flu vaccine

The WHO and drug regulators want to reformulate the flu vaccine. It’s easier said than done

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A syringe pokes to remove a piece up from a puzzle — health coverage from STAT

Last fall, the World Health Organization and some national drug regulators urged influenza vaccine manufacturers to drop the component known as B/Yamagata from flu vaccines as quickly as possible, citing the fact that this lineage of flu B viruses appears to have been snuffed out during the Covid-19 pandemic.

It might seem like that request would be as simple as deciding to leave blueberries out of a mixed-fruit smoothie. It turns out it is not.

While some experts have claimed that this transition should be doable in time for next fall’s Northern Hemisphere flu vaccination campaigns, the International Federation of Pharmaceutical Manufacturers and Associations, an organization that represents vaccine manufacturers and other pharmaceutical entities, is calling for a longer lead time for the shift, saying it will take flu vaccine makers until the 2025-2026 Northern Hemisphere cycle to be able to make the change across the board. The Southern Hemisphere flu vaccines would follow in the 2026 winter, the IFPMA said.

“There’s a bit of a perception that, ‘Industry, you change the components of the vaccine twice a year. Why is this so complicated?’” said Paula Barbosa, the IFPMA’s associate director for vaccine policy.

“It’s widely different.”

Dozens of manufacturers around the world make hundreds of millions of doses of flu vaccine every year. Most of those products are quadrivalent, meaning they target four types of influenza — the influenza A viruses H1N1 and H3N2, and two lineages of flu B viruses, B/Victoria and B/Yamagata.

The protection against two flu B viruses is a relatively new feature of flu vaccines. Prior to 2012, the vaccines were trivalents — protecting against the two A viruses and one of the Bs. But the choice of which B to target wasn’t always correct, leading in some cases to reduced effectiveness of the vaccines. Over the past 15 years or so, most manufacturers transitioned to a four-in-one vaccine, hoping to improve the protection their products offer.

However, in the years preceding the start of the Covid pandemic, B/Yamagata viruses seemed to lose steam. They were detected less frequently than B/Victoria viruses, and didn’t appear to be evolving as quickly as B/Victoria viruses. (The viral target for B/Yamagata in current flu vaccines dates all the way back to 2013.) The reduction in global travel and social distancing measures taken in 2020 to minimize transmission of Covid-19 drove all flu activity to very low levels for a year or so. The other viruses eventually bounced back, but not B/Yamagata. The last confirmed detection of a B/Yamagata virus was in late March 2020. Hence the recommendation to take it out of the vaccines.

Though some virologists remain unconvinced the lineage is actually gone, increasingly flu experts believe there is no longer a need to include protection against B/Yamagata in flu vaccines.

“There’s no [B/Yamagata] virus circulating, so why include the antigen?” asked Scott Hensley, a University of Pennsylvania professor of microbiology who specializes in influenza. “I think it’s definitely time.”

In the main, the rationale for removing the B/Yamagata component is that it isn’t needed. Why stimulate the immune system to be able to fend off a viral enemy it isn’t going to face? But there is also, at least in theory, some risk involved in using one kind of flu vaccine — live-attenuated vaccines like AstraZeneca’s FluMist — that contains live but weakened B/Yamagata viruses. The concern is that the viruses in the vaccine could reassort — swap genes — with the remaining flu B viruses and reseed B/Yamagata in the world.

“I think specifically for the live-attenuated vaccine it is a bad idea to keep Yamagata in that vaccine,” said Ben Cowling, chair of epidemiology at the University of Hong Kong’s School of Public Health.

Experts who advise the Food and Drug Administration on vaccine policy, the Vaccines and Related Biological Products Advisory Committee, endorsed the idea of removing the B/Yamagata component from flu vaccines as quickly as possible at a meeting in early October. And several objected to the claim, raised during the autumn meeting by an industry representative, that it would take until the 2025-2026 vaccine cycle to accomplish this task.

Barbosa said whereas in some jurisdictions — such as the United States — there’s a reasonably uncomplicated regulatory pathway for making the change, in other countries the process is not as clear cut.

There are roughly 350 trivalent vaccine licenses that either need to be reactivated, updated, or in some cases, applied for from scratch, she said, adding that the transition involves an estimated 170 regulatory agencies that will need to sign off on a combined total of about 1,500 variations that need to be made to existing licenses.

Regulatory dossiers are voluminous and detailed. If a flu vaccine producer changed, for example, the location where it conducted some testing of its product, licensing dossiers need to be amended in all places where that testing is referenced to reflect the change. If new production facilities were built in the period after a company started marketing a quadrivalent flu vaccine — in other words, if trivalent products were never made in that location — the new facilities would need to go through approval for trivalent production.

