Targets and mechanisms for anti-malaria vaccines.
\r\n\tIt is a relatively simple process and a standard tool in any industry. Because of the versatility of the titration techniques, nearly all aspects of society depend on various forms of titration to analyze key chemical compounds.
\r\n\tThe aims of this book is to provide the reader with an up-to-date coverage of experimental and theoretical aspects related to titration techniques used in environmental, pharmaceutical, biomedical and food sciences.
Malaria remains one of the major infectious diseases with a huge burden, affecting a large fraction of the world population. Although most of the deaths, caused by Plasmodium falciparum, P. vivax and to a lesser extent P. malariae and P. ovale, occurred in Africa; significant morbidity is evident in South America and Asia [1]. Different control measures such as insecticide-treated bed nets, powerful drugs (i.e., artemisinin-based combination therapies) and early diagnostics have had a positive impact in reducing malaria mortality worldwide [2]. However, these methods have led to complete eradication of malaria in only a few countries in intertropical zones [3]. This is mainly due to increasing drug resistance of the parasites and the failure of vector control strategies resulting from the change in mosquito behavior and the emergence of insecticide resistance [4, 5]. An antimalarial vaccine is thus a necessity to achieve the goal of complete global malaria eradication [6, 7].
\nVaccine development in malaria have employed a composite of rational and empirical approaches and depended on multiple epidemiological and experimental studies. Individuals living in endemic regions acquire immunity over time after repeated exposure to the parasites. Such immunity, also called premonition, is partial, species-specific and biphasic [8, 9]. In the first phase, the hosts still get infected but do not develop clinical symptoms. On the contrary, the second phase, which is the prevention or limitation of parasite multiplication, takes long to develop. This second phase is heavily dependent on parasite exposure - more the exposure the host gets, lesser the time this immunity takes to develop [9, 10]. Hence, the goal of vaccine strategies is to reduce the time needed to acquire protective immunity and to make the immunity long-lasting.
\nThe use of experimental models is critical to vaccine development. Many researchers advocate the use of human parasites in human hosts as it is the optimal experimental model for malaria [11]. However, field studies are inherently limited by the inability to control multiple experimental parameters such as the number of infective mosquito bites, the number of parasite per infective dose, and the genetic background of the host and parasite. In addition, there are numerous ethical considerations, which restrict access to peripheral blood samples for antibody and T cell studies, important for investigating long-term protection. Thus, many researchers have turned to more controllable models, such as monkey or human Plasmodium in monkeys [12, 13, 14] or rodent Plasmodium in mice [15]. Using these models, there have been numerous vaccination studies using genetically-attenuated parasites [16], irradiated parasites [17, 18], chemically-attenuated parasites [19, 20], live parasites under drug prophylaxis [21, 22, 23], and defined antigenic formulations [24, 25, 26, 27, 28, 29, 30]. These studies have demonstrated that vaccination can reduce parasite development, prevent pathology in infected animals, prevent transmission to mosquitoes, and even induce sterile immunity. Another major advantage of these models is that the outcomes following vaccination is well-defined and easily measurable, such as development of sterile immunity, inhibition of parasite development in the liver or in the blood, and/or prevention of certain pre-defined clinical signs or of pathologies. So far, only whole parasite formulations using irradiated sporozoites [31, 32] or live parasite immunization under chloroquine [33, 34, 35], and a limited number of sporozoite antigen formulations, such as RTS,S [36], have been shown to induce sterile immunity in significant proportion of the human volunteers.
Vaccine clinical testing in humans involves multiple phases. Phase IA involves a small group of naïve volunteers (<100), from non-endemic regions, with no previous experience of malaria, while Phase I involves malaria-exposed individuals from endemic regions. In both phases, vaccine safety and immunogenicity are assessed. Only after the vaccine has shown a good safety profile with encouraging immunogenicity data, phase IIa test study can be initiated with a larger set of volunteers (>100–1000) from non-endemic regions. In Phase IIa, vaccine efficacy is assessed by subjecting the volunteers to a challenge with mosquito bites or intravenous injections of infected red blood cells. Phase IIb involves assessing the vaccine efficacy in a larger set of volunteers from endemic regions. Promising Phase II results qualify moving the vaccine testing to Phase III, which comprises assessing vaccine safety (including potential side effects) and efficacy over a longer time period in a cohort consisting of thousands of volunteers from endemic regions. If sufficient safety and efficacy has been demonstrated in Phase III (2 to 5 years), the vaccine can then be licensed and marketed for human use, after which mass-deployment for endemic regions can be launched.
\nA malaria vaccine could potentially target many different stages of the infection. It could work by: (1) preventing de novo infection (either in the liver or the blood), (2) controlling parasite levels in the blood and duration of the blood infection, (3) preventing pathology induced by the infection and thus preventing or reducing morbidity or mortality, and (4) preventing or reducing transmission to mosquitoes. However, not all of these outcomes can be assessed accurately in the field. Only the first and fourth outcomes mentioned can be assessed accurately and experimentally with reproducible results, mainly due to the standard operating procedures that have been implemented over the years.
\nOutcome assessment in the field is complicated due to the nature of the infection itself. In endemic regions, malaria infections are usually chronic [37]. Low-level parasite persistence may affect immune reactivity by amplifying or down-regulating vaccine-induced immune responses. It may also confuse diagnostics such as fever detection [38]. Occurrence and extent of chronicity may vary according to age, endemicity and host genetics. Thus, in many trials, antimalarial treatments are applied to the tested cohorts to clear prior malarial infections to reduce confounding factors [39].
