Implementation of a Randomized, Placebo-Controlled Trial of Live Attenuated Malaria Sporozoite Vaccines in an Indonesian Military Study Population.

Malaria eradication efforts prioritize safe and efficient vaccination strategies, although none with high-level efficacy against malaria infection are yet available. Among several vaccine candidates, Sanaria® PfSPZ Vaccine and Sanaria PfSPZ-CVac are, respectively, live radiation- and chemo-attenuated sporozoite vaccines designed to prevent infection with Plasmodium falciparum, the leading cause of malaria-related morbidity and mortality. We are conducting a randomized normal saline placebo-controlled trial called IDSPZV1 that will analyze the safety, tolerability, immunogenicity, and efficacy of PfSPZ Vaccine and PfSPZ-CVac administered pre-deployment to malaria-naive Indonesian soldiers assigned to temporary duties in a high malaria transmission area. We describe the manifold challenges of enrolling and immunizing 345 soldier participants at their home base in western Indonesia before their nearly 6,000-km voyage to eastern Indonesia, where they are being monitored for incident P. falciparum and Plasmodium vivax malaria cases during 9 months of exposure. The unique regulatory, ethical, and operational complexities of this trial demonstrate the importance of thorough planning, frequent communication, and close follow-up with stakeholders. Effective engagement with the military community and the ability to adapt to unanticipated events have proven key to the success of this trial.

Protective efficacy and safety of radiation-attenuated and chemo-attenuated Plasmodium Falciparum sporozoite vaccines against controlled and natural malaria infection: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVE: Despite the significant burden of Plasmodium falciparum (Pf) malaria and the licensure of two vaccines for use in infants and young children that are partially effective in preventing clinical malaria caused by Pf, a highly effective vaccine against Pf infection is still lacking. Live attenuated vaccines using Pf sporozoites as the immunogen (PfSPZ Vaccines) hold promise for addressing this gap. Here we review the safety and efficacy of two of the most promising PfSPZ approaches: PfSPZ Vaccine (radiation attenuated PfSPZ) and PfSPZ-CVac (chemo-attenuated PfSPZ). METHODS: We conducted a systematic review and meta-analysis by searching PubMed, EMBASE, SCOPUS, CENTRAL, and WOS until 22nd December 2021. We included randomized controlled trials (RCTs) of these two vaccine approaches that measured protection against parasitaemia following controlled human malaria infection (CHMI) in malaria-naive and malaria-exposed adults or following exposure to naturally transmitted Pf malaria in African adults and children (primary outcome) and that also measured the incidence of solicited and unsolicited adverse events as indicators of safety and tolerability after vaccination (secondary outcome). We included randomized controlled trials (RCTs) that measured the detected parasitaemia after vaccination (primary outcome) and the incidence of various solicited and unsolicited adverse events (secondary outcome). The quality of the included RCTs using the Cochrane ROB 1 tool and the quality of evidence using the GRADE system were evaluated. We pooled dichotomous data using the risk ratio (RR) for development of parasitemia in vaccinees relative to controls as a measure of vaccine efficacy (VE), including the corresponding confidence interval (CI). This study was registered with PROSPERO (CRD42022308057). RESULTS: We included 19 RCTs. Pooled RR favoured PfSPZ Vaccine (RR: 0.65 with 95% CI [0.53, 0.79], P = 0.0001) and PfSPZ-table (RR: 0.42 with 95% CI [0.27, 0.67], P = 0.0002) for preventing parasitaemia, relative to normal saline placebo. Pooled RR showed no difference between PfSPZ Vaccine and the control in the occurrence of any solicited adverse event (RR: 1.00 with 95% CI [0.82, 1.23], P = 0.98), any local solicited adverse events (RR: 0.73 with 95% CI [0.49, 1.08], P = 0.11), any systemic solicited adverse events (RR: 0.94 with 95% CI [0.75, 1.17], P = 0.58), and any unsolicited adverse event (RR: 0.93 with 95% CI [0.78, 1.10], P = 0.37). CONCLUSION: PfSPZ and PfSPZ-CVacs showed comparable efficacy. Therefore, they can introduce a promising strategy for malaria prophylaxis, but more large-scale field trials are required to sustain efficacy and yield clinically applicable findings.

Child malaria vaccine uptake in Ghana: Factors influencing parents' willingness to allow vaccination of their children under five (5) years.

