The provision of global measurement standards is an important normative activity of WHO.
Biological reference preparations that are accepted internationally enable the efficacy, quality, purity
and safety of very many biological medicines, used in the prevention, treatment or diagnosis of
disease or conditions, to be stated in a common language worldwide. International biological
reference standards support the use of many biological and immunological assays for the quality
control of a wide range of biologicals including therapeutics, blood-derived products, vaccines and
immunological products of traditional types as well as those derived from modern biotechnological
approaches. They also have important applications in the standardization of materials and
approaches used in medical diagnostics such as diagnosing disease, monitoring therapy, blood safety,
and public health applications (e.g. monitoring immune status, screening for disease or susceptibility)
or otherwise characterizing biological material from individuals.
WHO biological reference standards are widely used in the development, evaluation, standardization
and control of products by industry; by regulatory authorities; and also in biological research in
academia and scientific organizations. They play a vital role in facilitating the transfer of laboratory
science into worldwide clinical practice and the development of safe and effective biologicals.
The timely development of new reference materials and standards is critically important to harness
scientific developments for new biologicals. At the same time, the active management of the
existing inventory of reference preparations requires a carefully planned programme of work to
replace established materials before the stock of containers, which comprises the standard, is
exhausted.
Considerations for assignment of priorities to development of WHO International Biological
Measurement Standards or Reference Reagents have been published (WHO TRS 932, Annex 2,
Appendix 1, 2005). These considerations are used as guiding principles by the Secretariat and the
WHO Collaborating Centres to develop a proposed programme of future work. To facilitate and to
improve transparency in the priority setting process, a simple tool has been developed which
describes the salient features of each new project proposal.
This document provides a means for the Committee and other stakeholders to review and comment
on new proposals that are under consideration. The proposals in this document
(WHO/BS/2016.2295) cover requests to initiate new projects in the areas of vaccines and related
substances (Appendix 1).
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Appendix 1 Vaccines and related substances
Proposed new projects
1) Sabin Inactivated Poliovirus vaccines -proposed 1st International Standard (page 4)
2) Group B Streptococcus polysaccharides and antiserum - proposed International Standards
(page 6)
3) Diphtheria Antitoxin Equine – proposed 2nd International Standard (page 8)
4) Human papillomavirus vaccine (HPV), antibodies to HPV6 and HPV11 – proposed 1st
International Reference Panel (page 10)
5) Human papillomavirus vaccine (HPV), antibodies to HPV31, HPV33, HPV45, HPV52 and
HPV58 – proposed 1st International Reference Panel (page 10)
6) Hepatitis A vaccine - proposed 2nd International Standard (page 14)
7) Oral Polio Vaccines - proposed International Standards for potency assays for the Global
Polio Eradication Endgame (page 16)
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Proposal (title) 1st International Standard for Sabin IPV vaccines
Proposer (name of Institution)
e.g. NIBSC Principal contact Javier Martin
Rationale Production of IPV using Sabin live-attenuated strains (sIPV) is safer in the context of containment requirements for the endgame of polio eradication
There is no International Standard for sIPV: contrary to cIPV products, the human dose for current sIPV products is significantly different between manufacturers. This makes the comparison of different sIPV products very difficult and complicates the standardization of in vitro and in vivo potency assays and the design of pre-clinical studies.
A preliminary collaborative study was undertaken to assess whether the current cIPV IS would be suitable for use with sIPV .The outcome established that a sIPV standard would be more appropriate
Anticipated uses and users
Calibration/ validation of in-house references for the determination of the sIPV antigen content of commercial vaccines and vaccines in development.
The IS would be evaluated for use for ELISA and for Immunogenicity – rat model.
Manufacturers, OMCL’s +NCL’s
Source/type of materials NIBSC would need to secure donations of sIPV concentrated bulk from global manufacturers of the vaccine.
Outline of proposed collaborative study
The collaborative study would evaluated the IS for vitro and in vivo potency assays and establish suitable unitage.
