European Malaria Vaccine Initiative
African Malaria Vaccine Testing Network
Clinical Trials Protocol Meeting, Hotel Richmond, Copenhagen, 22-23 May 2000

AGENDA

22 May

EMVI Welcome - Søren Jepsen

Purpose of Meeting and Expected Outcome, Practicalities - Chairperson Pedro Alonso

GCP/ICH - Wen Kilama
Short overview of essentials

Phase I Clinical Vaccine Trials - Francis Crawley
Ethical issues with special emphasis on problems relating to Developing Countries

GLURP – Michael Theisen
What is the evidence for selection of this molecule?
How did we come this far?
What do we expect?

MSP3 – Pierre Druilhe
What is the evidence for selection of this molecule?
How did we come this far?
What do we expect?

Long Synthetic Peptides – Giampietro Corradin
Concept, advantages and constraints

GMP Production – Ahmed Bouzidi
QC requirements

Phase I Clinical Vaccine Trials - Pedro Alonso
Aspects of going from adult Europeans via adult Africans to African infants
Time horizon for phase I - III clinical trials

Regulatory Authority Aspects – Patrick Corran
Approval from which authorities/committees?
Special issues relating to vaccine trials in Developing Countries
Ownership/audit?

Summary – Pedro Alonso, Michael Hollingdale

23 May

Presentation of Day’s Programme – Michael Hollingdale, Pedro Alonso

Phase I Trials – Dan Gordon
Planning to execution

Phase I Trials – Francois Spertini
A recent malaria vaccine trial

Phase I Trials – Jos van der Meer
The perspective from The Netherlands

CRFs – Opokua Ofori-Anyinam
What are they and why are they important?

SOP – Michael Hollingdale, Dan Gordon
What are they and why are they important?

Discussion and Summary – Søren Jepsen

Post Phase I Trials in Europe – Robert Sauerwein, Giampietro Corradin, Pierre Druilhe, Wen Kilama, Søren Jepsen
Critical steps in testing a malaria vaccine in humans

General discussion

Co-ordination with Other Agencies – Søren Jepsen
The European perspective

REPORT

Introduction

This meeting was convened to discuss the Clinical Protocols required for testing of EMVI-funded malaria vaccines in clinical trials in Europe and Africa.

EMVI has awarded contracts to three Investigators for current Good Manufacturing Process (cGMP) and Phase I clinical trials of their candidate vaccines, with a fourth award under final negotiation. The awarded contracts are: Merozoite Surface protein-3, MSP-3, and Liver Stage Antigen-3, LSA-3 (Dr. Pierre Druilhe, Institute Pasteur), and Glutamate Rich Protein GLURP (Dr. Michael Theisen, Statens Serum Institut, Copenhagen). The fourth contract is for a pre-erythrocytic liver stage vaccine (Dr. Adrian Hill, University of Oxford). CGMP manufacturing is in process at the time of the meeting, and is expected to be completed by the end of 2000 for MSP-3, LSA-3 and GLURP, and early 2001 for the pre-erythrocytic multi-epitope vaccine. Phase I safety and immunogenicity clinical trials are planned to begin in late 2000 and extend into 2001, and will be conducted at the University of Lausanne, Switzerland, and the University Hospital, Nijmegen, The Netherlands. Depending on the outcome of these European clinical trials, EMVI and AMVTN are starting to plan Phase I and later efficacy trials in Africa.

A series of experts from Europe and Africa were invited to Copenhagen to discuss the issues associated with clinical trials, particularly concerning their testing in Africa. Representatives from Industry, from the Walter Reed Army Institute of Research, who have conducted a series of malaria vaccine human trials, and the World Health Organization and the US Malaria Vaccine Initiative, were also invited. A total of 31 people attended the meeting, which was chaired by Dr. Pedro Alonso, Centro de Investigacao em Saude Manhica-Maputo, Mozambique, and Dr. Michael Hollingdale, University of Leeds. The meeting focused on the clinical and ethical issues associated with human clinical trials, the selection and cGMP manufacture of the EMVI-funded vaccines, regulatory requirements, and the prospects of clinical trials in Africa.