BACKGROUND: Malaria is a substantial health burden in Ghana, particularly among children. Despite the availability of malaria vaccines, uptake remains low. Notwithstanding, there is a paucity of nationally representative studies on the factors driving hesitance towards the new malaria vaccine. In response, this study, guided by the Theory of Planned Behaviors (TPB), seeks to understand the determinants of child malaria vaccine uptake in Ghana to inform strategies for improving coverage. MATERIALS AND METHODS: We employed multiple regression model to examine the association between maternal awareness, socioeconomic status, ethnicity, geographical location, and vaccine uptake using data from the 2019 Ghana Malaria Indicator Survey (MIS). RESULTS: Maternal awareness of vaccine (OR = 2.200; P<0.01) significantly predicted higher likelihood of vaccine uptake. Household wealth was associated with child vaccination as parents in middle-income households (OR = 9.342; P<0.01), and those in poorest households (OR = 9.409; P<0.05) recorded higher likelihood of allowing their children to be vaccinated. With regards to ethnicity, parents from the Mande ethnic group (OR = 0.106; P<0.05) were less likely to allow their children to be vaccinated when compared to parents from the Akan ethnic group. Knowing that malaria is covered by National Health Insurance (OR = 2.407; P<0.05) was associated with higher likelihood of allowing child vaccination compared to not knowing. More so, geographical variations were observed as parents who lived in rural areas (OR = 0.254; P<0.05) were significantly less likely to allow vaccination of their children compared to those in urban areas. CONCLUSIONS: Enhancing awareness through education campaigns can improve child malaria vaccine coverage. Observing socioeconomic disparities in uptake and ensuring equitable access to vaccines are vital. Tailored strategies considering ethnic background and geographical location, can as well enhance acceptance of the vaccine. This study provides valuable insights for developing effective strategies to reduce the burden of malaria in children and improve coverage of uptake. This study underscores the need to improve parental awareness and the relevance of the vaccine in preventing child mortality.

A perspective on Oxford's R21/Matrix-M™ malaria vaccine and the future of global eradication efforts.

Malaria affects millions of lives annually, particularly in tropical and subtropical regions. Despite being largely preventable, 2021 witnessed 247 million infections and over 600,000 deaths across 85 countries. In the ongoing battle against malaria, a promising development has emerged with the endorsement by the World Health Organization (WHO) of the R21/Matrix-M™ Malaria Vaccine. Developed through a collaboration between the University of Oxford and Novavax, this vaccine has demonstrated remarkable efficacy, reaching 77% effectiveness in Phase 2 clinical trials. It is designed to be low-dose, cost-effective, and accessible, with approval for use in children under three years old. This perspective paper critically examines the R21/Matrix-M malaria vaccine, its development, potential impact on global malaria eradication efforts, and the challenges and opportunities it presents.

Commodifying Vaccines to Curtail Antibiotic Resistance Impact in Malaria Endemic Countries.

Rampant and prevalent deployment of an efficient malaria vaccine in Pakistan, together with basic control and preventive measures, could significantly decrease the economic and healthcare burden caused by drug-resistant malaria. Moreover, RTS, S/AS01 vaccine has attained a much-needed breakthrough after decades of growth, as an innovative vaccine for malaria in Phase III clinical trials, and presently undergoing implementation studies. So far Gavi, WHO, and other stakeholders are contemplating on the practical issues, risk-benefit, and cost-effectiveness in resource-limited settings of vaccine implementation capacity. Imminent advances, like using a delayed as well as enhanced protection, divided schedule for dosing, and alternate adjuvants are likely to attain the vital goal of eradication of malaria. Vaccination is a potentially critical component of efforts to arrest the development and dissemination of antimicrobial resistance; though little is known about the impact vaccination may have within low-and-middle-income countries. Key Words: Antimicrobial resistance, Malaria, Vaccine.

Can incorporating genotyping data into efficacy estimators improve efficiency of early phase malaria vaccine trials?

