Table 1 The summary of major proposed changes in the revision of the draft guidelines for assuring the quality, safety, and efficacy of plasmid DNA vaccines.

Title of the document

Add “plasmid” to the title.

Likewise, it was agreed to refer to DNA vaccines as plasmid DNA vaccines rather than DNA plasmid vaccines.

Terminology

Provide the definitions of adjuvant and candidate vaccine to align with the relevant WHO guidelines.

Scope

Plasmid DNA expressing prophylactic monoclonal antibodies were outside of scope, but that like some immunotherapeutics based on plasmid DNA, that the quality (part A) section may have applicability to this product class, though parts B (nonclinical) and C (clinical) are unlikely to apply.

Introduction

Add a few more of the advantages of plasmid DNA vaccines.

Part A, manufacturing and control

• Definition: the International Non-Proprietary Names conventions would apply to DNA vaccines.

• General manufacturing guidelines: to clarify some language around potential for carryover or cross-contamination in multiuse facilities.

• Source, history, and generation of the host cell and plasmid: to discuss the potential use of novel strains or species of bacteria, and to reflect more currently the means of assessing and ensuring genetic stability of the plasmid DNA construct.

• Characterization of the bulk purified plasmid: clarification on characterizing the mode- or mechanism-of-action of the vaccine, including immunomodulatory elements.

• Consistency of manufacturing: clarification to reflect that this part is not referring to clinical studies, but to timing of manufacturing assessments of consistency.

• Manufacture and control of the final formulated vaccine: a subsection needed to be added to discuss measuring strength, dose, or content of the vaccine.

• Potency: to change some language, as mentioned above, to reflect that potency might be measured by content and percentage supercoiling rather than use of a bioassay. Further clarity was given to measuring the expression by mRNA rather than protein production.

• Safety, including sterility and endotoxin testing: to update to reference the monocyte activation test and to include the 3Rs concept.

Part B, nonclinical evaluation

• This section was considered to be generally satisfactory, though the need for more references that support the abbreviation of nonclinical programs would be useful to include for regulators in countries that have limited experience with this product type to date. Several references in this regard will be added.

• Furthermore, some changes in part C made it apparent that further discussion was needed in part B on the subject of the existing database of biodistribution data showing limited distribution and rapid degradation outside the injection site, which assuage historical concerns about germ-line involvement or genetic transfer. Likewise, a need to acknowledge the current evidence gap in developmental toxicology for DNA vaccines was raised.

Part C, clinical evaluation

• It was agreed that this section required some additions and modifications.

• Some language about the device/vaccine co-development should be included. The topics needed to be added included post-marketing surveillance issues, choice of control group (with or without use of device), and protocol/labeling language.

• Further, an issue that seemed to have some potential to complicate or confuse safety evaluations was the timing of adverse events, following boost doses in heterologous prime-boost regimens and whether to attribute them to the prime or the boost.

Part D, guidelines for national regulatory authorities

• Language in part D, two official release and certification needs to be further examined since it is likely that licensing of a new plasmid DNA vaccine will be reflected in a product/disease-specific WHO guideline at the time of such. Therefore, it might not be accurate to say the vaccine lot would only be released if it fulfilled the part A, quality section of this broad DNA vaccine guideline.

• Two appendices related to part D may need to be added to the guidelines.

– Model summary protocol for the manufacturing and control of DNA vaccines.

– Model national regulatory authority lot release certificate for DNA vaccines.