\nPresence of co-infections is another factor that makes outcome assessment in the field difficult. Often, endemic cohorts are also infected with other pathogens, such as worms, bacteria or viruses, without being overtly sick [40, 41, 42, 43, 44]. Immune responses to these pathogens may either potentiate or inhibit the development of the protective response induced by infection or vaccination [45]. Due to cost constraints, it is rarely possible to make a full analysis for all possible pathogens, but it is advisable to perform retrospective studies to assess their possible influence on the malaria vaccination outcomes.
\nAnother major roadblock for malaria vaccine development is the absence of correlates or surrogate markers of protection. These markers are crucial as they would facilitate the testing of large sets of vaccine formulations and would reduce costs and organization constraints [46]. As an example, vaccine development against Hepatitis B was greatly simplified when it was shown that concentration of Hepatitis B S antigen antibodies over 10 UI/ML level was a surrogate marker of protection (for review Plotkin et al.) [47]. This greatly accelerated the testing of multiple new formulations in a limited number of volunteers and also helped in the development of subsequent improved formulations. There is clearly a gap in our knowledge of the immune correlates of protection against malaria. It is still not clearly known what defense mechanisms are crucial in humans for mediating protection against malaria. This severely handicaps our progress towards effective vaccine development [48].
\nTo assess vaccine efficacy in the field, it is also critical to have epidemiological data concerning the vaccine site. The level of endemicity will have an impact on the surveillance time following the last immunization and also on the size of the cohort. Low endemic conditions will require longer follow-up and a larger cohort to obtain statistically significant results.
\nThe malaria parasite has a complex life cycle, alternating between the human and mosquito host. In the human host, the malaria parasite transits across different body compartments and alternates between intracellular and extracellular locations (Figure 1). This developmental complexity of the malaria parasite has a profound impact on the study design of the malaria vaccine and assessment efficacy (Table 1).
\nPlasmodium falciparum life cycle and vaccine strategies. The cycle in humans includes three stages: the pre-erythrocytic stage, which is asymptomatic; the asexual blood stage, which induces pathology; and the sexual stage, which is transmitted to Anopheles mosquitoes. At each of these stages, the parasite expresses various proteins that are targets of vaccine candidates. The different vaccine strategies for each stage are indicated.
Targets | \nInduced immunity | \nMechanisms | \nReadout | \n
Pre-erythrocytic vaccines | \n|||
Sporozoite antigens Liver stage antigens | \nInhibition of parasite development and replication/survival | \nAntibodies against sporozoites T cells against liver stage | \nPresence of parasites in the blood | \n
Blood stage vaccines | \n|||
Asexual blood stage antigens | \nInhibition of erythrocyte invasion and parasite replication/survival | \nAntibodies Antibody cell dependent inhibition (ADCI) Cellular immunity | \nBlood parasite load | \n
Parasite derived toxins Parasite adhesion ligands | \nInhibition of pathogenesis | \nAntibodies neutralizing inflammatory factors Antibodies inhibiting parasite/host interactions | \nFever Blood parasite load Severe complications* | \n
Transmission-blocking vaccines | \n|||
Sexual blood stage antigens Mosquito stage antigens | \nInhibition of parasite development in the mosquito | \n\n Antibodies blocking gamete mating, ookinete formation or oocyst maturation | \nPresence of parasites in the mosquito vector (midgut, salivary glands) | \n
Targets and mechanisms for anti-malaria vaccines.
During the pre-erythrocytic stage, the parasites exist as the extracellular motile sporozoite upon injection by the mosquito during feeding, and the intracellular liver parasites. Vaccines developed to target the pre-erythrocytic stage aim at inducing antibodies that target mainly the sporozoites and/or inducing T cells that will eliminate intracellular hepatic forms, thus preventing or controlling the extent of the subsequent blood stage development.
\nVaccines targeting the asexual blood stages of the parasites are divided into two categories. The vaccines can be anti-parasite, which aim to control and eliminate parasite development in the blood or anti-disease, which aim to prevent the pathologies induced by the parasite. These vaccines need to induce different types of immune responses targeting different phases of the asexual blood stage. Vaccines targeting the sexual stage parasites aim to prevent transmission of gametocytes to the mosquito and/or gamete mating and ookinete development in the mosquito midgut.
\nIt is worth noting that while the parasite expresses different set of genes at different stages of its life cycle, there are also many antigens that are expressed across the different parasite stages. Vaccination against these shared antigens may have an effect at different phases of the life cycle [22, 49, 50, 51, 52], making them just as attractive for vaccine against malaria.
\nFor anti-parasite vaccines targeting the pre-erythrocytic stage, the assessment of vaccine efficacy is relatively easy. Complete efficacy for this stage is defined as sterile protection, whereby no parasite can be detected in blood of immunized individuals after the sporozoite challenge. This is an all or none phenomenon, because a single sporozoite developing in the liver can lead to full-blown blood infections.