“So the whole end-to-end manufacturing — including the components of quality and validation in many sites — are [quadrivalent] specific, and now will need to be revalidated and submitted for [trivalent],” Barbosa said. “From a regulatory and procedural standpoint, this is an extremely complex picture.”

Some of the manufacturers are in discussions with not just one regulatory agency, but multiple agencies. Some have production plants in a number of countries; major manufacturers sell flu vaccines to multiple countries.

Sanofi, the world’s largest manufacturer of flu vaccines, makes its products in France, Mexico, China, as well as at two U.S. facilities. CSL Seqirus makes flu vaccines in Australia, the United Kingdom, and the U.S., and sells them to at least 14 countries in North and South America, Europe, Australasia, and Asia. GSK makes flu shots in Canada and Germany that are sold in 30 different countries.

The complexity of the regulatory realities facing manufacturers explains why the industry feels the 2024-2025 flu season target can’t be met and that 2025-2026 is more realistic, Barbosa told STAT in an interview.

“This is evolving information, but that’s what we are working on,” she said. “This change presents companies with a number of practical and technical challenges in implementation.”

The IFPMA is advocating for a synchronized global shift, arguing that to make the change sooner in some but not all countries could jeopardize the ability of manufacturers to fill the orders they get from countries that buy the vaccines.

“To make it very clear, the companies are fully committed to supporting the transition,” Barbosa said. “We just feel that it’s critical that the companies are given the appropriate amount of time to operationalize the proposed changes.”

One of the experts at the October VRBPAC meeting who objected to the IFPMA’s timeline was veteran influenza epidemiologist Arnold Monto of the University of Michigan, who believes the shift can be made — at least for the U.S. market — in time for the 2024-2025 flu vaccine rollout.

“The U.S. is a major user of the vaccines. We may not be able to do it — to get rid of the B/Yamagata — globally. But there seems to be a possibility it could happen in the United States,” Monto said in an interview.

All of the licensed quadrivalent flu vaccines in the U.S. were previously marketed as trivalent formulations — which makes the transition much simpler than if a manufacturer had to apply for a whole new license. None of the manufacturers relinquished those trivalent licenses, FDA spokesperson Cherie Duvall-Jones said via email. Instead they were put on a list of “discontinued products” — a kind of a marketing limbo that keeps a license in play but doesn’t require the manufacturer to pay annual program fees for products it isn’t selling.

There is a process for reactivating such licenses. But the FDA wasn’t especially forthcoming about how that process works, saying simply that manufacturers have to submit official requests to have a product removed from the discontinued product list, after which the FDA will ask a manufacturer to submit “a prior approval supplement.” What is required of a company in this prior approval supplement wasn’t spelled out.

The agency sidestepped the question of whether the FDA would be willing to allow manufacturers supplying the U.S. market to take part in a synchronized transition, following the IFPMA timeline.

“The FDA is working with the influenza vaccine manufacturers to assess their readiness to make available a trivalent vaccine and the timing, but it is premature for FDA to provide specific answers to your questions at this time,” Duvall-Jones wrote.

Individual flu vaccine manufacturers were unwilling to talk much about the situation while in negotiations with the FDA about what they must each do to reactivate their trivalent licenses.

“Given this is an ongoing discussion, we don’t have anything to share at this time,” said Chelsea Tressler, a spokesperson for AstraZeneca.

A spokesperson for Sanofi said the company supports the timeline proposed by the IFPMA.

“While the U.S. FDA has a mechanism in place to speed this process, the majority of countries require us to file new license applications for trivalent products, which then have to be reviewed and approved,” the spokesperson said in an email. “It is important to remember that the continued use of quadrivalent inactivated vaccines presents no safety issue, nor is there any lesser efficacy than a trivalent vaccine.”

Barbosa said the IFPMA and its members are hoping for clearer guidance from the WHO and regulatory agencies when global influenza experts convene in February for the twice-annual meeting to select the strains to be included in the next iteration of flu vaccines. The February meeting picks the strains for the following Northern Hemisphere flu shot; the same experts meet in September to select the strains for the next Southern Hemisphere winter.

As to the question of whether some countries or regions could make the transition on a more accelerated schedule, Barbosa said: “It’s a possibility. And I guess we’ll know more in February.”

New mRNA universal flu vaccine against all known subtypes takes promising first steps

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The vaccine provided protection for mouse and ferret models.

A new mRNA flu vaccine provides “broad protection” from lethal challenges by a variety of flu viruses, researchers have announced.

