Unlocking the potential of blood-stage vaccines for malaria elimination

Abstract

Malaria vaccines are crucial for advancing public health and achieving malaria elimination. Currently, pre-erythrocytic vaccines like RTS, S/AS01 and R21/Matrix-M are in use, but their effectiveness is limited. Ongoing research on blood-stage vaccine candidates such as RH5, MSP1 and MSP3 has shown promising results. Incorporating a blood-stage vaccine could greatly enhance malaria control by targeting the symptomatic phase of the infection, providing additional protection alongside pre-erythrocytic vaccines and other control methods. Understanding the structural biology and immunological interactions of blood-stage antigens is essential for developing effective vaccines. Combining pre-erythrocytic and erythrocytic-stage vaccines could lead to better protection, improved public health outcomes and significant progress toward malaria elimination.

The WHO aims to eliminate malaria in at least 35 countries by 2030.¹ A malaria vaccine, when used with existing control methods, could significantly boost elimination efforts. However, developing an effective and durable vaccine is challenging due to the parasite’s complex life cycle and diverse strains. Despite these hurdles, the RTS, S/AS01 vaccine, known as Mosquirix, has become the first licensed malaria vaccine and is currently being deployed in three African countries. The recent phase II trial of the R21 malaria vaccine, achieving 75% efficacy in African children, line up with the WHO 2030 malaria vaccine technology roadmap goal of vaccines having at least 75% efficacy against Plasmodium falciparum.¹ Although R21 and RTS, S have not been directly compared, both vaccines have shown to reduce malaria cases by >50% in the first year and prevent approximately 75% of malaria episodes with seasonal use in highly endemic areas. The WHO recommends both vaccines for P. falciparum malaria prevention in children in moderate to high transmission areas, initially endorsing RTS, S/AS01 in 2021 and later adding R21/Matrix-M in 2023.² However, pre-erythrocytic vaccines alone do not offer complete protection against malaria. They have shown limited and short-lived efficacy, are often strain-specific, require multiple doses and primarily offer individual protection without significantly reducing transmission, which limits their overall impact in fully preventing malaria spread and symptomatic infection. To address this gap, a blood-stage vaccine targeting the symptomatic phase of the infection is essential. Blood-stage vaccines are seen as more effective due to their ability to directly reduce symptoms, provide broader strain coverage and potentially offer long-lasting immunity compared with liver-stage vaccines, which have limited accessibility and antigen exposure in the body.³ Combining vaccines that target both pre-erythrocytic and blood stages could provide comprehensive protection, thereby enhancing our efforts toward malaria elimination. Several clinical trials have been carried out for the blood-stage antigens of P. falciparum, but to date, no vaccine has shown significant protective efficacy in phase II field trials.⁴ Vaccine development often fails due to insufficient understanding of the key antigens involved in merozoite invasion of red blood cells (RBCs). Several merozoite surface proteins are being investigated as candidate antigens for blood-stage vaccines (Table 1). A recent trial of RH5 blood-stage vaccine candidates in Tanzania showed higher anti-RH5 IgG responses in young children and infants compared with adults after a booster dose.⁵ RH5 plays a crucial role in the merozoite invasion of RBCs by binding to the receptor basigin on the RBC surface. The immune response generated by RH5-based vaccines primarily involves the production of neutralising antibodies that block this interaction, preventing merozoite invasion and subsequent replication. By inhibiting RBC invasion, RH5-based vaccines effectively reduce parasitaemia in the blood stage. RH5, combined with pre-erythrocytic vaccines, could synergise to block parasite progression at multiple stages, preventing liver-to-blood transition as well as blood-stage proliferation, thus enhancing overall immunity. However, PfRH5 has limitations as a vaccine: not all antibodies induced by PfRH5 immunisation are protective, and it is challenging and costly to produce for global scale coverage. The University of Oxford is conducting a phase Ib study in the Gambia to evaluate the safety and immunogenicity of the RH5.2 virus-like particle and R21 vaccines, both formulated with Matrix-MTM.⁶ Wheat germ cell-free systems for producing recombinant proteins and reverse vaccinology to find effective targets are being investigated, with candidates like P. falciparum merozoite Rh5 interacting protein (PfRipr) being evaluated.⁷ Another important protein, merozoite surface protein 1 (MSP1), has been extensively studied in clinical trials across diverse populations, age groups, dosing regimens and formulations. MSP1 vaccines stimulate antibody and T-cell responses that disrupt merozoite surface proteins critical for invasion. The SPf66 vaccine, targeting MSP1-83, reached phase III trials but, with 31% efficacy, failed to provide effective protection.⁸ Meanwhile, apical membrane antigen 1 (AMA1) vaccines inhibit the moving junction formation necessary for merozoite entry. Field trials have shown that the AMA1 vaccine’s efficacy has generally been limited, often >20% in reducing malaria infection rates. This low efficacy is mainly due to the high antigenic diversity of AMA1, which hampers its ability to provide broad protection against diverse P. falciparum strains. Other potential vaccine targets that are currently in phase II trials include merozoite surface protein 3 (MSP3), Rh5, Thrombospondin-related anonymous protein (TRAP), sporozoite threonine-asparagine-rich protein (STARP) and Pf11.1 (Table 1). Mapping merozoite surface antigens and receptor-ligand interactions may help in pinpointing key vaccine targets.⁹ Structural immunology is crucial for identifying these antigens and targeting them to block the molecular interactions enabling parasite invasion into RBCs. Techniques like proteomics and structural immunology may help in uncovering these antigenic targets, ultimately aiding in the development of vaccines that can provoke strong immune responses and prevent infection. Immunoinformatic (i.e. interface between computer science and experimental immunology) can also aid by predicting key immune epitopes, thus enhancing vaccine design by focusing on the most effective immune responses. Chimeric antigens, which combine B-cell and T-cell epitopes from native parasite proteins, are another promising avenue. For Plasmodium vivax, the Duffy-binding protein II/Matrix-M vaccine showed strong inhibition of blood-stage growth in early trials; however, field efficacy trials are still needed.¹⁰ Nanoparticle delivery systems, like biodegradable pullulan-coated iron oxide, may enhance blood-stage malaria vaccines. Further research is needed to evaluate their effectiveness.¹¹ The high genetic diversity of parasite strains and their ability to alter surface proteins to evade immunity pose challenges. To overcome this, vaccines should incorporate a variety of epitopes recognised by different MHC molecules.⁹

