Phase 1 Trial of AMA1-C1/Alhydrogel plus CPG 7909: An Asexual Blood-Stage Vaccine for Plasmodium falciparum Malaria

Abstract

BackgroundApical Membrane Antigen 1 (AMA1), a polymorphic merozoite surface protein, is a leading blood-stage malaria vaccine candidate. This is the first reported use in humans of an investigational vaccine, AMA1-C1/Alhydrogel, with the novel adjuvant CPG 7909.MethodsA phase 1 trial was conducted at the University of Rochester with 75 malaria-naive volunteers to assess the safety and immunogenicity of the AMA1-C1/Alhydrogel+CPG 7909 malaria vaccine. Participants were sequentially enrolled and randomized within dose escalating cohorts to receive three vaccinations on days 0, 28 and 56 of either 20 µg of AMA1-C1/Alhydrogel®+564 µg CPG 7909 (n = 15), 80 µg of AMA1-C1/Alhydrogel® (n = 30), or 80 µg of AMA1-C1/Alhydrogel+564 µg CPG 7909 (n = 30).ResultsLocal and systemic adverse events were significantly more likely to be of higher severity with the addition of CPG 7909. Anti-AMA1 immunoglobulin G (IgG) were detected by enzyme-linked immunosorbent assay (ELISA), and the immune sera of volunteers that received 20 µg or 80 µg of AMA1-C1/Alhydrogel+CPG 7909 had up to 14 fold significant increases in anti-AMA1 antibody concentration compared to 80 µg of AMA1-C1/Alhydrogel alone. The addition of CPG 7909 to the AMA1-C1/Alhydrogel vaccine in humans also elicited AMA1 specific immune IgG that significantly and dramatically increased the in vitro growth inhibition of homologous parasites to levels as high as 96% inhibition.Conclusion/SignificanceThe safety profile of the AMA1-C1/Alhydrogel+CPG 7909 malaria vaccine is acceptable, given the significant increase in immunogenicity observed. Further clinical development is ongoing.Trial RegistrationClinicalTrials.gov NCT00344539

Overcoming Allelic Specificity by Immunization with Five Allelic Forms of Plasmodium falciparum Apical Membrane Antigen 1

“…However, these two studies did not address whether C1L was the only critical region for antibodies other than AMA1-3D7 and AMA1-FVO antibodies. When U.S. adults were immunized with AMA1-C1, which is a mixture of AMA1-3D7 and FVO, the purified IgGs showed inhibitory activity against 3D7 and FVO parasites, as judged by GIA, as expected, but their activity was much less than their activity against L32 and M24 parasites (11). The data suggested that there may be other critical sites which are not covered by either 3D7 or FVO.…”

“…Indeed, there is evidence of balancing selection in domains I and III in field parasites from Nigeria (7), Papua New Guinea (8), Thailand (9), and Kenya (10). We and other investigators have conducted multiple phase 1 trials of AMA1 using AMA1-3D7, AMA1-FVO, or a mixture of both (AMA1-C1), and the antibodies induced by the vaccines showed strain-specific functional activities, as judged by the in vitro growth inhibition assay (GIA; also referred to as the invasion inhibition assay [IIA]) (11)(12)(13)(14). Only two phase 2 field trials with AMA1 vaccines have been conducted, and neither of them showed significant clinical protection in a target population of African children (15,16).…”

Non‐clinical safety evaluation of repeated intramuscular administration of the AS15 immunostimulant combined with various antigens in rabbits and cynomolgus monkeys

“…Furthermore, no signs of systemic toxicity were observed after single or repeated administrations of the malaria candidate vaccines formulated with AS01 or AS02 Adjuvant Systems in rabbits (Segal et al ., 2015). CpG ODNs have been tested as adjuvants in a number of non‐clinical and phase I–III clinical trials testing vaccines against infectious diseases (Cooper et al ., 2004a,2004b; Klinman et al ., 2006; Mullen et al ., 2008) and cancer (Brody et al ., 2010; Pilon‐Thomas et al ., 2006; Speiser et al ., 2005; Valmori et al ., 2007). In previous studies in non‐human primates or in humans, no significant toxicities were reported after injections of CpG 7909 even at high doses (Krieg et al ., 2004; Stewart et al ., 2008).…”

Molecular vaccines for malaria

“…68 Results from clinical studies using recombinant P. falciparum AMA1-C1/Alhydrogel plus CpG 7909 vaccine showed 14-fold-higher AMA1-specific IgG with significantly increased in vitro growth inhibitory activity against homologous parasites compared to AMA1/Alhydrogel alone. 69 Thus, TLR 9 agonists are effective immunomodulatory molecules for use as vaccine adjuvants.…”

“…As with adjuvants used with protein-based vaccines, adjuvants for gene-based vaccines require extensive safety evaluation. After nonclinical studies indicated that the oligonucleotide CPG 7909 significantly enhanced the immunogenicity of the recombinant protein-based malaria vaccine, AMA1-C1, 234,235 subsequent clinic testing raised concerns regarding the frequency of allergic reactions 69 and this in turn led to identification and testing of less allergenic formulations. 236 A major step in establishing safety of immunomodulatory adjuvant systems occurred with the co-administration of plasmids encoding human GM-CSF to healthy adults as an immunostimulant to improve the potency of the pentavalent MuStDO5 malaria vaccine (a mixture of five plasmids encoding pre-erythrocytic stage antigens).…”