\nIntuitively, one would expect great success of pre-erythrocytic vaccines since the limited numbers of sporozoites (a mean of 5–50) injected by infected mosquitoes [53] would be easily eliminated by the different arms of the immune system induced by the vaccine. However, this has proved to be the contrary. To date, only one vaccine formulation, RTS,S, an hybrid molecule containing a large segment of the circumsporozoite protein and S antigen of the Hepatitis B virus mixed with the AS02 adjuvant, has been shown to induce sterile protection in a substantial proportion of the naïve volunteers [36, 54] but to a much lower extent in field trials [55, 56, 57, 58].
\nOne reason that could contribute to the lack of success stories with pre-erythrocytic anti-parasite vaccines is the procedures implemented to assess protection. Immunized volunteers were subjected to five mosquito bites, a dose required to ensure that naïve control volunteers would develop patent parasitemia 7–14 days after challenge [59, 60]. Alternative protocols using purified sporozoites injected either intradermal or intravenously have been developed, and so far, have proven to be safe and reproducible [61, 62]. Detection of parasitemia is performed by microscopy on Giemsa-stained blood smears over a 20–25-day period. Once a positive blood film is confirmed, the volunteers were treated with blood schizonticides to eliminate blood parasites and prevent any blood stage parasite-induced pathologies [63]. One limitation of this method of detection is that the time taken to detect parasites in the blood can differ up to 7 days. Hence, a delay of parasitemia does not necessarily translate in reduction of liver load. Moreover, there might be other confounding factors affecting the ability to detect blood parasitemia that are not related to the vaccination. To address this problem, sensitive PCR methods have been developed to detect the first wave of released liver merozoites and to assess the efficacy of the vaccine against pre-erythrocytic parasites. Using elegant regression methods, quantitative PCR techniques [64, 65, 66, 67] allow an estimation of the reduction of the parasite liver load and an accurate measure of the effect on the growth rate of blood stage parasites.
\nAssessing pre-erythrocytic vaccine efficacy in the field is complicated due to factors mentioned earlier, such as the nature of the infection and presence of other co-infections. Evaluation of pre-erythrocytic vaccine in the field had mostly relied on microscopy and long follow-up (usually 6 to 24 months). As mentioned above, this assay may not be the most suitable to accurately assess the efficacy of any formulation targeting the pre-erythrocytic stage. In field conditions, many of the volunteers have been previously infected and, depending on age and exposure, may have developed some immunity against blood stage parasites. Thus, to eliminate possible confounding effects of a synergistic immunity of on-going blood stage infection with immunity induced by vaccination, it is important that volunteers are cleared by drug treatment of low-level parasitemia during immunization and before the surveillance period. It is also necessary that low-level blood infection occurrence be assessed by PCR. When implemented, this approach has reduced the follow-up time period to 1 month, saving costs and allowing the assessment of new formulations [39].
\nFor vaccines against the pre-erythrocytic stage of P. vivax, efficacy assessment is further complicated by the fact that this species may produce non-replicating liver form called hypnozoites. These hypnozoites are responsible for relapse up to 18 months after a sporozoite injection [68], thus complicating analysis and may require longer follow-up to detect relapse. Up to now, few challenges with P. vivax sporozoite have been performed [69]. There are no standard protocols and many issues need to be addressed [70]. First, the production of P. vivax sporozoites is limited since it requires infected blood from infected patients or monkeys to feed mosquitoes. Second, contrary to P. falciparum, no P. vivax cloned lines are available. Most of the lines available are derived from infected patients [71] or have been maintained in monkeys [72]. These lines contain multiple clones, which are poorly characterized at the molecular level [73]. This makes it difficult to obtain reproducible infection profile after experimental infection with mosquito bites of naïve volunteers and to characterize hypnozoite relapse profile. Moreover, as with anti-malarial drug studies in the field, the absence of validated genetic or serologic tools to distinguish between reinfection and relapse [74, 75, 76, 77] may also prevent detecting strain-specific effect. For anti-parasite vaccines targeting the blood stage, efficacy is assessed after sporozoite or asexual blood stage parasite challenge. Sterile protection occurs when no parasite can be detected in blood of immunized individuals. Detection of parasitemia can be monitored either by microscopy or by PCR, the latter providing more information. Due to its higher sensitivity, it allows the detection of at least 3–5 parasite cycles even before the parasite is detectable by microscopy. PCR [78, 79, 80, 81] bar-coding methods [82] can also be applied to genotype blood parasites. This allows assessing multiplicity of infection and determines whether the vaccine efficacy observed is strain-specific [83, 84]. Strain-specific vaccines have little interest since they will select vaccine-resistant parasites.
\nTo assess the vaccine efficacy of anti-parasite vaccines, a challenge is essential. As mentioned earlier, challenge can be performed using sporozoites or blood stage parasites. However, due to the limited availability of insectaries that can provide infected mosquitoes on a regular basis, and the absence of accepted surrogates of protection, there is a necessity for blood stage challenge in healthy volunteers. Contrary to murine or monkey models where direct challenge with blood stage parasites is common, challenge with blood stage parasites in human has only been performed in limited vaccine studies using naïve volunteers [85, 86]. Because of safety reasons, blood parasites used for challenge need to be fully characterized. For a long time, only 3D7, a clone of the NF54 line, has been used. This line is susceptible to a wide range of antimalarials. Other parasite lines have been recently developed [87, 88]. However, since most of blood stage candidates are polymorphic, it is of utmost importance to assess the effect of polymorphism to have an idea of potential vaccine coverage. In addition, blood cells used for blood stage parasite propagation need to be pre-screened for the presence of a wide range of potential pathogens [86].