The animal study, published in Science, represents yet another step towards vaccinology’s holy grail: a universal flu vaccine.

A new mRNA flu vaccine provides “broad protection” from a variety of flu viruses in mice and ferrets, a step towards vaccinology’s holy grail: a universal flu vaccine.

One vaccine that provides protection against a wide array of flu strains could potentially save thousands or, over the long-run, potentially millions of lives. It could take the guesswork out of picking strains for the flu shot, provide longer-lasting protection, and even reduce the risk from a new pandemic flu virus.

“The idea here is to have a vaccine that will give people a baseline level of immune memory to diverse flu strains, so that there will be far less disease and death when the next flu pandemic occurs,” Scott Hensley, professor of microbiology at UPenn’s Perelman School of Medicine and study senior author, said.

Aiming a broadside: The new universal flu vaccine candidate uses the mRNA platform to get the body to produce “immunogens” — an immune-response stimulating molecule — from every influenza subtype currently known.

There are four different types of influenza viruses, named — with refreshing simplicity for these kinds of things — A, B, C, and D. Of those four main types, A and B are known to cause disease in humans, with A viruses in particular having pandemic potential.

After those major groupings, the viruses get broken down more specifically. The A viruses are separated into numerous subtypes based on the spiky proteins on their surfaces, while the Bs get split into two different lineages, B/Victoria and B/Yamagata.

A universal flu vaccine could take the guesswork out of picking strains for the flu shot, provide longer-lasting protection, and even reduce the risk from a new pandemic flu virus, potentially saving millions of lives over the long-run.

The proteins that determine the A subtypes are called neuraminidase (N) and hemagglutinin (HA). Similar to SARS-CoV-2, influenza viruses use these proteins during their replication cycle. To really oversimplify it, the virus uses HA to help get into your cells, and N to help get out.

But even within each subtype, the “head” of the HA protein — a common vaccine target — also mutates. A lot.

Some universal flu vaccines are looking to get around that problem but taking aim at targets on the virus that mutate less, like the “stalk” or the “anchor.” But that approach has some drawbacks, Jennifer Nayak, a University of Rochester researcher who studies the immune response to influenza, told CNN.

There just aren’t too many places shared by multiple strains of viruses, Nayak, who was not involved with the study, said. And they aren’t generally “immunodominant,” or what the immune system really reacts to on the virus. 

“Instead of trying to find something that’s shared, let’s just put all of the 20 different HA proteins – let’s put the mRNAs from all of them into this vaccine,” Nayak said. And then let the immune system figure out the best way to deal with them.

Enter mRNA: To build their mRNA vaccine, the researchers first tested all of the different targets individually, CNN reported, making sure each one produced an immune response.

After ensuring they worked individually, they packed them together into one mRNA-delivered package. 

In a Science companion piece, University of Saskatchewan researchers Alyson A Kelvin and Darryl Fallzarano noted that mRNA’s flexibility, ability to use multiple targets, and the speed and economics of its production make it a platform suited for pandemics.

The vaccine mRNA platform to get the body to produce “immunogens” — an immune-response stimulating molecule — from every influenza subtype currently known.

“For a conventional vaccine, immunizing against all these subtypes would be a major challenge, but with mRNA technology it’s relatively easy,” Hensley said.

When the team tested their vaccine in mice and ferrets — ferrets being a gold-standard animal model for flu — they found that it created a high level of antibodies, reacting to all 20 subtypes and maintaining antibody levels for four months. 

“What we found is that these vaccines elicit very high levels of antibodies against all 20 subtypes,” Hensley told CNN. The vaccine antibodies reacted not only to the head portions of HA, but the stalk as well.

Mice that were given a placebo mRNA vaccine, which carried the code for an enzyme that had nothing to do with the flu, died after being exposed to the flu — a lethal challenge — while vaccinated animals survived their bout with the virus.

The team does not expect their vaccine to completely prevent infection. Instead, it would lay down the groundwork for a quick immune response to a wide array of viruses, reducing the risk of severe infection and death.

While a promising proof-of-concpet, further research will be needed to see if the vaccine works in people.

Next steps: While the results are a promising proof-of-concept, they are also, well… a promising proof-of-concept.

“Impressively the vaccine was able to induce similar immune responses to all 20” HA proteins despite their similarity, Joshua Blight, the CEO and co-founder of antigen-focused biotech Baseimmune, tells Freethink.

But, crucially, mice and ferrets aren’t people — and we’ve yet to see how the vaccine would work in people, Blight adds; humans have preexisting immune memories of different HA subtypes that may interfere with the vaccine response.

