Fig 1.
Development of antibody responses against P. vivax and the factors that might be involved in acquisition of long-lived antibody responses.
(Top) P. vivax malaria can implicate 3 different stages of infection including pre-erythrocytic stage, blood stage, and mosquito stage. During the pre-erythrocytic stage, sporozoites infect and develop inside hepatocytes before releasing as merozoite or remain dormant by forming hypnozoite. In the blood-stage, merozoites invade and mature in red blood cells and might contribute to cryptic erythrocytic infection in spleen and bone marrow, thereby becoming sheltered from immune recognition and antimalarial drugs. In mosquito stage, male and female gametocytes can be taken up by a feeding Anopheline mosquito and form zygote in midgut. (Middle) In response to P. vivax infection, IgM antibodies are acquired at the initial phase of antibody response, being replaced by IgG antibodies in following weeks of the immunological memory phase. Antibody response could vary in different individuals, rendering short-lived or long-lived responses. Among 4 subclasses (IgG1-4), 2 predominant subclasses were IgG1 and IgG3. (Bottom) Possible factors related to the acquisition of long-lived antibody responses were proposed including host age, immune status, intensity of transmission, nature of encountering antigens (i.e., polymorphism and location of antigens), parasite recrudescence as well as number of reinfection/exposure.
Table 1.
P. vivax antigens involved in induction of the longevity of antibody responses following natural infection.
Table 2.
P. vivax antigens reported to induce MBC responses following natural infection.
Fig 2.
Development and dynamics of MBC subset responses in P. vivax-infected individuals during acute and recovery phase of infection.
(Top) Following activation by encountering malaria antigen, dendritic cells induce the activation of naive T cells. The CD4+ T cells differentiate into effector T helper cells (Th1, 2 and 17), regulatory T and follicular T cells, which secrete characteristic cytokines including IFN-γ, IL-4/IL-5, IL-17, IL-10, and IL-21, respectively (A). The interaction between follicular helper T (Tfh) and naive B cells through cytokine and co-stimulatory molecules drives B cell activation, leading to the generation of MBC subsets (B). The phenotyping of MBCs reaveals 3 phenotypically distinct subsets, including CD21- CD27+ activated MBCs, CD21-CD27- atypical MBCs and CD21+CD27+ classical MBCs (C). Atypical MBCs were expanded during P. vivax infection. However, the functions of these cells in anti-malarial humoral immunity are still unclear. Several biomolecules related to atypical MBCs have been investigated, including co-stimulatory molecules (CD11c, CD86, CD95, CXCR3), inhibitory receptors (FcRL5, CD22, CD85), and T-bet transcription factor. (Bottom) The responses of atypical and classical MBCs during acute (AC) and recovery (RC) phase of P. falciparum and P. vivax infection are shown. In P. falciparum infection (A, B), subjects with primary and previous infection showed an expansion of atypical MBCs during AC malaria, with higher frequency in previously infected subjects. These MBCs decreased but remained higher than frequencies of non-malaria subjects after recovery from infection. The frequencies of classical MBCs during AC infection were lower than baseline of non-malaria subjects. They increased in RC phase both in primary and previous infection. In cases of P. vivax infection (C, D), individuals with acute primary infection exhibited an elevated frequency of atypical MBCs. Although this frequency decreased over time at RC phase, it remained higher than that observed in non-malaria infections. In contrast, primary infection showed lower number of classical MBCs during AC illness, compared to non-malaria infection. In RC phase, frequency of classical MBCs slowly increased. To date, the boosting response of both atypical and classical MBCs in previously P. vivax-infected individuals is still unclear. Solid green line represents primary infection, solid red line represents previous infection, dashed red line indicates unclear data in P. vivax, and dashed black line indicates non-malaria infection.