Malaria vaccine

Abstract

Malaria remains one of the few diseases those continue to scourge human civilization despite the significant advances in disease control strategies over the last century. Malaria is responsible for more than 500 million cases and 1–3 million deaths annually. Approximately 85% of these deaths are among children, mostly in Africa, primarily due to P. falciparum. Whole cell vaccines, irradiated sporozoites and genetically attenuated sporozoites have demonstrated long lasting, sterile protection against plasmodium infection in animal and experimental clinical studies. Atypical membrane protein 1 and merozoite surface protein 1 are the two most extensively studied asexual blood stage vaccine candidates. The most promising candidate vaccine under development is RTS, S combined with AS01 adjuvant. Initial results from phase III trials of this candidate vaccine show 50% reduction of malaria in 5–17 mo aged children during the 12 mo after vaccination. WHO anticipates that the RTS,S/AS01 vaccine will be recommended for the 6–14 week age group for co-administration together with other vaccines as part of routine immunization programs in malaria endemic countries. Malaria vaccine could play an important role in elimination and eventual eradication of malaria.

Keywords: :

• AMA1
• RTS,S vaccine
• control
• elimination
• falciparum
• malaria
• sporozoite

Introduction

Malaria remains one of the few diseases those continue to scourge human civilization despite the advances in science and disease control strategies over the last century.¹ This disease, clinically recognized by Hippocrates in ~500 BC, affects disproportionately the developing, and resource-poor regions of the world.^2,3 After the World War - II, with the advent of newer insecticides and drugs, eradication programs were put in place in several parts of the world. These efforts resulted in marked reductions in disease burden especially in temperate zones, although it is argued that the decline in malaria cases was due to improvements in socio-economic conditions. However, in most areas of tropical Africa there was no significant progress because of increased technical, political, socio-economic and other hindrances.¹

Malaria is an arthropod-borne disease, caused by protozoan parasites of the genus Plasmodium. Among various malarial species infecting man the most deadly is P. falciparum, causing the vast majority of deaths. Despite progress in battle against malaria, these organisms affect 40% of the world’s population with more than 500 million clinical infections and 1–3 million deaths annually. Approximately 85% of these deaths are among children, mostly in Africa, primarily due to P. falciparum.^4-6

Currently drug treatment, insecticide treated bed nets and indoor insecticide spray for mosquito control constitute the main weapons for malaria control.³ Despite decades of these efforts to disrupt the life cycle of the parasite, we have had only limited success. The usefulness of anti-malarial drugs is hindered by their lack of availability to those most in need and to the rapid evolution of drug resistant parasites.⁷ Furthermore, enormous disease toll in terms of morbidity and mortality, increasing incidence among travelers from non-endemic areas, huge socioeconomic impact and increasing development of insecticide resistance in the vector highlight the need for new control methods, none more important than an effective vaccine.^5,8 Several lines of evidence suggest that a prophylactic malaria vaccine for humans is feasible.⁹

Vaccines remain one of the most effective and efficient public health interventions to reduce morbidity and mortality due to infectious diseases. Effective and efficient vaccines have been created for a range of simple pathogens which cause acute disease and express a limited number of potential vaccine targets. However, many of the diseases for which effective vaccines are not yet available are chronic infections caused by complex pathogens, adapted to long-term coexistence with the human immune system. Malaria is one such disease.^5,10 Over the past couple of decades, global interest in malaria has increased substantially leading to increase in research funding.¹

The quest for an effective malaria vaccine has been ongoing for nearly a century with limited success.³ The development of a method for growing the asexual blood stages of Plasmodium falciparum in vitro by Trager and Jensen (1976)¹¹ and subsequently, of gene cloning technologies provided the impulsion for an increased effort into the malaria vaccine evolution. It has been more than 30 y of pronouncements of the development and implementation of a highly effective malaria vaccine is impending.¹²

Whole cell vaccines

A vaccine based on a single isolate of a single antigen may not be able to elicit an immune response that is sufficient to protect individuals against heterogeneous population of malaria parasite. Therefore, an efficacious malaria vaccine may need to induce an immune response against multiple malaria antigens, a belief that has propelled the development of whole cell pre-erythrocytic malaria vaccines, such as the irradiation attenuated sporozoite (irrSPZ) vaccine and the genetically attenuated sporozoite vaccine.¹³