Table 1. Current status of blood-stage malaria antigens (source: WHO).

S. no.	Target antigen	Clinical trial phase	Adjuvant	Stage	Trial status	Clinical trials ID
1	Merozoite surface protein 1 (MSP1)	Phase I	GLA-SE	Blood stage	Ongoing	NCT05644067
2	Merozoite surface protein 2 (MSP2)	Phase I	Montanide ISA720	Blood stage	Completed	ACTRN12607000552482
3	Merozoite surface protein 3 (MSP3)	Phase II	Alhydrogel	Blood stage	Ongoing	NCT05776017
4	Glutamate-rich protein	Phase I, II	CAF01, Alhydrogel	Blood stage	Completed	PACTR201503001038304
5	Apical merozoite antigen 1 (AMA1)	Phase I	Alhydrogel, CPG7909	Blood stage	Completed	NCT00740090
6	Reticulocyte-binding protein homolog 5 (RH5)	Phase I, II	Matrix M1	Blood stage	Ongoing	NCT05978037
7	VAR2CSA	Phase I	Alhydrogel, GLA-SE	Blood stage	Completed	NCT02658253; PACTR201610001796177
8	Plasmodium falciparum Serine repeat antigen 5	Phase I	Alhydrogel, CpG	Blood stage	Completed	PACTR201701001921166
9	Plasmodium falciparum Thrombospondin-related adhesive protein	Phase I, II	-	Blood stage, pre-erythrocytic	Completed	NCT01169077
10	Plasmodium falciparum Sporozoite threonine-asparagine-rich protein	Phase II	-	Blood stage, pre-erythrocytic	Completed	NCT00374998; NCT00375128
11	Plasmodium falciparum Liver-stage antigen 1	Phase I, II	AS01B, AS02A	Blood stage, pre-erythrocytic	Completed	NCT03203421; EUCTR2017-001049-28-GB
12	Plasmodium falciparum exported protein 1	Phase I, II	-	Blood stage, pre-erythrocytic	Completed	NCT01169077
13	PfF2	Phase I	Alhydrogel, Montanide ISA720	Blood stage	Completed	CTRI/2010/091/000301; CTRI/2 02 0/03/02 3 739
14	Multiple epitope thrombospondin-related adhesion protein (ME-TRAP)	Phase I, II	Matrix M1, AS01B	Blood stage, pre-erythrocytic	Completed	NCT01635647; NCT01450293; NCT01373879; NCT01379430; NCT01658696; PACTR201303000499409
15	Erythrocyte binding antigen-175 (EBA-175)	Phase I	-	Blood stage	Completed	NCT01026246; NCT00347555
16	Pf11.1	Phase II	Alhydrogel	Blood stage, pre-erythrocytic	Completed	NCT01605786

Safety and tolerability are critical in vaccine development.⁹ Blood-stage vaccines require careful monitoring for adverse effects like inflammation or autoimmunity due to complex immune interactions. To ensure widespread acceptance, the vaccine must be both effective and safe, with rigorous testing to identify and address potential risks. Practical challenges in vaccine development include ensuring affordable production and distribution, particularly in remote and underserved regions.⁹ Addressing these issues requires a comprehensive and multi-disciplinary approach. Reducing production costs through optimised manufacturing processes is crucial. Developing effective logistical strategies for storage, distribution and administration is essential to ensure that vaccines reach hard-to-reach areas.⁹ Manufacturing costs can be reduced using single delivery systems like pox-viral vectors. Effective management of complex immune responses might require multiple doses, necessitating cost-sharing strategies or improved formulations. Investing in healthcare infrastructure and training for healthcare workers in remote regions further supports vaccine accessibility.⁹ Launched in 1974, the WHO’s Expanded Program on Immunization recently marked its 50th anniversary, emphasising the critical role of vaccination in advancing public health and preventing infectious diseases.¹² Combining malaria vaccines with control programmes targets different parasite stages, with vaccines preventing infection and control measures reducing mosquito transmission. This approach lowers infection rates, boosts herd immunity and tackles challenges like insecticide resistance, resulting in more effective, sustainable malaria control and elimination. The scientific community should remember that achieving malaria elimination requires a comprehensive approach. Despite past efforts, malaria has repeatedly resurfaced as a major public health issue due to negligence and inadequate management. However, we are optimistic about developing an effective vaccine. Success hinges on integrating structural biology, proteomics and immunology to design and refine vaccines that address past challenges and offer long-lasting protection.

Data availability

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