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Safety and Immunogenicity of a Malaria Vaccine, Plasmodium falciparum AMA-1/MSP-1 Chimeric Protein Formulated in Montanide ISA 720 in Healthy Adults

6 Aug 2008

Maria Victoria Valero

Citation: Hu J, Chen Z, Gu J, Wan M, Shen Q, et al. (2008) Safety and Immunogenicity of a Malaria Vaccine, Plasmodium falciparum AMA-1/MSP-1 Chimeric Protein Formulated in Montanide ISA 720 in Healthy Adults. PLoS ONE 3(4): e1952.

The development and spread of antimalarial drug resistance is among several factors hindering the control of Plasmodium falciparum malaria. Several malaria vaccine candidates have been evaluated in preclinical, clinical and field studies Unfortunately, a vaccine will not be available for many years (1,2).

Merozoite surface protein-1 (MSP1) and the apical membrane antigen-1 (AMA-1) of Plasmodium falciparum are two proteins of the asexual blood-stages. Both are located on merozoite surface protein and have been implicated in parasite invasion of red cells. Both candidate proteins induce inhibitory antibodies in rabbits and monkeys (3,4). However, the small size of the antigens limits the ability of each alone to adequately induce the high titre of antibodies that may be required to be effective in vivo. Chimeric protein vaccine constructs may offer a good approach. Pf CP29, was constructed with both antigens. Anti-PfCP-2.9 sera from rabbits and rhesus monkeys at a six to seven-fold dilution nearly completely inhibited in vitro growth of the P. falciparum FCC1/HN and 3D7 strains (5).

The Phase I clinical trial reported by Hu et al., was designed to evaluate (in healthy adults) the safety, immunogenicity and reactogenicity of PfCP-2.9 recombinant vaccine formulated with the novel adjuvant Montanide ISA720. The randomized, single-blinded, placebo controlled, dose-escalation study was conducted at the Chinese National Medicament Clinical Study Base, Changhai Hospital in Shanghai, China. From the 62 subjects, 52 were randomly allocated to five groups and 10 standbys. Four groups (10 participants in each group) received the vaccine formulation of either 20 mg, 50 mg, 100 mg or 200 mg, while the fifth (12 participants) received placebo.

The most common adverse event reported was tenderness (58%). This was followed by swelling (18%), induration (9%) and pain at the injection site (10%). Ninety-three per cent of these events were graded as grade 1 or mild in intensity. Fifty-eight per cent of participants in the placebo control group, compared with 80% of total participants in the vaccine groups, experienced at least one local adverse event. Systemic adverse reactions observed in this study include fever, rash, headache, hypotension and hypertension, abdominal pain, diarrhoea, and the common cold. Hypotension (78%) and hypertension (20%) were the most frequently reported. Moreover, the events were similar for participants receiving the vaccine or placebo, and there was no trend towards increased reactions with increasing doses of the vaccine. The results of the immunogenicity evaluation of the PfCP2.9 vaccine showed that antigen-specific antibody responses were induced in the participants receiving the test vaccine. In addition these antibodies recognize natural antigens by immunofluorescent antibodies, but were not related with significantly inhibited growth of cultured parasites in an in vitro growth inhibition assay.

These results suggest complementary studies must be carried out, in order to establish the possible protective efficacy of the antibody titre under natural or induced parasite challenge. Other studies suggest that inhibition studies have limited validity (2,3). On the other hand, it is important to evaluate the adverse effects associated with the adjuvant in which the construct was formulated (Montanide). This adjuvant induces a high immune response in animals but it use has been restricted in humans. The use of this kind of adjuvant must be carefully studied, not only for child vaccination but also for possible implementation in Expanded Programmes of Immunization.

Barriers to vaccine development include an inadequate understanding of certain aspects of host-parasite biology and protective immune responses. Other challenges are to increase the antigenicity of some antigens, and to optimize the quality of the immune response (5). However, it looks like research funding remains the main obstacle.

