Tables on the Clinical trials of pandemic influenza prototype vaccines

Introduction

Influenza vaccines are considered to be the most important and potentially effective intervention for mitigating the effects of an influenza pandemic. However, uncertainty remains on the optimal choice of strain and formulation for an effective vaccine, and this will be the case until the pandemic influenza strain has emerged. Current global production capacity for manufacturing of influenza vaccines is far from approaching what is needed in order to protect the world's population, and considerable efforts are invested to increase the production capacity for influenza.

At present, manufacturers from several countries have reported to WHO their work to develop prototype pandemic influenza vaccines against H5 hemagglutinin subtype influenza A viruses. Some manufacturers are also involved in the development of vaccines against other avian viruses (such as H7 or H9 hemagglutinin subtype influenza A viruses). More then 70 clinical trials have been completed or are ongoing as of June 2008. While most of the clinical trials have focused on healthy adults, new data is now available on safety and immunogenicity of vaccine candidates in the elderly and in children.

Vaccines reported to WHO at its meetings held in 2005-2008 were described as safe and well tolerated in the age groups studied. More information on safety/reactogenicity is available in publications or abstracts (See columns Reference of the Tables). Vaccine immunogenicity was demonstrated to vary based on type of vaccine, dose, and the presence of adjuvants.

Aluminum adjuvanted split vaccines have shown modest increase in immunogenicity over unadjuvanted vaccines, but not sufficient to allow significant dose sparing. Some split and subunit vaccines formulated with proprietary adjuvants (such as MF59, AS and AF03) show encouraging increase in immunogenicity. Several manufacturers have established formulations likely to meet regulatory requirements. In Europe, H5N1 inactivated vaccines “Daronix” from GlaxoSmithKline Biologicals and “Focetria” from Novartis V&D were granted EMEA approval on the basis of their mock-up dossier on 21 March and 2 May, 2007, respectively. In the USA, Sanofi Pasteur became the first manufacturer with a licensed H5 inactivated influenza vaccine on 17 April, 2007. In Japan, H5N1 vaccines from Biken and Kitasato were approved by MHLW in October 2007. In China, H5N1 inactivated vaccine from Sinovac was approved in April 2008, and “Fluval” vaccine from Omninvest was approved in Hungary. “Panvax” (CSL) and “Prepandrix” (GlaxoSmithKline Biologicals) H5N1 vaccines were approved for use by EMEA and TGA (Australia) in April and May 2008, respectively. Some studies suggest that vaccination with currently available H5N1 prototype vaccines can also induce immune response against antigenically drifted H5N1 virus isolated at different times in a variety of geographical locations, similar to what is seen with seasonal influenza viruses.

The table, compiled by WHO upon request of its Member States and various stakeholders in the area of pandemic preparedness, provides an abbreviated description of data provided in preliminary form to WHO on the status of recent (last 6 years) development of vaccines directed against influenza strains with pandemic potential. The table is revised periodically. WHO also calls on those who have not participated in its previous consultations to make available information on planned on ongoing vaccine trials for inclusion into the Table.

Because of inherent variability in the hemagglutination inhibition and neutralization antibody assay systems used to measure immunogenicity, and the lack of standardized methods for these assays, it is unwise to attempt to make direct comparisons of results from different clinical trials. Moreover, data presented was in some cases obtained in small groups of volunteers, and further trials will be needed.

This tables were originally developed using data compiled by IFPMA (on IFPMA website; http://www.ifpma.org/Documents/NR5877/Table_Avian_Pandemic_Influenza_RnD_17Oct06.pdf), which is gratefully acknowledged. Other sources of the information include materials presented at technical meetings convened by WHO, publications and direct contacts with manufacturers and investigators in charge of clinical trials. Upon specific request of clinical investigators or manufacturers, some data has not been included in the table, as indicated by the mention (RESULT NOT PUBLICLY AVAILABLE).

The current version of the Table is proposed as an Excel document. This allows users to filter (using a drop down menu) the data for the following variables:

• Type of vaccine
• Producer
• Subtype of influenza virus
• Strain of influenza virus
• Substrate for production
• Adjuvant used
• Dose
• Clinical development phase
• Number of subjects
• Age
• Schedule
• Route of administration of the vaccine

The Government of Canada is thanked for generous support to this work.