Tamiflu and Abnormal Behavior

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It’s a particularly nasty flu season, right – what should we do??

Last week, a student in my daughter’s elementary school died. An apparently healthy, active, and vital 10-year old child suddenly departed. Despite an initial announcement of “cause unknown,” the administrators followed up with a suddenly clear pronouncement that he died “from the flu.” Looking beyond the fact that now even school administrators feel entitled to give clinical advice (“if you haven’t yet received your flu shot, please do”), I was interested to see that this child’s flu vaccine status was not mentioned. I wondered if he had received the flu shot or taken Tamiflu – especially since both have been associated with sudden death in the pediatric population. 1

It’s a “deadly” flu season, and the pharmaceutically-funded media would have you believe that you must head on over to CVS and get your flu shot to make it through the year. And if the flu shot doesn’t work – even the CDC estimates its effectiveness around 39%2 – well then, just head to your doctor and get treated with Tamiflu!

But is it really that simple? Is it possible that we are bumping up against the glass ceiling of the Simple Solution for Sickness? Many of us are rolling our eyes at the “10% off your shopping order!” flu shot incentives, and our sniffles don’t send us running to the doctor for antibiotics “just in case.” As our own memories tell a different story from the scary stories on TV (wait…the chicken pox and the flu are deadly? Mom, Dad…didn’t you both have Measles and live to tell the tale?), we are becoming less and less susceptible to fabricated lore. We are harder to scare into action. We are beginning to accept that the magic pill is a fantasy, and that this crisis of confidence in our medical system is no small hurdle to overcome. It is an initiation into a new belief system.

I believe that this initiation begins with information and understanding. This understanding leads to informed choices. These empowered choices lead to a new experience of trust in your bodyand in the natural world.

Let’s bring this back to earth with an example. Let’s look at the Simple Solution for the flu: Tamiflu.

Conventional medicine tells us that you can pull one thread of the spider web without impacting the whole design. So, is it possible that Tamiflu can enter your system, kill those nasty flu germs, and quietly exit without harming any innocents?

What is Tamiflu, and how does it work?

Tamiflu (oseltamivir) is prescription medication that is FDA-approved for anyone 2 weeks of age and older.3 It is designed to prevent the influenza virus from replicating and invading other cells. The pharmaceutical company that developed Tamiflu, Roche (also called Hoffmann–LaRoche), claims that Tamiflu can protect against getting the flu and reduce the severity of flu symptoms. Roche cites studies like a 1999 article in JAMA, in which authors write that Tamiflu “…provided significant antiviral, biochemical, and clinical effects in experimental human influenza virus infection. Prophylactic administration either once or twice daily completely protected against viral recovery in the upper respiratory tract and against infection-associated respiratory tract illness.” 4

Well that sounds good, right? In 1999, Roche presented this study, along with two clinical trials involving 1,358 patients,5 to an FDA committee of medical advisors – but the committee declined to approve Tamiflu due to a lack of convincing data.

Let’s dive a bit deeper to see if the data are indeed unconvincing (the full-text of this article is free!). This study involved 117 young adults (median age was 21), split into several groups that ranged from 11 to 64 subjects. Any scientist or statistician will immediately warn you that those group sizes (called sample sizes) are too small to draw statistically significant conclusions. With that in mind, let’s continue unpacking this study…

To measure the prophylactic effects of Tamiflu, researchers gave 12 people a placebo pill, and they gave 21 people various doses of Tamiflu before they stuck influenza virus into their noses. Flu-like symptoms were measured after viral inoculation, and people who had received Tamiflu were rated to exhibit lower symptom scores. From this experiment (based on a paltry 33 subjects), researchers concluded that Tamiflu indeed protects against getting the flu.

Next, to determine if Tamiflu reduced the severity of flu symptoms, researchers infected 80 people with the influenza virus (again in their noses). They gave Tamiflu to 56 people and a placebo to the rest. Then, researchers washed out people’s noses and measured the number of virus particles in their mucus. They reported that Tamiflu treatment reduced the number of viral copies in people’s nasal passages.