Fortunately, irrSPZ and genetically attenuated sporozoites have demonstrated long lasting, sterile protection against Plasmodium infection in animal and experimental clinical studies. The limited data available for irrSPZ immunization studies in humans indicate that live-attenuated whole parasites induce sterilizing immunity against challenge with infectious P. falciparum SPZs. In coming years a clinical dose escalation study with a cryopreserved formulation of irrSPZs that is administered intradermally or subcutaneously will likely yield clear data on the safety and protective efficacy of this class of vaccines. The discovery of genetically engineered parasite strains that are fully attenuated during the early asymptomatic liver infection and confer complete sterile protection in animal malaria models support the development of a live attenuated sporozoite vaccine for Plasmodium falciparum. The SanariaTM PfSPZ (Plasmodium falciparum sporozoite) vaccine has now been manufactured, released, and cleared for testing in clinical trials by the FDA, and has entered into Phase 1 clinical testing.^3,12

These early successful vaccinations with live-attenuated malaria parasites did not however, promote a developmental path forward for such a vaccine approach.

Molecular vaccines

Malaria represents a poster child for the molecular vaccines, due to its supreme public health importance. The presence of multiple parasite-host molecular interfaces, good animal models and the ability to safely challenge humans with infectious sporozoites to look for protection strongly facilitate the repeated testing and refinement of molecular vaccines. Molecular vaccines are rationally designed at the molecular level to induce long-term immunity, optimally comprising both antibody and T cell-mediated responses specifically targeting one or more protective antigens. Molecular vaccine approach is appealing, especially for pathogens where the development of attenuated vaccines is limited due to difficulty with in vitro production such as malaria.¹⁴

Recombinant proteins corresponding many different asexual blood stage antigens of P. falciparum have shown promise as vaccine candidates in preclinical studies but none has yet been fully assessed for efficacy in clinical trials.¹⁵

Merozoite surface protein 1 (MSP1) and atypical membrane protein 1 (AMA1) are the two most extensively studied asexual blood stage vaccine candidates. They were identified initially with monoclonal antibodies in rodent and simian parasites, respectively. Merozoite surface protein 2 (MSP2) was first identified with a monoclonal antibody in P. falciparum and several years later the corresponding gene was identified in an expression library. The screening of expression libraries with human antibodies resulted in the cloning of genes for a large number of antigens, the majority of which have not been assessed for their potential as vaccine components.¹⁵

In P. falciparum, at least two of the relevant antigens, liver stage antigen-1 (PfLSA-1) and liver stage antigen-3 (PfLSA-3), have been identified and characterized. These proteins are both surface proteins, are expressed solely in infected hepatocytes, and are thought to play a role in liver schizogony and merozoite release. Specific humoral, cellular, and cytokine immune responses to PfLSA-1 and PfLSA-3 are well documented, with identified epitopes that correlate with antibody production, proliferative T-cell responses, or cytokine induction. Both antigens have been considered as vaccine candidates against P. falciparum due to their antigenic and protective immunogenic properties.¹⁶

AMA1 is one of the most promising candidate vaccines against blood stage of malaria, although to date numerous clinical trials using mainly protein-in-adjuvant vaccines have shown limited success.¹⁰ AMA1 vaccine candidates were evaluated in a Phase 1–2b trial in malaria-exposed children in Mali. The vaccine was moderately immunogenic and no overall impact of vaccination on disease was seen.¹⁷

Optimized transgene inserts encoding two divergent alleles of the same antigen can be successfully inserted into adeno- and pox-viral vaccine vectors. Adenovirus-MVA immunization leads to the induction of T-cell responses common to both alleles, as well as functional antibody responses that are effective against both of the encoded strains of P. falciparum in vitro. Available data support the further clinical development of these vaccine candidates in Phase I/IIa clinical trials.¹⁰

CSP protein/ RTS vaccine

Even with a molecular approach, malaria’s complex life cycle and immune invasion adaptations pose extraordinary challenges for the vaccine developer. Despite all these, RTS,S candidate vaccine has shown promising results.

