Antibodies play major roles in immunity to malaria; however, a limited understanding of mechanisms mediating protection is a major barrier to vaccine development. We have demonstrated that acquired ...human anti-malarial antibodies promote complement deposition on the merozoite to mediate inhibition of erythrocyte invasion through C1q fixation and activation of the classical complement pathway. Antibody-mediated complement-dependent (Ab-C′) inhibition was the predominant invasion-inhibitory activity of human antibodies; most antibodies were non-inhibitory without complement. Inhibitory activity was mediated predominately via C1q fixation, and merozoite surface proteins 1 and 2 were identified as major targets. Complement fixation by antibodies was very strongly associated with protection from both clinical malaria and high-density parasitemia in a prospective longitudinal study of children. Ab-C′ inhibitory activity could be induced by human immunization with a candidate merozoite surface-protein vaccine. Our findings demonstrate that human anti-malarial antibodies have evolved to function by fixing complement for potent invasion-inhibitory activity and protective immunity.
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•Antibodies function with complement to inhibit P. falciparum replication•Antibodies fix C1q to block invasion and lyse merozoites•Complement-fixing antibodies are strongly associated with immunity in children•Antibody-complement inhibition can be induced by human vaccination
Antibodies are important in immunity to malaria, but their protective function has been unclear. Boyle and colleagues report that acquired and vaccine-induced human antibodies recruit complement to block infection of erythrocytes and blood-stage replication of Plasmodium falciparum.
Complement is integral to a healthy functioning immune system and orchestrates various innate and adaptive responses against viruses and other pathogens. Despite its importance, the potential ...beneficial role of complement in immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been overshadowed by reports of extensive complement activation in severe coronavirus disease 2019 (COVID-19) patients. Here, we hypothesize that complement may also have a protective role and could function to enhance virus neutralization by antibodies, promote virus phagocytosis by immune cells, and lysis of virus. These functions might be exploited in the development of effective therapeutics and vaccines against SARS-CoV-2.
Complement has been implicated in playing some role in severe COVID-19 pathogenesis. However, the evidence to support this is largely inferred from case–control studies.The potential protective role of complement has been largely ignored, which might contribute to innate and adaptive immunity against SARS-CoV-2 infection.Immunity to many pathogens relies on complement to enhance antibody-mediated neutralization and mediate phagocytosis and lysis. These mechanisms might also contribute to immunity against SARS-CoV-2 infection, and complement might be potentially exploited in antibody-based therapeutics and vaccines.Careful selection of vaccine adjuvants and epitopes included in vaccine constructs can influence whether vaccine-induced antibodies activate complement.Mutations in monoclonal antibodies can be used to promote hexamer formation between antibodies, which can significantly improve complement binding and activation.
One of the criteria to objectively prioritize merozoite antigens for malaria vaccine development is the demonstration that naturally acquired antibodies are associated with protection from malaria. ...However, published evidence of the protective effect of these antibodies is conflicting.
We performed a systematic review with meta-analysis of prospective cohort studies examining the association between anti-merozoite immunoglobin (Ig) G responses and incidence of Plasmodium falciparum malaria. Two independent researchers searched six databases and identified 33 studies that met predefined inclusion and quality criteria, including a rigorous definition of symptomatic malaria. We found that only five studies were performed outside sub-Saharan Africa and that there was a deficiency in studies investigating antibodies to leading vaccine candidates merozoite surface protein (MSP)-1(42) and erythrocyte binding antigen (EBA)-175. Meta-analyses of most-studied antigens were conducted to obtain summary estimates of the association between antibodies and incidence of P. falciparum malaria. The largest effect was observed with IgG to MSP-3 C terminus and MSP-1(19) (responders versus nonresponders, 54%, 95% confidence interval CI 33%-68% and 18% 4%-30% relative reduction in risk, respectively) and there was evidence of a dose-response relationship. A tendency towards protective risk ratios (RR<1) was also observed for individual study estimates for apical membrane antigen (AMA)-1 and glutamate-rich protein (GLURP)-R0. Pooled estimates showed limited evidence of a protective effect for antibodies to MSP-1 N-terminal regions or MSP-1-EGF (epidermal growth factor-like modules). There was no significant evidence for the protective effect for MSP-2 (responders versus nonresponders pooled RR, MSP-2(FC27) 0.82, 95% CI 0.62-1.08, p = 0.16 and MSP-2(3D7) 0.92, 95% CI 0.75-1.13, p = 0.43). Heterogeneity, in terms of clinical and methodological diversity between studies, was an important issue in the meta-analysis of IgG responses to merozoite antigens.
These findings are valuable for advancing vaccine development by providing evidence supporting merozoite antigens as targets of protective immunity in humans, and to help identify antigens that confer protection from malaria. Further prospective cohort studies that include a larger number of lead antigens and populations outside Africa are greatly needed to ensure generalizability of results. The reporting of results needs to be standardized to maximize comparability of studies. We therefore propose a set of guidelines to facilitate the uniform reporting of malaria immuno-epidemiology observational studies. Please see later in the article for the Editors' Summary.
