The World Health Organization has published the following, detailed explanation of the pandemic flu vaccine development process.

Pandemic (H1N1) 2009 briefing note 7

6 AUGUST 2009 | GENEVA — It takes approximately five to six months for the first supplies of approved vaccine to become available once a new strain of influenza virus with pandemic potential is identified and isolated. These months are needed because the process of producing a new vaccine involves many sequential steps, and each of these steps requires a certain amount of time to complete. The vaccine development process from start (obtaining a virus sample) to end (availability of vaccine for use) is summarized below.

Activities at WHO Collaborating Centers

1. Identification of a new virus: As part of a network set up for surveillance, laboratories around the world routinely collect samples of circulating influenza viruses and submit these to WHO Collaborating Centres for Reference and Research on Influenza for analysis. The first step towards the production of a pandemic vaccine starts when a Centre detects a novel influenza virus that differs significantly from circulating strains and reports this finding to WHO.

2. Preparation of the vaccine strain (called vaccine virus): The virus must first be adapted for use in manufacturing vaccine. To make the vaccine virus less dangerous and better able to grow in hen’s eggs (the production method used by most manufacturers), the virus is mixed with a standard laboratory virus strain and the two are allowed to grow together. After a while, a hybrid is formed which contains the inner components of the laboratory strain, and the outer components of the pandemic strain. It takes roughly three weeks to prepare the hybrid virus.

3. Verification of the vaccine strain: After its preparation, the hybrid virus needs to be tested to make sure that it truly produces the outer proteins of the pandemic strain, is safe and grows in eggs. Upon completion of this process, which takes roughly another three weeks, the vaccine strain is distributed to vaccine manufacturers.

4. Preparation of reagents to test the vaccine (with reference reagents): In parallel, WHO Collaborating Centres produce standardized substances (called reagents) that are given to all vaccine manufacturers to enable them to measure how much virus they are producing, and to ensure they are all packaging the correct dose of vaccine. This requires at least three months and often represents a bottleneck for manufacturers.

Activities at vaccine manufacturers

1. Optimization of virus growth conditions: The vaccine manufacturer takes the hybrid vaccine virus that it has received from the WHO laboratories, and tests different growth conditions in eggs to find the best conditions. This process requires roughly three weeks.

2. Vaccine bulk manufacture: For most influenza vaccine production, this is performed in nine to twelve-days old fertilized hen’s eggs. The vaccine virus is injected into thousands of eggs, and the eggs are then incubated for two to three days during which time the virus multiplies. The egg white, which now contains many millions of vaccine viruses, is then harvested, and the virus is separated from the egg white. The partially pure virus is killed with chemicals. The outer proteins of the virus are then purified and the result is several hundred or thousand liters of purified virus protein that is referred to as antigen, the active ingredient in the vaccine. Producing each batch, or lot, of antigen takes approximately two weeks, and a new batch can be started every few days. The size of the batch depends on how many eggs a manufacturer can obtain, inoculate and incubate. Another factor is the yield per egg. When one batch has been produced, the process is repeated as often as needed to generate the required amount of vaccine.

3. Quality control: This can only begin once the reagents for testing the vaccine are supplied by WHO laboratories, as described above. Each batch is tested and the sterility of bulk antigen is verified. This process takes two weeks.

4. Vaccine filling and release: The batch of vaccine is diluted to give the desired concentration of antigen, and put into vials or syringes, and labeled. A number of these are then tested:

• for sterility
• to confirm the protein concentration and
• for safety by testing in animals.

This process takes two weeks.

5. Clinical studies: In certain countries, each new influenza vaccine has to be tested in a few people to show that it performs as expected. This requires at least four weeks. In some countries this may not be required as many clinical trials were done with similar annual vaccine preparation, and the assumption is that the new pandemic vaccine will behave similarly.

Activities at regulatory agencies – regulatory approval

Before the vaccine can be sold or administered to people, regulatory approval is required. Each country has its own regulatory agency and rules. If the vaccine is made with the same processes as the seasonal influenza vaccine, and in the same manufacturing plant, this can be very rapid (one to two days). Regulatory agencies in some countries may require clinical testing before approving the vaccine, which adds to the time before the vaccine is available.

The full process, in a best case scenario, can be completed in five to six months. Then the first final pandemic vaccine lot would be available for distribution and use.

Key: The arrows with dotted lines preceded by non-broken arrows indicate the time period required for the first time an activity is done (non-broken arrow line) that is then repeated (dotted arrow line). The solid lines signify that the activity takes place within a finite period.

© Copyright World Health Organization (WHO), 2009. All Rights Reserved.

The WHO also offers these comments on vaccine safety:

Influenza vaccines have been used for more than 60 years and have an established record of safety in all age groups. While some serious adverse events have been reported, these have been rare.

Nonetheless, special safety issues will inevitably arise during a pandemic when vaccine is administered on a massive scale. For example, adverse events too rare to show up even in a large clinical trial may become apparent when very large numbers of people receive a pandemic vaccine.

Some adverse events will be coincidental – that is, associated in time with vaccine administration, yet not directly caused by the vaccine. Genuine adverse events directly caused by the vaccine may also occur, but cannot be predicted in advance. Given the safety record of seasonal vaccines, such events are expected to be rare.

Time constraints mean that clinical data at the time when pandemic vaccines are first administered will inevitably be limited. Further testing of safety and effectiveness will need to take place after administration of the vaccine has begun.

This past week, the World Health Organization chose to stop requesting individual case counts from nations with outbreaks of pandemic swine flu / novel H1N1. The world case count has become more and more inaccurate as nations stop counting every case or stop publicly posting counts.

The seasonal influenza season in the Southern Hemisphere seems to be dominated by pandemic influenza. The tropics, Africa and Asia, are almost certainly having similar outbreaks but the poverty and poor medical care in most of these nations is resulting in little or no reporting.

This will be the last world pandemic flu report from us until the Fall wave appears. If the counting process changes and data is readily available again, we will resume reporting the numbers.

Here is the world pandemic flu report for today. It consists of the WHO report dated July 1, 2009 plus the latest reports from Australia, Canada and the United States and other countries marked in this color. The totals are those posted at those sites at the time this report was produced. Those sites will change as they receive new data. We will post a new report as we are able.

Here is the world pandemic flu report for today. It consists of the WHO report dated June 29, 2009 plus the latest reports from Australia, Canada and the United States and other countries marked in this color. The totals are those posted at those sites at the time this report was produced. Those sites will change as they receive new data. We will post a new report as we are able.

Chart of pandemic swine flu case counts by world region for June 29 2009. Click on the chart for a larger version.

Here is the world pandemic flu report for today. It consists of the WHO report dated June 26, 2009 plus the latest reports from Australia, Canada and the United States. The totals are those posted at those sites at the time this report was produced. Those sites will change as they receive new data. We will post a new report as we are able.

Pie chart showing pandemic H1N1 flu cases by world region as of June 27, 2009. Click on this chart for a larger image.

The World Health Organization is reporting a total of 55,867 cases of pandemic swine flu, also called pandemic novel H1N1. 238 related deaths are also reported.

This table shows all the nations reporting over 100 cases. It is mid-winter south of the equator, the heart of the seasonal flu season. Nations all or partially south of the equator are marked in this color. Brazil and Uruguay are notable for a sharp increase in cases in the last few days.