Dr. Søren Jepsen from EMVI opened the meeting by identifying the challenges of malaria vaccine development and a request that the meeting defines guidelines for the Clinical Protocols for European and African clinical trials. This was followed by Dr. Wen Kilama, AMVTN, Dar es Salaam, who discussed Good Clinical Practice (GCP) and the International Conference of Harmonization (ICH). GCP required that human clinical trials conform to international ethical and scientific quality standards, and fulfil the public assurance that the rights, safety, and well being of trial subjects are protected. The ICH GCP guidelines are a unified standard for the EU, Japan and USA and are being considered by the WHO. They are based on the Helsinki Declaration, and require that human trials are: supported by adequate pre-clinical and clinical data; scientifically sound and described in a detailed Clinical Protocol; comply with the Clinical Protocol that has prior approval of the relevant Internal Review Board and Ethical Committee; conducted by qualified investigators; obtain informed consent from every subject; record, handle and store all clinical data to allow accurate reporting, interpretation and verification; keep all records confidential; and manufacture, handle and store all products according to GMP. Dr. Kilama defined the responsibilities of the Investigators, Sponsors, and Monitors, which will be included in the Clinical Protocols.

Ethical concerns are of paramount importance for clinical trials, and Dr. Francis Crawly, Vrie University, Brussels, discussed current ethical issues, European ethical review systems, a proposed revised directive on GCP and ethical committees. Like Dr. Kilama, he emphasized that the role of the clinical Investigator is to protect the rights, safety, and well being of the trial participant. He emphasized the International Guidelines for ethical Review of Epidemiological Studies require that all research involving human subjects should be conducted in accordance with basic ethical principles, respect for persons, obligation to maximise benefits, and to safeguard against harm or abuse. Dr. Crawly urged that EMVI and AMVTN form an Ethics Committee to participate in the European and African trials.

Dr. Theisen described the evidence that GLURP is a candidate malaria vaccine. GLURP is a large secreted protein localized in the parasitophorous vacuole surrounding red blood cell parasites. Anti-GLURP antibodies were positively correlated with protection in children from disease in Ghana and Senegal, and protective antibodies mediate ADCI (antibody dependent cellular Inhibition) via monocytes. ADCI-effective antibodies identified B-cell epitopes in the R0 region, and a long synthetic peptide (LSP) representing these is being cGMP manufactured. Dr. Pierre Druihle described the evidence for MSP-3, a merozoite surface protein. Cytophilic ADCI-effective antibodies were targeted to a region within MSP-3, and clinical-epidemiological studies in Senegal demonstrated a close correlation between malaria attacks and the ratio of cytophilic to non-cytophilic antibodies. Levels of IgG3 antibodies against MSP-3 were strongly predictive of the clinical outcome. An MSP-3 LSP vaccine based on the ACDI activity is currently being cGMP manufactured.

Dr. G. Corradin, University of Lausanne, who described the concept, advantages and constraints of synthetic peptide vaccines as opposed to recombinant proteins or other vaccine platforms, is synthesizing LSP vaccines. He discussed the synthesis of LSP’s up to at least 100 amino acids using an ABI Synthesiser. By capping at each step, deletions (missing amino acids) can be minimised. Dr. Corradin emphasised the speed and purity of synthesis of LSP’s. Dr. Corradin emphasised that deletions were minimal, and impurities represented shorter sequences of the final polypeptide, unlike contaminants in recombinant proteins, which would include non-antigen polypeptides. After synthesis, LSP’s are to be purified to GMP standards by Dr. A. Bouzidi, SEDAC Therapeutics, Lille. He described the Quality Assurance requirements for the cGMP production of LSP’s, including the description of the chemistry, manufacturing and control information, final product controls to ensure acceptable limits, stability studies, pre-clinical and toxicological studies, and clinical study protocols to define study objectives.

The final part of the meeting focused on regulatory requirements, which were discussed by Dr. P. Corran, London School of Hygiene and Tropical Medicine. He emphasised that approval for Phase I clinical trials largely rests with each EU member State, and usually though not always with the IRB of the Institution performing the trials. It was essential that candidate vaccines were fully tested for safety in Europe before any clinical trials were conducted in Africa. A problem that was identified during this discussion, and by Dr. Robert Sauerwein, University Hospital, Nijmegen, was the feasibility of parasite challenge of volunteers immunized with blood stage vaccines, such as GLURP or MSP-3. The ethical problems associated with allowing a patent parasitemia to develop long enough for vaccine efficacy to be determined were fully discussed. Resolution of this problem was left with Dr. Sauerwein and EMVI as the funding Organisation. It will be important to decide the clinical outcome that must be fulfilled before a candidate vaccine can be moved from the EU to Africa. These will be based primarily on safety, and then immunogenicity. Dr. P. Alonso discussed the specific ethical and safety issues in moving from adult Europeans via African adults to African infants in Phase I clinical trials. His comments supported those of Drs. Kilama, Crawley and Corran in emphasising the ethical constraints.

