The Power of Malaria Vaccine Trials Using Controlled Human Malaria Infection

PLoS Comput Biol. 2017 Jan 12;13(1):e1005255. doi: 10.1371/journal.pcbi.1005255. eCollection 2017 Jan.

Abstract

Controlled human malaria infection (CHMI) in healthy human volunteers is an important and powerful tool in clinical malaria vaccine development. However, power calculations are essential to obtain meaningful estimates of protective efficacy, while minimizing the risk of adverse events. To optimize power calculations for CHMI-based malaria vaccine trials, we developed a novel non-linear statistical model for parasite kinetics as measured by qPCR, using data from mosquito-based CHMI experiments in 57 individuals. We robustly account for important sources of variation between and within individuals using a Bayesian framework. Study power is most dependent on the number of individuals in each treatment arm; inter-individual variation in vaccine efficacy and the number of blood samples taken per day matter relatively little. Due to high inter-individual variation in the number of first-generation parasites, hepatic vaccine trials required significantly more study subjects than erythrocytic vaccine trials. We provide power calculations for hypothetical malaria vaccine trials of various designs and conclude that so far, power calculations have been overly optimistic. We further illustrate how upcoming techniques like needle-injected CHMI may reduce required sample sizes.

Trial registration: ClinicalTrials.gov NCT00442377 NCT00757887 NCT00509158 NCT01002833 NCT01236612.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bayes Theorem
  • Biomedical Research* / methods
  • Biomedical Research* / standards
  • Clinical Trials as Topic
  • Computational Biology
  • Computer Simulation
  • Healthy Volunteers
  • Humans
  • Malaria Vaccines*
  • Malaria, Falciparum / parasitology*
  • Malaria, Falciparum / prevention & control*
  • Models, Statistical*
  • Plasmodium falciparum / pathogenicity*

Substances

  • Malaria Vaccines

Associated data

  • ClinicalTrials.gov/NCT00442377
  • ClinicalTrials.gov/NCT00757887
  • ClinicalTrials.gov/NCT00509158
  • ClinicalTrials.gov/NCT01002833
  • ClinicalTrials.gov/NCT01236612

Grants and funding

The CHMI experiments from studies 0004-00900 (subjects marked EHMI-2), 0011–0262 (EHMI-3), 2001/203 (EHMI-4), and 2002/170 (EHMI-5) were financially supported by the European Commission Fifth Framework Programme, contract numbers QLK2-CT-1999-01293 and QLK2-CT-2002-01197. Studies NCT00442377 and NCT00757887 (EHMI-8A, B) were supported by the Dioraphte Foundation (http://www.dioraphte.nl). Study NCT00509158 (LSA3) was sponsored by Dictagene SA, Epalinges, Switzerland (no longer in existence). Study NCT01002833 (TIP-1) was supported by Top Institute Pharma (grant T4-102) and the European Malaria Vaccine Development Association (http://www.emvda.org). Last, study NCT01236612 (ZonMw) was funded by The Netherlands Organisation for Health Research and Development (ZonMw, project 95110086) and the Dioraphte Foundation (project 12010100). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.