TY - JOUR
T1 - Full-length plasmodium falciparum circumsporozoite protein administered with long-chain poly(I·C) or the toll-like receptor 4 agonist glucopyranosyl lipid adjuvant-stable emulsion elicits potent antibody and CD4+ T cell immunity and protection in mice
AU - Kastenmüller, Kathrin
AU - Espinosa, Diego A.
AU - Trager, Lauren
AU - Stoyanov, Cristina
AU - Salazar, Andres M.
AU - Pokalwar, Santosh
AU - Singh, Sanjay
AU - Dutta, Sheetij
AU - Ockenhouse, Christian F.
AU - Zavala, Fidel
AU - Sedera, Robert A.
PY - 2013/3
Y1 - 2013/3
N2 - The Plasmodium falciparum circumsporozoite (CS) protein (CSP) is a major vaccine target for preventing malaria infection. Thus, developing strong and durable antibody and T cell responses against CSP with novel immunogens and potent adjuvants may improve upon the success of current approaches. Here, we compare four distinct full-length P. falciparum CS proteins expressed in Escherichia coli or Pichia pastoris for their ability to induce immunity and protection in mice when administered with long-chain poly(I·C) [poly(I·C)LC] as an adjuvant. CS proteins expressed in E. coli induced high-titer antibody responses against the NANP repeat region and potent CSP-specific CD4+ T cell responses. Moreover, E. coli-derived CS proteins in combination with poly(I·C)LC induced potent multifunctional (interleukin 2-positive [IL-2+], tumor necrosis factor alpha-positive [TNF-α+], gamma interferon-positive [IFN-γ+]) CD4+ effector T cell responses in blood, in spleen, and particularly in liver. Using transgenic Plasmodium berghei expressing the repeat region of P. falciparum CSP [Pb-CS(Pf)], we showed that there was a 1-to 4-log decrease in malaria rRNA in the liver following a high-dose challenge and+50% sterilizing protection with a lowdose challenge compared to control levels. Protection was directly correlated with high-level antibody titers but not CD4+ T cell responses. Finally, protective immunity was also induced using the Toll-like receptor 4 agonist glucopyranosyl lipid adjuvantstable emulsion (GLA-SE) as the adjuvant, which also correlated with high antibody titers yet CD4+ T cell immunity that was significantly less potent than that with poly(I·C)LC. Overall, these data suggest that full-length CS proteins and poly(I·C)LC or GLA-SE offer a simple vaccine formulation to be used alone or in combination with other vaccines for preventing malaria infection.
AB - The Plasmodium falciparum circumsporozoite (CS) protein (CSP) is a major vaccine target for preventing malaria infection. Thus, developing strong and durable antibody and T cell responses against CSP with novel immunogens and potent adjuvants may improve upon the success of current approaches. Here, we compare four distinct full-length P. falciparum CS proteins expressed in Escherichia coli or Pichia pastoris for their ability to induce immunity and protection in mice when administered with long-chain poly(I·C) [poly(I·C)LC] as an adjuvant. CS proteins expressed in E. coli induced high-titer antibody responses against the NANP repeat region and potent CSP-specific CD4+ T cell responses. Moreover, E. coli-derived CS proteins in combination with poly(I·C)LC induced potent multifunctional (interleukin 2-positive [IL-2+], tumor necrosis factor alpha-positive [TNF-α+], gamma interferon-positive [IFN-γ+]) CD4+ effector T cell responses in blood, in spleen, and particularly in liver. Using transgenic Plasmodium berghei expressing the repeat region of P. falciparum CSP [Pb-CS(Pf)], we showed that there was a 1-to 4-log decrease in malaria rRNA in the liver following a high-dose challenge and+50% sterilizing protection with a lowdose challenge compared to control levels. Protection was directly correlated with high-level antibody titers but not CD4+ T cell responses. Finally, protective immunity was also induced using the Toll-like receptor 4 agonist glucopyranosyl lipid adjuvantstable emulsion (GLA-SE) as the adjuvant, which also correlated with high antibody titers yet CD4+ T cell immunity that was significantly less potent than that with poly(I·C)LC. Overall, these data suggest that full-length CS proteins and poly(I·C)LC or GLA-SE offer a simple vaccine formulation to be used alone or in combination with other vaccines for preventing malaria infection.
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U2 - 10.1128/IAI.01108-12
DO - 10.1128/IAI.01108-12
M3 - Article
C2 - 23275094
AN - SCOPUS:84874721348
VL - 81
SP - 789
EP - 800
JO - Infection and Immunity
JF - Infection and Immunity
SN - 0019-9567
IS - 3
ER -