Recombinant Liver Stage Antigen-1 (LSA-1) formulated with AS01 or AS02 is safe, elicits high titer antibody and induces IFN-γ/IL-2 CD4+ T cells but does not protect against experimental Plasmodium falciparum infection

James F. Cummings, Michele D. Spring, Robert J. Schwenk, Christian F. Ockenhouse, Kent E. Kester, Mark E. Polhemus, Douglas S. Walsh, In Kyu Yoon, Christine Prosperi, Laure Y. Juompan, David E. Lanar, Urszula Krzych, B. Ted Hall, Lisa A. Ware, V. Ann Stewart, Jack Williams, Megan Dowler, Robin K. Nielsen, Collette J. Hillier, Birgitte K. GiersingFilip Dubovsky, Elissa Malkin, Kathryn Tucker, Marie Claude Dubois, Joe D. Cohen, W. Ripley Ballou, G. Heppner

Research output: Contribution to journalArticle

Abstract

Plasmodium falciparum Liver Stage Antigen 1 (LSA-1) is a pre-erythrocytic stage antigen. Our LSA-1 vaccine candidate is a recombinant protein with full-length C- and N-terminal flanking domains and two of the 17 amino acid repeats from the central repeat region termed " LSA-NRC." We describe the first Phase I/II study of this recombinant LSA-NRC protein formulated with either the AS01 or AS02 adjuvant system. We conducted an open-label Phase I/II study. Thirty-six healthy malaria-naïve adults received one of four formulations by intra-deltoid injection on a 0 and 1 month schedule; low dose (LD) LSA-NRC/AS01:10 μg LSA-NRC/0.5. ml AS01 (n= 5), high dose (HD) LSA-NRC/AS01: 50 μg LSA-NRC/0.5. ml AS01 (n= 13); LD LSA-NRC/AS02: 10 μg LSA-NRC/0.5. ml AS02 (n= 5) and HD LSA-NRC/AS02: 50 μg LSA-NRC/0.5. ml AS02 (n= 13). Two weeks post-second immunization, the high dose vaccinees and 6 non-immunized infectivity controls underwent experimental malaria sporozoite challenge. The vaccines showed a reassuring safety profile but were moderately reactogenic. There were no serious adverse events. All subjects seroconverted after the first immunization. Following the second immunization, LSA-1-specific CD4+ T cells producing two cytokines (IL-2 and IFN-γ) were found by intra-cellular staining in all subjects in the LD LSA-NRC/AS01B group and in 3 of 5 subjects in the LD LSA-NRC/AS02 group. In contrast, the HD LSA-NRC/AS01 and HD LSA-NRC/AS02 group subjects had fewer LSA-1-specific CD4+ T cells, and minimal to no IFN-γ responses. There was no increase in LSA-1-specific CD8+ T cells found in any group. Per protocol, 22 high dose vaccinees, but no low dose vaccinees, underwent P. falciparum homologous malaria challenge (3D7 clone). All vaccinees became parasitemic and there was no delay in their pre-patent period versus controls (p= 0.95).LSA-NRC/AS01 and LSA-NRC/AS02 elicited antigen-specific antibody and CD4+ T cell responses, but elicited no protective immunity. Although the optimal antigen dose of LSA-NRC may not have been selected for the challenge portion of the protocol, further vaccine development based upon LSA-1 should not be excluded and should include alternative vaccine platforms able to elicit additional effector mechanisms such as CD8+ T cells.

Original languageEnglish (US)
Pages (from-to)5135-5144
Number of pages10
JournalVaccine
Volume28
Issue number31
DOIs
StatePublished - Jul 2010
Externally publishedYes

Fingerprint

Plasmodium falciparum
interleukin-2
Malaria
Interleukin-2
T-lymphocytes
antigens
T-Lymphocytes
Antigens
liver
antibodies
Antibodies
Liver
dosage
infection
Vaccines
Immunization
malaria
immunization
vaccines
Sporozoites

Keywords

  • Liver Stage Antigen
  • Malaria vaccine
  • Plasmodium falciparum

ASJC Scopus subject areas

  • Immunology and Microbiology(all)
  • Infectious Diseases
  • Public Health, Environmental and Occupational Health
  • veterinary(all)
  • Molecular Medicine
  • Medicine(all)