The COVID-19 pandemic has resulted in millions of infections, hundreds of thousands of deaths and major societal disruption due to lockdowns and other restrictions introduced to limit disease spread. ...Relatively little attention has been paid to understanding how the pandemic has affected treatment, prevention and control of malaria, which is a major cause of death and disease and predominantly affects people in less well-resourced settings.
Recent successes in malaria control and elimination have reduced the global malaria burden, but these gains are fragile and progress has stalled in the past 5 years. Withdrawing successful interventions often results in rapid malaria resurgence, primarily threatening vulnerable young children and pregnant women. Malaria programmes are being affected in many ways by COVID-19. For prevention of malaria, insecticide-treated nets need regular renewal, but distribution campaigns have been delayed or cancelled. For detection and treatment of malaria, individuals may stop attending health facilities, out of fear of exposure to COVID-19, or because they cannot afford transport, and health care workers require additional resources to protect themselves from COVID-19. Supplies of diagnostics and drugs are being interrupted, which is compounded by production of substandard and falsified medicines and diagnostics. These disruptions are predicted to double the number of young African children dying of malaria in the coming year and may impact efforts to control the spread of drug resistance. Using examples from successful malaria control and elimination campaigns, we propose strategies to re-establish malaria control activities and maintain elimination efforts in the context of the COVID-19 pandemic, which is likely to be a long-term challenge. All sectors of society, including governments, donors, private sector and civil society organisations, have crucial roles to play to prevent malaria resurgence. Sparse resources must be allocated efficiently to ensure integrated health care systems that can sustain control activities against COVID-19 as well as malaria and other priority infectious diseases.
As we deal with the COVID-19 pandemic, it is crucial that other major killers such as malaria are not ignored. History tells us that if we do, the consequences will be dire, particularly in vulnerable populations.
Malaria accounts for an enormous burden of disease globally, with Plasmodium falciparum accounting for the majority of malaria, and P. vivax being a second important cause, especially in Asia, the ...Americas and the Pacific. During infection with Plasmodium spp., the merozoite form of the parasite invades red blood cells and replicates inside them. It is during the blood-stage of infection that malaria disease occurs and, therefore, understanding merozoite invasion, host immune responses to merozoite surface antigens, and targeting merozoite surface proteins and invasion ligands by novel vaccines and therapeutics have been important areas of research. Merozoite invasion involves multiple interactions and events, and substantial processing of merozoite surface proteins occurs before, during and after invasion. The merozoite surface is highly complex, presenting a multitude of antigens to the immune system. This complexity has proved challenging to our efforts to understand merozoite invasion and malaria immunity, and to developing merozoite antigens as malaria vaccines. In recent years, there has been major progress in this field, and several merozoite surface proteins show strong potential as malaria vaccines. Our current knowledge on this topic is reviewed, highlighting recent advances and research priorities.
The authors summarize current knowledge of merozoite surface proteins of malaria parasites; their function in invasion, processing of surface proteins before, during and after invasion, their importance as targets of immunity, and the current status of malaria vaccines that target merozoite surface proteins.
Graphical Abstract Figure.
The authors summarize current knowledge of merozoite surface proteins of malaria parasites; their function in invasion, processing of surface proteins before, during and after invasion, their importance as targets of immunity, and the current status of malaria vaccines that target merozoite surface proteins.
Numerous efforts to understand the functional roles of antibodies demonstrated that they can protect against malaria. However, it is unclear which antibody responses are the best correlates of ...immunity, and which antibody functions are most important in protection from disease. Understanding the role of antibodies in protection against malaria is crucial for antimalarial vaccine design. In this review, the specific functional properties of naturally acquired and vaccine-induced antibodies that correlate to protection from the blood stages of Plasmodium falciparum malaria are re-examined and the gaps in knowledge related to antibody function in malarial immunity are highlighted.
In a previous Phase 1/2b malaria vaccine trial testing the 3D7 isoform of the malaria vaccine candidate Merozoite surface protein 2 (MSP2), parasite densities in children were reduced by 62%. ...However, breakthrough parasitemias were disproportionately of the alternate dimorphic form of MSP2, the FC27 genotype. We therefore undertook a dose-escalating, double-blinded, placebo-controlled Phase 1 trial in healthy, malaria-naïve adults of MSP2-C1, a vaccine containing recombinant forms of the two families of msp2 alleles, 3D7 and FC27 (EcMSP2-3D7 and EcMSP2-FC27), formulated in equal amounts with Montanide® ISA 720 as a water-in-oil emulsion.
