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Guidelines on the nonclinical evaluation of vaccine adjuvants and adjuvanted vaccines


These Guidelines are intended to provide guidance to NRAs and manufacturers

on the nonclinical and initial clinical evaluation of vaccine adjuvants and

adjuvanted vaccines by outlining international regulatory expectations in this

area. The Guidelines should be read in conjunction with existing WHO guidelines

on nonclinical (1) and clinical (2) evaluation of vaccines. There is substantial

diversity among vaccine adjuvants and adjuvanted vaccines and their nonclinical

and clinical testing programmes will depend upon product-specific features and

their clinical indications. Therefore, the following text is written in the form

of WHO Guidelines instead of Recommendations. Guidelines allow greater

flexibility than Recommendations with respect to specific issues related to

particular adjuvanted vaccines.

Over the past decades, strategies and approaches for the development

and delivery of vaccine antigens have been expanded. Some of these antigens are

weakly immunogenic and require the presence of adjuvants for the induction or

enhancement of an adequate immune response. Vaccines with aluminium-based

adjuvants have been used extensively in immunization programmes worldwide

and a significant body of safety information has accumulated for them (3, 4).

As the knowledge of immunology and the mechanisms of vaccine adjuvant

action have developed, the number of vaccines containing novel adjuvants being

evaluated in clinical trials has increased. Vaccines containing adjuvants other

than aluminium-containing compounds have been authorized for use in many

countries (e.g. human papillomavirus and hepatitis B vaccines), and a number

of vaccines with novel adjuvants are currently under development, including,

but not limited to, vaccines against human immunodeficiency virus (HIV),

malaria and tuberculosis, as well as new-generation vaccines against influenza

and other diseases. However, the development and evaluation of adjuvanted

vaccines present regulatory challenges. Vaccine manufacturers and regulators

have questions about the type of information and extent of data that would be

required to support proceeding to clinical trials with adjuvanted vaccines and to

eventual authorization.

Existing WHO guidelines on nonclinical evaluation of vaccines (1)

provide valuable general guidance; however, they provide limited information

specifically related to new adjuvants and adjuvanted vaccines. Some of the issues

addressed here are also discussed in national or regional guidance documents

(5, 6). Given the importance and the complexity of the issues, this updated and

more extensive guidance on the nonclinical and preclinical testing of adjuvants

and adjuvanted vaccines should allow manufacturers and regulators to proceed

in an efficient manner on the critical path towards development and licensure

of adjuvanted vaccines indicated for the control of diseases with an important

global public health impact.62

WHO Technical Report Series No. 987, 2014

WHO Expert Committee on Biological Standardization Sixty-fourth report


Over the past decades, there have been a number of international workshops

and meetings in which the issues covered by these WHO Guidelines have been

discussed (7–12). To address the need for additional international guidance on

nonclinical evaluation of adjuvanted vaccines, a consultation was organized by

WHO on 7–8 September 2011 in Rockville, Maryland, United States, to initiate

the process of developing new WHO guidance on the subject. The consultation

was attended by experts from academia, NRAs, national control laboratories

and industry involved in the research, manufacture and approval of adjuvanted

vaccines from countries around the world. The purpose was to review the

scientific information and available data and to discuss and identify the issues

to be considered for the development of such international guidance. On 27–28

November 2012, WHO organized an informal consultation at its headquarters in

Geneva, Switzerland attended by academics, researchers, vaccine manufacturers

and regulators involved in the evaluation of adjuvanted vaccines, to review draft

WHO Guidelines prepared by the drafting group and to seek consensus on key

regulatory issues. The approaches to nonclinical and initial clinical evaluation

of vaccine adjuvants and adjuvanted vaccines discussed in this document are a

result of the efforts of this and other international working groups...

For more information, please rrefer to : http://www.who.int/biologicals/areas/vaccines/TRS_987_Annex2.pdf?ua=1