Cite this

Recombinant Liver Stage Antigen-1 (LSA-1) formulated with AS01 or AS02 is safe, elicits high titer antibody and induces IFN-γ/IL-2 CD4+ T cells but does not protect against experimental Plasmodium falciparum infection. / Cummings, James F.; Spring, Michele D.; Schwenk, Robert J.; Ockenhouse, Christian F.; Kester, Kent E.; Polhemus, Mark E.; Walsh, Douglas S.; Yoon, In Kyu; Prosperi, Christine; Juompan, Laure Y.; Lanar, David E.; Krzych, Urszula; Hall, B. Ted; Ware, Lisa A.; Stewart, V. Ann; Williams, Jack; Dowler, Megan; Nielsen, Robin K.; Hillier, Collette J.; Giersing, Birgitte K.; Dubovsky, Filip; Malkin, Elissa; Tucker, Kathryn; Dubois, Marie Claude; Cohen, Joe D.; Ballou, W. Ripley; Heppner, G.

In: Vaccine, Vol. 28, No. 31, 07.2010, p. 5135-5144.

Research output: Contribution to journalArticle

Cummings, JF, Spring, MD, Schwenk, RJ, Ockenhouse, CF, Kester, KE, Polhemus, ME, Walsh, DS, Yoon, IK, Prosperi, C, Juompan, LY, Lanar, DE, Krzych, U, Hall, BT, Ware, LA, Stewart, VA, Williams, J, Dowler, M, Nielsen, RK, Hillier, CJ, Giersing, BK, Dubovsky, F, Malkin, E, Tucker, K, Dubois, MC, Cohen, JD, Ballou, WR & Heppner, G 2010, 'Recombinant Liver Stage Antigen-1 (LSA-1) formulated with AS01 or AS02 is safe, elicits high titer antibody and induces IFN-γ/IL-2 CD4+ T cells but does not protect against experimental Plasmodium falciparum infection', Vaccine, vol. 28, no. 31, pp. 5135-5144. https://doi.org/10.1016/j.vaccine.2009.08.046
Cummings, James F. ; Spring, Michele D. ; Schwenk, Robert J. ; Ockenhouse, Christian F. ; Kester, Kent E. ; Polhemus, Mark E. ; Walsh, Douglas S. ; Yoon, In Kyu ; Prosperi, Christine ; Juompan, Laure Y. ; Lanar, David E. ; Krzych, Urszula ; Hall, B. Ted ; Ware, Lisa A. ; Stewart, V. Ann ; Williams, Jack ; Dowler, Megan ; Nielsen, Robin K. ; Hillier, Collette J. ; Giersing, Birgitte K. ; Dubovsky, Filip ; Malkin, Elissa ; Tucker, Kathryn ; Dubois, Marie Claude ; Cohen, Joe D. ; Ballou, W. Ripley ; Heppner, G. / Recombinant Liver Stage Antigen-1 (LSA-1) formulated with AS01 or AS02 is safe, elicits high titer antibody and induces IFN-γ/IL-2 CD4+ T cells but does not protect against experimental Plasmodium falciparum infection. In: Vaccine. 2010 ; Vol. 28, No. 31. pp. 5135-5144.
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title = "Recombinant Liver Stage Antigen-1 (LSA-1) formulated with AS01 or AS02 is safe, elicits high titer antibody and induces IFN-γ/IL-2 CD4+ T cells but does not protect against experimental Plasmodium falciparum infection",
