A Population-Based Clinical Trial with the SPf66 Synthetic Plasmodium falciparum Malaria Vaccine in Venezuela

G., O. Noya; Berti, Y. G.; Noya, B Alarcón de; Zerpa, Noraida; ez, J. D. Urb; Madonna, A.; Garrido, E.; Jimenez, M. Auxiliadora; Borges, Rodrigo; García, Pablo; Reyes, I. Gomez; Prieto, WH; Colmenares, Cecilia; Pabón, Rosalba; Barraez, T.; Cáceres, Lorenzo; Godoy, Natalia Bustos de; Sifontes, R.

doi:10.1093/infdis/170.2.396

Cited by 86 publications

(37 citation statements)

References 19 publications

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“…This finding is supported by the observation of antibodies against the peptide in non-vaccinated populations from endemic areas (Valero et al 1993, Noya et al 1994, Teuscher et al 1994. It is noteworthy that a correlation has also been found between the low IgG antibody response to the vaccine and the presence of HLA-DR4 allele in vaccinees (Murillo et al 1991).…”

supporting

confidence: 56%

“…This can be explained by the fact that in the latter study the cutoff point used for the determination of antibody titers was 0.2 (Valero et al 1993), unlike the 0.1 cutoff point used by the other studies (Sempertegui et al 1994, Noya et al 1994.…”

Section: Discussionmentioning

confidence: 82%

“…Immunogenicity of the SPf66 vaccine has been expressed in terms of the relative frequency of positive individuals for specific IgG antibodies against the peptide one month after completion of the immunization schedule (Valero et al 1993, Sempertegui et al 1994, Noya et al 1994. These antibodies are known to recognize native proteins in the merozoite such as 135Kd, 83 Kd and 115 Kd (Salcedo et al 1991).…”

mentioning

confidence: 99%

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Humoral Immune Response to the Anti-malaria Vaccine SPf66 in the Colombian Atrato River Region

Lopera

Restrepo

Blair

et al. 1998

Mem. Inst. Oswaldo Cruz

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supporting

confidence: 56%

Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

See 1 more Smart Citation

Humoral Immune Response to the Anti-malaria Vaccine SPf66 in the Colombian Atrato River Region

Lopera

Restrepo

Blair

et al. 1998

Mem. Inst. Oswaldo Cruz

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“…26 After all monkey trials and safety and immunogenicity trials involving thousands of humans, this first synthetic vaccine (produced 20 years ago) was safe and immunogenic and provided ∼35% protection in people older than 1 year in large field trials carried out in different parts of the world. [27][28][29] One lot produced elsewhere proved nonprotective. 30 It was also found that two out of the three merozoite-derived amino acid sequences included in this vaccine 31 were derived from peptides that bound with high affinity to RBC.…”

Section: The Basis Of Our Approachmentioning

confidence: 99%

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

2008

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S eventeen million people die of transmittable diseases and 2/3 of the world's population suffer them annually. Malaria, tuberculosis, AIDS, hepatitis, and reemerging and new diseases are a great threat to humankind. A logical and rational approach for vaccine development is thus desperately needed.Protein chemistry provides the best tools for tackling these problems. The tremendous complexity of microbes, the different pathways they use for invading host cells, and the immune responses they induce can only be resolved by using the minimum subunit-based (chemically produced ∼20-mer peptides), multiantigenic (most proteins involved in invasion), multistage (different invasion mechanisms) vaccine development approach.The most lethal form of malaria caused by Plasmodium falciparum (killing 3 million and affecting 500 million people worldwide annually) was used as target disease since many of its proteins, its invasion pathways, and its genome have been described recently. A New World primate (the Aotus monkey) is highly susceptibly to human malaria; its immune system molecules are 80 -100% identical to those of its human counterpart, making it an excellent model for vaccine development.Chemically synthesized ∼20-mer peptides, covering all the P. falciparum malaria proteins involved in red blood cell (RBC) invasion were synthesized by the classical t-Boc technology (based on synthetic SPf66 antimalarial vaccine information for identifying targets) and assayed in a highly sensitive, specific, and robust test for detecting receptor-ligand interactions between high-activity binding peptides (HABPs) and RBCs. HABPs were identified, some in which the molecule displays genetic variability (to be discarded due to their tremendous complexity) and elicits a strain-specific immune response and others that are conserved (no amino acid sequence variation).Conserved HABPs were synthesized in a polymeric form by adding cysteines at their N-and C-terminal ends to be used for monkey immunization. They became nonimmunogenic (no antibodies were induced) nonprotection inducers (monkeys were not protected against P. falciparum malaria challenge with a highly infective strain) suggesting a code of immunological silence or nonresponsiveness for these conserved HABPs.A large number of monkey trials involving a considerable number of Aotus monkeys were performed to break this code of immunological silence by replacing critical residues (determined by glycine peptide analogue scanning) to find that the following amino acid changes had to be made to render them antibody and protection inducing: FTR; WTY; LTH; ITN; MTK; PTD; QTE; CTT.The three-dimensional (3D) structure of >100 of these native modified HABPs (determined by 1 H NMR) revealed that the following structural changes had all to be achieved to allow a better fit into the major histocompatibility complex class II (MHC II)-peptide-TCR complex to properly activate the immune system: R-helix shortening, modifying their -turn, adopting segmental R-helix configuration, changing residue or...