Issues raised by the proposal
The cIPV IS was found to be not universally suitable to determine the D-Ag potency of sIPV products as consistency between labs was only achieved when using common reagents in the ELISA method
A new specific IS for sIPV will be established
The IS should be evaluated for in vitro and in vivo potency assays
Action required e.g. ECBS to endorse proposal
Proposer's project reference
To be added Date proposed: June 2016
CONSIDERATIONS FOR ASSIGNMENT OF PRIORITIES (TRS932)
Approval status of medicine or in vitro diagnostic method
Licensed sIPV vaccines produced globally.
Number of products or Licensed sIPV vaccines produced globally. There are a large number of
WHO/BS/2016.2295
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methods sIPV manufacturers and therefore 17 sIPV vaccines could be available.
Public health importance
Provision of an International standard will support the standardization of potency assays of licensed and newly developed sIPV and aid National Control Laboratories in the control of sIPV. Thus ensuring safe, effective vaccines are available for disease prevention and control in the Polio post eradication period.
Global importance
Prevention of disease caused by Poliomyelitis with the eradication of the virus globally.
Global need from regulatory & scientific considerations
Provision of an International Standard will support the standardization of potency of sIPV vaccines globally and aid National Control Laboratories in the control of sIPV vaccines.
ECBS outcome [BLANK]
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Proposal (title) GBS human reference serum and polysaccharides International Standards
Proposer (name of Institution)
NIBSC Principal contact Fatme Mawas
Rationale GBS vaccine is in development by 3 manufacturers
Two vaccine candidates are PS-based conjugate vaccines based on the 5 most common serotypes Ia, Ib, II, III and V and one vaccine is protein vaccine based on a fusion protein of the alpha and Rib OMPs.
The GBS vaccines are likely to be licensed based on surrogate of protection (IgG level and assessment of functional antibody by opsonophagocytosis assay), rather than incredibly large field trials, as the incidence of disease is very low (~3/1000 live births).
Therefore, there is now an urgent need to establish such standardized
assays to measure concentration and function of antibody against GBS. This requires the development of various standards and reference reagents (human reference serum and PS standards) to calibrate these assays and for the quality control testing of the GBS vaccines when licensed.
Anticipated uses and users
Use of PS standards
As an antigen to measure antibody response to GBS-PS
Quality control testing of GBS vaccines (Identity, Total & free PS)
Calibrate internal controls in various physico-chemical and immuno-assays
Use of Human reference sera
For use as standards in assays for quantification of antibody response and of functional activity in clinical trials materials
Users
Vaccine manufacturers (evaluation of clinical response to vaccination and QC testing of vaccines), diagnostic kit manufacturers, public and national health authorities, academic researchers, National Control Laboratories
Source/type of materials PS standards
- vaccine manufacturers
Human serum reference standards
- vaccine manufacturers (clinical trials).
- Volunteers immunized with the conjugate vaccine conjugate.
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- IVIg, available at NIBSC
Outline of proposed collaborative study
Value will be assigned using physico-chemical tests for PS.
Issues raised by the proposal
We propose to use monovalent sera developed by Prof. Carol Baker to calibrate the candidate human reference serum.
These monovalent sera have been calibrated by radio-immunoassays for antibody concentration and have been as gold standards in various studies to establish correlates of protection and by vaccine manufacturers to evaluate immune response during clinical trials.
Action required ECBS to endorse proposal
Proposer's project reference
BAC000 Date proposed: 2016
CONSIDERATIONS FOR ASSIGNMENT OF PRIORITIES (TRS932)
Approval status of medicine or in vitro diagnostic method
Standardization of assays, including the preparation of reference standards, for GBS vaccines evaluation is urgently needed to establish surrogate of protection to expedite the development and licensing of GBS vaccines
Preparation of relevant international standard will expedite the development
and licensing of GBS vaccines for immunizing pregnant women to prevent GBS disease in the newborns.
Global importance
GBS disease is a worldwide and the use of vaccine is the most effective prevention strategy to reduce the incidence of the disease especially in low income countries, where the use of intrapartum antibiotic prophylactic is not feasible.