References

1. Ringwald P (2007). Current antimalarial drugs: resistance and new strategies. Bull Acad Natl Med 191(7):1273-1284. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18447049 (abstract only)

2. Leroy O (2007). Perspectives and challenges of malaria vaccine. Why we must do more. Bull Acad Natl Med 191(7):1249-1259. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18447047 (abstract only)

3. Lozano JM, Espejo F, Vera R, Vargas LE, Rosas J, Lesmes L, Torres E, Cortés J, Silva Y, Patarroyo ME (2005). Protection against malaria induced by chirally modified Plasmodium falciparum's MSP-1 42 pseudopeptides. Biochem Biophys Res Commun; 329(3):1053-1066. Available from: http://dx.doi.org/10.1016/j.bbrc.2005.01.165

4. Lozano JM, Alba MP, Vanegas M, Silva Y, Torres-Castellanos JL, Patarroyo ME (2003). MSP-1 malaria pseudopeptide analogs: biological and immunological significance and three-dimensional structure. Biol Chem; 384(1):71-82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12674501 (abstract only)

5. Pan W, Huang D, Zhang Q, Qu L, Zhang D, et al. (2004). Fusion of two malaria vaccine candidate antigens enhances product yield, immunogenicity, and antibody-mediated inhibition of parasite growth in vitro. J Immunol 172; 6167-6174. Available from: http://www.jimmunol.org/cgi/content/abstract/172/10/6167

2008 Hu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Source

Title:
Safety and immunogenicity of a malaria vaccine, Plasmodium falciparum AMA-1/MSP-1 chimeric protein formulated in montanide ISA 720 in healthy adults.

Authors:
Hu J, Chen Z, Gu J, Wan M, Shen Q, Kieny MP, He J, Li Z, Zhang Q, Reed ZH, Zhu Y, Li W, Cao Y, Qu L, Cao Z, Wang Q, Liu H, Pan X, Huang X, Zhang D, Xue X, Pan W

References:
PLoS ONE 2008: Vol. 3 no. 4, pp. e1952

Abstract:
BACKGROUND: The P. falciparum chimeric protein 2.9 (PfCP-2.9) consisting of the sequences of MSP1-19 and AMA-1 (III) is a malaria vaccine candidate that was found to induce inhibitory antibodies in rabbits and monkeys. This was a phase I randomized, single-blind, placebo-controlled, dose-escalation study to evaluate the safety and immunogenicity of the PfCP-2.9 formulated with a novel adjuvant Montanide ISA720. Fifty-two subjects were randomly assigned to 4 dose groups of 10 participants, each receiving the test vaccine of 20, 50, 100, or 200 microg respectively, and 1 placebo group of 12 participants receiving the adjuvant only. METHODS AND FINDINGS: The vaccine formulation was shown to be safe and well-tolerated, and none of the participants withdrew. The total incidence of local adverse events (AEs) was 75%, distributed among 58% of the placebo group and 80% of those vaccinated. Among the vaccinated, 65% had events that were mild and 15% experienced moderate AEs. Almost all systemic adverse reactions observed in this study were graded as mild and required no therapy. The participants receiving the test vaccine developed detectable antibody responses which were boosted by the repeated vaccinations. Sixty percent of the vaccinated participants had high ELISA titers (>1:10,000) of antigen-specific antibodies which could also recognize native parasite proteins in an immunofluorescence assay (IFA). CONCLUSION: This study is the first clinical trial for this candidate and builds on previous investigations supporting PfCP-2.9/ISA720 as a promising blood-stage malaria vaccine. Results demonstrate safety, tolerability (particularly at the lower doses tested) and immunogenicity of the formulation. Further clinical development is ongoing to explore optimizing the dose and schedule of the formulation to decrease reactogenicity without compromising immunogenicity. TRIAL REGISTRATION: Chinese State Food and Drug Administration (SFDA) 2002SL0046; Controlled-Trials.com ISRCTN66850051 [66850051].

PMID: 18398475
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