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Safety and immunogenicity of a recombinant Plasmodium falciparum AMA1 malaria vaccine adjuvanted with Alhydrogel, Montanide ISA 720 or AS02.

Roestenberg M, Remarque E, de Jonge E, Hermsen R, Blythman H, Leroy O, Imoukhuede E, Jepsen S, Ofori-Anyinam O, Faber B, Kocken CH, Arnold M, Walraven V, Teelen K, Roeffen W, de Mast Q, Ballou WR, Cohen J, Dubois MC, Ascarateil S, van der Ven A, Thomas A, Sauerwein R - PLoS ONE (2008)

Bottom Line: Induration occurred in the Montanide 50 microg group, resulting in a sterile abscess in two volunteers.All adverse events resolved.There were no vaccine-related serious adverse events.

View Article: PubMed Central - PubMed

Affiliation: Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. M.Roestenberg@mmb.umcn.nl

ABSTRACT

Background: Plasmodium falciparum Apical Membrane Antigen 1 (PfAMA1) is a candidate vaccine antigen expressed by merozoites and sporozoites. It plays a key role in red blood cell and hepatocyte invasion that can be blocked by antibodies.

Methodology/principal findings: We assessed the safety and immunogenicity of recombinant PfAMA1 in a dose-escalating, phase Ia trial. PfAMA1 FVO strain, produced in Pichia pastoris, was reconstituted at 10 microg and 50 microg doses with three different adjuvants, Alhydrogel, Montanide ISA720 and AS02 Adjuvant System. Six randomised groups of healthy male volunteers, 8-10 volunteers each, were scheduled to receive three immunisations at 4-week intervals. Safety and immunogenicity data were collected over one year. Transient pain was the predominant injection site reaction (80-100%). Induration occurred in the Montanide 50 microg group, resulting in a sterile abscess in two volunteers. Systemic adverse events occurred mainly in the AS02 groups lasting for 1-2 days. Erythema was observed in 22% of Montanide and 59% of AS02 group volunteers. After the second dose, six volunteers in the AS02 group and one in the Montanide group who reported grade 3 erythema (>50 mm) were withdrawn as they met the stopping criteria. All adverse events resolved. There were no vaccine-related serious adverse events. Humoral responses were highest in the AS02 groups. Antibodies showed activity in an in vitro growth inhibition assay up to 80%. Upon stimulation with the vaccine, peripheral mononuclear cells from all groups proliferated and secreted IFNgamma and IL-5 cytokines.

Conclusions/significance: All formulations showed distinct reactogenicity profiles. All formulations with PfAMA1 were immunogenic and induced functional antibodies.

Trial registration: (Clinicaltrials.gov) NCT00730782.

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Related in: MedlinePlus

Study flow chart showing number of volunteers randomised, withdrawn and completing follow-up.Coding for adjuvant as follows: Alum = Alhydrogel™, Mon = Montanide. Reasons for withdrawal are given: “rash” = allergic rash unrelated to study procedure, “erythema” = grade 3 injection site erythema leading to withdrawal, “other vac.” = concomitant Hepatitis B vaccination leading to exclusion.
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pone-0003960-g001: Study flow chart showing number of volunteers randomised, withdrawn and completing follow-up.Coding for adjuvant as follows: Alum = Alhydrogel™, Mon = Montanide. Reasons for withdrawal are given: “rash” = allergic rash unrelated to study procedure, “erythema” = grade 3 injection site erythema leading to withdrawal, “other vac.” = concomitant Hepatitis B vaccination leading to exclusion.

Mentions: Participants were recruited at the Radboud University Nijmegen Medical Centre from September to October 2005. Of 92 adult males screened in and having provided informed consent, 56 were eligible and enrolled (fig. 1). Main reasons for exclusion were abnormal laboratory parameters or unable to be closely monitored for social, geographic or psychological reasons. Table 1 shows the demographics of volunteers per randomised group. The mean age was 23 years old (range 18–42 years) and all but one were Caucasian.


