**4. Toxicity of the antimalarial drugs**

The most important determinant of drug use and its effectiveness is the patient compliance. The toxicity of the drug must be balanced with the efficacy of the drug and the risk from malaria, i.e., the drug should cause less harm than the disease itself. The doses given to the patients should be taken into account in determining the treatment of malaria. The assessment of the tolerability of many antimalarial drugs is ongoing, but evaluating adverse drug reactions, events, side effects, and drug-related toxicity is difficult due to the unavailability of good techniques to measure the side effects.[21]

The most promising naturally occurring sesquiterpene lactone drug and its derivatives (artemether, arteether, and sodium artesunate) did not show any serious side effects. However, insufficient clinical trials to detect the toxicity stopped us from declaring artemisinin 100% safe. However, they have excellent safety profile and remarkable efficacy. The current knowledge obtained from the laboratory and clinical study is that the long-term availability of artemisinins may cause toxicity (rarely produce neurotoxicity and allergic reactions).[22] The short-term peak concentrations followed by rapid elimination of artemisinins after oral intake is relatively safe compared to administration by intramuscular injection. Evidently, the majority of animal experiments showed considerable toxicities in contrast to human studies.

Chloroquine, considered being a safe drug even at higher doses, also causes mild side effects such as reversible effect on optical accommodation, which can potentially affect eyesight. It also binds irreversibly to melanin. Hence, the patients with rheumatoid arthritis treated with the long-term use of high dose chloroquine suffer from accumulation of chloroquine in retinal melanin. Some reports also suggest that chloroquine administered to patients with light intolerant disease can aggravate psoriasis.[22] Proguanil is also assumed to be safe at a dose of 200 mg a day. However, for doses higher than 200 mg, there are reports of reversible alopecia and aphthous ulceration, nausea, and gastric irritation.[23] These side effects are common with other antimalarial agents as well. The combination of chloroquine with proguanil has good tolerability. However, gastrointestinal upset and mouth ulcers are still observed. Sulfadoxine/ pyrimethamine is also well tolerated, but it is no longer used because it causes Stevens–Johnson syndrome and toxic epidermal necrolysis. Mefloquine is another valuable drug for the treatment of malaria. Despite good tolerability to most patients, dose-related serious neuro‐ psychiatric toxicity can occur. Cardiovascular or CNS toxicity is rare for quinine but hypogly‐ cemia may occur. Further, due to its potential for cardiotoxicity, halofantrine is unsuitable for widespread use. Mepacrine, sulfonamides, dapsone, and amodiaquine are also withdrawn from the use because of the high frequency of adverse side effects.[24]

## **5. Malaria vaccine**

Malaria vaccine development is a challenging and difficult task because of the antigenic complexity and the complex life cycle of malaria parasite. Research on the development of malaria vaccine is of prime importance because such a discovery can prevent millions of deaths worldwide. The currently available tools are insufficient for malaria eradication. Malaria vaccine could be a transformative tool to help in reduced transmission and future eradication. Extensive research has been carried out in the last two decades, and several vaccines have reached clinical trials, but there is none in the clinical practice due to insufficient immunoge‐ nicity. Although parasite vaccines are in development, there is no FDA-approved vaccine for organisms more complex than viruses and bacteria.[25]

#### **5.1. Scientific challenges**

The significant hurdle in the development of malaria vaccine is insufficient knowledge about the malaria parasite. Understanding the structure and antigenic variation of parasite popula‐ tion requires lengthy, tedious, and difficult lab and field studies. Antigenic variation and parasite polymorphism also create a major scientific barrier. Unfortunately, in nature, there are not many good examples of immunity to malaria, and many vaccine development programs are based only on naturally acquired immunity. Since the mechanism of immune protection is still unknown, it is difficult to comprehend why certain people are protected while others are not. Inadequate animal models and lack of clarity in the definition of desired outcomes create confusion in choosing the best approach to develop a malaria vaccine. Even in particular animal model systems with defined outcomes, there is always uncertainty in translating the success of protection in the model systems with success in humans.[26]

insufficient clinical trials to detect the toxicity stopped us from declaring artemisinin 100% safe. However, they have excellent safety profile and remarkable efficacy. The current knowledge obtained from the laboratory and clinical study is that the long-term availability of artemisinins may cause toxicity (rarely produce neurotoxicity and allergic reactions).[22] The short-term peak concentrations followed by rapid elimination of artemisinins after oral intake is relatively safe compared to administration by intramuscular injection. Evidently, the majority of animal experiments showed considerable toxicities in contrast to human studies.