\nDespite these limitations, studies have shown that blood stage challenge can be safe and may allow the assessment of anti-asexual blood stage vaccine efficacy [89, 90]. Moreover, as recently reported, blood stage growth in vivo could be quantified more accurately after challenge with asexual blood stage parasites than with sporozoites [91], highlighting the advantage of this procedure. However, as it is not possible for safety reasons to let the parasitemia develop to high levels, its application might be limited. Vaccine efficacy may depend on the development of additional immune responses by the host during infection, which requires more time to be active as shown in mouse model [92]. In addition, some immune mechanisms may need higher parasite challenge dose to be triggered. Antibody-dependent cell immunity or ADCI has been proposed to be effective with parasitemia approaching level detectable by microscopy [93].
\nIn endemic settings, efficacy of blood stage vaccines has been assessed in natural conditions after challenge by mosquito bites. This type of challenge is perfectly suited if the vaccine can induce sterile immunity. However, it might not be the most appropriate when blood parasite multiplication rate must be measured. This rate depends on the numbers of liver merozoites released and timing of their release. As mentioned above, liver merozoite release is not a homogenous phenomenon in terms of quantity and timing. Thus, to obtain parasite growth curve suitable for comparative analysis between individuals and groups, blood sampling must be carefully planned. Indeed, this implies an active and close follow-up of the volunteers to obtain multiple time points. One possibility to obtain more homogenous results would be to perform the challenge with defined number of infected red blood cells at a same time of infection across all groups [86, 94]. However, this requires overcoming a series of hurdles such as the development of standardized inoculums with known number of parasites at the same stage of development and the availability of donor blood, which have to be heavily tested for the presence of any pathogens. In addition, the parasite in the challenge inoculums would also need to be fully characterized and clearly defined in term of parasite clonality.
\nTo accurately assess the efficacy of anti-parasite blood stage vaccine, it is necessary to evaluate any pre-existing immune responses to the antigens in the blood stage vaccine. Individuals leaving in endemic areas acquire immunity over time. The time required to develop this immunity depends on the endemicity level and their genetic background. This immunity may influence growth rate of the parasite. Pre-existing immunity can synergize with the immunity induced by the vaccination. Vaccination may also boost pre-existing antigen-specific immune responses, which would be ideal for any vaccine formulations. On the contrary, pre-existing immune response may inhibit or mask the immune response induced by vaccination. It has been shown that the antibodies to the N-terminal of P. falciparum merozoite surface protein 1 can block the inhibitory activity of antibodies recognizing the C-terminal part [95]. Thus, if such an antibody interference mechanism exists for antigen(s) used in vaccine formulation, it would be necessary to evaluate carefully pre-existing immune responses to these antigens.
\nAnti-disease vaccines aim to prevent the pathologies induced by the parasite. Hence, to assess the efficacy of these vaccines, it is important to clearly define the symptoms. Symptomatic malaria infections are characterized by recurrent fever and if not treated could develop into more severe complications (i.e. anemia, multi-organ dysfunctions affecting the lungs, kidneys, liver and brain…), and ultimately leading to death. These different clinical occurrences can be considered as end-points when assessing vaccine efficacy. For safety and ethical reasons, these end-points are looked for in experimental clinical trials. However, they are not measured in many field trials. Active and passive case detections are undertaken to detect clinical malaria episodes and define rate of the first episode or all episodes. Criteria to define a malaria case include presence of fever (≥37.5°C) and detection of malarial parasites in peripheral blood. Careful clinical assessment of the origin of fever is needed to ensure the fever is due to the parasite but not due to concomitant bacterial or viral infection. It should be mandatory to prevent undermining the vaccine efficacy. It is also crucial to clear any asymptomatic infections prior to vaccine testing. Clearing asymptomatic parasitemia allows a better identification of malaria-attributable fever [38]. Assessment of the reduction of severe symptom occurrence and mortality is more difficult to use as end-point. Because of active intervention (drug treatment and patient management), severity and mortality occur only in small fraction of clinical cases. Thus, in order to have sufficient statistical power to assess the vaccine testing, very large cohort is required, resulting in huge cost. Moreover, there have been concerns that decreasing the level of exposure to the parasites might, in return, results in an increase in mortality in the long–term [96]. It has been suggested that reduced exposure prevents the development of naturally-acquired clinical immunity [93], which is thought to result from constant parasite exposure. Thus, for any vaccines entering in Phase III trials, these end-points need to be assessed.
\nTwo types of vaccine strategies aimed at reducing specifically morbidity and mortality are being developed. Anti-sequestration vaccines are based on the assumption that cytoadherence of infected red blood cells leading to parasite sequestration in deep tissues is responsible for most of malaria pathologies. These vaccines are designed to target parasite ligands such as members of the var. multigene family encoding the proteins Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1), which mediates cytoadherence [97, 98]. It has been proposed that parasites sequester to avoid splenic elimination [99]. The more clinically-advanced anti-sequestration vaccine candidate aims at preventing pregnancy-associated malaria [100]. Few var. genes, which encode PfEMP-1 binding to chondroitin sulfate A (CSA), have been implicated in placental sequestration, thus making them attractive vaccine candidates [101, 102]. Anti-sequestration vaccines are designed to produce antibodies, which prevent the interactions between infected red blood cells and their cognate host cells (endothelial cells, syncytiotrophoblast…). This will lead to an increase in the circulation of blood parasites at all development stages and hence their elimination by the spleen. Primary end-point measures for such vaccines are both parasitological and clinical. Efficacy of desequestration as measured by the number of mature blood forms can be evaluated simply by microscopical observation of Giemsa stained-blood smears. However, preventing sequestration may lead to rapid increase of parasitemia and possibly a faster development of fever episodes and faster treatment application. Thus, the time-window for monitoring parasite development might be limited. Ultimately, assessment of severity and mortality are the most relevant measures for desequestration vaccines. A large cohort is needed to assess efficacy, like any blood stage vaccine targeting parasite growth.
