Ellis, RD, Mullen, GE, Pierce, M, Martin, LB, Miura, K, Fay, MP et al.. A Phase 1 study of the blood-stage malaria vaccine candidate AMA1-C1/Alhydrogel with CPG 7909, using two different formulations and dosing intervals. Vaccine 27: 4104-4109

Malaria Vaccine Development Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Twinbrook I, MD 20852, USA.
Vaccine (Impact Factor: 3.62). 06/2009; 27(31):4104-9. DOI: 10.1016/j.vaccine.2009.04.077
Source: PubMed


A Phase 1 study was conducted in 24 malaria naïve adults to assess the safety and immunogenicity of the recombinant protein vaccine apical membrane antigen 1-Combination 1 (AMA1-C1)/Alhydrogel with CPG 7909 in two different formulations (phosphate buffer and saline), and given at two different dosing schedules, 0 and 1 month or 0 and 2 months. Both formulations were well tolerated and frequency of local reactions and solicited adverse events was similar among the groups. Peak antibody levels in the groups receiving CPG 7909 in saline were not significantly different than those receiving CPG 7909 in phosphate. Peak antibody levels in the groups vaccinated at a 0,2 month interval were 2.52-fold higher than those vaccinated at a 0,1 month interval (p=0.037, 95% CI 1.03, 4.28). In vitro growth inhibition followed the antibody level: median inhibition was 51% (0,1 month interval) versus 85% (0,2 month interval) in antibody from samples taken 2 weeks post-second vaccination (p=0.056).

Download full-text


Available from: Greg Mullen,
44 Reads
  • Source
    • "The combination of Al(OH) 3 and a CpG oligodeoxynucleotide (CpG) that activates via TLR9 can enhance antibody titers 10-fold or more over either adjuvant alone in mice [14]. In humans, CpG combined with Al(OH) 3 enhanced antibody titers against four different antigens by at least 5-fold compared to Al(OH) 3 as sole adjuvant,[15] [16] [17] [18] and, in one study where it was evaluated, also significantly enhanced antibody affinity[19]. Herein, we describe our findings in mice and monkeys testing the ability of CpG to enhance anti-nicotine antibody functionality induced in response to a model anti-nicotine vaccine comprised of trans-3′ aminomethylnicotine conjugated to diphtheria toxoid (3′AmNic-DT) as antigen and Al(OH) 3 as adjuvant. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tobacco smoking is one of the most preventable causes of morbidity and mortality, but current smoking cessation treatments have relatively poor long term efficacy. Anti-nicotine vaccines offer a novel mechanism of action whereby anti-nicotine antibodies (Ab) in circulation prevent nicotine from entering the brain, thus avoiding the reward mechanisms that underpin nicotine addiction. Since antibody responses are typically long lasting, such vaccines could potentially lead to better long-term smoking cessation outcomes. Clinical trials of anti-nicotine vaccines to date have not succeeded, although there was evidence that very high anti-nicotine Ab titers could lead to improved smoking cessation outcomes, suggesting that achieving higher titers in more subjects might result in better efficacy overall. In this study, we evaluated CpG (TLR9 agonist) and aluminum hydroxide (Al(OH)3) adjuvants with a model anti-nicotine antigen comprising trans-3'aminomethylnicotine (3'AmNic) conjugated to diphtheria toxoid (DT). Anti-nicotine Ab titers were significantly higher in both mice and non-human primates (NHP) when 3'AmNic-DT was administered with CpG/Al(OH)3 than with Al(OH)3 alone, and affinity was enhanced in mice. CpG also improved functional responses, as measured by nicotine brain levels in mice after intravenous administration of radiolabeled nicotine (30% versus 3% without CpG), or by nicotine binding capacity of NHP antisera (15-fold higher with CpG). Further improvement should focus on maximizing Ab function, which takes into account both titer and avidity, and this may require improved conjugate design in addition to adjuvants.
    International immunopharmacology 04/2013; 16(1). DOI:10.1016/j.intimp.2013.03.021 · 2.47 Impact Factor
  • Source
    • "While they may reduce the parasite load of individuals living in endemic areas, they do not mediate sterile protection or total suppression of parasites in the blood (Genton et al., 2002). Recently, an apical merozoite antigen (AMA)-1 based vaccine that induces high antibody titers, and high GIA responses in vitro in human vaccinees (Ellis et al., 2009) was evaluated for its protective effect in a blood challenge. To this end, the vaccinees were immunized and then challenged with blood infected with the 3D7 parasite clone. "
    Malaria Parasites, 03/2012; , ISBN: 978-953-51-0326-4
  • Source
    • "Bc activation and proliferation can also be induced by CpG acting through Toll-like receptor 9 (TLR-9). TLR-9 agonists improve production of antibody by Bc responding to vaccine12, and are in clinical trials as vaccine adjuvants13. We have previously shown that a combination of CpG2008 ODN and cytokines (IL-2, IL-10, IL-15, and BAFF) can induce in vitro mBc differentiation into CD138+ plasma cells9. "
    [Show abstract] [Hide abstract]
    ABSTRACT: During the human B cell (Bc) recall response, rapid cell division results in multiple Bc subpopulations. The TLR-9 agonist CpG oligodeoxynucleotide, combined with cytokines, causes Bc activation and division in vitro and increased CD27 surface expression in a sub-population of Bc. We hypothesized that the proliferating CD27(lo) subpopulation, which has a lower frequency of antibody-secreting cells (ASC) than CD27(hi) plasmablasts, provides alternative functions such as cytokine secretion, costimulation, or antigen presentation. We performed genome-wide transcriptional analysis of CpG activated Bc sorted into undivided, proliferating CD27(lo) and proliferating CD27(hi) subpopulations. Our data supported an alternative hypothesis, that CD27(lo) cells are a transient pre-plasmablast population, expressing genes associated with Bc receptor editing. Undivided cells had an active transcriptional program of non-ASC B cell functions, including cytokine secretion and costimulation, suggesting a link between innate and adaptive Bc responses. Transcriptome analysis suggested a gene regulatory network for CD27(lo) and CD27(hi) Bc differentiation.
    Scientific Reports 03/2012; 2:345. DOI:10.1038/srep00345 · 5.58 Impact Factor
Show more