Malaria vaccine clinical trials have been conducted at WRAIR in the USA since 1986. Dr. D. Gordon, WRAIR, gave a thorough analysis of the structure of these trials, expected outcomes, and their ethical, scientific, clinical and regulatory requirements. He emphasised development of the Clinical Protocol including the hypothesis to be tested, inclusion and exclusion criteria, informed consent, confidentiality and GCP, which are of concern to the EU and African participants. According to Dr. Gordon, development, execution and orderly closeout of a clinical trial is a complicated and time-consuming undertaking, which requires significant resources including funding, personnel, facilities, equipment, and ancillary support activities. It is essential that these trials are done in a scientifically sound, safe and ethical manner that provides critical information in the vaccine licensure process. These are issues that will have to be addressed and solved before trials can begin in Africa. These cGMP and GCP requirements were further emphasised by Dr. O. Ofori-Anyinam, SmithKline Beecham, Belgium.

The meeting then spent sometime discussing these presentations with many comments from individual participants. It was recognized that EMVI and AMVTN are making significant progress towards an integrated approach to malaria vaccine manufacture and clinical testing. The Chairs of the meeting summarised these discussions as a basis for developing the Clinical Protocols.

The clinical trials investigators from Lausanne and Nijmegen will, in close collaboration with Michael Hollingdale of EMVI, finalise the clinical trials protocols.

A full development plan will also be elaborated by an individual developer from Phase I clinical trials all the way to license application.

Michael Hollingdale

LIST OF PARTICIPANTS

Pedro Alonso, Centro de Investigacao em Saude Manhica-Maputo
epidemia@medicina.ub.es

David Arnot, University of Edinburgh
dea@holyrood.ed.ac.uk

Jorge Barreto, Ministry of Health, Maputo
deptimun@cdins.uem.mz

Ahmed Bouzid, SEDAC Therapeutics SA, Lille
ahmed.bouzidi@wanadoo.fr

Qijun Chen, Karolinska Institutet, Stockholm
qijun.chen@mtc.ki.se

Giampietro Corradin, University of Lausanne
giampietro.corradin@ib.unil.ch

Patrick Corran, London School of Hygiene and Tropical Medicine
pcorran@nibsc.ac.uk

Francis Crawley, Vrie Universiteit, Brussels
fpc@village.uunet.be

Pierre Druilhe, Institut Pasteur, Paris
druilhe@pasteur.fr

Filip Dubovsky, MVI (Bill and Melinda Gates Foundation)
fdubovsky@malariavaccine.org

Daniel Gordon, DoD, Washington
daniel.Gordon@na.amedd.army.mil

Beatrice Halpaap, WHO/TDR, Geneva
halpaapb@who.ch

Michael Hollingdale, Leeds University
bgymrh@leeds.ac.uk

Søren Jepsen, European Malaria Vaccine Initiative, Copenhagen
sje@ssi.dk

Juntra Karbwang, WHO/TDR, Geneva
karbwangj@who.ch

C.M. Kihamia, Muhimbili Medical Centre, Dar es Salaam
ckihamia@muchs.ac.tz

Wen Kilama, African Malaria Vaccine Testing Network, Dar es Salaam
wkilama@africaonline.co.tz

Shirley Longacre, Institut Pasteur, Paris
longacre@pasteur.fr

Jos van der Meer, University Hospital Nijmegen
j.vandermeer@aig.azn.nl

K.S. Mnyika, Muhimbili Medical Centre, Dar es Salaam
kmnyika@muchs.ac.tz

Issa Nebie, Centre Nat. de Recherche. et de Formation sur le Paludisme, Burkina Faso
immuno.cnlp@fasonet.bf

Opokua Ofori-Anyinam, SmithKline Beecham, Belgium
ofori-anyinam@sbbio.be

Robert Sauerwein, University Hospital Nijmegen
r.sauerwein@mmb.azn.nl

Francisco Saute, London School of Hygiene & Tropical Medicine, London
francisco.saute@lshtm.ac.uk

Sodiomon Sirima, Centre Nat. de Recherche. et de Formation sur le Paludisme, Burkina Faso
s.sirima.cnlp@fasonet.bf

Francois Spertini, University of Lausanne
francois.spertini@chuv.hospvd.ch

Denise Telgt, University Hospital Nijmegen
d.telgt@aig.azn.nl

Thor Theander, University of Copenhagen
theander@biobase.dk

Michael Theisen, Statens Serum Institut, Copenhagen
mth@ssi.dk

Mamadou Traoré, European Commission, DG Research, INCO-DEV
mamadou.traore@cec.eu.int

Juan Diego Velez, Clinica Valle de Lili, Cali
jdvelez@clinicalili.org.co