A landscape review of malaria vaccine candidates in the pipeline
Authors: Tajudeen Yusuf Amuda , Oladipo Habeebullah Jayeola , Yusuff Sodiq Inaolaji , Abimbola Samuel O. , Abdulkadir Muritala , Oladunjoye Iyiola Olatunji , Omotosho Abass Olawale , Egbewande Oluwaseyi Muyiwa , Shittu Hameedat Damilola , Yusuf Rashidat Onyinoyi , Ogundipe Oluwatosin , Muili Abdulbasit Opeyemi , Afolabi Abdullateef Opeyemi , Dahesh Salwa M. A. , Gameil Marwa Ahmed Mahmoud , El-Sherbini Mona Said 
Published: August 2024

Abstract
Background
Globally, malaria continues to pose a major health challenge, with approximately 247 million cases of the illness and 627,000 deaths reported in 2021. However, the threat is particularly pronounced in sub-Saharan African countries, where pregnant women and children under the age of five face heightened vulnerability to the disease. As a result, the imperative to develop malaria vaccines especially for these vulnerable populations, remains crucial in the pursuit of malaria eradication. However, despite decades of research, effective vaccine development faces technical challenges, including the rapid spread of drug-resistant parasite strains, the complex parasite lifecycle, the development of liver hypnozoites with potential for relapse, and evasion of the host immune system. This review aims to discuss the different malaria vaccine candidates in the pipeline, highlighting different approaches used for adjuvating these candidates, their benefits, and outcomes, and summarizing the progress of these vaccine candidates under development.

Method
A comprehensive web-based search for peer-reviewed journal articles published in SCOPUS, MEDLINE (via PubMed), Science Direct, WHO, and Advanced Google Scholar databases was conducted from 1990 to May 2022. Context-specific keywords such as “Malaria”, “Malaria Vaccine”, “Malaria Vaccine Candidates”, “Vaccine Development”, “Vaccine Safety”, “Clinical Trials”, “mRNA Vaccines”, “Viral Vector Vaccines”, “Protein-based Vaccines”, “Subunit Vaccines”, “Vaccine Adjuvants”, “Vaccine-induced Immune Responses”, and “Immunogenicity” were emphatically considered. Articles not directly related to malaria vaccine candidates in preclinical and clinical stages of development were excluded.

Results
Various approaches have been studied for malaria vaccine development, targeting different parasite lifecycle stages, including the pre-erythrocytic, erythrocytic, and sexual stages. The RTS, S/AS01 vaccine, the first human parasite vaccine reaching WHO-listed authority maturity level 4, has demonstrated efficacy in preventing clinical malaria in African children. However, progress was slow in introducing other safe, and feasible malaria vaccines through clinical trials . Recent studies highlight the potential effectiveness of combining pre-erythrocytic and blood-stage vaccines, along with the advantages of mRNA vaccines for prophylaxis and treatment, and nonstructural vaccines for large-scale production.

Conclusion
Malaria vaccine candidates targeting different lifecycle stages of the parasite range from chemoprophylaxis vaccination to cross-species immune protection. The use of a multi-antigen, multi-stage combinational vaccine is therefore essential in the context of global health. This demands careful understanding and critical consideration of the long-term multi-faceted interplay of immune interference, co-dominance, complementary immune response, molecular targets, and adjuvants affecting the overall vaccine-induced immune response. Despite challenges, advancements in clinical trials and vaccination technology offer promising possibilities for novel approaches in malaria vaccine development.