BACKGROUND: Early phase malaria vaccine field trials typically measure malaria infection by PCR or thick blood smear microscopy performed on serially sampled blood. Vaccine efficacy (VE) is the proportion reduction in an endpoint due to vaccination and is often calculated as VEHR = 1-hazard ratio or VERR = 1-risk ratio. Genotyping information can distinguish different clones and distinguish multiple infections over time, potentially increasing statistical power. This paper investigates two alternative VE endpoints incorporating genotyping information: VEmolFOI, the vaccine-induced proportion reduction in incidence of new clones acquired over time, and VEC, the vaccine-induced proportion reduction in mean number of infecting clones per exposure. METHODS: Power of VEmolFOI and VEC was compared to that of VEHR and VERR by simulations and analytic derivations, and the four VE methods were applied to three data sets: a Phase 3 trial of RTS,S malaria vaccine in 6912 African infants, a Phase 2 trial of PfSPZ Vaccine in 80 Burkina Faso adults, and a trial comparing Plasmodium vivax incidence in 466 Papua New Guinean children after receiving chloroquine + artemether lumefantrine with or without primaquine (as these VE methods can also quantify effects of other prevention measures). By destroying hibernating liver-stage P. vivax, primaquine reduces subsequent reactivations after treatment completion. RESULTS: In the trial of RTS,S vaccine, a significantly reduced number of clones at first infection was observed, but this was not the case in trials of PfSPZ Vaccine or primaquine, although the PfSPZ trial lacked power to show a reduction. Resampling smaller data sets from the large RTS,S trial to simulate phase 2 trials showed modest power gains from VEC compared to VEHR for data like those from RTS,S, but VEC is less powerful than VEHR for trials in which the number of clones at first infection is not reduced. VEmolFOI was most powerful in model-based simulations, but only the primaquine trial collected enough serial samples to precisely estimate VEmolFOI. The primaquine VEmolFOI estimate decreased after most control arm liver-stage infections reactivated (which mathematically resembles a waning vaccine), preventing VEmolFOI from improving power. CONCLUSIONS: The power gain from the genotyping methods depends on the context. Because input parameters for early phase power calculations are often uncertain, these estimators are not recommended as primary endpoints for small trials unless supported by targeted data analysis. TRIAL REGISTRATIONS: NCT00866619, NCT02663700, NCT02143934.

First malaria vaccine slashes childhood deaths.

Final evaluation brings good news from RTS,S rollout.

Second malaria vaccine gets WHO green light.

New shots could make malaria protection more plentiful, saving tens of thousands of lives.

Malaria & mRNA Vaccines: A Possible Salvation from One of the Most Relevant Infectious Diseases of the Global South.

Malaria is one of the most dangerous infectious diseases in the world. It occurs in tropical and subtropical regions and affects about 40% of the world´s population. In endemic regions, an estimated 200 million people contract malaria each year. Three-quarters of all global deaths (about 600 per year) are children under 5 years of age. Thus, malaria is one of the most relevant tropical and also childhood diseases in the world. Thanks to various public health measures such as vector control through mosquito nets or the targeted use of insecticides as well as the use of antimalarial prophylaxis drugs, the incidence has already been successfully reduced in recent years. However, to reduce the risk of malaria and to protect children effectively, further measures are necessary. An important part of these measures is an effective vaccination against malaria. However, the history of research shows that the development of an effective malaria vaccine is not an easy undertaking and is associated with some complications. Research into possible vaccines began as early as the 1960s. However, the results achieved were rather sobering and the various vaccines fell short of their expectations. It was not until 2015 that the vaccine RTS,S/AS01 received a positive evaluation from the European Medicines Agency. Since then, the vaccine has been tested in Africa. However, with the COVID-19 pandemic, there are new developments in vaccine research that could also benefit malaria research. These include, among others, the so-called mRNA vaccines. Already in the early 1990s, an immune response triggered by an mRNA vaccine was described for the first time. Since then, mRNA vaccines have been researched and discussed for possible prophylaxis. However, it was not until the COVID-19 pandemic that these vaccines experienced a veritable progress. mRNA vaccines against SARS-CoV-2 were rapidly developed and achieved high efficacy in studies. Based on this success, it is not surprising that companies are also focusing on other diseases and pathogens. Besides viral diseases, such as influenza or AIDS, malaria is high on this list. Many pharmaceutical companies (including the German companies BioNTech and CureVac) have already confirmed that they are researching mRNA vaccines against malaria. However, this is not an easy task. The aim of this article is to describe and discuss possible antigens that could be considered for mRNA vaccination. However, this topic is currently still very speculative.

Pre-vaccination monocyte-to-lymphocyte ratio as a biomarker for the efficacy of malaria candidate vaccines: A subgroup analysis of pooled clinical trial data.

