The World Health Organization has issued a briefing on its website discussing the safety of new pandemic vaccines, a topic that has been the subject of much media speculation in recent weeks. It says that the public needs reassurance about the regulation procedures involved in the licensing of pandemic vaccines and assurance that, despite their large-scale production, the various steps in vaccine production are safe and meet stringent quality requirements.
It also states that, with the widespread use of pandemic flu vaccine compared to seasonal vaccines, it is possible that some serious adverse effects will be reported, although these are likely to be rare occurrences and difficult to predict in advance. Unfortunately, full clinical data on the safety of the vaccine is unlikely to be available by the time the vaccine is distributed so monitoring of its safety and effectiveness will need to take place after administration of the vaccine has begun.
The World Health Organization (WHO) advises that all countries administering pandemic vaccines conduct intensive checks for safety and effectiveness, and that sharing of this data will be needed to inform vaccine policies further. The WHO has also developed guidance to help countries formulate country-specific guidelines, as well as a standard set of protocols that should be used in data collection and reporting.
How were the guidelines produced?
The WHO guidelines are entitled Regulatory Preparedness for Human Pandemic Influenza Vaccines. They were produced in collaboration with Health Canada, the United States Food and Drug Administration (US-FDA), the Government of Japan and the Government of Spain, who convened three technical workshops with representatives of National Regulatory Authorities (NRAs) from various countries interested in the development of a vaccine.
The aim of these workshops was to build a network of international authorities to develop and regulate influenza vaccine production and develop guidelines on being prepared for the use of pandemic influenza vaccines.
The report produced is intended to cover different scenarios of vaccine production:
- Vaccine development between pandemics in anticipation of a pandemic (vaccines containing an influenza A virus subtype not currently circulating in humans).
- Vaccine development for stockpiling against novel flu viruses.
- Vaccine development only once an influenza pandemic is declared (only developed once the pandemic human influenza A virus strain is identified).
The guidelines also cover the issue of using vaccines prior to the declaration of pandemic, and regulations for this type of use. In addition, they cover the use of both inactivated influenza viruses and live attenuated influenza vaccines (LAIV) produced in either chicken eggs or cell cultures.
What are the main points of the guidelines?
The guidelines are very extensive and as such it is not possible to cover all of them in detail here. Of particular interest to both the public and medical professionals are sections setting out guidelines on the safety and monitoring of the vaccine, sumarised below.
Regulation in the development and evaluation of vaccines against novel human influenza
This section discusses general quality manufacturing requirements, such as the need to have an appropriate containment facility when handling live influenza viruses.
- The WHO recommends certain standards in the production and control of inactivated influenza vaccines, such as observing the viral protein content per human dose and general packaging and labelling requirements.
- Novel vaccine production systems, such as the technique of using ‘cell substrates’, are also addressed, given that their safety and efficacy have not yet been firmly established.
- The section also addresses the safety testing that is required before a new human influenza virus can be moved from the laboratory to the clinic, and also clinical studies that look for adverse effects once the vaccine is used in humans.
- The optimal dose and schedule of the vaccine may depend upon the antigen content and type found in the vaccine, population factors, such as age groups’ likely immune response to the potential pandemic virus strain(s), and likelihood of individual contact with the virus, for example poultry workers, veterinarians or healthcare workers.
- Studies with children will also be needed as they are likely to require different doses and may have different immunological responses, clinical benefits and possible safety issues. Specific issues for conducting such studies in children are further addressed in the report.
Quality control and preparedness:
This will be based on the processes and policies for seasonal vaccines and usually subject to testing by the National Control Laboratory. Pandemic vaccines are likely to undergo larger scale production than seasonal vaccines.
In an emergency pandemic this may mean that quality control tests need to be modified. Different testing and requirements will be needed for inactivated and live attenuated viruses. A risk assessment should be carried out by each National Control Laboratory to ensure pandemic vaccine batch release is not compromised by problems that could have been prevented.
This section of the document covers the need to study the risks and benefits of pandemic flu vaccines post-distribution. It says that protocols need to be in place to ensure that efficacy, immunogenicity and safety of the pandemic vaccine are adequately documented, analysed and assessed.
Ideally, information needs to be available from people of different ages and population groups, for example pregnant women. Also, aspects of distribution, use in different settings and different health organisations worldwide will need to be examined and monitored.
Regulatory considerations for stockpiled vaccines:
- The report states that any decisions to use stockpiled vaccines before a pandemic is declared are required to be in line with national policies and are the responsibility of individual governments.
- Stockpiled vaccines have to undergo defined stability testing to ensure there are no issues of deterioration, genetic changes or safety of the stored vaccine.
What is the implication and importance of this?
As the WHO says, strategies to shorten the time between emergence of a flu pandemic and the availability of a safe and effective vaccine are of the greatest priority in global health security. Although seasonal influenza viruses are routinely produced, with the advent of a new influenza strain that has not previously circulated among humans, production is likely to be different, and the demand for the vaccine will possibly exceed the supply.
As a result of this, various different technical solutions and manufacturing options are in development and investigation, and are the subject of WHO guidelines. The WHO has developed a Global Action Plan for pandemic flu vaccines in order to identify and prioritise practical solutions to meet the vaccine demand. To facilitate increased production it is likely that governments will turn to new vaccine manufacturers in addition to those used during current seasonal flu vaccine production.
The WHO acknowledges the need for the public to be provided with consistent and balanced communication of the vaccine situation, its safety and efficacy, and that this should be a collaborative undertaking with input from industry, regulators and the healthcare profession.
The WHO says that the guidelines may be updated as new knowledge and approaches become available, and that any revisions to the guidelines will be published on the WHO website.