abstract = "Plasmodium falciparum Liver Stage Antigen 1 (LSA-1) is a pre-erythrocytic stage antigen. Our LSA-1 vaccine candidate is a recombinant protein with full-length C- and N-terminal flanking domains and two of the 17 amino acid repeats from the central repeat region termed {"} LSA-NRC.{"} We describe the first Phase I/II study of this recombinant LSA-NRC protein formulated with either the AS01 or AS02 adjuvant system. We conducted an open-label Phase I/II study. Thirty-six healthy malaria-na{\"i}ve adults received one of four formulations by intra-deltoid injection on a 0 and 1 month schedule; low dose (LD) LSA-NRC/AS01:10 μg LSA-NRC/0.5. ml AS01 (n= 5), high dose (HD) LSA-NRC/AS01: 50 μg LSA-NRC/0.5. ml AS01 (n= 13); LD LSA-NRC/AS02: 10 μg LSA-NRC/0.5. ml AS02 (n= 5) and HD LSA-NRC/AS02: 50 μg LSA-NRC/0.5. ml AS02 (n= 13). Two weeks post-second immunization, the high dose vaccinees and 6 non-immunized infectivity controls underwent experimental malaria sporozoite challenge. The vaccines showed a reassuring safety profile but were moderately reactogenic. There were no serious adverse events. All subjects seroconverted after the first immunization. Following the second immunization, LSA-1-specific CD4+ T cells producing two cytokines (IL-2 and IFN-γ) were found by intra-cellular staining in all subjects in the LD LSA-NRC/AS01B group and in 3 of 5 subjects in the LD LSA-NRC/AS02 group. In contrast, the HD LSA-NRC/AS01 and HD LSA-NRC/AS02 group subjects had fewer LSA-1-specific CD4+ T cells, and minimal to no IFN-γ responses. There was no increase in LSA-1-specific CD8+ T cells found in any group. Per protocol, 22 high dose vaccinees, but no low dose vaccinees, underwent P. falciparum homologous malaria challenge (3D7 clone). All vaccinees became parasitemic and there was no delay in their pre-patent period versus controls (p= 0.95).LSA-NRC/AS01 and LSA-NRC/AS02 elicited antigen-specific antibody and CD4+ T cell responses, but elicited no protective immunity. Although the optimal antigen dose of LSA-NRC may not have been selected for the challenge portion of the protocol, further vaccine development based upon LSA-1 should not be excluded and should include alternative vaccine platforms able to elicit additional effector mechanisms such as CD8+ T cells.",
keywords = "Liver Stage Antigen, Malaria vaccine, Plasmodium falciparum",
author = "Cummings, {James F.} and Spring, {Michele D.} and Schwenk, {Robert J.} and Ockenhouse, {Christian F.} and Kester, {Kent E.} and Polhemus, {Mark E.} and Walsh, {Douglas S.} and Yoon, {In Kyu} and Christine Prosperi and Juompan, {Laure Y.} and Lanar, {David E.} and Urszula Krzych and Hall, {B. Ted} and Ware, {Lisa A.} and Stewart, {V. Ann} and Jack Williams and Megan Dowler and Nielsen, {Robin K.} and Hillier, {Collette J.} and Giersing, {Birgitte K.} and Filip Dubovsky and Elissa Malkin and Kathryn Tucker and Dubois, {Marie Claude} and Cohen, {Joe D.} and Ballou, {W. Ripley} and G. Heppner",
year = "2010",
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TY - JOUR