BACKGROUND: Pre-vaccination monocyte-to-lymphocyte ratio was previously suggested as a marker for malaria vaccine effectiveness. We investigated the potential of this cell ratio as a marker for malaria vaccine efficacy and effectiveness. Effectiveness was investigated by using clinical malaria endpoint, and efficacy was investigated by using surrogate endpoints of Plasmodium falciparum prepatent period, parasite density, and multiplication rates in a controlled human malaria infection trial (CHMI). METHODS: We evaluated the correlation between monocyte-to-lymphocyte ratio and RTS,S vaccine effectiveness using Cox regression modeling with clinical malaria as the primary endpoint. Of the 1704 participants in the RTS,S field trial, data on monocyte-to-lymphocyte ratio was available for 842 participants, of whom our analyses were restricted. We further used Spearman Correlations and Cox regression modeling to evaluate the correlation between monocyte-to-lymphocyte ratio and Whole Sporozoite malaria vaccine efficacy using the surrogate endpoints. Of the 97 participants in the controlled human malaria infection vaccine trials, hematology and parasitology information were available for 82 participants, of whom our analyses were restricted. RESULTS: The unadjusted efficacy of RTS,S malaria vaccine was 54% (95% CI: 37%-66%, p <0.001). No correlation was observed between monocyte-to-lymphocyte ratio and RTS,S vaccine efficacy (Hazard Rate (HR):0.90, 95%CI:0.45-1.80; p = 0.77). The unadjusted efficacy of Whole Sporozoite malaria vaccine in the appended dataset was 17.6% (95%CI:10%-28.5%, p<0.001). No association between monocyte-to-lymphocyte ratio and the Whole Sporozoite malaria vaccine was found against either the prepatent period (HR = 1.16; 95%CI:0.51-2.62, p = 0.72), parasite density (rho = 0.004, p = 0.97) or multiplication rates (rho = 0.031, p = 0.80). CONCLUSION: Monocyte-to-lymphocyte ratio alone may not be an adequate marker for malaria vaccine efficacy. Further investigations on immune correlates and underlying mechanisms of immune protection against malaria could provide a clearer explanation of the differences between those protected in comparison with those not protected against malaria by vaccination.

Malaria Vaccines: Progress to Date.

Malaria is a mosquito-borne disease caused by protozoan parasites of the genus Plasmodium. Despite significant declines in malaria-attributable morbidity and mortality over the last two decades, it remains a major public health burden in many countries. This underscores the critical need for improved strategies to prevent, treat and control malaria if we are to ultimately progress towards the eradication of this disease. Ideally, this will include the development and deployment of a highly effective malaria vaccine that is able to induce long-lasting protective immunity. There are many malaria vaccine candidates in development, with more than a dozen of these in clinical development. RTS,S/AS01 (also known as Mosquirix) is the most advanced malaria vaccine and was shown to have modest efficacy against clinical malaria in phase III trials in 5- to 17-month-old infants. Following pilot implementation trials, the World Health Organisation has recommended it for use in Africa in young children who are most at risk of infection with P. falciparum, the deadliest of the human malaria parasites. It is well recognised that more effective malaria vaccines are needed. In this review, we discuss malaria vaccine candidates that have progressed into clinical evaluation and highlight the most advanced candidates: Sanaria's irradiated sporozoite vaccine (PfSPZ Vaccine), the chemoattenuated sporozoite vaccine (PfSPZ-CVac), RTS,S/AS01 and the novel malaria vaccine candidate, R21, which displayed promising, high-level efficacy in a recent small phase IIb trial in Africa.

[Vaccination against malaria]. / Vaccination contre le paludisme.

Vaccination against malaria is an old dream that reemerged in 2015 with the European Medicines Agency's favourable opinion on a first antimalarial vaccine, RTS,S/ AS01. Six years later, the World Health Organization (WHO) is advising a wide deployment of this vaccine in sub-Saharan Africa and in regions with high and moderate transmission where Plasmodium falciparum circulates. This follows favourable results from the pilot programme in Ghana, Kenya and Malawi involving over 800,000 children since 2019. This article addresses the objectives and main vaccine candidates targeting the different stages of parasite development, highlighting the progress and limitations of these different approaches. The RTS,S saga has been a milestone in vaccine development, with a first-generation vaccine recommended by the WHO for use in children over 5 months of age in sub-Saharan Africa and other areas of moderate to high transmission of P. falciparum malaria, in combination with other prevention measures. Research efforts continue to better understand the correlates of protection. With advances in vaccine platforms, new multi-antigen, multi-stage, and even multi-species approaches might emerge and brighten the horizon for malaria control.