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“…[5][6][7][8][9][10][11] Although there has been no evidence of serious toxicity during these studies, the efficacy of SPf66 has been controversial (ranging from Ϫ9% to ϩ74%).…”

Section: C-g-d-e-l-e-a-e-t-q-n-v-y-a-a-p-n-a-n-p-y-s-l-f-q-k-e-k-m-v-mentioning

confidence: 99%

Immunization with SPf66 and subsequent infection with homologous and heterologous Plasmodium falciparum parasites.

Masinde¹,

Krogstad²,

Gordon³

et al. 1998

The American Journal of Tropical Medicine and Hygiene

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Abstract. In an area of intense transmission, a malaria vaccine could reduce infection due to the parasite types represented in the vaccine, but have no detectable effect on the overall frequency of infection if it did not protect against infection with heterologous parasites. These studies were performed to determine whether immunization with SPf66 decreased infection with homologous parasites containing the 11 amino acid peptide from merozoite surface protein-1 (MSP-1) in SPf66, or increased infection due to heterologous parasites containing heterologous (alternative) MSP-1 sequences. Based on this 11 amino acid peptide (YSLFQKEKMVL), three forward primers (S,Q,V) were designed to amplify the MSP-1 sequence present in SPf66, and 3 additional forward primers (G,H,I) to amplify the alternative MSP-1 sequence (YGLFHKEKMIL). This strategy was validated by polymerase chain reaction (PCR) amplification and dideoxy sequencing with 14 cloned laboratory isolates, which demonstrated that each primer amplified one MSP-1 sequence or the other, but not both. The technique was then used to examine filter paper blots from an SPf66 vaccine study of 69 subjects in Saradidi, Kenya. In that study, the prevalence of infection with YSLFQKEKMVL or YGLFHKEKMIL type parasites was unaffected by immunization with SPf66 (based on PCR amplification with the S, Q, V, G, H and I primers, respectively). These results suggest that immunization with SPf66 does not produce a selective effect in vivo. They demonstrate a molecular method to test for selection in vivo as an indirect measure of vaccine efficacy.Between one and two million deaths result from falciparum malaria each year, 90% of which occur among children less than five years of age in sub-Saharan Africa.1 In addition, the recent worldwide increase in the morbidity and mortality of malaria caused by drug-resistant Plasmodium falciparum has strengthened the argument for development of a malaria vaccine.2,3 SPf66 is a synthetic peptide vaccine candidate with the following sequence: 4,5

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A Population-Based Clinical Trial with the SPf66 Synthetic Plasmodium falciparum Malaria Vaccine in Venezuela

Cited by 86 publications

References 19 publications

Humoral Immune Response to the Anti-malaria Vaccine SPf66 in the Colombian Atrato River Region

Humoral Immune Response to the Anti-malaria Vaccine SPf66 in the Colombian Atrato River Region

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

Immunization with SPf66 and subsequent infection with homologous and heterologous Plasmodium falciparum parasites.

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