A T-cell response to a liver-stagePlasmodiumantigen is not boosted by repeated sporozoite immunizations

Abstract

Development of an antimalarial subunit vaccine inducing protective cytotoxic T lymphocyte (CTL)-mediated immunity could pave the way for malaria eradication. Experimental immunization with sporozoites induces this type of protective response, but the extremely large number of proteins expressed by Plasmodium parasites has so far prohibited the identification of sufficient discrete T-cell antigens to develop subunit vaccines that produce sterile immunity. Here, using mice singly immunized with Plasmodium yoelii sporozoites and high-throughput screening, we identified a unique CTL response against the parasite ribosomal L3 protein. Unlike CTL responses to the circumsporozoite protein (CSP), the population of L3-specific CTLs was not expanded by multiple sporozoite immunizations. CSP is abundant in the sporozoite itself, whereas L3 expression does not increase until the liver stage. The response induced by a single immunization with sporozoites reduces the parasite load in the liver so greatly during subsequent immunizations that L3-specific responses are only generated during the primary exposure. Functional L3-specific CTLs can, however, be expanded by heterologous prime-boost regimens. Thus, although repeat sporozoite immunization expands responses to preformed antigens like CSP that are present in the sporozoite itself, this immunization strategy may not expand CTLs targeting parasite proteins that are synthesized later. Heterologous strategies may be needed to increase CTL responses across the entire spectrum of Plasmodium liver-stage proteins.

Attenuated PfSPZ Vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection

“…Therefore, rapid induction of anti-PfSPZ immunity may limit boosting by subsequent administrations of PfSPZ Vaccine, especially at the higher vaccine doses used here compared with prior studies. Indeed, limited boosting after irradiated SPZ vaccination has been demonstrated in mouse models (32,33). These data raise the question of whether equivalent protective efficacy may be possible with fewer than three immunizations, especially with higher doses of the vaccine.…”

Purification of Plasmodium Sporozoites Enhances Parasite-Specific CD8 + T Cell Responses

“…Construction of wild-type Listeria monocytogenes expressing an H2-K d -specific epitope from P. yoelii L3 (strain LmL3) was previously reported (27). Doubly attenuated L. monocytogenes (actA and inlB deficient) expressing an H2-K d -specific epitope, SYVPSAEQI, from P. yoelii CSP (strain LmCSP) was a kind gift of Aduro Biotech.…”

“…CSP is a critical component for subunit vaccines, and CTL responses to CSP appear to increase in frequency with repeated immunization in the typical immunization regimen of three doses of 1 ϫ 10 4 P. yoelii radiation-attenuated sporozoites (RAS) (27). CSP-specific responses can markedly reduce the liver burden in animal models of malaria.…”

“…We (27) and others have searched for non-CSP antigens that can augment the partial protection afforded by CSP-specific immunity (28)(29)(30)(31)(32). Using sporozoite hyperimmunization, we recently proposed that responses to preerythrocytic Plasmodium CD8 antigens could be divided into two groups, a group boosted by repeated homologous sporozoite exposure (e.g., CSP-specific CD8 ϩ T cell responses) and a group that is not (27). Building on these two classes of antigens, we have attempted to use novel whole-sporozoite vaccination strategies to increase responses to boostable antigens in an effort to reduce the number of sporozoite doses required to achieve protection.…”

Artesunate versus Chloroquine Infection–Treatment–Vaccination Defines Stage-Specific Immune Responses Associated with Prolonged Sterile Protection against Both Pre-erythrocytic and Erythrocytic Plasmodium yoelii Infection

“…+ T cells play a major role in protection against pre-erythrocytic infection induced by vaccination with drug-attenuated spz (16,17,27). Moreover, protection against preerythrocytic infection has been recently demonstrated to correlate with the induction of malaria-specific CD8 + effector memory T cells (T EM ) (28).…”