On June 11, 2009, the World Health Organization (WHO) signaled that a global pandemic of novel influenza A (H1N1) was underway by raising the worldwide pandemic alert level to Phase 6. This action was a reflection of the spread of the new H1N1 virus, not the severity of illness caused by the virus. At the time, more than 70 countries had reported cases of novel influenza A (H1N1) infection and there were ongoing community level outbreaks of novel H1N1 in multiple parts of the world.

Since the WHO declaration of a pandemic, the new H1N1 virus has continued to spread, with the number of countries reporting cases of novel H1N1 nearly doubling. The Southern Hemisphere¡¯s regular influenza season has begun and countries there are reporting that the new H1N1 virus is spreading and causing illness along with regular seasonal influenza viruses. In the United States, significant novel H1N1 illness has continued into the summer, with localized and in some cases intense outbreaks occurring. The United States continues to report the largest number of novel H1N1 cases of any country worldwide, however, most people who have become ill have recovered without requiring medical treatment.

Given ongoing novel H1N1 activity to date, CDC anticipates that there will be more cases, more hospitalizations and more deaths associated with this pandemic in the United States over the summer and into the fall and winter. The novel H1N1 virus, in conjunction with regular seasonal influenza viruses, poses the potential to cause significant illness with associated hospitalizations and deaths during the U.S. influenza season.

A Virus Emerges

Novel influenza A (H1N1) is a new flu virus of swine origin that first caused illness in Mexico and the United States in March and April, 2009. It¡¯s thought that novel influenza A (H1N1) flu spreads in the same way that regular seasonal influenza viruses spread, mainly through the coughs and sneezes of people who are sick with the virus, but it may also be spread by touching infected objects and then touching your nose or mouth. Novel H1N1 infection has been reported to cause a wide range of flu-like symptoms, including fever, cough, sore throat, body aches, headache, chills and fatigue. In addition, many people also have reported nausea, vomiting and/or diarrhea.

The first novel H1N1 patient in the United States was confirmed by laboratory testing at CDC on April 15, 2009. The second patient was confirmed on April 17, 2009. It was quickly determined that the virus was spreading from person-to-person. On April 22, CDC activated its Emergency Operations Center to better coordinate the public health response. On April 26, 2009, the United States Government declared a public health emergency and has been actively and aggressively implementing the nation¡¯s pandemic response plan

By June 19, 2009, all 50 states in the United States, the District of Columbia, Puerto Rico, and the U.S. Virgin Islands have reported novel H1N1 infection. While nationwide U.S. influenza surveillance systems indicate that overall influenza activity is decreasing in the country at this time, novel H1N1 outbreaks are ongoing in parts of the U.S., in some cases with intense activity.

CDC is continuing to watch the situation carefully, to support the public health response and to gather information about this virus and its characteristics. The Southern Hemisphere is just beginning its influenza season and the experience there may provide valuable clues about what may occur in the Northern Hemisphere this fall and winter.

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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.

Vaccine virus is grown in eggs because the flu virus grows well in them, and eggs are readily available.

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.