Safety and Immunogenicity of a Recombinant Plasmodium falciparum AMA1 Malaria Vaccine Adjuvanted with Alhydrogel™, Montanide ISA 720 or AS02

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 FindingsWe 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 µg and 50 µg 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 µg 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50 mm) were withdrawn as they met the stopping criteria.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 IFNγ and IL-5 cytokines.Conclusions/SignificanceAll formulations showed distinct reactogenicity profiles. All formulations with PfAMA1 were immunogenic and induced functional antibodies.Trial RegistrationClinicaltrials.gov NCT00730782

Enhancing Blood-Stage Malaria Subunit Vaccine Immunogenicity in Rhesus Macaques by Combining Adenovirus, Poxvirus, and Protein-in-Adjuvant Vaccines

“…4C, 4D) (50). Overall, in vitro GIA was lower in all samples when purified IgG was assayed at 5 mg/ml, in agreement with other studies (41,51), and confirming that the growth inhibitory effect can be titrated out. In agreement with the trend for better maintenance of IgG titers following protein immunization in CoVaccine HT (Fig.…”

Phase I Safety and Immunogenicity Trial of Plasmodium vivax CS Derived Long Synthetic Peptides Adjuvanted with Montanide ISA 720 or Montanide ISA 51

“…Their intensity usually have been classified as mild to moderate, and SAEs reported such as erythema nodosum-like syndrome and transient leukemoid cases, seems to be more related to the antigen used than attributable directly to the adjuvant. 28,36,48 Montanide ISA 720 a squalenebased adjuvant, has also been tested in multiple malaria antigens clinical trials, which have reported from minor, 25 to mild and moderate local reactogenicity 37,49,50 ; however, a trial conducted with a malaria vaccine candidate formulated in this adjuvant had to be suspended because of the presence of SAEs. 43 In this study, all formulations were immunogenic inducing both, specific anti-peptide antibodies and IFN-γ production.…”

“…33 Several phase I clinical trials have been conducted using different malaria vaccine antigens in which these two adjuvants have been able to stimulate both humoral and cellular immune responses. [34][35][36][37] We present here a phase I clinical trial conducted with the same P. vivax CS derived peptides formulated in two different adjuvants, and provide further safety and immunogenicity data as part of a clinical development plan that aims at developing vaccines to prevent malaria.…”

Molecular vaccines for malaria

“…Although very potent immunologically, results from more recent malaria trials using montanides (ISA 51and ISA 720) have led to the conclusion that this class of adjuvant may have limited potential for further development due to local reactogenicity, including the induction of sterile abscesses and erythema multiforme. 57,58 Even as these various peptide/protein adjuvants are actively developed, understanding of the molecular mechanisms underlying their immunopotentiating properties remains modest. Development is driven empirically by the safety, immunogenicity and protection identified in pre-clinical and clinical testing, with purposeful molecular design playing a less central role.…”