Global need from regulatory & scientific considerations
When GBS vaccines are licensed there will be a need to quality control test them to ensure the quality and efficacy of the vaccines. International standards will be required to calibrate the various assays needed for this purpose
ECBS outcome
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Running Title: Proposed 2nd International Standard for Diphtheria Antitoxin Equine (DI)
Proposal (title) Proposed 2nd International Standard for Diphtheria Antitoxin Equine (DI)
Proposer (name of Institution)
NIBSC Principal contact Laura Coombes
Rationale The 1st International Standard for Diphtheria Antitoxin Equine (DI) is a dried hyperimmune horse serum standard that was prepared in 1934 at the Statens Serum Institut in Copenhagen. The IU is defined as the activity contained in 0.0628 mg of the dried serum. This dried serum is used to prepare a standard preparation in 66% v/v glycerol/saline approximately every 2 years. This standard is distributed in vials containing 10 ml at 10 IU/ml. The current preparation has the code number 14/266.
The stock of the original dried serum is running low and a replacement is needed. It is proposed to prepare a freeze-dried standard to provide a single homogenous batch that can be in use for a number of years.
Anticipated uses and users
The standard is used to calibrate potency assays for diphtheria antitoxin. These assays are lethal or non-lethal toxin neutralization tests performed in guinea pigs and are used to determine the antitoxin potency of therapeutic antitoxin products produced from equine serum.
The standard can also be used to calibrate in-house equine serum standards.
Approximately 50-100 vials are distributed per year.
Source/type of materials Equine diphtheria antitoxin from an Indian manufacturer.
The proposed batch size is at least 2500 which at current rate of use will be sufficient for >20 years. The actual batch size will depend on the potency of the bulk material and the dilution factor applied before filling.
Outline of proposed collaborative study
Value will be assigned using in vivo toxin neutralization tests relative to the 1st IS. In vitro toxin neutralization tests will also be included for comparison purposes (and for value assignment if results are in good agreement).
Issues raised by the proposal
Shortage of equine diphtheria antitoxin globally means that source material has been difficult to identify and cannot be freely donated. Although an International Standard for Diphtheria Antitoxin Human (10/262) was established in 2012 there is a need for an equine standard for calibration of equine products.
Action required ECBS to endorse proposal
Proposer's project reference
BAC00059 Date proposed: 2016
CONSIDERATIONS FOR ASSIGNMENT OF PRIORITIES (TRS932)
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Approval status of medicine or in vitro diagnostic method
Equine diphtheria antitoxin is used for diphtheria therapy and prophylaxis against suspected cases. It is licensed nationally in some countries and imported to others for stockpiling for emergency use.
Number of products or methods
The number of producers has fallen in recent years but there are at least 4 active producers of DAT globally.
Public health importance
DAT is an essential medicine for diphtheria therapy and is used in countries where disease is endemic. In countries with good vaccination coverage, DAT is stockpiled for emergency use. Stockpiled DAT is periodically assessed for potency by some National Control Authorities for which an antitoxin standard is essential.
Global importance
DAT is used and/or stockpiled globally
Global need from regulatory & scientific considerations
There are minimum requirements for potency of DAT (expressed in IU) in many national and regional Pharmacopoeias and it is important to ensure continuity of the IU for DAT by establishment of the 2nd IS.
ECBS outcome
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Proposal (title) 1st International Reference Panel for antibodies to HPV6 and HPV11
1st International Reference Panel for antibodies to HPV31, HPV33, HPV45, HPV52 and HPV58
Proposer (name of Institution)
NIBSC Principal contact Dianna Wilkinson
Rationale A second generation vaccine against human papillomavirus (HPV), the cause of cervical cancer, has been licensed, containing nine different HPV types. Other second generation vaccines are under clinical development. Assessing their immunogenicity will be crucial in defining a correlate of protection, and in monitoring their quality and performance in different populations. There are also increasing demands to standardize HPV serological methods as a measure of past or present HPV infection in epidemiological studies, e.g. to monitor the spread of HPV infections in different populations – a key feature for both planning of optimal HPV control programs and to follow up on their success.
International Standards for antibodies against high-risk HPV16 and HPV18 were established by WHO ECBS in 2009 and 2012, respectively. The development and establishment of International Standards for antibodies against low-risk types HPV6 and HPV11 and against high risk types HPV31, HPV33, HPV45, HPV52 and HPV58 will provide the full complement of ISs for use in standardising HPV serology assays used in the epidemiological and vaccinological studies of licensed HPV vaccines as well as HPV vaccines under development.
