Oxford University Clinical Research Unit, Vietnam

Overview: In 2022-2023, Sanaria® PfSPZ Vaccine and Sanaria® PfSPZ-CVac (CQ) malaria vaccines were assessed in a phase 2 clinical trial in Papua, Indonesia, against genetically diverse, naturally transmitted Plasmodium falciparum in malaria naïve, Indonesian military personnel. On July 17, 2024, the Faculty of Medicine, Universitas Indonesia (FMUI) hosted a scientific meeting in Jakarta, Indonesia attended by representatives of all the stakeholders to review the trial. The Trial: The Sanaria-sponsored IDSPZV1 Clinical Trial was the first malaria vaccine trial ever conducted in Indonesia and the first in Southeast Asia in 30 years. This randomized, double-blind, placebo-controlled trial assessed the safety, tolerability and protective efficacy of Sanaria® PfSPZ Vaccine (radiation attenuated) and Sanaria® PfSPZ-CVac (CQ) (chemically attenuated) against naturally transmitted Plasmodium falciparum highly divergent from the vaccine strain in the vaccines. The trial was conducted by the Oxford University Clinical Research Unit (OUCRU), Indonesia, in collaboration with the FMUI, the Republic of Indonesia Army Health Centre (PUSKESAD RI), the Eijkman Molecular Biology Research Centre at the National Innovation Research Agency. Funding was provided by the US Congressionally Directed Medical Research Program and the Wellcome Trust. The study research team consisted of over 90 individuals and there were 345 Indonesian volunteers from an Army battalion located in Pekan Baru, Riau Province,. After being fully immunized with a vaccine or normal saline placebo between May and September 2022, the battalion deployed to the Keerom District of northeastern Papua Province on the island of New Guinea until August 2023. During deployment the research team surveilled and treated more than 700 malaria cases over nine months. The team continued surveilling the volunteers for 6 months after the soldiers returned to their home base in Sumatra, treating more than 300 malaria relapses. Sanaria® PfSPZ Vaccine was immunogenic and as well-tolerated and safe as saline placebo. Sanaria® PfSPZ-CVac was also safe and well-tolerated, with expected minor transient side effects. Both vaccines provided significant protection against Plasmodium falciparum infection. Historic first for malaria vaccines. The IDSPZV1 malaria vaccine trial is the first in history in which malaria-naive (non-exposed) individuals were immunized in a malaria-free area and then exposed to naturally transmitted malaria in a different, malaria-endemic area, thereby mimicking the situation faced by many travelers, including military personnel. Most rigorous test of vaccine efficacy. It also provided a stringent test of vaccine efficacy because both PfSPZ Vaccine and PfSPZ-CVac (CQ) are based on a West African strain of Plasmodium falciparum and were tested for protection against malaria parasites indigenous to the island of New Guinea. These Pf parasites are genetically much more divergent from the West African strain used in the vaccine than any Plasmodium falciparum parasites anywhere in the world. The trial thus tested the ability of the vaccine to induce strong protective immunity against genetically heterogeneous malaria parasites. The efficacy results will be made public after being approved for peer-reviewed publication later this year. The meeting: Distinguished attendees: The meeting was attended by retired General Noch Tiranduk Mallisa, the Principal Medical Advisor to President Joko Widodo; Roy Himawan, Director of Pharmaceutical and Medical Device Resilience, Ministry of Health; Isnabarika, Clinical Trial Working Team, who represented the Director of Drugs Registration Department, Indonesian National Agency for Drugs and Food Control (BPOM RI), and additional representatives from the Indonesian Army, the Ministry of Health, the National Innovation Research Agency, the Indonesian National Agency Drugs and Food Control, FMUI, the trial’s Safety Monitoring Committee and the two Ethical Committees that provided research oversight during the trial. The program: The more than 60 in-person attendees and 80 online attendees were welcomed by Dr. Rahayusalim, Director of Research and Community Service at FMUI, and Professor Kevin Baird, Director of OUCRU. Colonel Dr. Soni Endro Cahyo from PUSKESAD RI described the infectious threat posed by malaria to the Indonesian Armed Forces, Dr. Helen Dewi Prameswari, Chair of the Malaria Working Team, Ministry of Health, described the malaria situation in Indonesia, and Dr. Thomas L. Richie, Sanaria’s Chief Medical Officer, described the global threat posed by malaria, the need for a malaria vaccine, and Sanaria’s mission to develop a next generation product meeting the requirements set forth by the World Health Organization in 2022. The OUCRU team then showed a video describing trial implementation, including the testimony from Dr. Kennedy Siregar, the Health Commander of the battalion: “Our battalion received great benefit by participating in the trial; the study team provided important knowledge about malaria treatment,” he said. Dr. Krisin Chand, Site Medical Officer, shared the many challenges faced by the clinical team in the field, and Prof. Erni Nelwan, M.D, Ph.D, principal investigator for the trial and a professor at FMUI, described the safety, tolerability, immunogenicity and efficacy results. After a lively question and answer session moderated by Dr. Iqbal Elyazar, Program Manager of Geospatial Epidemiology and malaria expert at OUCRU, Dr. Richie described pending analyses and Sanaria’s clinical development plan for bringing a genetically attenuated, genetically engineered, next generation malaria vaccine, called Sanaria® PfSPZ-LARC2 Vaccine, to international licensure and deployment. Dr. Baird closed the meeting with a summary of key accomplishments and plans.