The trial was designed to include three dose cohorts (10, 40, and 80 µg), each with twelve subjects receiving the vaccine and three control subjects receiving Montanide® ISA 720 adjuvant emulsion alone, in a schedule of three doses at 12-week intervals. Due to unexpected local reactogenicity and concern regarding vaccine stability, the trial was terminated after the second immunisation of the cohort receiving the 40 µg dose; no subjects received the 80 µg dose. Immunization induced significant IgG responses to both isoforms of MSP2 in the 10 µg and 40 µg dose cohorts, with antibody levels by ELISA higher in the 40 µg cohort. Vaccine-induced antibodies recognised native protein by Western blots of parasite protein extracts and by immunofluorescence microscopy. Although the induced anti-MSP2 antibodies did not directly inhibit parasite growth in vitro, IgG from the majority of individuals tested caused significant antibody-dependent cellular inhibition (ADCI) of parasite growth.
As the majority of subjects vaccinated with MSP2-C1 developed an antibody responses to both forms of MSP2, and that these antibodies mediated ADCI provide further support for MSP2 as a malaria vaccine candidate. However, in view of the reactogenicity of this formulation, further clinical development of MSP2-C1 will require formulation of MSP2 in an alternative adjuvant.
Australian New Zealand Clinical Trials Registry 12607000552482.
Infection with Plasmodium falciparum parasites results in approximately 627,000 deaths from malaria annually. Key to the parasite’s success is their ability to invade and subsequently grow within ...human erythrocytes. Parasite proteins involved in parasite invasion and proliferation are therefore intrinsically of great interest, as targeting these proteins could provide novel means of therapeutic intervention. One such protein is P113 which has been reported to be both an invasion protein and an intracellular protein located within the parasitophorous vacuole (PV). The PV is delimited by a membrane (PVM) across which a plethora of parasite‐specific proteins are exported via the Plasmodium Translocon of Exported proteins (PTEX) into the erythrocyte to enact various immune evasion functions. To better understand the role of P113 we isolated its binding partners from in vitro cultures of P. falciparum. We detected interactions with the protein export machinery (PTEX and exported protein‐interacting complex) and a variety of proteins that either transit through the PV or reside on the parasite plasma membrane. Genetic knockdown or partial deletion of P113 did not significantly reduce parasite growth or protein export but did disrupt the morphology of the PVM, suggesting that P113 may play a role in maintaining normal PVM architecture.
P113 is a parasitophorous vacuole‐resident protein in Plasmodium falciparum. It interacts with proteins in the parasitophorous vacuole space to assist in maintaining normal vacuole architecture.
•Therapeutic antibodies (ThAb) to infectious diseases are an important and emerging field.•Most ThAb that are licenced or in development are of the human IgG1 subclass.•Molecular properties of IgG ...subclasses can be utilised to design effective ThAb.•Understanding infectious disease immunity should be used to guide ThAb development.•A wider array of disease-specific functional assays is needed for evaluating ThAb.
Monoclonal antibodies are being developed as therapeutics to complement drugs and vaccines or to fill the gap where no drugs or vaccines exist. These therapeutic antibodies (ThAb) may be especially important for infectious diseases in which there is antibiotic resistance, toxin-mediated pathogenesis, or for emerging pathogens. The unique structure of antibodies determines the specific nature of the effector function, so when developing ThAb, the desired effector functions need to be considered and integrated into the design and development processes to ensure maximum efficacy and safety. Antibody subclass is a critical consideration, but it is noteworthy that almost all ThAb that are licenced or currently in development utilise an IgG1 backbone. This review outlines the major structural properties that vary across subclasses, how these properties affect functional immunity, and discusses the various approaches used to study subclass responses to infectious diseases. We also review the factors associated with the selection of antibody subclasses when designing ThAb and highlight circumstances where different subclass properties might be beneficial when applied to particular infectious diseases. These approaches are critical to the future design of ThAb and to the study of naturally-acquired and vaccine-induced immunity.
Individuals in areas of Plasmodium falciparum endemicity develop immunity to malaria after repeated exposure. Knowledge of the acquisition and nature of protective immune responses to P. falciparum ...is presently limited, particularly for young children. We examined antibodies (IgM, IgG, and IgG subclasses) to merozoite antigens and their relationship to the prospective risk of malaria in children 1 to 4 years of age in a region of malaria endemicity in Papua New Guinea. IgG, IgG1, and IgG3 responses generally increased with age, were higher in children with active infection, and reflected geographic heterogeneity in malaria transmission. Antigenic properties, rather than host factors, appeared to be the main determinant of the type of IgG subclass produced. High antibody levels were not associated with protection from malaria; in contrast, they were typically associated with an increased risk of malaria. Adjustment for malaria exposure, using a novel molecular measure of the force of infection by P. falciparum, accounted for much of the increased risk, suggesting that the antibodies were markers of higher exposure to P. falciparum. Comparisons between antibodies in this cohort of young children and in a longitudinal cohort of older children suggested that the lack of protective association was explained by lower antibody levels among young children and that there is a threshold level of antibodies required for protection from malaria. Our results suggest that in populations with low immunity, such as young children, antibodies to merozoite antigens may act as biomarkers of malaria exposure and that, with increasing exposure and responses of higher magnitude, antibodies may act as biomarkers of protective immunity.
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