Abstract:
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.
GMZ2
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