Chloroquine, considered being a safe drug even at higher doses, also causes mild side effects such as reversible effect on optical accommodation, which can potentially affect eyesight. It also binds irreversibly to melanin. Hence, the patients with rheumatoid arthritis treated with the long-term use of high dose chloroquine suffer from accumulation of chloroquine in retinal melanin. Some reports also suggest that chloroquine administered to patients with light intolerant disease can aggravate psoriasis.[22] Proguanil is also assumed to be safe at a dose of 200 mg a day. However, for doses higher than 200 mg, there are reports of reversible alopecia and aphthous ulceration, nausea, and gastric irritation.[23] These side effects are common with other antimalarial agents as well. The combination of chloroquine with proguanil has good tolerability. However, gastrointestinal upset and mouth ulcers are still observed. Sulfadoxine/ pyrimethamine is also well tolerated, but it is no longer used because it causes Stevens–Johnson syndrome and toxic epidermal necrolysis. Mefloquine is another valuable drug for the treatment of malaria. Despite good tolerability to most patients, dose-related serious neuro‐ psychiatric toxicity can occur. Cardiovascular or CNS toxicity is rare for quinine but hypogly‐ cemia may occur. Further, due to its potential for cardiotoxicity, halofantrine is unsuitable for widespread use. Mepacrine, sulfonamides, dapsone, and amodiaquine are also withdrawn

Malaria vaccine development is a challenging and difficult task because of the antigenic complexity and the complex life cycle of malaria parasite. Research on the development of malaria vaccine is of prime importance because such a discovery can prevent millions of deaths worldwide. The currently available tools are insufficient for malaria eradication. Malaria vaccine could be a transformative tool to help in reduced transmission and future eradication. Extensive research has been carried out in the last two decades, and several vaccines have reached clinical trials, but there is none in the clinical practice due to insufficient immunoge‐ nicity. Although parasite vaccines are in development, there is no FDA-approved vaccine for

The significant hurdle in the development of malaria vaccine is insufficient knowledge about the malaria parasite. Understanding the structure and antigenic variation of parasite popula‐

from the use because of the high frequency of adverse side effects.[24]

organisms more complex than viruses and bacteria.[25]

**5. Malaria vaccine**

44 An Overview of Tropical Diseases

**5.1. Scientific challenges**

The malaria vaccine development includes recombinant proteins, gene-based (DNA or viral vector) vaccines, attenuated whole organisms, peptides, and prime-boost strategy, which involves a combination of different antigen delivery systems encoding the same epitopes or antigen using various adjuvants. Reports dating back to 1960s[26] demonstrated speciesspecific and strain cross-reactive protection on immunization with radiation-attenuated sporozoites in primate and experimental rodent models. Studies showed optimistic levels of protective immunity. However, the volunteers immunized against multiple strains of *P. falciparum* malaria were not protected against *P. vivax.* The target antigens were identified from the sera cells of experimental hosts immunized with attenuated sporozoite vaccine and protected volunteers. Circumsporozoite protein, the first cloned and sequenced malaria parasite in *P. knowlesi* and *P. falciparum*, is also the first antigen identified by serological screening. It plays an important role in protection. When the sporozoite was irradiated in the rodent models, antibody and cells showed different roles in malaria species and different strains. Although multifaceted cellular responses are observed, the basic mechanism of immunity is believed to target the intracellular hepatic exoerythrocytic forms by the produc‐ tion of interferon. The antibody eliminates most of the infectious sporozoite inoculum, when the vaccines prove a multipronged approach. The cellular responses target the rest of the intracellular exoerythrocytic forms by direct cytotoxicity or inhibitory cytokines.

The understanding of the research related to vaccine development is greatly benefitted by the lessons learned from discontinued and inactive projects. Recent findings allow us to be optimistic about the possibility of an effective malaria vaccine. Several malaria vaccine candidates have entered field trials. It is now possible to impact the host–parasite relationship using different platforms through vaccine-induced immune responses to multiple antigenic targets. The field has grown rapidly over the last two decades from the first clinical trials to the successful conduct of large-scale field studies, and substantial progress has been made in evaluating many antigens. Despite the daunting task, researchers have produced surprising progress in several areas. The malaria vaccination program has progressed to an assessment and clinical evaluation of RTS,S/AS01E in phase 3 trial.[27] The first malaria vaccine may be considered for licensure in the coming years. Further, there is a possibility of developing more efficacious second-generation vaccines. Researchers are now better equipped to establish clear product profiles. The lessons learned in terms of safety, immunogenicity, efficacy, and trial methodology from malaria vaccine research is summarized in Table 2.


**Table 2.** Lessons from two decades of malaria vaccine development research.