Anticipated uses and users
Standardization of HPV serology assays used in the epidemiological and vaccinological studies of licensed HPV vaccines as well as HPV vaccines under development. Users include HPV vaccine developers and manufacturers, epidemiologists, research laboratories, public health laboratories, developers of assay kits.
Source/type of materials For each anti-HPV type, donations will be obtained from at least 2 (preferably more than 2) different individuals naturally infected with the vaccine types of interest.
Sera will preferably be reactive with only one genital HPV type. Previous International Standards were obtained from sample donors had that indicated that they had had only 1 lifetime sexual partner (to minimize the risk of multiple exposures). For this study, sexual history will not be an inclusion criterion but suitability of standards will instead be assessed by testing for antibodies against multiple genital HPV types. Documentation of cervical HPV infection by HPV DNA detection is preferable.
For inclusion, subjects must indicate that they are willing to donate blood in standard blood donor amounts of 450 ml every third month.
Because there is data suggesting that women have higher antibody levels, only women will be included.
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Outline of proposed collaborative study
Joakim Dillner, Professor in Infectious Disease Epidemiology (International HPV Reference Center, Karolinska Institutet , Stockholm, Sweden) will be involved in enrolling donors. Candidate sera have also be obtained by collaborators at the National Institutes for Food and Drug control (NIFDC), PR China. NIFDC is a WHO Collaborating Center for Standardization and Evaluation of Biologicals.
However sourced, the donated samples will be tested in Prof Dillner’s lab
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and the most suitable samples will be selected for further development.
NIBSC will undertake filling and freeze-drying operations for each candidate standard according to standard operating procedures and WHO guidelines. The freeze-dried candidates will be validated before their assessment in an international collaborative study involving 10-15 laboratories. The study will include the use of virus-like particle (VLP)-binding, pseudovirion-binding and pseudovirion neutralisation (PsN) assays.
Additional coded samples will be distributed along with the candidate standards These materials may include
• A duplicate ampoule of the candidate standard • Serum samples from naturally infected individuals • Negative serum • Sera from recipients of HPV vaccines
Participants will be requested to perform 3 independent assays on different days for antibodies to HPV types routinely assayed in their laboratory in pseudovirion/VLP binding and PsN tests. Participants will be asked to prepare and test a series of dilutions from the candidate standard and each of the coded samples and include all study samples in each assay so that the concentration of antibodies relative to the candidate standard could be calculated.
Assay data will be analysed at NIBSC by an experienced biometrician using standard statistical techniques. Stability studies of the candidate standards will be undertaken.
Issues raised by the proposal
Sourcing suitable samples from naturally infected individuals to produce 7 International Standards may be the rate-limiting step for this project.
Action required ECBS to endorse proposal
Proposer's project reference
Date proposed: 1 July 2016
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CONSIDERATIONS FOR ASSIGNMENT OF PRIORITIES (TRS932)
Approval status of medicine or in vitro diagnostic method
There currently are 3 licensed HPV vaccines with more vaccines under development in countries including China and India.
Number of products or methods
N/A
Public health importance
Cervical cancer is the second most common cancer in women living in less developed regions with an estimated 445 000 new cases in 2012 (84% of the new cases worldwide).
In 2012, approximately 270 000 women died from cervical cancer; more than 85% of these deaths occurring in low- and middle-income countries.
Global importance
The Global Alliance for Vaccines and Immunisation (GAVI), a funding organisation devoted to improved access to affordable vaccines, has HPV vaccination as one of its strategic priorities
Global need from regulatory & scientific considerations
Recent adoption of WHO Technical Report Series No. 999, 2016: Recommendations to assure the quality, safety and efficacy of recombinant human papillomavirus virus-like particle vaccines (Replacement of Annex 1 of WHO Technical Report Series, No. 962)
ECBS outcome
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Proposal (title) 2nd International Standard for Hepatitis A vaccine
Proposer (name of Institution)
e.g. NIBSC Principal contact Gillian Cooper
Rationale Hepatitis A vaccine (HAV) is formalin inactivated purified cell- grown hepatitis A virus which is adsorbed onto aluminum. The vaccines are crucial in the prevention of Hepatitis A virus and are used predominately as travel vaccines globally. They are liquid preparations stored between 2- 8oC and often combined with Hepatitis B or Typhoid.
