Malaria Infection Diagnosed by Polymerase Chain Reaction (PCR) as a Means of Evaluating Pre-erythrocytic Candidate Malaria Vaccines
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The ability to test candidate pre-erythrocytic stage malaria vaccines, using a
      well-established sporozoite challenge model, in a field setting with group sizes of tens
      rather than hundreds of volunteers would greatly facilitate identification of the most
      promising vaccine candidates. The investigators assessed the suitability and acceptability of
      this method in a field trial in semi-immune volunteers exposed to natural infection during
      the high malaria transmission season.
    

Detailed description: 
      Objective

      The primary objective of the study was to determine if the very sensitive PCR technique,
      capable of detecting malaria parasites at low densities could be used as an economical method
      of undertaking preliminary field evaluation of pre-erythrocytic malaria vaccines. A secondary
      objective was to determine if the intensive blood sampling that this method requires would be
      acceptable.

      Study area

      This study was conducted from June to October 2004 when the incidence of malaria in The
      Gambia is highest. Volunteers were recruited from 9 villages east of Farafenni, a town which
      is 200km east of the capital city, Banjul. Malaria is highly seasonal in this area with an
      entomological inoculation rate between 10 and 50 infectious bites per year.

      Study population

      Healthy volunteers aged between 15-45 years were screened at two centres for their
      eligibility to take part in the study. Screening involved a thorough physical examination as
      well as blood sampling tests for haematological (full blood count, packed cell volume [PCV]),
      renal (plasma creatinine level) and hepatic (alanine amino transferase) tests and for HIV 1
      and 2 tests by ELISA. A glucose-6-phosphate dehydrogenase (G6PD) deficiency test was carried
      out because of the risk involved with administering the study drugs Primaquine and Lapdap to
      volunteers who are G6PD deficient. Exclusion criteria included a PCV < 30%, raised plasma
      creatinine (> 130 micromoles/litre) or ALT levels (> 42 IU/litre), G6PD deficiency,
      simultaneous participation in another clinical trial, blood transfusion in the month prior to
      vaccination, previous experimental malaria vaccination, administration of another vaccine
      within 2 weeks of vaccination, allergy to any previous vaccination or to
      sulphadoxine/pyrimethamine, history of splenectomy and any treatment with immunosuppressive
      drugs.

      Study procedure

      Eligible volunteers were enrolled into the study after written, informed consent was
      obtained. All eligible volunteers were issued a unique number and a photo identification
      card. Volunteers were randomly allocated into three groups to receive either two 5 x10^7 pfu
      doses of FP9 ME-TRAP followed by a single dose of 1 x 10^8 pfu MVA ME-TRAP (malaria vaccine
      group) or 3 doses of rabies vaccine (Fansidar and rabies groups). All vaccines were give 4
      weeks apart and were administered intradermally. Following vaccination, all volunteers were
      observed for 1 hr and given a course of anti-pyretic (paracetamol) to take if required. In
      addition, home visits were made by field workers on days 1, 2, 7 and 28 after each
      vaccination to record adverse events using a standard diary card. All volunteers received a
      single dose of Primaquine (30mg) 7 days before the final dose of vaccination as radical cure
      for gametocytes and a 3-day course of the short acting anti-malaria drugs, Lapdap and
      Artesunate in combination starting on the day of final vaccination to clear any asexual forms
      of the parasite before the follow-up period. Additionally, volunteers in the Fansidar group
      received the long acting anti-malarial drug and were expected to remain PCR negative
      throughout the follow-up period. Volunteers were followed up intensively for 28 days starting
      7days after the last vaccination. The period of follow-up was timed to correspond with the
      period of high malaria transmission. Follow-up was by daily finger-pricks to obtain 0.5mls of
      blood in a microtainer for PCR analysis and a duplicate blood film for estimation of malaria
      parasites. Laboratory staff that conducted immunoassays and PCR analysis were blind to the
      group allocation of volunteers until after approval of the analysis plan by the Data Safety
      Monitoring Board (DSMB).

      Sample size

      Based on practical and statistical considerations the researchers proposed to enroll 40
      volunteers per group (a total of 120). Allowing for a steady rate of drop-out during follow
      up amounting to total of 20% of subjects by the end of the trial, the trial has at least 80%
      power to detect a difference in time to infection between the malaria vaccine and rabies
      groups, if the vaccine efficacy is at least 60%, and at least 70% of the control group
      volunteers develop detected parasitaemia during the trial.

      Data Safety Monitoring Board (DSMB)

      A DSMB was set up to oversee the conduct of the trial and approve the analytical plan before
      unblinding the laboratory staff. The trial was conducted according to ICH Good Clinical
      Practice guidelines and was guided by the Medical Research Council regulations for the
      conduct of clinical trials.
    

Intervention name(s): FP9 ME-TRAP; MVA ME-TRAP
Intervention type(s): Biological; Biological
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Single
Primary purpose: Prevention
Keywords: Malaria; PCR; Vaccines; Acceptability