Safety and immunogenicity of GMZ2 adjuvanted with aluminum hydroxide and CAF01 in semi-immune Gabonese volunteers and the impact of helminth infection on vaccine immunogenicity

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Dokumentart: PhDThesis
Date: 2020-10-19
Language: English
Faculty: 4 Medizinische Fakultät
Department: Medizin
Advisor: Mordmüller, Benjamin (Prof. Dr.)
Day of Oral Examination: 2020-07-28
DDC Classifikation: 610 - Medicine and health
Keywords: Malaria , Impfstoff , Plasmodium falciparum
Other Keywords:
candidate vaccine
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Despite a vast reduction of incidence and mortality rates during the beginning of the twenty-first century, malaria continues to be a threat to mankind. Especially in the recent years achievements have plateaued. In 2017 approximately 219 million cases occurred, of which 435,000 ended fatal. The majority of deaths occur in children and pregnant women. Previous successes are fragile and current key tools against malaria (ITN, IRS, and ACT) are under constant threat from emerging resistances. Especially the increased report of resistance of Plasmodiumm spp. strains to anti-malarial drugs in South Asia add to the complexity of the situation and indicate the urgent need to improve the strategy to control the disease. This is endorsed by the WHO and reflected in the “Global Technical Strategy for Malaria 2016–2030” that recognized the urgent need and pivotal importance of developing a vaccine against malaria for successful control and possible eradication of the disease. Until now RTS,S, a pre-erythrocytic malaria vaccine, has been the only vaccine to complete phase III development. It is currently undergoing an implementation phase IV study in three African countries after receiving scientific approval from the EMA and the WHO. Beside RTS,S, several others malaria vaccine candidates are currently assessed in clinical trials. GMZ2 is one of these vaccines and is a recombinant fusion protein consisting of conserved domains of GLURP and MSP3, two asexual blood-stage antigens of P. falciparum. It is designed mimicking naturally acquired anti-malarial blood-stage immunity. Clinical development of GMZ2 adjuvanted with Alhydrogel comprises several phase I trials conducted with children and adults in Africa as well as a recent phase II multi-center and multi-country trial. This phase II trial involving 1849 participants 12 to 60 months of age confirmed the good tolerability of the vaccine candidate. Even though the protection conferred by the vaccine was modest, it has demonstrated that the vaccine efficacy may be increased by improving the vaccine immunogenicity. A straight-forward approach is to modify the adjuvant in order to enhance the immunogenicity with the final aim to increase the overall vaccine efficacy. CAF01 is a novel liposomal adjuvant system inducing a robust and long lived humoral and cellular immune response characterized by a TH1 profile. Pre-clinical head-to-head comparison of CAF01 with Alhydrogel proved its superiority in immune enhancing properties. The current study was designed to assess tolerability and immunogenicity of GMZ2- CAF01, as a new formulation of the GMZ2 vaccine candidate. In addition, the impact of helminth infection on vaccine induced immune response was determined. The study was designed as a randomized, double blind, single-center phase I clinical trial conducted in Lambaréné, Gabon. Fifty healthy young males with an history of at least 10 years of malaria transmission were recruited and allocated to 4 different study arms: A (Rabies, as comparator vaccine; n = 8), B (100μg GMZ2-Alhydrogel; n = 12), C (30µg GMZ2- CAF01; n = 8), and D (100µg GMZ2-CAF01; n = 22). The participants were vaccinated on D0, D28, and D56 i.m. in alternating deltoid muscles. Safety and tolerability were assessed during the follow up with non-leading questions, symptom focused clinical examination and recurrent laboratory analysis. Immunogenicity was examined through the altitude of vaccine specific immunoglobulin titers measured with ELISA. Helminth infection status was evaluated by analyzing stool and blood samples at screening and on day 84. We confirmed that the vaccine candidate GMZ2 adjuvanted with CAF01 is well tolerated and safe. No serious or Grade 3 AE occurred. The predominant number of AEs was mild and pain at infection site. Safety signals were equivalent among study groups and GMZ2 formulations. Regarding the immunogenicity, GMZ2-CAF01 formulations elicited a robust immune response, which however was not superior to GMZ2-Alhydrogel. Interestingly, helminth infection positively affected the altitude of vaccine specific IgG. This contradicts previous findings. So far, depending on the helminth species, rather negative implications were demonstrated if helminths infections were present during vaccination. Particularly, a GMZ2 precursor trial, conducted by Esen et al. reported reduced immune response in the presence of T. trichiura. Reasons for the differences in immunogenicity outcome may be the distinct study populations, since Esen et al. assessed the immune response in children, whereas this study worked with semi-immune adult subjects. Moreover, any conclusions drawn from these results is limited by the low observation numbers. To evaluate these effects further, larger clinical trials are recommended. In reference to the induced vaccine efficacy and immunogenicity it is unlikely, that GMZ2 formulated with Alhydrogel or CAF01 can contribute to the fight against malaria. Still, it is proven that GMZ2 can elicit functional antibodies and that the vaccine efficacy increases with higher immunogenicity. Thus, a different GMZ2 formulation may still induce a sufficient vaccine efficacy. Among the potential adjuvant candidates immunopotentiating reconstituted influenza virosomes offer a promising proprietary vaccine platform. An improved GMZ2 formulation may further be combined with other malaria vaccines (e.g. sexual, sporogonic or mosquito stage vaccines interrupting malaria transmission) and complement current malaria control efforts in a potential malaria eradication program.

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