Potencies of these vaccines are expressed in units unique to each manufacturer .Standardization of potency requires establishment of an internationally recognized reference material.
Stocks of the current IS 95/500 are now low and there is a need to consider a replacement strategy.
Anticipated uses and users
The IS would be used by manufacturers and control laboratories for the calibration/ validation of in-house references for the determination of the HAV antigen content of commercial vaccines. This is usually by ELISA or using the mouse potency immunogenicity test.
Source/type of materials NIBSC would need to secure donations of HAV concentrated non absorbed bulk from global manufacturers of the vaccine.
Outline of proposed collaborative study
The collaborative study would assign potency in IU to the Hepatitis A standard by in vitro ELISA and also for mouse immunogenicity.
Issues raised by the proposal
Sourcing Material as now there are global manufacturers, previously only European suppliers. Important to be able to evaluate the different HAV strains- different cell lines – different manufacturing processes.
Stability profile for new producers bulk for storage at -70 will need to be addressed as concentrated bulk is normally stored at +4
Action required e.g. ECBS to endorse proposal
Proposer's project reference
To be added Date proposed: June 2016
CONSIDERATIONS FOR ASSIGNMENT OF PRIORITIES (TRS932)
Approval status of medicine or in vitro diagnostic method
Licensed Hepatitis A vaccine
Number of products or methods
Presentations : Adult, pediatric plain and combined travel vaccines (A+B, A + typhoid)
Public health Provision of an IS will support the standardization of potency of Hepatitis A
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importance
vaccines globally and aid National Control Laboratories in the control of Hepatitis A vaccines. So ensuring safe effective vaccines are available for disease prevention and control.
Global importance
Prevention of Hepatitis A disease globally.
Global need from regulatory & scientific considerations
Provision of an IS will support the standardization of potency of Hepatitis A vaccines globally and aid National Control Laboratories in the control of Hepatitis A vaccines.
ECBS outcome [BLANK]
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Proposal (title) International Standards for potency assays of Oral Polio Vaccines for the Global Polio Eradication Endgame
Proposer (name of Institution)
e.g. NIBSC Principal contact Gillian Cooper
Rationale Oral polio vaccine is a live attenuated vaccine that has been used
Due to the Polio end game reaching its climax and the global eradication of type 2 Polio, the current vaccine which is a trivalent blend of all three polio serotypes has been replaced by monovalent and bi valent vaccines, without the type 2 component.
The current IS for the assay of OPV is a trivalent standard and due to the containment of type 2 can no longer be used.
In order to provide suitable OPV standards for current vaccines, stockpiles and those in development a range of OPV references will be made for use with these vaccines.
NIBSC in tend to produce standards bOPV 1+3, mOPV1, 2 and 3
Anticipated uses and users
Potency assays of current OPV vaccines.
Assessment of titre for monovalent bulks.
Titration reference for TgMNVT for dose preparation
Validation of in-house references.
Control of stockpiles i.e. mOPV 2
Important tool for new sIPV bulks
Manufacturers, National Control labs, consortiums developing new safer strains.
Source/type of materials Suitable monovalent Polio type 1, 2 and 3 already available at NIBSC
Outline of proposed collaborative study
The collaborative study would assign potency in Log10/CCID50 for each of the serotypes based on infectivity assays using Hep2C cell system.
Issues raised by the proposal
Fast track – containment issues for Polio in particular type 2
Action required e.g. ECBS to endorse proposal
Proposer's project reference
To be added Date proposed: June 2016
CONSIDERATIONS FOR ASSIGNMENT OF PRIORITIES (TRS932)
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Approval status of medicine or in vitro diagnostic method
Licensed OPV in different presentations for global immunization campaigns
Number of products or methods
Monovalent (mOPV) type 1, 2 and 3. bOPV 1+3
Public health importance
Provision of International standards will support the standardization of potency assays of OPV globally and aid National Control Laboratories in the control of OPV and to maintain vaccine stockpiles in the post eradication period. So ensuring safe effective vaccines are available for disease prevention and control.
Global importance
Prevention of disease caused by Poliomyelitis with the eradication of the virus globally.
Global need from regulatory & scientific considerations
Provision of an International Standards will support the standardization of potency of OPV vaccines globally and aid National Control Laboratories in the control of OPV vaccines.