A new antimalarial drug is being introduced at a dose that is too low to be effective for all patients who need it, according to a new report. A new antimalarial drug is being introduced at a dose that is too low to be effective for all patients who need it, according to a report published today in eLife. The study suggests that the current 300 mg adult dose of tafenoquine reduces recurrent vivax malaria infection by 70%, whereas increasing it to 450 mg would reduce recurrence by 85%. This means that for every 11 people treated with the higher dose, an additional person would be cured. Tafenoquine is the first newly approved anti-relapse drug for 70 years, and its main advantage is that it can be taken as a single dose, unlike primaquine (the current treatment) which needs to be taken daily for 7-14 days. "The same single dose of tafenoquine is recommended for all adults and this has important practical advantages. However, because of variation in body weight, that dose results in substantial variation in drug exposure," explains lead author James Watson, a researcher at the Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. "The tafenoquine studies suggested that this single 300 mg dose was inferior to primaquine doses which are lower than those recommended by the WHO in Southeast Asia. Overall, it seems that the currently recommended adult dose of tafenoquine is not as good as optimal primaquine treatment in preventing vivax malaria relapses in all endemic regions." To understand more about tafenoquine's mechanism of action and optimal dosing, the team conducted a meta-analysis in which they pooled data from individual malaria patients who took part in the three clinical trials that led to the drug's approval, and healthy volunteers involved in an earlier pharmacokinetics study. They then used statistical models to characterise the relationship between the weight-adjusted dose of tafenoquine or primaquine treatment and the likelihood of a recurrent malaria infection. They found that each additional mg/kg of tafenoquine substantially reduced the chance of having a recurrent vivax malaria infection within four months. For example, increasing the dose from 3mg/kg to 4mg/kg reduces the proportion of patients with a recurrent infection from ~30% to 20%. This association between tafenoquine dose and the proportion relapsing was seen in patients from Asia, Africa and the Americas. They then used patients' weight data from the three efficacy trials to calculate the likely average efficacy of tafenoquine with either a 300 mg or 450 mg dose. A fixed tafenoquine dose of 300 mg would result in around 15% of the patients having a recurrence, whereas a dose of 450mg would reduce this proportion to 6%. Given that approximately half the patients given no anti-relapse treatment had a recurrence, this suggests that the lower 300 mg dose prevents 70% of recurrences whereas the 450 mg dose prevents 85% of recurrences. To study the mechanism of action of tafenoquine, the team combined pharmacokinetics data from the healthy volunteers in the initial study with patients from the efficacy trials -- nearly 4,500 drug measurements from 718 individuals. They also measured levels of methaemoglobin, a measure of oxidative activity in the body. These two analyses revealed the drug's metabolism, reflected by its rate of elimination from the body, rather than exposure to the parent compound, determined its activity in preventing vivax malaria recurrences, and it suggests that the conversion of tafenoquine into oxidative metabolites was responsible for its antimalarial activity, just as for primaquine. "Our analysis provides strong evidence that the currently recommended adult dose of tafenoquine is insufficient for radical cure in all adults," concludes senior author Nicholas White, Professor of Tropical Medicine at the Faculty of Tropical Medicine, Mahidol University, Thailand and the Centre for Tropical Medicine and Global Health, University of Oxford. "In endemic areas, relapse of Plasmodium vivax malaria causes substantial morbidity and contributes to mortality, particularly in young children. Tafenoquine can prevent malaria relapses in one treatment dose and is therefore, potentially, a major advance in antimalarial therapeutics. Getting the dose right is critical. The efficacy, tolerability and safety of increased doses should now be evaluated in prospective studies."