T1 - Recombinant Liver Stage Antigen-1 (LSA-1) formulated with AS01 or AS02 is safe, elicits high titer antibody and induces IFN-γ/IL-2 CD4+ T cells but does not protect against experimental Plasmodium falciparum infection

AU - Cummings, James F.

AU - Spring, Michele D.

AU - Schwenk, Robert J.

AU - Ockenhouse, Christian F.

AU - Kester, Kent E.

AU - Polhemus, Mark E.

AU - Walsh, Douglas S.

AU - Yoon, In Kyu

AU - Prosperi, Christine

AU - Juompan, Laure Y.

AU - Lanar, David E.

AU - Krzych, Urszula

AU - Hall, B. Ted

AU - Ware, Lisa A.

AU - Stewart, V. Ann

AU - Williams, Jack

AU - Dowler, Megan

AU - Nielsen, Robin K.

AU - Hillier, Collette J.

AU - Giersing, Birgitte K.

AU - Dubovsky, Filip

AU - Malkin, Elissa

AU - Tucker, Kathryn

AU - Dubois, Marie Claude

AU - Cohen, Joe D.

AU - Ballou, W. Ripley

AU - Heppner, G.

PY - 2010/7

Y1 - 2010/7

N2 - Plasmodium falciparum Liver Stage Antigen 1 (LSA-1) is a pre-erythrocytic stage antigen. Our LSA-1 vaccine candidate is a recombinant protein with full-length C- and N-terminal flanking domains and two of the 17 amino acid repeats from the central repeat region termed " LSA-NRC." We describe the first Phase I/II study of this recombinant LSA-NRC protein formulated with either the AS01 or AS02 adjuvant system. We conducted an open-label Phase I/II study. Thirty-six healthy malaria-naïve adults received one of four formulations by intra-deltoid injection on a 0 and 1 month schedule; low dose (LD) LSA-NRC/AS01:10 μg LSA-NRC/0.5. ml AS01 (n= 5), high dose (HD) LSA-NRC/AS01: 50 μg LSA-NRC/0.5. ml AS01 (n= 13); LD LSA-NRC/AS02: 10 μg LSA-NRC/0.5. ml AS02 (n= 5) and HD LSA-NRC/AS02: 50 μg LSA-NRC/0.5. ml AS02 (n= 13). Two weeks post-second immunization, the high dose vaccinees and 6 non-immunized infectivity controls underwent experimental malaria sporozoite challenge. The vaccines showed a reassuring safety profile but were moderately reactogenic. There were no serious adverse events. All subjects seroconverted after the first immunization. Following the second immunization, LSA-1-specific CD4+ T cells producing two cytokines (IL-2 and IFN-γ) were found by intra-cellular staining in all subjects in the LD LSA-NRC/AS01B group and in 3 of 5 subjects in the LD LSA-NRC/AS02 group. In contrast, the HD LSA-NRC/AS01 and HD LSA-NRC/AS02 group subjects had fewer LSA-1-specific CD4+ T cells, and minimal to no IFN-γ responses. There was no increase in LSA-1-specific CD8+ T cells found in any group. Per protocol, 22 high dose vaccinees, but no low dose vaccinees, underwent P. falciparum homologous malaria challenge (3D7 clone). All vaccinees became parasitemic and there was no delay in their pre-patent period versus controls (p= 0.95).LSA-NRC/AS01 and LSA-NRC/AS02 elicited antigen-specific antibody and CD4+ T cell responses, but elicited no protective immunity. Although the optimal antigen dose of LSA-NRC may not have been selected for the challenge portion of the protocol, further vaccine development based upon LSA-1 should not be excluded and should include alternative vaccine platforms able to elicit additional effector mechanisms such as CD8+ T cells.

AB - Plasmodium falciparum Liver Stage Antigen 1 (LSA-1) is a pre-erythrocytic stage antigen. Our LSA-1 vaccine candidate is a recombinant protein with full-length C- and N-terminal flanking domains and two of the 17 amino acid repeats from the central repeat region termed " LSA-NRC." We describe the first Phase I/II study of this recombinant LSA-NRC protein formulated with either the AS01 or AS02 adjuvant system. We conducted an open-label Phase I/II study. Thirty-six healthy malaria-naïve adults received one of four formulations by intra-deltoid injection on a 0 and 1 month schedule; low dose (LD) LSA-NRC/AS01:10 μg LSA-NRC/0.5. ml AS01 (n= 5), high dose (HD) LSA-NRC/AS01: 50 μg LSA-NRC/0.5. ml AS01 (n= 13); LD LSA-NRC/AS02: 10 μg LSA-NRC/0.5. ml AS02 (n= 5) and HD LSA-NRC/AS02: 50 μg LSA-NRC/0.5. ml AS02 (n= 13). Two weeks post-second immunization, the high dose vaccinees and 6 non-immunized infectivity controls underwent experimental malaria sporozoite challenge. The vaccines showed a reassuring safety profile but were moderately reactogenic. There were no serious adverse events. All subjects seroconverted after the first immunization. Following the second immunization, LSA-1-specific CD4+ T cells producing two cytokines (IL-2 and IFN-γ) were found by intra-cellular staining in all subjects in the LD LSA-NRC/AS01B group and in 3 of 5 subjects in the LD LSA-NRC/AS02 group. In contrast, the HD LSA-NRC/AS01 and HD LSA-NRC/AS02 group subjects had fewer LSA-1-specific CD4+ T cells, and minimal to no IFN-γ responses. There was no increase in LSA-1-specific CD8+ T cells found in any group. Per protocol, 22 high dose vaccinees, but no low dose vaccinees, underwent P. falciparum homologous malaria challenge (3D7 clone). All vaccinees became parasitemic and there was no delay in their pre-patent period versus controls (p= 0.95).LSA-NRC/AS01 and LSA-NRC/AS02 elicited antigen-specific antibody and CD4+ T cell responses, but elicited no protective immunity. Although the optimal antigen dose of LSA-NRC may not have been selected for the challenge portion of the protocol, further vaccine development based upon LSA-1 should not be excluded and should include alternative vaccine platforms able to elicit additional effector mechanisms such as CD8+ T cells.

KW - Liver Stage Antigen

KW - Malaria vaccine

KW - Plasmodium falciparum

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