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How Flu Vaccines Are Made

Ten years ago, in the midst of the 2009 swine flu pandemic, I wrote about the manufacturing process for the H1N1 flu vaccine. It involves billions of chicken eggs.

The most striking feature of the H1N1 flu vaccine manufacturing process is the 1,200,000,000 chicken eggs required to make the 3 billion doses of vaccine that may be required worldwide. There are entire chicken farms in the US and around the world dedicated to producing eggs for the purpose of incubating influenza viruses for use in vaccines. No wonder it takes six months from start to finish.

The post holds up pretty well because, according to the CDC, this is still the way most flu vaccines in America are manufactured. Here’s a look at pharmaceutical company GSK’s egg-based process:

Two other techniques for making flu vaccines were approved for use in the US in 2012 and 2013 respectively, cell-based flu vaccines:

‘Cell-based’ refers to how the flu vaccine is made. Most inactivated influenza vaccines are produced by growing influenza viruses in eggs. The influenza viruses used in the cell-based vaccine are grown in cultured cells of mammalian origin instead of in hens’ eggs.

A cell-based flu vaccine was developed as an alternative to the egg-based manufacturing process. Cell culture technology is potentially more flexible than the traditional technology, which relies upon adequate supply of eggs. In addition, the cell-based flu vaccine that uses cell-based candidate vaccine viruses (CVVs) has the potential to offer better protection than traditional, egg-based flu vaccines as a result of being more similar to flu viruses in circulation.

And recombinant flu vaccines:

NIAID and its industry partners have made progress in moving from both the egg-based and cell-based flu vaccine production methods toward recombinant DNA manufacturing for flu vaccines. This method does not require an egg-grown vaccine virus and does not use chicken eggs at all in the production process. Instead, manufacturers isolate a certain protein from a naturally occurring (“wild type”) recommended flu vaccine virus. These proteins are then combined with portions of another virus that grows well in insect cells. The resulting “recombinant” vaccine virus is then mixed with insect cells and allowed to replicate. The flu surface protein called hemagglutinin is then harvested from these cells and purified.

Both of these new techniques make production quicker, thereby resulting in more effective vaccines because they are more likely to match the strains of whatever’s “going around”.

As a reminder, you should get a flu shot every year in the fall. The CDC recommends that “everyone 6 months of age and older should get a flu vaccine every season with rare exception”, especially those “who are at high risk of serious complications from influenza”. Flu vaccines are covered by your health insurance without copay (thanks, Obama!) and are often available at drug stores without an appointment or a long wait. So go get one!

The non-alarmist guide to the flu

Flu season is here and it’s horrible. Jennifer Cain at Kicker has written a No-Nonsense, Non-Alarmist, Essential Guide to the Flu. The sections on how to tell the flu from other illnesses and what to do to avoid the flu are especially helpful.

There are four big telltale signs that can help you distinguish among a cold, a flu, norovirus and whooping cough:

#1. Fever equals flu. You might get a slight temperature from a cold, but if you’re really heating up, it’s probably the flu.

#2. Colds are mild and long lasting. Colds usually start with a sore throat, then progress to symptoms like a runny nose and congestion, followed by a cough that won’t go away. And they don’t usually cause fevers. Sometimes it can take up to 3 weeks to get rid of a cold entirely. The flu, though, tends to come on quickly all at once and be more intense, but it doesn’t linger. If you’re running a fever and your body aches and you can’t get out of bed and don’t feel like eating anything, it’s flu time.

Bad flu season this year

According to Google’s search tracking, this is the worst flu season in more than 6 years.

2013 Flu Trend

Google’s trends tend to follow the official CDC data closely and indeed the CDC concurs about the scope of the flu this year but their data is lagging behind Google’s by what looks like about 2 weeks. See also my post on how flu vaccines are made. (via @kellan)

Top secret vaccine chicken farms

The eggs for the swine flu vaccine are produced by dozens of farms classified by the US government as part of our country’s “critical infrastructure”.