The RTS,S vaccine is a recombinant protein that fuses a part of the P. falciparum circumsporozoite protein (CSP) with the hepatitis B surface antigen. The CSP protein is found at the surface of the sporozoite and of the infected hepatocyte. The CSP based RTS,S vaccine is an elegant example of molecular design applied to a recombinant protein.¹⁴ Combined with an adjuvant system (AS01 or AS02), RTS,S induces the production of antibodies and T cells that are believed to diminish the capacity of the malaria parasite to infect, survive, and develop in the human liver. This candidate vaccine was invented, developed, and manufactured in laboratories at GSK Bio’s headquarters in Belgium, with the research starting in the late 1980s.^9,18

It has demonstrated significant efficacy during early development and was shown to have a promising safety and tolerability profile when used alongside the standard WHO infant vaccines. The most promising candidate vaccine under development is RTS, S combined with Glaxo-SmithKline’s AS01 adjuvant. It is an infection-blocking vaccine. This vaccine has completed Phase II trials and demonstrated significant efficacy against time to first infection (45% - 65.2% reduction), clinical malaria (29.9% - 56% reduction) and severe malaria (57.7% reduction).¹⁹ An ongoing phase 3 field evaluation for the efficacy, safety, and immunogenicity of candidate malaria vaccine in African children has completed enrollment with 15,461 children in the seven countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique and Tanzania) in sub-Saharan Africa. The children are in two age groups: 1) children aged 5–17 mo at first immunization, receiving RTS,S/AS01 without co-administration of other vaccines; and 2) infants of 6–12 weeks at first immunization in co-administration with pentavalent vaccines in the routine immunization schedule. These groups receive 3 doses of RTS,S/AS01 vaccine at 1 mo intervals.^9,19-21 Initial results show that the RTS,S/AS01 vaccine reduced malaria by 50% in children 5–17 mo of age during the 12 mo after vaccination. These results are promising and consistent with findings from phase 2 trials. The level of protection, provided by the RTS,S/AS01 vaccine to the 6000 children aged 5–17 mo, was lower at the end of the 12 mo surveillance period than shortly after vaccination. However, varying study designs and statistical methods have led to different interpretations of the dynamics of efficacy over time, with some studies suggesting persistent protection and others suggesting waning protection. Decreasing protection over time could reflect waning immunity, acquisition of natural immunity in the control group, or heterogeneity of exposure. Further follow-up and evaluation of the effect of a booster dose will provide a better understanding of the relative contribution of these factors.²²

Additional information on vaccine efficacy among young infants and the duration of protection will be critical to determining how this vaccine could be used most effectively to control malaria. Final results from the trial are expected in late 2014. The World Health Organization (WHO) has indicated that a policy recommendation for RTS, S is possible as early as 2015, paving the way for implementation in countries through their expanded programs on immunization if efficacy trial confirms earlier findings.²¹ This good news of a possible vaccine against malaria in the foreseeable future has revived the possibility of enhanced malaria control and perhaps incited the call for malaria elimination and eventual eradication.²³

The results of clinical trials to date indicate that the RTS,S vaccine will be only partially effective and a second generation vaccine will be required if the goal of a vaccine with a protective efficacy of greater than 80% against clinical disease and lasting longer than four years by 2025 is to be achieved.¹⁵ While this may be considered a success, an effective vaccine would be an important addition to the current suite of anti-malaria interventions.⁸

Scope of vaccine

Malaria vaccines have long been awaited by public health planners. Malaria vaccine development benefits from two fundamental advantages than other neglected disease vaccines. First, a safe, reproducible experimental challenge system allows for multiple, relatively small studies in volunteers in the developed world. Second, because there is a developed world market, one can anticipate licensure of the vaccine for use in these countries by regulatory authorities like the FDA, the European Medicines Agency (EMEA), and comparable institutions around the world.^12,24

It is anticipated that the RTS,S/AS01 vaccine will be recommended for the 6–14 weeks age group for co-administration together with other vaccines as part of routine immunization programmes in malaria endemic countries, if approved for large scale use. Other vaccines with higher efficacy are desirable, but currently promising vaccine candidates under development are at least a decade behind RTS,S/AS01.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.