Safety and immunogenicity of a recombinant Plasmodium falciparum AMA1 malaria vaccine adjuvanted with Alhydrogel, Montanide ISA 720 or AS02.

Roestenberg M, Remarque E, de Jonge E, Hermsen R, Blythman H, Leroy O, Imoukhuede E, Jepsen S, Ofori-Anyinam O, Faber B, Kocken CH, Arnold M, Walraven V, Teelen K, Roeffen W, de Mast Q, Ballou WR, Cohen J, Dubois MC, Ascarateil S, van der Ven A, Thomas A, Sauerwein R - PLoS ONE (2008)

Study flow chart showing number of volunteers randomised, withdrawn and completing follow-up.Coding for adjuvant as follows: Alum = Alhydrogel™, Mon = Montanide. Reasons for withdrawal are given: “rash” = allergic rash unrelated to study procedure, “erythema” = grade 3 injection site erythema leading to withdrawal, “other vac.” = concomitant Hepatitis B vaccination leading to exclusion.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2602972&req=5

pone-0003960-g001: Study flow chart showing number of volunteers randomised, withdrawn and completing follow-up.Coding for adjuvant as follows: Alum = Alhydrogel™, Mon = Montanide. Reasons for withdrawal are given: “rash” = allergic rash unrelated to study procedure, “erythema” = grade 3 injection site erythema leading to withdrawal, “other vac.” = concomitant Hepatitis B vaccination leading to exclusion.
Mentions: Participants were recruited at the Radboud University Nijmegen Medical Centre from September to October 2005. Of 92 adult males screened in and having provided informed consent, 56 were eligible and enrolled (fig. 1). Main reasons for exclusion were abnormal laboratory parameters or unable to be closely monitored for social, geographic or psychological reasons. Table 1 shows the demographics of volunteers per randomised group. The mean age was 23 years old (range 18–42 years) and all but one were Caucasian.

Bottom Line: Induration occurred in the Montanide 50 microg group, resulting in a sterile abscess in two volunteers.All adverse events resolved.There were no vaccine-related serious adverse events.

View Article: PubMed Central - PubMed

Affiliation: Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. M.Roestenberg@mmb.umcn.nl

ABSTRACT

Background: Plasmodium falciparum Apical Membrane Antigen 1 (PfAMA1) is a candidate vaccine antigen expressed by merozoites and sporozoites. It plays a key role in red blood cell and hepatocyte invasion that can be blocked by antibodies.

Methodology/principal findings: We assessed the safety and immunogenicity of recombinant PfAMA1 in a dose-escalating, phase Ia trial. PfAMA1 FVO strain, produced in Pichia pastoris, was reconstituted at 10 microg and 50 microg doses with three different adjuvants, Alhydrogel, Montanide ISA720 and AS02 Adjuvant System. Six randomised groups of healthy male volunteers, 8-10 volunteers each, were scheduled to receive three immunisations at 4-week intervals. Safety and immunogenicity data were collected over one year. Transient pain was the predominant injection site reaction (80-100%). Induration occurred in the Montanide 50 microg group, resulting in a sterile abscess in two volunteers. Systemic adverse events occurred mainly in the AS02 groups lasting for 1-2 days. Erythema was observed in 22% of Montanide and 59% of AS02 group volunteers. After the second dose, six volunteers in the AS02 group and one in the Montanide group who reported grade 3 erythema (>50 mm) were withdrawn as they met the stopping criteria. All adverse events resolved. There were no vaccine-related serious adverse events. Humoral responses were highest in the AS02 groups. Antibodies showed activity in an in vitro growth inhibition assay up to 80%. Upon stimulation with the vaccine, peripheral mononuclear cells from all groups proliferated and secreted IFNgamma and IL-5 cytokines.

Conclusions/significance: All formulations showed distinct reactogenicity profiles. All formulations with PfAMA1 were immunogenic and induced functional antibodies.

Trial registration: (Clinicaltrials.gov) NCT00730782.

Show MeSH
Related in: MedlinePlus