IMRAS-A clinical trial of mosquito-bite immunization with live, radiation-attenuated P. falciparum sporozoites: Impact of immunization parameters on protective efficacy and generation of a repository of immunologic reagents.

BACKGROUND: Immunization with radiation-attenuated sporozoites (RAS) by mosquito bite provides >90% sterile protection against Plasmodium falciparum (Pf) malaria in humans. RAS invade hepatocytes but do not replicate. CD8+ T cells recognizing parasite-derived peptides on the surface of infected hepatocytes are likely the primary protective mechanism. We conducted a randomized clinical trial of RAS immunization to assess safety, to achieve 50% vaccine efficacy (VE) against controlled human malaria infection (CHMI), and to generate reagents from protected and non-protected subjects for future identification of protective immune mechanisms and antigens. METHODS: Two cohorts (Cohort 1 and Cohort 2) of healthy, malaria-naïve, non-pregnant adults age 18-50 received five monthly immunizations with infected (true-immunized, n = 21) or non-infected (mock-immunized, n = 5) mosquito bites and underwent homologous CHMI at 3 weeks. Immunization parameters were selected for 50% protection based on prior clinical data. Leukapheresis was done to collect plasma and peripheral blood mononuclear cells. RESULTS: Adverse event rates were similar in true- and mock-immunized subjects. Two true- and two mock-immunized subjects developed large local reactions likely caused by mosquito salivary gland antigens. In Cohort 1, 11 subjects received 810-1235 infected bites; 6/11 (55%) were protected against CHMI vs. 0/3 mock-immunized and 0/6 infectivity controls (VE 55%). In Cohort 2, 10 subjects received 839-1131 infected bites with a higher first dose and a reduced fifth dose; 9/10 (90%) were protected vs. 0/2 mock-immunized and 0/6 controls (VE 90%). Three/3 (100%) protected subjects administered three booster immunizations were protected against repeat CHMI vs. 0/6 controls (VE 100%). Cohort 2 uniquely showed a significant rise in IFN-γ responses after the third and fifth immunizations and higher antibody responses to CSP. CONCLUSIONS: PfRAS were generally safe and well tolerated. Cohort 2 had a higher first dose, reduced final dose, higher antibody responses to CSP and significant rise of IFN-γ responses after the third and fifth immunizations. Whether any of these factors contributed to increased protection in Cohort 2 requires further investigation. A cryobank of sera and cells from protected and non-protected individuals was generated for future immunological studies and antigen discovery. TRIAL REGISTRATION: ClinicalTrials.gov NCT01994525.

A systematic review of safety data reporting in clinical trials of vaccines against malaria, tuberculosis, and human immunodeficiency virus.

INTRODUCTION: Malaria, tuberculosis (TB) and human immunodeficiency virus (HIV) are diseases with devastating effects on global public health, especially in the developing world. Clinical trials of candidate vaccines for these diseases are being conducted at an accelerating rate, and require accurate and consistent methods for safety data collection and reporting. We performed a systematic review of publications describing the safety results from clinical trials of malaria, TB and HIV vaccines, to ascertain the nature and consistency of safety data collection and reporting. METHODS: The target for the review was pre-licensure trials for malaria, TB and HIV vaccines published in English from 2000 to 2009. Search strategies were customized for each of the databases utilized (MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Database of Reviews and Effects). Data extracted included age of trial participants, vaccine platform, route and method of vaccine administration, duration of participant follow-up, reporting of laboratory abnormalities, and the type, case definitions, severity, reporting methods and internal reporting consistency of adverse events. RESULTS: Of 2278 publications screened, 124 were eligible for inclusion (malaria: 66, TB: 9, HIV: 49). Safety data reporting was found to be highly variable among publications and often incomplete: overall, 269 overlapping terms were used to describe specific adverse events. 17% of publications did not mention fever. Descriptions of severity or degree of relatedness to immunization of adverse events were frequently omitted. 26% (32/124) of publications failed to report data on serious adverse events. CONCLUSIONS: The review demonstrated lack of standardized safety data reporting in trials for vaccines against malaria, TB and HIV. Standardization of safety data collection and reporting should be encouraged to improve data quality and comparability. LIMITATIONS: The search strategy missed studies published in languages other than English and excluded studies reporting on vaccine trials for diseases besides malaria, TB and HIV.