Quantifying the number of viral particles in people’s noses – after the flu virus was stuck into people’s noses – does not tell us anything about how the flu virus is spreading throughout the body. Anyway, for whatever reasons (you can use your imagination), FDA administrators overruled the medical expert committee’s suggestion and approved Tamiflu in October 1999. 6 But the FDA hedged a bit and required the drugmaker to issue the following statement:

“Tamiflu has not been proven to have a positive impact on the potential consequences (such as hospitalizations, mortality, or economic impact) of seasonal, avian, or pandemic influenza.” 7

Since its FDA approval, clinical trials touting the effectiveness of Tamiflu have been published – though a look at the authors and footnotes of these studies may give you pause. For example, Penelope Ward, MD has authored dozens of scientific studies that support Tamiflu,8 including the 1999 JAMA study we just deconstructed, a 2001 JAMA study with similar methods and conclusions,9 study of Tamiflu a mechanistic study of Tamiflu,10 and an oft-cited 1999 study in the New England Journal of Medicine (NEJM) entitled ‘Use of the Selective Oral Neuraminidase Inhibitor Oseltamivir to Prevent Influenza’ – and she served as the Head of Clinical Development for Hoffman-LaRoche.11 Actually, let’s look at the footnote of the 1999 NEJM study:12

Interesting…

Overall, it appears that all the studies that support the efficacy of Tamiflu are funded by the pharmaceutical companies that stand to profit from its sales.

Fortunately, a group of unbiased medical experts at the US Cochrane Center13 re-analyzed data from 20 clinical trials like these, reporting their results in a 2009 BMJ article. Their meta-analysis showed that there was no significant evidence that Tamiflu reduced influenza symptoms or complications – the only possible positive association was that Tamiflu might decrease the length of time people exhibited symptoms by a few hours.14 Further, the reanalysis found that Tamiflu increased nausea.

As an interesting aside, Cochrane Center researchers noted that it took years-long concerted efforts to obtain clinical data from drugmakers.15 Along these lines, investigative articles published in The Atlantic in 200916 and 201317 suggest that political and financial motivations (to the tune of billions of dollars) underpin this Tamiflu delusion.

So where does this leave us? Perhaps Tamiflu doesn’t work that well, but is there any harm in taking it anyway, just to be safe?

Is Tamiflu safe?

A 2007 scientific report18 suggests that Tamiflu is in fact exceedingly dangerous. In the 6 years that Tamiflu was marketed in Japan, the Japanese Ministry of Health Labour and Welfare received 1377 reports of adverse reactions. Approximately half of these reactions were serious neuropsychiatric cases, including delirium, convulsions, and encephalitis. Eighty deaths were reported, though only 71 were considered to be directly related to Tamiflu. Two of the most alarming deaths were suicides by 14-year-old teens on Tamiflu.19

As such, Japanese authorities advised against Tamiflu for adolescents, and the National Institute for Health and Clinical Excellence (the UK’s version of the FDA) recommends against Tamiflu as a preventative strategy in healthy people.20 Yet, American agencies like the CDC and FDA continue to push Tamiflu in spite of its documented side effects of hallucinations.21

Several recent news stories have highlighted these side effects of Tamiflu. For example, on January 15, 2018 a 6-year-old Texan girl took Tamiflu, hallucinated, and tried to jump out of a window22. About a week later, another Texan child, this time a two-year-old boy, suffered from hallucinations that caused him to repeatedly slap his mother.23

In a news article from January 24, 2018, the mother of a five-year-old girl who experienced severe hallucinations and seizure-like symptoms stated, “The flu is bad, it’s horrible, you feel helpless your child’s sick…I would take that a hundred times over the reaction she had to the Tamiflu.”24Perhaps most telling is an article in Time entitled ‘Tamiflu Made My Kid Hallucinate. I Think the Flu is Preferable to Delirium.’25

Very sadly, a 6-year old girl named Emily Muth from North Carolina died this week – three days after being given Tamiflu.26 According to her mother, Emily suffered from labored breathing (a known side effect of Tamiflu) right before her tragic passing.

Emily Muth

Unfortunately, Tamiflu is neither safe nor effective. I hope that presenting the terrible experiences of the children and families mentioned in this article will serve as a warning to prevent more tragedies.

Fighting won’t win this fight

When you understand that the preschool analogy of foreign invaders (germs) fighting your inner soldiers (immune system) has been rendered obsolete by our awareness of the microbiome(including the virome!), and the poetic reality that we are made up of the very organisms we thought that we were fighting…well, then pharmaceutical medicine seems something like cutting off your nose to spite your face.

This is when you can graduate to a deeper sense that illness is purposeful, that the body recalibrates through fever, and that we are simply here to support the body’s innate wisdom…the less fear, the better.

There are many evidence-based tools for supporting your body’s detoxification process including vitamins A and D, herbs like ginseng, elderberry, and ginger, and food-derived compounds like AHCC and beta glucan, and, my favorite in this case, homeopathy (Oscillococcinum).27 Take the cue to stop, rest, and just be – while your body does its wise work.