\nAnother type of anti-disease vaccine is targeting parasite moieties behaving as toxins and inducing immune-mediated pathologies [28, 103]. As these vaccines may have no effect on the parasitemia, the assessment of their efficacies will require very large cohorts to assess clinical outcomes with both active and passive case detection. In terms of safety, a strict clinical follow-up starting as early as the last vaccine dose administration is needed since these may perturb the immune network and induce immunopathology.
\nTransmission blocking vaccines (TBV) are designed to prevent or reduce the development of the sporogonic stage inside the mosquito host. This leads to a reduction in the numbers of infected mosquitoes and hence lesser malaria transmission in the population. As such, experimental clinical trials cannot provide straightforward answers of vaccine efficacy since the effect of such vaccine is at the population level and not at individual level. Assessment of TBV efficacy is done using in vitro assays and the membrane-feeding assay. Mosquitoes are fed in vitro with Plasmodium gametocytes mixed with serums from immunized individuals and the level of sporogonic development is assessed by counting the oocysts in dissected mosquito midguts [104] or, more rarely, the sporozoites in the mosquito salivary glands. Although this assay has been instrumental in identifying target antigens, it remains to be seen whether it might help to define correlate of protections for TBV development.
\nCurrently, none of the TBV has progressed to clinical trials in the field. As the principal outcome of TBV is to reduce the number of infected mosquitoes at the population level, methods for assessing their number in field conditions should be implemented in a timely manner. There are, to date, no standardized methods to estimate the number of infected mosquitoes in the field and estimation would require large sampling size. Moreover, it seems that infected mosquitoes can cluster in discrete locations [105], thus requiring extensive studies on the distribution of infected mosquitos before and after vaccine trials. Since the number of infected mosquitoes depend on the number of circulating gametocytes [106], defining the number of gametocyte carrier prior to vaccine implementation is also a pre-requisite. In addition, defining transmission intensity of the vaccine site is important since it may influence the outcome of the vaccination. This can be defined by seroepidemiology and geographical information system (GIS) applications. For the latter, GPS mapping of mosquitoes and infected humans needs be done. It must be noted that one major limitation of these trials is that they assume that the human and mosquito populations tested are not mobile, which is often not true. An influx of infected individuals can modify the outcome by creating new reservoirs, and an influx of external infected mosquitoes would maintain transmission. It has been suggested that TBV can be tested with accuracy only in enclaved locations such as islands. Ultimately, the main expected outcome is that TBV will reduce transmission and thus reduce morbidity and mortality. The effect of such vaccine is at the population level, a large and costly cohort will be needed to be assessed over a long period of time. However, recent advances in modeling might facilitate TBV assessment by identifying end-point measures, which may serve as correlates of protection [107, 108]. Different end-point measures have been developed to assess TBV efficacy. For TBV that targets gametocytes, numbers of gametocytes and duration of gametocytes are important measures since it is expected that reduction in the number of gametocyte-carriers (reservoir) will decrease transmission. Microscopic determination of gametocytes on Giemsa-stained smears has long been used but they must be complemented with PCR methods since they have shown to underestimate gametocyte load [109]. Gametocyte infectivity to mosquitoes can be measured with the membrane-feeding assay mentioned earlier or with feeding of mosquitoes directly on the skin of gametocyte carriers, which reproduces the natural situation. An honest correlation between the two assays has been described in few studies [110] but the membrane-feeding assay still awaits definitive validation [111]. In summary, it would be relevant for future TBV trials to perform feeding directly on gametocyte carriers using local mosquitoes. These mosquitoes would have to be raised in local insectaries and tested for the absence of any other human pathogens. Measures of TBV efficacy should not be limited to development of oocysts but also to salivary glands sporozoites since the latter are the infectious forms to humans. Hence, future studies should aim at measuring salivary gland sporozoite loads and sporozoite infectivity.
\nHere we discussed the different types of malaria vaccines and the different ways to access the vaccine efficacy. We also highlighted the limitations involved and the difficulties encountered by researchers aiming to develop an efficacious vaccine against a complex parasite such as Plasmodium. Despite decades of research efforts in vaccine development, no efficient malaria vaccine (i.e. with an efficacy >50%) has been developed. The most clinically-advanced RTS,S, which has been tested in Phase III, conferred at best 30–40% protection against clinical malaria [112]. Modeling studies have been proposed that, together with other malaria interventions, RTS,S vaccination may reduce the incidence of clinical malaria and deaths in many sub-Saharan African countries [113, 114]. Thus, this has led to the approval of licensure for the RTS,S vaccines by the European Union. However, the World Health Organization has not recommended its use in the extended program of immunization for children due to its discouraging vaccine efficacy data. Thus, the future of this vaccine for mass deployment remains uncertain. One of the major reasons of the limited efficacy of RTS,S vaccines and the discontinuation of various other vaccine development efforts is certainly due to antigen polymorphism [83]. In addition to antigen polymorphism, the malaria parasite utilizes many other immune escape mechanisms [115], which have severely hampered the development of malaria vaccines. With the renewed interest in malaria eradication, the development of an effective malaria vaccine is high on the agenda. Diverse strategies are being proposed to develop better vaccines: identification of new vaccine candidate [116], combinations of different antigens targeting the same stage or different stages [117]; new delivery systems and prime-boost strategies using different modalities [118]; and new adjuvants to induce stronger and longer lasting efficient immune responses [119, 120, 121, 122]. However, for all vaccine types described, the absence of validated surrogates of protection to help select and prioritize different vaccine formulations is a major roadblock, which should be given priority to accelerate vaccine testing.
