BioWorld International Correspondent
BRUSSELS, Belgium - The European Medicines Agency has admitted that there are serious gaps in its approach to biotechnology-derived vaccines, and it plans to act in coming months to remedy the deficiency.
The EMA said in a late-July statement that it is particularly concerned that current European guidance on DNA vaccines and live recombinant vector vaccines are out of date or almost completely lacking, and that filling the gap will help streamline clinical development and speed marketing authorizations.
Increased experience with the development of DNA vaccines demands an update to guidance on their use, according to the agency. The existing guidance on gene transfer medicinal products, dating from 2001, is no longer valid in the light of the wealth of new clinical and non-clinical data that has become available on their safety.
The agency cites recent work on plasmid DNA vaccines against infectious diseases, notably those expressing HIV or malaria antigens, as well as those directed at influenza, tuberculosis and Ebola virus. Although no marketing authorization for such a vaccine for human use has been granted in the European Union, the first DNA vaccines for veterinary use, West Nile-Innovator and Apex-IHN have been authorized elsewhere.
It plans to focus on manufacture and control, and the studies required for preclinical safety testing, including biodistribution, plasmid persistence and chromosomal integration.
"For DNA plasmid vaccines, many of the hypothetical concerns that are highlighted in the current note for guidance can now be re-evaluated based on non-clinical and clinical experience gained," it said.
It also wants to give attention to investigations now under way into therapeutic uses of plasmid DNA, in addition to its use in prophylaxis of infectious disease. And it wants to update quality aspects to ensure they are in line with state-of-the-art DNA manufacture and control.
The agency says its new guidance, to be developed over the coming months, will cover the scope, genetic development, manufacture, quality control, non-clinical safety testing and clinical assessment specific to these vaccines. Microorganisms such as bacteria intended for transferring plasmid DNA to human somatic cells in vivo for prevention of infectious disease will also be covered.
On live recombinant vector vaccines, it says specific guidance for their use in prevention of infectious disease "does not exist," although vaccines against infectious diseases based on a live microorganism expressing the antigen of a heterologous infectious agent have been under development for years now - such as pox virus expressing heterologous antigens derived from HIV or malaria.
As with plasmid DNA vaccines, no marketing authorization for human use has yet been granted in the EU. But work is more advanced, with many candidates in clinical development, and at least two in Phase III studies (including a reportedly successful Phase III trial by Acambis of a yellow fever vector-expressing JE antigen). Live recombinant veterinary vaccines based on canary-pox (such as Purevax FeLV) or herpes virus (Vaxxitek HVT+IBD) have already been authorized in the EU.
The agency plans to issue guidance on the use of live viral vectors such as vaccinia, yellow fever and measles viruses, viral vectors with restricted replication in humans due to the species barrier, such as avipox, and vectors that have been genetically engineered to be replication-incompetent, such as adenoviral vectors deleted in the E1A region, or MVA. Live bacterial vectors also will be included.
The guidance will look particularly at the level of attenuation of the live recombinant vaccine (often already based upon a live attenuated vaccine strain), the replication restriction of the vaccine vector and its design, the extent of immunity raised against the vector itself (with consequences on the reuse of the vector with other antigens), alteration of the host and tissue tropism of the vector, the possibility of reversion to virulence and the possibility of recombination with wild-type strains of the vector.
Other issues include the method of manufacture, biosafety, clinical follow-up in a healthy patient population and environmental risk.