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.

The World Health Organization reports that as of June 17 there are 39,520 cases reported of pandemic swine flu or pandemic novel H1N1. 167 deaths due to the pandemic are reported. Of course, the country with the greatest number of cases, the U.S, only reports on Friday so the total is very understated. We are reporting 20,630 cases in the United States as of June 17.

Latin American nations marked with this color.

Here is a list of every nation reporting over 100 cases of pandemic swine flu.

The WHO is set to announce officially that novel H1N1 or swine flu has reached official pandemic status. That is a phase six. This is the first influenza pandemic since the Hong Kong flu of 1968.

A pandemic declaration is based on the spread of the illness and not necessarily upon how deadly it is. Of the four influenza pandemics in modern times, 1918 Spanish Flu, the 1957 Asian Flu and the 1968 Hong Kong Flu, this outbreak appears to be the mildest. That could change but for now we have an influenza pandemic from a mild strain.

This declaration puts national governments on the spot. Most have prepared a pandemic flu plan with the steps that they would take when a pandemic is declared. For many nations, this means expenditure of money and resources they do not have. As with many international agreements, the wealthier countries are far readier and able to comply.

The United States plan can be found at PandemicFlu.gov. The plan provides for eventualities such as a very deadly illness that might require internal travel restrictions and quarantines.

The Centers for Disease Control (CDC) are your best source for authoritative information about influenza, swine flu, and the steps you should be taking.

WHO has gone to reporting cases counts on Monday, Wednesday and Friday. That is probably because the U.S. is doing so and half the cases of swine flu or novel H1N1 are in the U.S.

As of this morning, WHO reports that 69 nations have reported cases, for a total of 21,940. 125 deaths have been reported.

The way this will work is that the CDC will make its report after 11 am today, and the next WHO report will be in three days, on Monday. Current public data is not important to the various public health agencies, based on their inability to synchronize their reports.

Australia, Canada, Mexico and the United States have the most new cases. The outbreak is not finished in Mexico despite their lifting of the various restrictions on public activity. Central and South American countries are at the very beginning of their outbreaks, with small total numbers but significant new cases.

There are no reports of cases in Africa except the lone individual in Egypt.

The World Health Organization reports 19,273 cases of novel H1N1 or swine flu as of this morning. There have been 117 related deaths.

WHO map of nations reporting cases of novel H1N1 or swine flu as of June 3, 2009. Click on image for a larger map.

The table below shows the top ten countries reporting outbreaks.

Here is the weekend summary of swine flu / novel H1N1 cases around the globe. Because of various reporting deadlines the numbers may not appear the same on all reports. In addition, many of the states and Federal agencies in the United States have reduced or eliminated regular reporting.

WHO for May 23, 2009: 12,022 cases and 86 deaths in 43 countries.

Nicaragua, Venezuela and Bolivia have not reported any cases of swine flu. Is it true, or are their politics keeping them from reporting?

Canada as of May 22, 2009: 805 cases in 9 provinces and 1 territory, with 1 death. The median age of the cases is 21, meaning that half of the cases are age 21 or younger.

Department of Defense as of May 20, 2009: Reporting once a week now. 294 total cases. All cases are included in the counts by state health agencies and the CDC. Largest new outbreak is at Fort Riley, Kansas with 13 cases since the last DoD report.

CDC Report as of May 22, 2009: 6,552 cases and 9 deaths. CDC numbers continue to vary from state website numbers in some cases. It is not just reporting times differ. It appears that CDC is not pursuing updates from states as there have been occasions that CDC number has remained the same for several days despite state site changes.

Swine flu cases by city/metro area: Milwaukee=706, Chicago=668, Seattle=499, Phoenix=261, NYC and nearby counties=323.

Swine flu cases in Update NY counties: Erie=17 Buffalo area, Onondaga=11 Syracuse area.

Texas exploding with swine flu cases. Only rpting twice a week. 1,359 cases as of today. Rio Grande counties Cameron + Hildalgo=381 cases Milwaukee +194 cases in 4 days, Chicago +155, Seattle +132.

Florida is no longer reporting swine flu numbers on their site. Louisiana’s numbers make little sense. CO and SC counts difficult to locate on website.

