Malaria vaccines in the eradication era: current status and future perspectives

The challenge to eradicate malaria is an enormous task that will not be achieved by current control measures, thus an efficacious and long-lasting malaria vaccine is required. The licensing of RTS, S/AS01 is a step forward in providing some protection, but a malaria vaccine that protects across multiple transmission seasons is still needed. To achieve this, inducing beneficial immune responses while minimising deleterious non-targeted effects will be essential. Areas covered: This article discusses the current challenges and advances in malaria vaccine development and reviews recent human clinical trials for each stage of infection. Pubmed and ScienceDirect were searched, focusing on cell mediated immunity and how T cell subsets might be targeted in future vaccines using novel adjuvants and emerging vaccine technologies. Expert commentary: Despite decades of research there is no highly effective licensed malaria vaccine. However, there is cause for optimism as new adjuvants and vaccine systems emerge, and our understanding of correlates of protection increases, especially regarding cellular immunity. The new field of heterologous (non-specific) effects of vaccines also highlights the broader consequences of immunization. Importantly, the WHO led Malaria Vaccine Technology Roadmap illustrates that there is a political will among the global health community to make it happen

Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children

BACKGROUND: Antibodies targeting Plasmodium falciparum sporozoites play a key role in human immunity to malaria. However, antibody mechanisms that neutralize sporozoites are poorly understood. This has been a major constraint in developing highly efficacious vaccines, as we lack strong correlates of protective immunity. METHODS: We quantified the ability of human antibodies from malaria-exposed populations to interact with human complement, examined the functional effects of complement activity against P. falciparum sporozoites in vitro, and identified targets of functional antibodies. In children and adults from malaria-endemic regions, we determined the acquisition of complement-fixing antibodies to sporozoites and their relationship with antibody isotypes and subclasses. We also investigated associations with protective immunity in a longitudinal cohort of children (n = 206) residing in a malaria-endemic region. RESULTS: We found that antibodies to the major sporozoite surface antigen, circumsporozoite protein (CSP), were predominately IgG1, IgG3, and IgM, and could interact with complement through recruitment of C1q and activation of the classical pathway. The central repeat region of CSP, included in leading vaccines, was a key target of complement-fixing antibodies. We show that antibodies activate human complement on P. falciparum sporozoites, which consequently inhibited hepatocyte cell traversal that is essential for establishing liver-stage infection, and led to sporozoite death in vitro. The natural acquisition of complement-fixing antibodies in malaria-exposed populations was age-dependent, and was acquired more slowly to sporozoite antigens than to merozoite antigens. In a longitudinal cohort of children, high levels of complement-fixing antibodies were significantly associated with protection against clinical malaria. CONCLUSIONS: These novel findings point to complement activation by antibodies as an important mechanism of anti-sporozoite human immunity, thereby enabling new strategies for developing highly efficacious malaria vaccines. We also present evidence that complement-fixing antibodies may be a valuable correlate of protective immunity in humans

A Plasmodium berghei sporozoite-based vaccination platform against human malaria

Malaria: Programming non-pathogenic parasites as vaccine candidates A genetically engineered parasite, related to malaria-causing Plasmodium falciparum, excels as a vaccine in preclinical tests. A team led by Miguel Prudêncio, of the University of Lisbon, Portugal, developed a genetically altered vaccine candidate based on Plasmodium berghei, which is pathogenic to rodents but, in humans, fails to progress from a harmless, transient liver infection to causing full, blood-borne malaria. The candidate expresses a human form of ‘circumsporozoite protein,’ a known antigen, and is designed to provoke a more comprehensive immune response as it presents a whole pathogen to the host. In preclinical tests, the candidate generated antibodies able to neutralize infection in human hepatocytes and also provoked a cellular immune response in rabbits. The team’s candidate proved safe and efficacious, warranting further trials and clinical testing