is urgently needed to eliminate this disease. The blood stage of the malarial parasite life cycle is responsible for all the clinical symptoms of malaria [3]. The goal of blood stage malaria vaccines is to inhibit the proliferation of intraerythrocytic malaria parasites, so as to control the symptoms of malaria and prevent the disease. The protection of blood stage malaria vaccines depends on acquisition of antibodies against parasite target antigens [4]. Infrequent malaria infections can induce antigen-specific, long-lived antibody, and antigen-specific memory B cell (MBC) responses in a significant proportion of malaria-exposed individuals [5]. Inadequate maintenance of the function of long-term, effective malaria parasite-specific MBCs is an urgent problem that needs to be solved
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