Safety, immunogenicity, and efficacy of a Plasmodium falciparum vaccine comprising a circumsporozoite protein repeat region peptide conjugated to Pseudomonas aeruginosa toxin A

L. F. Fries, D. M. Gordon, I. Schneider, John C Beier, G. W. Long, M. Gross, J. U. Que, S. J. Cryz, J. C. Sadoff

Research output: Contribution to journalArticle

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Abstract

Twenty-one malaria-naive volunteers were immunized with a vaccine consisting of a 22-kDa recombinant peptide (R32LR), derived from the repeat region of Plasmodium falciparum circumsporozoite (CS) protein, covalently coupled to detoxified Pseudomonas aeruginosa toxin A. Nineteen volunteers received a second dose of vaccine at 8 weeks, and eighteen received a third dose at 8 to 12 months. The vaccine was well tolerated, with only one volunteer developing local discomfort and induration at the site of injection which limited function for 48 h. The geometric mean anti-CS immunoglobulin G antibody concentration 2 weeks after the second dose of vaccine was 10.6 μg/ml (standard deviation = 3.0 μg/ml). Eleven volunteers (52%) developed anti-CS antibody levels of >9.8 μg/ml, the level measured in the one volunteer protected against P. falciparum challenge after immunization with the alum-adjuvanted recombinant protein R32tet32 in a prior study. Three separate experimental challenges were conducted with 10 volunteers 2 to 4 weeks after the third dose of vaccine. The four best responders, on the basis of antibody levels (6 to 26 μg/ml), were challenged with two infected- mosquito bites, but only one of four immunized volunteers and one of three malaria-naive controls became parasitemic. In a second challenge study using five infected-mosquito bites as the challenge dose, three of three malaria- naive control volunteers and two of three immunized volunteers developed malaria. The third vaccinee was apparently completely protected. In the third and last challenge, three of three controls and five of five vaccinees became infected. Sera obtained on the days of challenge inhibited sporozoite invasion of hepatocytes variably in vitro (range, 45 to 90% inhibition), but the degree of inhibition did not correlate with protection. Although antibody against the CS repeat region may protect some individuals against experimental challenge, this protection cannot be predicted from antibody levels by current in vitro assays. The functionality and fine specificity of anti-CS antibody are probably critical determinants.

Original languageEnglish
Pages (from-to)1834-1839
Number of pages6
JournalInfection and Immunity
Volume60
Issue number5
StatePublished - Jan 1 1992
Externally publishedYes

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Plasmodium falciparum
Pseudomonas aeruginosa
Volunteers
Vaccines
Safety
Peptides
Proteins
Malaria
Antibodies
Bites and Stings
Culicidae
Anti-Idiotypic Antibodies
Sporozoites
Recombinant Proteins
Hepatocytes
Immunization
Immunoglobulin G
Injections
Serum

ASJC Scopus subject areas

  • Immunology

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Safety, immunogenicity, and efficacy of a Plasmodium falciparum vaccine comprising a circumsporozoite protein repeat region peptide conjugated to Pseudomonas aeruginosa toxin A. / Fries, L. F.; Gordon, D. M.; Schneider, I.; Beier, John C; Long, G. W.; Gross, M.; Que, J. U.; Cryz, S. J.; Sadoff, J. C.

In: Infection and Immunity, Vol. 60, No. 5, 01.01.1992, p. 1834-1839.

Research output: Contribution to journalArticle

Fries, L. F. ; Gordon, D. M. ; Schneider, I. ; Beier, John C ; Long, G. W. ; Gross, M. ; Que, J. U. ; Cryz, S. J. ; Sadoff, J. C. / Safety, immunogenicity, and efficacy of a Plasmodium falciparum vaccine comprising a circumsporozoite protein repeat region peptide conjugated to Pseudomonas aeruginosa toxin A. In: Infection and Immunity. 1992 ; Vol. 60, No. 5. pp. 1834-1839.
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abstract = "Twenty-one malaria-naive volunteers were immunized with a vaccine consisting of a 22-kDa recombinant peptide (R32LR), derived from the repeat region of Plasmodium falciparum circumsporozoite (CS) protein, covalently coupled to detoxified Pseudomonas aeruginosa toxin A. Nineteen volunteers received a second dose of vaccine at 8 weeks, and eighteen received a third dose at 8 to 12 months. The vaccine was well tolerated, with only one volunteer developing local discomfort and induration at the site of injection which limited function for 48 h. The geometric mean anti-CS immunoglobulin G antibody concentration 2 weeks after the second dose of vaccine was 10.6 μg/ml (standard deviation = 3.0 μg/ml). Eleven volunteers (52{\%}) developed anti-CS antibody levels of >9.8 μg/ml, the level measured in the one volunteer protected against P. falciparum challenge after immunization with the alum-adjuvanted recombinant protein R32tet32 in a prior study. Three separate experimental challenges were conducted with 10 volunteers 2 to 4 weeks after the third dose of vaccine. The four best responders, on the basis of antibody levels (6 to 26 μg/ml), were challenged with two infected- mosquito bites, but only one of four immunized volunteers and one of three malaria-naive controls became parasitemic. In a second challenge study using five infected-mosquito bites as the challenge dose, three of three malaria- naive control volunteers and two of three immunized volunteers developed malaria. The third vaccinee was apparently completely protected. In the third and last challenge, three of three controls and five of five vaccinees became infected. Sera obtained on the days of challenge inhibited sporozoite invasion of hepatocytes variably in vitro (range, 45 to 90{\%} inhibition), but the degree of inhibition did not correlate with protection. Although antibody against the CS repeat region may protect some individuals against experimental challenge, this protection cannot be predicted from antibody levels by current in vitro assays. The functionality and fine specificity of anti-CS antibody are probably critical determinants.",
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AU - Schneider, I.

AU - Beier, John C

AU - Long, G. W.

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AU - Que, J. U.

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