Clinical Study to Assess Minimum Mosquito Bites for P. Vivax Infection in Thai Adults

Controlled Human Malaria Infection (CHMI) has become an essential approach in the accelerated development of malaria vaccines and therapeutic interventions. This methodology involves the inoculation of human volunteers with malaria parasites, either via mosquito bites or direct administration of sporozoites or parasitized erythrocytes. CHMI facilitates the evaluation of vaccine and drug candidates in well-controlled early-phase clinical studies, enabling the selection of the most promising candidates for further evaluation in malaria-endemic regions.

While intravenous injections of parasites can be employed in such studies, the natural route of infection via mosquito bite has notable advantages, particularly in stimulating immune responses at the site of infection in the skin and closely mimic the natural infection process, allowing both liver and blood stage infections to develop. Additionally, mosquito-based challenge models provide a valuable platform for the evaluation of pre-erythrocytic (sporozoite) vaccine candidates. Effective sporozoite vaccines are expected to induce the production of serum antibodies capable of neutralizing sporozoites before they invade hepatocytes, thereby preventing liver-stage and blood-stage malaria.

Historically, numerous challenge studies using P. falciparum-infected mosquito bites or malaria parasite have been conducted in well-established research centers, including the Walter Reed Army Institute of Research, Sanaria Inc., the University of Maryland, Seattle Biomedical Research Institute, University of Oxford, and Radboud University Medical Centre. These studies have involved large cohorts, with over 45 trials involving P. falciparum-infected mosquitoes. However, studies utilizing P. vivax-infected mosquito bites have been fewer in number, with 8 trials conducted in regions such as Colombia, the UK, and Thailand.

P. vivax is the most prevalent malaria species outside of sub-Saharan Africa and represents a significant cause of malaria in countries such as Thailand. Given the substantial burden of P. vivax in Thailand and Southeast Asia, an international collaborative research team has proposed to advance the development and evaluation of P. vivax malaria vaccine candidates in an endemic region. This initiative is designed to include volunteers with genetic and immunological characteristics similar to those of the target population, thereby ensuring the relevance and applicability of the findings.

The first human challenge study in Thailand using P. vivax sporozoite infection known as "Malaria Infection Study in Thailand 1 (MIST1)," is currently being conducted at the Faculty of Tropical Medicine, an institution internationally recognized for its expertise in malaria research. The study aims to assess the feasibility and safety of P. vivax sporozoite human challenge in the local population. It represents a critical milestone in supporting the development and evaluation of effective malaria vaccines in regions where P. vivax is endemic.

Majority of malaria sporozoite challenge studies (75%, 39 out of 52 studies) have traditionally relied upon the bites of five infected mosquitoes to induce malaria. The rationale for using 5 mosquito bites is based on the extensive previous experience with P. falciparum, where sporozoite inoculated by fewer than five mosquitoes has led to inconsistent infections in malaria-naïve volunteers. However, this pattern does not appear to hold for P. Vivax-infected mosquito, as most studies demonstrated 100% infectivity rates using 2-4 mosquito bites and 5 mosquito bites. One study using P. Vivax-infected mosquito reported that 1 out of 18 participants did not develop malaria infection following a mosquito challenge. However, since antimalarial drug level were not measured in that study, the cause of this outcome remains inconclusive. Notably, no study used as few as one mosquito bite to induce P. Vivax malaria.

Individuals rarely bitten by more than one infected mosquito per night under natural condition, except in settings with very high malaria transmission intensity. In a very low transmission site on the Thai-Myanmar border a recent study reported a geometric mean of 57 sporozoites per mosquito (range 9-11,428). This compares to earlier studies in Africa and PNG where endemicity was higher and geometric means were \>4000 (range 150-10,000). The probability of infection increases with the number of infectious bites. There are relatively little data on the number of sporozoites in naturally infected mosquitoes. It has been demonstrated that highly infected mosquitoes being more likely to have caused infection than lightly infected mosquitoes in a dose-response relationship.

The MIST1 study initially employed five mosquito bites to ensure consistent infection in a small cohort of six volunteers. However, using five mosquito bites may create an unrealistic challenge and could hinder the assessment of true vaccine efficacy. One out of five volunteers in the MIST1 study developed a relapsed Plasmodium vivax infection, suggesting that the standard challenge involving five Plasmodium vivax -infected mosquitoes might contribute to an overwhelming infection.

The primary aim of this study is to determine the minimum number of Plasmodium vivax-infected mosquito bites required to reliably induce malaria infection in healthy individuals. This study will begin with a challenge dose of one mosquito bite, as only a limited number of studies have evaluated challenge models using as few as 2-4 infected mosquitoes, and some involved small sample sizes. Furthermore, no study has used as one mosquito bite to induce P. vivax malaria.

The investigators aim to confirm whether 1 - 3 bites are sufficient to consistently induce P. vivax infection while maintaining a challenge model that more closely reflects natural transmission, avoids excessive parasite exposure, and could undermine the vaccine efficacy assessments. If at least one volunteer who receives one mosquito bite is not successfully infected, the investigators will increase the challenge dose to two bites. If at least one volunteer remains uninfected after three bites, the investigators will not escalate the challenge to four bites as reducing from standard five bites to four may not provide a meaningful advantage as suggested by the Steering Committee.

The study will provide important information for the development of P-vivax mosquito delivered CHMI trials platform, enabling a safer and more accurate assessment of vaccine efficacy in malaria research. Moreover, conducting this trial in a local population will enhance the applicability of the findings to real-world endemic settings

• Prepatent period across different groups. [Срок оценки: Up to 21 days after the individual CHMI]
• Humoral immune responses [Срок оценки: Up to one year after antimalarial initiation]
• Humoral immune responses [Срок оценки: Up to one year after antimalarial initiation]
• Cellular immune responses [Срок оценки: Up to one year after antimalarial initiation]
• Cellular immune responses [Срок оценки: Up to one year after antimalarial initiation]
• Gametocytaemia across different groups [Срок оценки: Up to 21 days after the individual CHMI]
• AEs stratified by groups [Срок оценки: Up to one year after antimalarial initiation]