To ensure it had enough eggs to meet pandemic-level demand, the government invested more than $44 million in the program over five years; more than 35 farms are now involved in this feathered Manhattan Project. No signs advertise the farms’ involvement in the program, and visits from the outside world are discouraged. The government won’t disclose where the farms are located, and the farmers are told to keep quiet about their work โ€” not even the neighbors are to know.

These don’t exactly sound like free-range operations:

After nine months of service, [the chickens] are typically euthanized because they can no longer lay “optimal eggs,” Mr. Robinson said. “They’ve served their government,” he said.

(thx, micah)

The H1N1 vaccine manufacturing process

If you missed it last week in the Thanksgiving flurry, here’s my post on how the H1N1 vaccine is made.

The most striking feature of the H1N1 flu vaccine manufacturing process is the 1,200,000,000 chicken eggs required to make the 3 billion doses of vaccine that may be required worldwide.

How the H1N1 vaccine is made

The most striking feature of the H1N1 flu vaccine manufacturing process is the 1,200,000,000 chicken eggs required to make the 3 billion doses of vaccine that may be required worldwide. There are entire chicken farms in the US and around the world dedicated to producing eggs for the purpose of incubating influenza viruses for use in vaccines. No wonder it takes six months from start to finish. But we’ll get to that in a minute.

The most commonly used process for manufacturing an influenza vaccine was developed in the 1940s โ€” one of its co-inventors was Jonas Salk, who would go on to develop the polio vaccine โ€” and has remained basically unchanged since then. The process is coordinated by the World Health Organization and begins with the detection of a new virus (or rather one that differs significantly from those already going around); in this instance, the Pandemic H1N1/09 virus. Once the pandemic strain has been identified and isolated, it is mixed with a standard laboratory virus through a technique called genetic reassortment, the purpose of which is to create a hybrid virus (also called the “reference virus strain”) with the pandemic strain’s surface antigens and the lab strain’s core components (which allows the virus to grow really well in chicken eggs). Then the hybrid is tested to make sure that it grows well, is safe, and produces the proper antigen response. This takes about six to nine weeks.

[Quick definitional pause. Antigen: “An antigen is any substance that causes your immune system to produce antibodies against it. An antigen may be a foreign substance from the environment such as chemicals, bacteria, viruses, or pollen. An antigen may also be formed within the body, as with bacterial toxins or tissue cells.” So, when the H1N1 vaccine gets inside your body, the pandemic strain’s surface antigens will produce antibodies against it.]

At roughly the same time, a parallel effort to produce what are referred to as reference reagents is undertaken. The deliverable here is a standardized kit provided to vaccine manufacturers so that they can test how much virus they are making and how effective it is. This process serves to standardize vaccine doses across manufacturers and takes four months to complete. WHO notes that this part of the process is “often a bottleneck to the overall timeline for manufacturers to generate the vaccine”.

Once the reference virus strain is produced, it is sent to pharmaceutical companies (Novartis, Sanofi Pasteur, etc.) for large-scale production of the vaccine. The companies fine-tune the virus to increase yields and produce seed virus banks that will be used in the bulk production.

And this is where the 1.2 billion chicken eggs come in. A portion of the seed virus is injected into each 9- to 12-day old fertilized egg. The virus incubates in the egg white for two to three days and is then separated from the egg.

Vaccine eggs

For the shot vaccine, the virus is sterilized so that it won’t make anyone sick. This is the magic part of the vaccine: it’s got the pandemic virus antigens that make your body produce the antibodies to fight the virus but the virus is inactive so it won’t make you ill. For the nasal spray vaccine, the virus is left alive and attenuated to survive only in the nose and not the warmer lungs; it’ll infect you enough to produce antibodies but not enough to make you sick. Either way, the surface antigens are separated out and purified to produce the active ingredient in the vaccine. Each batch of antigen takes about two weeks to produce. With enough laboratory space and chicken eggs, the companies can crank out an infinite amount of purified antigens, but those resources are limited in practice.