The World Health Organization is the primary source for case information for nations outside of North America. It issues its report daily at 6 am GMT, which a couple of hours after midnight on the East Coast of the U.S.

Its case numbers for the United States, Canada and Mexico are “yesterday’s” numbers. The lag will continue as long as WHO stays on its current reporting schedule.

There are 9,830 cases of novel H1N1, or swine flu, that have been diagnosed worldwide. 79 deaths are due to this illness.

Several things leap out from the report. Nicaragua and Belize have not reported any cases, even though other nations in Central America have. Neither have Bolivia or Venezuela.

They may not have any cases. A more concerning scenario is that they do not have the capability to detect or diagnose the illness. A truly concerning scenario for Nicaragua, Bolivia or Venezuela would be that their political issues with the United States are preventing testing and diagnosis.

The nightmare for public health officials is the populous country that does not cooperate with international bodies when it comes to epidemics. It may be politics, or, in the cases of a nation like Somalia, they may not have the capacity to work with WHO or the CDC. This creates a “black hole” in the web of detection, prevention and treatment that public health authorities are weaving.

What can be done about a country that clearly could be a threat to the health of its neighbors and the world? Today it is the relatively benign swine flu, but tomorrow it could be something far worse.

As of 1600 GMT, 3 May 2009, 18 countries have officially reported 898 cases of influenza A(H1N1) infection.

Mexico has reported 506 confirmed human cases of infection, including 19 deaths. The higher number of cases from Mexico in the past 48 hours reflects ongoing testing of previously collected specimens. The United States Government has reported 226 laboratory confirmed human cases, including one death.

The following countries have reported laboratory confirmed cases with no deaths – Austria (1), Canada (85), China, Hong Kong Special Administrative Region (1), Costa Rica (1), Denmark (1), France (2), Germany (8), Ireland (1), Israel (3), Italy (1), Netherlands (1), New Zealand (4), Republic of Korea (1), Spain (40), Switzerland (1) and the United Kingdom (15).

Further information on the situation will be available on the WHO website on a regular basis.

WHO advises no restriction of regular travel or closure of borders.It is considered prudent for people who are ill to delay international travel and for people developing symptoms following international travel to seek medical attention, in line with guidance from national authorities.

Canada on 2 May reported the identification of the A(H1N1) virus in a swine herd in Alberta. It is highly probable that the pigs were exposed to the virus from a Canadian farm worker recently returned from Mexico, who had exhibited flu-like symptoms and had contact with the pigs. There is no indication of virus adaptation through transfer from human to pigs at this time.

There is no risk of infection from this virus from consumption of well-cooked pork and pork products.

Individuals are advised to wash hands thoroughly with soap and water on a regular basis and should seek medical attention if they develop any symptoms of influenza-like illness.

WHO

The situation continues to evolve rapidly. As of 06:00 GMT, 1 May 2009, 11 countries have officially reported 331 cases of influenza A(H1N1) infection.

The United States Government has reported 109 laboratory confirmed human cases, including one death. Mexico has reported 156 confirmed human cases of infection, including nine deaths.

The following countries have reported laboratory confirmed cases with no deaths – Austria (1), Canada (34), Germany (3), Israel (2), Netherlands (1), New Zealand (3), Spain (13), Switzerland (1) and the United Kingdom (8).

Further information on the situation will be available on the WHO website on a regular basis. WHO advises no restriction of regular travel or closure of borders. It is considered prudent for people who are ill to delay international travel and for people developing symptoms following international travel to seek medical attention, in line with guidance from national authorities.

There is also no risk of infection from this virus from consumption of well-cooked pork and pork products. Individuals are advised to wash hands thoroughly with soap and water on a regular basis and should seek medical attention if they develop any symptoms of influenza-like illness.

WHO

Cannot reach CDC or WHO sites at this moment. Media is reporting that WHO has raised the pandemic alert level to 5.

Phase 5 is characterized by human-to-human spread of the virus into at least two countries in one WHO region. While most countries will not be affected at this stage, the declaration of Phase 5 is a strong signal that a pandemic is imminent and that the time to finalize the organization, communication, and implementation of the planned mitigation measures is short.

So far, all this means is that human to human [h2h] transmission has been seen in two or more parts of the globe.

I will update this article as more information becomes available.