\nThis work was supported by the Agency for Science Technology and Research (A*STAR), Singapore.
\nColloids are heterogeneous mixtures of at least two distinct phases, with the material of one of the phases in a finely divided form (solid, liquid or gas), called dispersed phase, mixed with the continuous phase (solid, liquid or gas), called medium dispersion [1].
Understanding and controlling the stability of colloidal dispersions is essential for its satisfactory use. For both economic and environmental reasons, water is often required as a dispersing phase, even when the particles that need to be kept in suspension are hydrophobic, as is the case with cellulose [1].
Cellulose has been gaining importance in the industrial scenario due to the growing interest in sustainability and environmental protection, becoming a competitive material since it is renewable, abundant, low cost, non-petroleum and non-toxic [2].
Suspended cellulose has a tendency to aggregate. In this way, some strategies to avoid cellulose self-agglomeration in aqueous medium have been used in order to reduce the hydrophilic character of cellulose, avoiding the formation of additional hydrogen bonds between cellulose fibers [3].
Therefore, this chapter aims to contribute to the field of study of colloids and their characteristics, in addition to cellulose with regard to its characteristics and behavior of aqueous solutions of cellulose and alternatives sought to improve the colloidal stability of cellulose suspensions.
Colloids are systems formed by macromolecules or particles dispersed in a medium, in which one or more components have at least one of their dimensions within the range of 1 nm to 1000 nm [4].
Colloidal systems have been used since the dawn of humanity. Ancient people used gels from natural products as food, clay dispersions for the manufacture of ceramic utensils and colloidal pigment dispersions to decorate cave walls [5].
Colloidal systems are present in our daily lives in several products and technologies, such as personal hygiene (shampoo, toothpaste, foam, shaving cream, makeup, cosmetics) and in food (milk, coffee, butter, vegetable creams, fruit jellies, beer, soda or ice cream). During a single day we are consuming several colloids [5]. Colloids are also present in several consumer goods production processes, including drinking water, in the separation processes in the biotechnology industries and in the treatment of the environment.
In addition, colloidal phenomena are frequently used in industrial processes for the production of polymers, detergents, paper, soil analysis, food products, fabrics, precipitation, chromatography, ion exchange, flotation and heterogeneous catalysis. In orthomolecular therapeutic medicine, knowledge of the properties of colloidal systems can assist in the elucidation of diseases, such as Alzheimer’s and Parkinson’s [5].
The factors that most contribute to the characteristics of a colloid are:
The particle dimensions;
The shape and flexibility of the particles;
Surface properties;
Particle-particle interactions;
Particle-solvent interactions.
Colloids have specific characteristics such as high mass, high particle area/volume ratio and are relatively large. On the separation surfaces (interfaces) between the dispersed phase and the dispersion medium, characteristic surface phenomena are manifested, such as adsorption and double electrical layer effects, phenomena of great importance in determining the physicochemical properties of the system as a whole [6].
Depending on the affinity between the particles of a dispersion and the medium in which they are dispersed, we can classify colloids in two ways: lyophilic and lyophobic colloids. Lyophilic colloids are those in which the particle surface has an affinity for the solvent, keeping the dispersion more stable and minimizing aggregation. Lyophobic colloids, on the other hand, are those in which the particles have greater interaction with each other, which ends up leading to a rapid aggregation process [7].
Regarding the colloid classification, there are the following categories:
Aerosol: consists of a solid or a liquid dissolved in a gas.
Foam: consists of a gas dispersed in solid or liquid.
Emulsion: are colloids formed by liquid dispersed in another liquid.
Sol: are colloids formed by the dispersion of a solid in a liquid or solid.
Gel: solid of gelatinous material formed from a colloidal dispersion, in which the dispersed is in the liquid state and the dispersant in the solid state.
The Table 1 shows some different types of colloids according to the state of the continuous and dispersed phases, and examples found in everyday life.
Scattered | ||||
---|---|---|---|---|
Gas | Liquid | Solid | ||
Dispersant | Gas | Does not exist. All gases are soluble with each other | Aerosol Liquid Examples: cloud, fog | Aerosol solid Examples: smoke, dust in suspension |
Liquid | Liquid foam Example: soap foam, shaving cream, whipped cream | Emulsion Examples: milk, honey, mayonnaise, creams | Sol Example: paints, colored glass | |
Solid | Solid foam Example: pumice, expanded polystyrene | Gel Examples: gelatin, cheese, jam | Solid Sun Example: ruby and sapphire crystal, metal alloys |
Classification of colloids according to the dispersed phase and dispersion medium.
