Posted by: Daan Kersbergen
Trials around Vaccines
In the previous post, an overview was provided about several types of candidate vaccines and their working mechanisms. In this topic, we will evaluate several trials around the Sm-p80 vaccine against Schistosomiasis.
Probably one of the most promising candidate vaccines based on clinical outcomes is the Sm-p80 vaccine which is based on a subunit (Sm-p80) of the Calpain protein on the skin of adult schistosomes. The vaccine is tested in primates (e.g., baboons) and has already reached a Phase-I trial among naive adults in the United States (Phase-Ia). This will be followed by a larger setup in Africa among adults and school children (Phase-Ib). To evaluate this protein-based type of vaccine, we will assess the next articles about a study setup of the Sm-p80 vaccine among baboons:
Zhang W et al. Sm-p80-based schistosomiasis vaccine: double-blind preclinical trial in baboons demonstrates comprehensive prophylactic and parasite transmission-blocking efficacy. Ann N Y Acad Sci. (1)
Siddiqui AJ et al. Sm-p80-based vaccine trial in baboons: efficacy when mimicking natural conditions of chronic disease, praziquantel therapy, immunization, and Schistosoma mansoni re-encounter: Sm-p80 vaccine mimicking natural conditions. Ann N Y Acad Sci. (2)
Study setups
In the study of Zhang et al., 10 specific pathogen-free (SPF) olive baboons were selected to test the Sm-p80 vaccine. All baboons were prescreened to check for parasites and Sm-p80 cross-reactive antibodies. The baboons were divided into two groups: a control group (n = 5) and an experimental group (n = 5). Each baboon of the experimental group was injected with 50 μg GLA-SE (a Toll-like receptor ligand that is used to formulate the vaccine (3)). The experimental group got 250 g of Sm-p80 formulated in 50 g GLA-SE. Both groups received a boost vaccine intramuscularly 3 times within 12 weeks (each 4 weeks). 8 weeks after the last boost, all baboons were challenged with 1000 cercariae of Schistosomiasis mansoni. This whole setup was done 4 times, independent and double-blind (this means a total of 40 baboons in the study).
Figure 1 : Overview of the setup of the Zhang et al. study.
The study of Siddiqui et al., has a slightly different study setup compared to the Zhang et al. study. In this study, a group of 10 baboons were selected and again divided into a control group (n = 5) and an experimental group (n = 5). All baboons were negative for parasites and cross-reactive antibodies. Before giving the vaccine, all baboons (independent on the group they belong to) were infected with 200 S. mansoni cercariae 5 times at 1-week intervals. Seven weeks following the last cercarial infection, the baboons were treated 3 times with a 60 mg/kg oral dose of praziquantel (PZQ, an antihelminthic frequently given in helminth infections (4)) at 4-week intervals to recreate natural conditions, disease progression and treatment like in human Schistosomiasis infections. Efficacy of PZQ treatment was monitored. After this treatment, the experimental group was immunized with 250 μg Sm-p80 in 250 μg CpG-ODN (short ss-DNA molecules), while the control group received 250 μg CpG-ODN only. The vaccine and placebo were given three times at 4-week intervals. 4 weeks after the last immunization, each baboon was challenged with 1000 S. mansoni cercariae.
Figure 2: Overview of the setup of the Siddiqui et al. study. (2)
Study results
After explaining the study setups, we will provide an overview of the most important results of the studies.
In the Zhang et al. study, the researchers evaluated the number of eggs per gram tissue (via necroscopy), an important parameter for the efficacy of the vaccine in preventing severe disease. Results are shown in the following graph:
Figure 3: Zhang et al. Number of eggs per gram of tissue (1)
As shown in the graph, in all the tissues that were evaluated, the reduction of eggs was in all tissues above 86% in vaccinated primates, so this might be a promising effect due to the Sm-p80 vaccine. Egg expulsion in the feces was also reduced 35-fold in vaccinated animals, which could play an important role in the transmission of the disease.
In the Siddiqui et al. study, the researchers mainly focused on the amount of eggs in the tissue of the baboons as the most important indicator of severe disease. As in the previous study, outcomes were shown as reduction in the number of eggs in several tissues. Results are presented in the next graph:
Figure 4: Siddiqui et al. Number of eggs per gram of tissue (2)
The reduction the researchers found in the vaccinated baboons differs between 37-72%. The highest reduction of eggs was found in the small intestine (72,17%), while reduction in the liver tissue was 37,97%.
Critical Appraisal of the Sm-p80 vaccine
With the results of the studies shown above, it is important to consider if the Sm-p80 vaccine might be helpful in preventing disease due to S. mansoni. As already said, the number of eggs in tissue is an important parameter in assessing the efficacy of the vaccine in preventing severe sickness or transmission via water. One of the most striking differences between the studies is the reduction in the amount of eggs in mainly the liver and large intestine. This is probably caused by the more natural setup of the Siddiqui et al. study compared to the Zhang et al. study (where they firstly encountered the baboons with S. mansoni and treated them with PZQ). The Siddiqui et al. study shows perhaps a more obvious situation: when a vaccine is launched, it will be given to both infected and uninfected humans. When the different study setup is responsible for the different outcomes, it may be the case that the Sm-p80 vaccine results from the Zhang et al. study are not as promising as it is presented. The Siddiqui et al. study presents a more likely situation of a human population eligible for vaccination and this study shows a lower reduction of eggs compared to the Zang et al. study (see also figure 1 and 2).
Another issue that arises from these studies, is the focus on eggs or on worms. When evaluating the total reduction of worms, the Zhang et al. study found a total survival rate of 7% of the female worms, while the Siddiqui et al. study reports a total worm burden reduction of 13.9%, so a survival of above 80%. This is a huge difference, the question again arises if this can be explained by the different study setup. It is questionable if the focus only on eggs or IgG antibody titers is correct. Antibody titers do not provide information about the reduction in disease burden, so the IgG antibody titer might not be a suitable parameter.
We want to address another topic in evaluating these studies. When we look at the big difference in efficacy of the vaccine the studies show us, it is questionable if the studies are useful in a human population. If results differ between baboons, the question arises whether this vaccine works in humans. This should be tested, but how to set up a study to test the vaccine in a safe way? To design a study in humans, it will be necessary to have control about their infection status, the time they were infected and the amount of cercariae they have encountered. This information will be essential in starting up a Phase II or III trial. For example, this can be done by performing a Controlled Human Infection trail. And what about vaccination of a human population that had probably already encountered an infection with S. mansoni or other parasitic infections? The baboons were all free of parasites, but the question still remains whether the vaccine works for infected subjects. Further research is needed to explore this field.
In conclusion, the literature shows some promising results of the Sm-p80 vaccine. However, current research shows that this vaccine will not completely eliminate the disease burden due to infection with Schistosomiasis. Further research around this vaccine is necessary. Furthermore, new techniques and innovations have to be examined in terms of vaccine development. In the next topic, we will show you some of these innovations.
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