Malaria vaccine development in Mali: a step towards transmission-blocking strategies
Authors: Amira Mohamed Taha, Dang Nguyen, Juan J Montenegro-Idrogo, Alfonso J Rodriguez-Morales
Journal: The Lancet Infectious Diseases (2024)

Malaria, primarily caused by Plasmodium falciparum, has witnessed a resurgence in some countries since 2019, highlighting the need for effective vaccines. In 2021, WHO recommended the RTS,S/AS01 vaccine (GSK Vaccines, Rixensart, Belgium), the first approved antiparasite vaccine, effectively reducing clinical malaria and deaths in children under five.1WHOWHO recommends groundbreaking malaria vaccine for children at risk.https://www.who.int/news/item/06-10-2021-who-recommends-groundbreaking-malaria-vaccine-for-children-at-riskDate: Oct 6, 2021Date accessed: November 3, 2023Google Scholar However, current eradication tools are insufficient, particularly in malaria-endemic areas, requiring new integrated interventions. Developing new transmission-blocking vaccines (TBVs), specifically Pfs230 domain 1 (Pfs230D1)-ExoProtein A (EPA) and Pfs25-EPA, have marked an advance in prevention. Preclinical studies have yielded promising results regarding immunogenicity, particularly for Pfs230D1-EPA.2Rausch KM Barnafo EK Lambert LE et al.Preclinical evaluations of Pfs25-EPA and Pfs230D1-EPA in AS01 for a vaccine to reduce malaria transmission.iScience. 2023; 26107192 Summary Full Text Full Text PDF Scopus (2) Google Scholar However, the safety and immunogenicity of these vaccines in humans are still to be fully assessed. In The Lancet Infectious Diseases, Sagara and colleagues3Sagara I Healy SA Assadou MH et al.Malaria transmission-blocking vaccines Pfs230D1-EPA and Pfs25-EPA in Alhydrogel in healthy Malian adults; a phase 1, randomised, controlled trial.Lancet Infect Dis. 2023; 23: 1266-1279Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar conducted a phase 1 randomised controlled trial in Bancoumana, Mali, investigating the effectiveness of the malaria TBVs Pfs25-EPA formulated in Alhydrogel (Pfs25-EPA/Alhydrogel) and Pfs230D1-EPA/Alhydrogel. The trial, enrolling 200 healthy residents aged 18–50 years in a malaria-hyperendemic area, assessed vaccines Pfs25-EPA/Alhydrogel, Pfs230D1-EPA/Alhydrogel, and their combination against comparators (Twinrix [GSK Vaccines, Rixensart, Belgium] or Menactra [Sanofi Pasteur, Swiftwater, PA, USA]).3Sagara I Healy SA Assadou MH et al.Malaria transmission-blocking vaccines Pfs230D1-EPA and Pfs25-EPA in Alhydrogel in healthy Malian adults; a phase 1, randomised, controlled trial.Lancet Infect Dis. 2023; 23: 1266-1279Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar Pfs230D1 alone showed superiority in seroconversion and antibody persistence, with 71% of participants showing significant responses after two doses compared with 44% for Pfs25 alone.3Sagara I Healy SA Assadou MH et al.Malaria transmission-blocking vaccines Pfs230D1-EPA and Pfs25-EPA in Alhydrogel in healthy Malian adults; a phase 1, randomised, controlled trial.Lancet Infect Dis. 2023; 23: 1266-1279Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar Additionally, Pfs230D1 induced durable functional activity after the third dose. However, Pfs25 did not, and combining it with Pfs230D1 did not improve immunogenicity, which is consistent with preclinical findings.2Rausch KM Barnafo EK Lambert LE et al.Preclinical evaluations of Pfs25-EPA and Pfs230D1-EPA in AS01 for a vaccine to reduce malaria transmission.iScience. 2023; 26107192 Summary Full Text Full Text PDF Scopus (2) Google Scholar The concept of so-called original antigenic sin, in which pre-existing immunity alters responses to subsequent cross-reactive serotypes or pathogens, is a substantial concern in malaria vaccine development, particularly for blood-stage vaccines (BSVs).4Davenport FM Hennessy AV Francis Jr, T Epidemiologic and immunologic significance of age distribution of antibody to antigenic influenza virus variants.J Exp Med. 1953; 98: 641-656Crossref PubMed Scopus (236) Google Scholar This situation is complicated by the age-dependent nature of natural immunity to malaria, which builds up from recurrent infections and is initially allele-specific, adapted to specific malaria parasite populations. A study in Mali on the AMA-1 malaria antigen revealed 214 unique haplotypes among 748 sequences, emphasising the substantial genetic diversity of the malaria parasite in the region and the necessity for multiallelic vaccine formulations for adequate protection.5Takala SL Coulibaly D Thera MA et al.Extreme polymorphism in a vaccine antigen and risk of clinical malaria: implications