Colloidal systems can be divided into three types: colloidal dispersions, true macromolecule solutions and association colloids [8].
Colloidal dispersions are heterogeneous systems composed of two or more phases, as shown in Table 1, and these systems are thermodynamically unstable, due to their high surface free energy. In a colloidal dispersion, the interfacial area of the dispersed phase is very large, which requires a lot of energy to keep it dispersed. In an attempt to minimize the free energy of the surface, the system tends to minimize the area, based on the aggregation of the dispersed phase [8].
True macromolecule solutions are thermodynamically stable colloidal systems, that is, they will not separate phase. Polymeric solutions are examples of this class of colloids. Association colloids, which are also thermodynamically stable, are formed by the association of surfactant molecules, that is, micellar aggregates [8].
For the production of colloids there are two groups with different production methods, they are: dispersion methods and condensation methods [3].
Mechanical spraying: for the production of colloids a solid substance is used added to a liquid, using colodal mills, which is a method used in the industry for the production of colloidal pigments.
Electric spraying: produced using the Bredig method, in which two electrodes are immersed in water to generate an arc. Spraying results in a coarse suspension from the metal particles. In the suspension you get the hydrosol. Electric spraying is used in the production of metallic colloids. In the reaction of substances such as benzene and ethyl ether, alkaline and alkaline earth colloids are produced.
Spraying by Ultrasound: from mechanical vibrations, which can be produced under a piezoelectric quartz generator in an excitation process, the formation spray of colloidal solutions is generated.
Peptization: performed with peptizing agents that have the ability to disintegrate, with colloids as the final product. These materials are used, for example, in the food industry in the production of gelatins, gums, and agar from the use of hot water, which is a peptizing agent.
The condensation method is a means of producing colloids carried out with the precipitation of an insoluble substance by means of a chemical transformation between solvent substances. During its chemical transformation, the insoluble product is in the molecular state, occurring after condensation.
The different interactions between the dispersed phase (particles) and the dispersion phase (continuous) constitute one of the critical points in the study of the behavior and stability of colloids. The interactions between the particles that make up a dispersion and the dispersing medium are fundamental to understand colloidal stability [9].
The stability of a dispersion can be thermodynamic or kinetic and one of the ways to understand the difference between them is in terms of the colloid stabilization time. While a thermodynamically stable colloid will remain unchanged for an infinite time, maintaining properties like temperature and concentration unchanged, kinetically stable colloids tend to aggregate over time. Therefore, the study of colloidal chemistry makes it possible to change the time in which the colloid remains kinetically stable [8].
When it comes to particles, the energy in van der Waals’ interactions comes from integrating the potential of all the molecules that make it up [10]. Van der Waals interactions between two particles will always be attractive if the particles are made of the same material, no matter what medium they are in [11]. If the particles are different in nature, van der Waals interactions can be attractive or repulsive [12]. In the study of colloidal dispersions, the focus is mostly on the interaction of particles of the same nature, that is, they are attractive interactions [13].
To increase the stability of a colloidal dispersion the steric effect of macromolecules is used to prevent the particles from aggregating by adding a stabilizer that will adsorb on the surface of the particle [13]. If the adsorbed macromolecule is in a good solvent, its chains expand. When it encounters a chain from another particle, there is a restriction in the conformation of both chains in the volume between the two particles, causing a decrease in configurational entropy and an increase in free energy [14]. To minimize this effect, the chains of the macromolecules repel each other, causing a repulsive effect between the particles, preventing aggregation.
Regarding the stability of aqueous colloidal dispersions, they are sensitive to the presence of electrolytes and polyelectrolytes (charged polymers of high molecular mass), since the colloidal particles can irreversibly aggregate in the presence of electrolytes and result in large and compact aggregates (clots) by a process called coagulation, while in the presence of polyelectrolytes there may be the formation of less dense aggregates (floccules), which can be easily broken and dispersed by mechanical agitation [15].
Understanding and controlling the stability of colloidal dispersions is essential for its satisfactory use. Some specific applications require that such dispersions be maintained over a wide range of temperatures and chemical conditions [8].
For both economic and environmental reasons, water is often required as a dispersing phase, even when the particles that need to be kept in suspension are hydrophobic. Water is a highly structured material, due to the hydrogen bonds that connect the molecules to each other. In the vicinity of a hydrophobic surface, ruptures of the hydrogen bonds between water molecules occur, increasing the free energy in relation to the solution. As a consequence, water is expelled to regions more favorable to hydrogen bonding. The migration of water molecules results in a mutual attraction between hydrophobic surfaces that implies a reduction in the free energy of the system [11].
Cellulose has stood out in the last 20 years as a study material for several applications, as it is the most abundant, renewable and natural polymer on the face of the Earth [15], and can be found mainly in woody plants (wood), annuals and in grasses [16]. Cellulose is located mainly in the secondary cell wall, corresponding to approximately 40 to 45% of the wood mass [17].
Cellulose (C6H10O5) n is a polysaccharide, linear chain containing from hundreds to thousands of chemical bonds involving carbon, hydrogen and oxygen atoms (Figure 1) [18]. The cellulose chain is of high molecular weight, which tends to form hydrogen bonds between the molecules [19, 20]. The hydroxyl groups of cellulose molecules form hydrogen bonds that can be intramolecular or intermolecular, directing the crystalline packaging, and it is these bonds that make cellulose a stable polymer and appreciated as reinforcement in composites [21, 22].