[Side note. You may have noticed that the H1N1 vaccine has been difficult to find in some places around the US. The vaccine manufacturers have said that the Pandemic H1N1/09 virus when combined with the standard laboratory virus does not grow as fast in the eggs as they anticipated. The batches of antigens from each egg have been smaller than expected, up to five or even ten times smaller in some cases. Hence the slow rollout of the vaccine.]

The purified antigen is then tested against the aforementioned reference reagents once they are ready. The antigen is diluted to the required concentration and placed into properly labelled vials or syringes. Further testing is performed to make sure the vaccine won’t make anyone ill, to confirm the correct concentration, and for general safety. At this point clinical testing in humans is required in western Europe but not in the United States. Finally, each company’s vaccine has to be approved by the appropriate regulatory body in each country โ€” that’s the FDA in the case of the US โ€” and then the vaccine is distributed to medical facilities around the country.

Sources and more information: WHO, WHO, WHO, WHO, CDC, Time, Washington Post, The Big Picture, Influenza Report, NPR, Wikipedia, Wikipedia, Wikipedia, Wikipedia.

Update: Included in a recent 60 Minutes segment on the H1N1 vaccine is a look at the manufacturing process. (thx, @briandigital)

What to do about the swine flu?

Should you vaccinate your kids against the swine flu this winter? Will it even work against the H1N1 virus? Or will it even be available? Maybe we should be focused on a much simplier solution: keeping our hands clean.

Using soap and water or a sanitizer virtually eliminated the presence of the [H1N1] virus [in an Australian study].

Update: I’ve gotten a few emails so a clarification: vaccines are obviously not bad. Vaccinate your kids against the H1N1 virus when a vaccine becomes available if you feel that’s the right thing to do. It’s just that in the United States people often emphasize the quick fix over something that can be effective but requires a change in behavior. Much of what you hear about the damn swine flu is people being infected, the deaths, the coming vaccine, and how to protect our precious children from THE KILLER VIRUS THAT KILLS PEOPLE SO LET’S PANIC!! I thought it was important to call out something common sensical, unsexy, and effective like hand washing.

Update: I give up. Don’t wash your hands. It is completely ineffective and has never saved anyone from anything. Get vaccinated and stay inside. When you do go outside, wear a surgical mask and try not to go near other people.

Old folks vs. swine flu

Older people may be more immune to the swine flu than everyone else.

The protection theory, Dr. Jernigan explained, is that from 1918 to 1957, all circulating seasonal type-A flus were weakened descendants of the 1918 Spanish flu, which was an H1N1, as the current swine is. […] Then in 1957, an H2N2, the Asian flu, emerged and displaced it. It was replaced in 1968 by the H3N2, called Hong Kong flu, which has persisted as a seasonal strain. A different and milder H1N1 emerged in 1977. It was isolated in China but is called the Russian flu because of a suspicion it escaped from a Soviet laboratory. That H1N1, the 1968 H3N2 and a B strain have all circulated in humans ever since, and the seasonal flu shot is aimed at them.

One in a row

From the Effects Measure blog:

Influenza is a virus full of mystery and surprises. The more we study it the more complicated it becomes. Remember the adage: “If you’ve seen one flu pandemic, you’ve seen one flu pandemic.”

This reminds me of the first line of Anna Karenina:

Happy families are all alike; every unhappy family is unhappy in its own way.

(via david archer)

Google Flu Trends

Google is tracking search terms to predict when the flu is going to hit different areas in the US.

During the 2007-2008 flu season, an early version of Google Flu Trends was used to share results each week with the Epidemiology and Prevention Branch of the Influenza Division at CDC. Across each of the nine surveillance regions of the United States, we were able to accurately estimate current flu levels one to two weeks faster than published CDC reports.