for vaccine development.Sci Transl Med. 2009; 12ra5 Crossref PubMed Scopus (146) Google Scholar As evidenced by phase 2b trials, existing BSVs also cause allele-specific immunity, indicating the need to develop multiallelic formulations to provide widespread protection.6Bergmann-Leitner ES Duncan EH Mease RM Angov E Impact of pre-existing MSP1(42)-allele specific immunity on potency of an erythrocytic Plasmodium falciparum vaccine.Malar J. 2012; 11: 315Crossref PubMed Scopus (11) Google Scholar Contrary to BSVs, pre-existing Pfs230 antibodies in the Malian population, possibly present due to natural exposure, did not appear to impair TBV responses.3Sagara I Healy SA Assadou MH et al.Malaria transmission-blocking vaccines Pfs230D1-EPA and Pfs25-EPA in Alhydrogel in healthy Malian adults; a phase 1, randomised, controlled trial.Lancet Infect Dis. 2023; 23: 1266-1279Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar This variable immune response is insightful and could be attributed to the distinct targets and mechanisms, with TBVs impeding parasite development in mosquitoes to disrupt transmission. In contrast, BSVs target parasite proliferation within the human host.7Yu S Wang J Luo X et al.Transmission-blocking strategies against malaria parasites during their mosquito stages.Front Cell Infect Microbiol. 2022; 12820650 Crossref Scopus (12) Google Scholar Given that differential scanning fluorimetry (DSF) assays detected transmission events in a small percentage of participants, future trials could benefit from less frequent but longer DSF periods and possibly target younger demographics with higher transmission rates. Improving assays such as DSF and direct membrane feeding assays (DMFA),8Coulibaly MB Gabriel EE Sinaba Y et al.Optimizing direct membrane and direct skin feeding assays for Plasmodium falciparum transmission-blocking vaccine trials in Bancoumana, Mali.Am J Trop Med Hyg. 2017; 97: 719-725Crossref PubMed Scopus (6) Google Scholar possibly through the incorporation of advanced molecular technologies and the optimisation of assay parameters, is crucial for accurately assessing the vaccine's effectiveness in preventing malaria transmission. In 2021, WHO estimated 4·9 million cases of Plasmodium vivax, particularly in regions with coendemic plasmodium species. Therefore, expanding research to include a comprehensive strategy to address the immense global diversity of parasite populations is crucial for more effective vaccine development.9Poespoprodjo JR Douglas NM Ansong D Kho S Anstey NM Malaria.Lancet. 2023; 402: 2328-2345Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar This strategy should involve rigorous data collection and analysis of genetic data from natural parasite populations, including sequencing and population genetic analyses of targeted genes.10Barry AE Arnott A Strategies for designing and monitoring malaria vaccines targeting diverse antigens.Front Immunol. 2014; 5: 359Crossref PubMed Scopus (79) Google Scholar Focusing on accurately measuring allele frequencies, identifying immune selection regions, and evaluating strain is essential for recognising antigenic variation.10Barry AE Arnott A Strategies for designing and monitoring malaria vaccines targeting diverse antigens.Front Immunol. 2014; 5: 359Crossref PubMed Scopus (79) Google Scholar Combining multiple TBVs with existing vaccines, such as RTS and S/AS01, could enhance effectiveness in regions with high malaria transmission. Understanding the effect of human behaviour, environmental factors, and mosquito ecology on vaccine effectiveness is fundamental for successful deployment in endemic areas. Research should extend beyond biology to include socioeconomic and environmental influences on vaccination strategies, allowing for tailored responses to regional challenges. Community engagement and education are imperative for addressing vaccine hesitancy and ensuring high vaccine uptake and compliance in endemic areas. Integrating community initiatives with research could effectively combat malaria in high-prevalence areas. In conclusion, although the Pfs25 and Pfs230D1 conjugate vaccines with Alhydrogel were safe, well tolerated, and immunogenic in the Malian adult population, Pfs230D1 showed superior functional immunogenicity. The study highlights the importance of further optimising DSF assays with complementary in-vitro measures, such as DMFA, to improve their statistical power as effective endpoints in vaccine trials. These vaccine trials are urgently needed for malaria, especially due to P falciparum in Africa and other endemic regions. We declare no competing interests.