Chemical structure of cellulose.
Its organized structure is formed by cellulose microfibrils, which due to intermolecular bonds form the fibrils, which in turn are composed in an orderly fashion in order to form cellulosic fibers. Cellulose fibers are made up of two regions, the crystalline region, in which the microfibrils are presented in an extremely orderly manner, and the amorphous region, in which they are arranged in a less ordered manner [17], and for some lignocellulosic sources the amorphous regions can reach 50% of the structure [22].
Despite the hygroscopic nature of the individual cellulose molecules, the absorption of water molecules is only possible in the amorphous zones, since there is a lack of empty spaces in the crystalline structure. Hydroxy groups are the most abundant groups in the cellulose molecule, followed by the acetal bonds that form the ring of pyraneses [23].
In the crystalline regions of cellulose, we also have that the intra and intermolecular interactions can vary, giving rise to the various polymorphs [18]. The degree of polymerization and the crystallinity of cellulose vary according to the lignocellulosic source [1]. Due to the presence of crystalline and amorphous regions, cellulose can be classified as a semicrystalline fibrillar material [24].
Using cellulosic materials has several advantages, such as: its low cost, low density, high mechanical resistance and high elastic modulus. Due to the stable structure of their crystalline regions, cellulose fibrils have high mechanical properties along the longitudinal direction [24]. It is also possible to benefit from the high stiffness of the cellulose crystal which, when used on a nanometer scale for the production of composite materials, makes it possible to preserve the optical properties of the original material while improving the mechanical properties [25].
Cellulosic pulp is a material whose characteristics and properties are determined by its origin. Cellulose modification methods are used when carrying out processes carried out in an aqueous medium, but cellulose is an amphiphilic polymer, that is, it presents a hydrophilic region that dissolves in water, and another hydrophobic region that does not dissolve in water, due to the presence of crystalline and amorphous regions.
The geometry, size and surface density of the particles are also properties that interfere with the processes of coagulation and flocculation. The polymers used with water retention agents increase the forces of colloidal attraction and induce flocculation through different mechanisms, based on different effects. We can mention: flocculation by bridge effect, flocculation by depletion effect and flocculation by reinforced bridge effect [1].
In the case of cellulose fibers, these properties are not well defined due to the variety in the size and shape of the fibers. However, it is known that cellulose fibers when dispersed in water have a pH of around 6, which indicates the acidic character of the surface, therefore a tendency to preferentially adsorb OH- group. In this way, the aqueous dispersions of cellulose fibers are influenced in their colloidal stability by the presence of a double electrical layer under their surface, resulting from the dissociation of different functional groups, such as carboxylics [26].
The pure cellulose fiber in suspension has a high tendency to aggregate and form clots by the action of gravity. However, studies show that through the addition of symmetrical or asymmetric electrolytes the tendency to coagulate the cellulose fiber suspension can be maximized or minimized depending on the final objective. The addition of cationic starch and calcium carbonate to the cellulose fiber suspension causes a change in the charge signal of the fiber surface, resulting in phenomena of fiber-fiber interaction that guarantees greater stability in relation to pure cellulose fiber [1].
In the refining process, for example for the production of paper, cellulose fibers are immersed in water. The fibrils, which make up the cells, are composed of crystalline regions that, when immersed in water, absorb a quantity of this water across all exposed crystalline surfaces, causing their swelling and decreased attraction between the fibrils. The mechanical action of shearing the fibers through refiners speeds up this swelling, as it exposes the surfaces previously located inside the fibers, causing an increase in surface exposure, which promotes a greater number of contacts and connections between the fibers, resulting in this stronger paper [1].
The steps of converting cellulose to paper involve many surface chemical interactions, interactions between fibers and colloidal particles. Understanding these interactions is useful for product development and improving the resolution of operational problems.
This chapter sought to define the main characteristics of colloids, as well as their classification, methods of preparation and finally to address characteristics of colloid stability. Cellulose, the most abundant biopolymer in the world, is a colloid widely used in several industries. This colloid proves challenging for some segments due to its detailed characteristics throughout of the chapter. Studies continue to be carried out on this topic in order to bring solutions to improve the colloidal stability of cellulose.
I thank IntechOpen for the opportunity and the Federal University of Paraná for my training from undergraduate to doctorate.
IntechOpen aims to ensure that original material is published while at the same time giving significant freedom to our Authors. To that end we maintain a flexible Copyright Policy guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Chapters",metaDescription:"IN TECH aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.\n\nWhen submitting a manuscript the Corresponding Author is required to accept the terms and conditions set forth in our Publication Agreement as follows:",metaKeywords:null,canonicalURL:"/page/publication-agreement-chapters",contentRaw:'[{"type":"htmlEditorComponent","content":"The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\\n\\n1. DEFINITIONS
\\n\\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\\n\\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\\n\\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\\n\\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\\n\\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\\n\\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\\n\\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\\n\\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\\n\\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\\n\\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\\n\\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
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\\n\\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\\n\\n3. CORRESPONDING AUTHOR'S DUTIES
\\n\\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\\n\\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\\n\\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\\n\\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\\n\\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\\n\\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\\n\\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\n4. CORRESPONDING AUTHOR'S WARRANTY
\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
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\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
\n\n\n\n
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