A Phase I Study of a Candidate Malaria VaccineShanda Hand, RN, BSN, CCRP; B. Gayle Johnson, RN, CCRP; C. Buddy Creech, MD, MPH; Kathryn M. Edwards, MD

Vanderbilt Vaccine Research Program, Vanderbilt University Medical Center, Nashville, Tennessee

Abstract

Background: Malaria represents one of the most prevalent infections in tropical and sub-tropical areas in the world. Each year, malaria affects approximately 300 million people and kills 1 to 3 million people in developing countries. Malaria is caused by a mosquito-borne hematoprotozoan parasite which belongs to four different species. Malaria has a life cycle consisting of several stages which occur in the liver and blood. Vanderbilt Uni-versity and Stanford University are conducting a phase I study of a vaccine that targets the malaria parasite prior to entry into the liver that is being sponsored by the National In-stitute of Health. Objective: To discuss a phase I malaria vaccine study that is being conducted at Vander-bilt and Stanford Universities. Study Design: This study is conducted in four dose cohorts starting from the lowest dose to the highest dose. Eighteen volunteers will be enrolled in each of the four cohorts. Af-ter enrollment has been met in each group a Safety Monitoring Committee will meet and discuss any safety issues or concerns and then determine if it is safe to proceed to the next dose cohort. Conclusion: Vanderbilt and Stanford are still enrolling for the last cohort with 8 remain-ing subjects to be enrolled in this group. Plans for a Phase 1 trial in malaria endemic areas of Africa are underway at this time.

I. Worldwide Importance of Malaria

Approximately half of the world’s population is at risk for malaria, particularly those living at or near the equator and those in develop-ing nations.Each year, malaria infects approximately 300 million individuals.Of these, 1-3 million individuals die, most of whom are under 5 years of age, resulting in one death every 30 seconds.Most infections occur in regions near the equator - Central and South America, Africa, and Southeast Asia - areas that also contain a large proportion of the world’s population.In recent years, an increase in anti-malarial drug resistance has complicated both prevention and treatment of the malaria parasite.

II. Life Cycle of Malaria - Opportunities for Prevention

The Anopheles mosquito is responsible for the development of ma-laria parasites. Sporozoites from the mosquito travel from the gut to the salivary glands of infected female mosquitos to the human dur-ing a bite.Upon entry of sporozoites into the lymphatic system, the malaria parasite (Plasmodium sp.) enters the liver and undergoes amplifica-tion.These parasites enter the bloodstream and infect red blood cells. Parasites mature in the red blood cell and, upon rupture, will either infect additional RBCs or will become gametocytes, capable of being ingested by mosquitos when another bite occurs.

Therefore, the opportunities to intervene include:1. Stop mosquito transmission of malaria (mosquito control, use of

sleeping nets, insecticides).2. Increase immunity to the earliest forms of the malaria parasite so that

there is no opportunity for amplification in the liver3. Increase immunity to the red blood cell forms of the malaria parasite,

making further replication ineffective.

III. Study Design

Multicenter, placebo-controlled, randomized, dosage escalation trial assessing the safety and immunogenicity of four doses (108-1011) of an adenovirus-based circumsporozoite malaria vaccine.Healthy adults, 18-40 years of age, with no significant medical prob-lems and no recent or planned travel to malaria endemic regions of the world.Vaccine is given on 3 occasions (enrollment, 1 month, 6 months) in-tramuscularlyAfter each dose, reactogenicity and adverse events are evaluated.Starting with the lowest dose, 18 subjects are vaccinated. Subse-quent higher doses are not given until the safety of the previous dose is confirmed by an independent Safety Monitoring Committee (SMC).

IV. Challenges with Current Study

Phase I study: As a result of travel restrictions, stringent laboratory criteria, and subjects’ tolerance of risk, the screening failure has been high. Only 1 in 3 subjects interested in the study remain eligi-ble after screening.Initially, extraneous laboratory studies (e.g., obtaining a basic meta-bolic panel rather than only a sodium concentration) had to be modified so that inappropriate screen failures did not occur. During the study, the HIV STEP trial results were released, question-ing the safety of an adenovirus-based vaccine vector.In addition to halting due to the STEP trial, halting rules for adverse events have been met on multiple occasions, resulting in review of data to ensure subject safety.

V. Conclusions

Phase I clinical trials are unique in their risk, need for healthy volun-teers, and, often, their requirement for dose-escalation to ensure safe doses of the investigational product.Attention to detail in protocol development and protocol implemen-tation is critical given that the product has no track record in humans and may, indeed, not be safe.Clinical trials must always assess even minor complaints in subjects in order to adequately monitor for safety.Despite the lack of malaria in the United States, it is important to conduct trials in healthy adults prior to implementation in other re-gions of the world.

VI. Acknowledgements

This study is being conducted through the National Institutes of Health-sponsored Vanderbilt Vaccine Treatment and Evaluation Unit (VTEU).