FluBlok: Not Your Father's Flu Vaccine

There are very good reasons why many infectious disease experts spend a lot of time focused on the threat of influenza. This virus is a known pandemic threat and has producing such devastating phenomenon at regular intervals throughout human history. 

Our chief means of defense against this threat -- as it is with almost all infectious disease threats -- is vaccination. However, as I and many others have written, we largely battle flu with a vaccine technology from the 1940s that has many limitations and at best is possibly about 60% protective and its worst not so protective at all.

Influenza is a tricky virus and has the capacity to drift, shift, mutate, and reassort in a manner that renders vaccines obsolete and requires an intensive process of regular reformulation (because we do not have a universal evergreen flu vaccine). This process is further complicated because the vaccine is grown in chicken eggs -- a cumbersome process that not only is dependent on a supply of chicken eggs but can itself mutate the vaccine strain during growth further handicapping the vaccine.

One solution to this problem is to move out of chicken eggs altogether and to cell lines -- something that is the norm for many other vaccines. To date, however, only one totally cell-based vaccine is available (there is another partial cell-based vaccine as well which relies on an egg derived viral reference strains that is then grown in MDCK cells): Flublok, a recombinant vaccine grown in insect cells through a baculovirus vector.

It's no secret that I am a huge fan of this vaccine, insisted on receiving it this season, recommend it to my friends, and even got to tour their vaccine plant. The value of FluBlok is not only that it frees flu vaccine production from the tyranny of eggs from a production standpoint, but that its recombinant nature results in a better vaccine. A recent study, published in The New England Journal of Medicine, illustrates this latter point. 

During the 2014-2015 influenza season -- a season  characterized by influenza A/H3N2 dominance and vaccine mismatch-- a randomized clinical trial was conducted on 9000 individuals aged 50 years of age and older. Participants were randomized to quadrivalent FluBlok vs. a standard quadrivalent GSK flu vaccine. The primary endpoint was PCR confirmed influenza-like illness.

Fully 30% less participants randomized to FluBlok experienced PCR-positive influenza reaching statistical superiority. In subgroup analysis, this appeared to be derived from enhanced protection against influenza A. Since no influenza A/H1N1 was detected in the study, the result was driven from enhanced efficacy against A/H3N2 -- a usually more severe strain of seasonal flu. No safety concerns arose.

This trial is very significant and should help physicians and the public understand that moving away from eggs in vaccine production will have many important effects including rapid scale up, flexibility in plugging in new strains of flu and other viruses (e.g. Zika), and no susceptibility to egg supply shocks (a real concern during an avian flu outbreak that could make chicken egg supplies dwindle), less mutation of vaccine strains induced by adaptation to egg growth, and -- as this trial illustrates -- better protection during seasonal flu.

Kiss A Frog, Fight the Flu

There is always speculation about particular compounds that exist naturally in the wild that may have benefits for human health. Indeed, history is full of stories like this from quinine to aspirin. New research from Emory shows that frog mucus contains a potentially flu-fighting antimicrobial peptide. 

For the study peptides contained in the mucus from Hydrophylax bahuvistara frogs were screening for both anti-influenza activity and non-toxicity to human cells. Of these screens, one peptide, named urumin, emerged as the leading candidate. Urumin was noted to interact directly with the influenza virus at an important site: the conserved stalk area of the H1 hemagglutinin. Because it is a "conserved" region (i.e. one not highly mutable) the frog peptide retained activity against drug-resistant variants. This region is one of the targets of the long sought after universal flu vaccine. In the study, urumin worked not only in vitro but also in a mouse model.  The peptide was specific for just H1 variant influenza A viruses.

I found the paper to be very interesting and the discoveries may have wide-ranging implications not only for novel antivirals but for understanding influenza. As the authors note, innate defense mechanisms are less likely to be prone to resistance because they presumably were selected  via natural selection for their durability against their target. It is unclear what role amphibians have with influenza A epidemiology but it appears they can be infected and perhaps urumin is one of its natural defenses against the virus. Future studies with ferrets will be important to perform as they are important surrogates for humans.

Cats Beware: Eating Tweety Bird May Be Hazardous to Your Health

Though buried among Christmas season headlines, the report of a veterinarian contracting an avian flu strain from a cat is, to me, highly significant. When people speak of avian influenza viruses it is the highly lethal H5N1 or H7N9 that are being discussed as these two viruses are high on many threat lists. 

In this incident, a New York City veterinarian caring for sick cats contracted the H7N2 virus which had not been known to infect cats before this event. It has been speculated the cat may have contracted it from a pigeon. It had been diagnosed in humans at least twice since 2002: once from someone involved in a Virginia avian outbreak and once before, interestingly, from a person in New York City without an unknown exposure. The veterinarian, like the two other human cases, recovered uneventfully and no secondary spread of this virus to other humans was detected via a robust surveillance operation conducted by the New York City Department of Health. 

This event, to those who track influenza, transcends the minor illness that results as it is an important example of how zoonotic flu viruses could take hold. These types of incursions into new species are important to study and the viral characteristics and changes that made such a jump possible should be compared to wild-type viruses that circulate in avian species. 

Influenza possesses many capacities that bestow it with the the capacity to cause cataclysmic (no pun intended) pandemics. Among these capacities, its ability to infect a variety of different types of animal species and shuffle viral genes inside them is probably the most valuable. Moving from birds to cats to humans is one such example. Indeed, the pandemic H1N1 virus has a complex genealogical origin that is a triple-reassortant virus that reassorted again. When a virus has a wide host range, it can take all sorts of turns and jumps some of which may lead to a human pandemic. These types of events can be predicted but the precision may not be perfect as our last pandemic emerged, not from China, but from Mexico.

While there has been a much needed focus on H5N1, we also know that H7 (H7N2, H7N3, H7N7, H7N9) flu viruses have an ability to jump into humans and, in the case of H7N9 cause severe disease. I wonder if the fact that multiple H7's have been making incursions into humans is a sign of what our next pandemic flu virus may be. Thus far, it appears the most prolific of these H7's, H7N9, has not changed substantially through its 4 waves of infection. 

While it appears that, fortunately, H7N2 does not lead to severe disease in humans this event should remind people of the prowess of flu viruses and the eternal vigilance needed to protect the human race from this extremely successful virus.

A Field Trip Fit Only For an Infectious Disease Nerd: A Flu Vaccine Plant

A couple of weeks ago, I had the pleasure of taking the ultimate nerd field trip. Where did I go?  To an influenza vaccine plant, naturally. This was no ordinary vaccine plant I got to see though, it belongs to Protein Sciences Corporation: the sole supplier of the only recombinant influenza vaccine, Flublok. 

I am someone who has been a critic of the ordinary flu vaccine for myriad reasons, chief among them are its poor efficacy and the cumbersome and snail-like manufacturing process. These two deficiencies will spell doom in the face of a flu pandemic when speed, adaptability, and high efficacy could crucially alter the trajectory of the viral spread. Recombinant vaccines, not reliant on chicken eggs, fulfill these criteria and, as such, they are the vaccines of the future (not just for flu, but possibly for many other infections). 

Currently, the FDA has approved a 3-strain version of Flublok for use in adults. Many people, however, believe Flublok to be the vaccine of choice for those with severe egg allergies -- which it is -- and fail to realize there are more reasons to possibly prefer this vaccine over other options.

There is a growing body of data, for example, showing that this vaccine, in a yet-to-be-approved 4-strain form, provides superior protection when compared to the ordinary vaccine. "So what?" you might think, "4 is better than 3 and there is no 4 strain Flublok yet." Indeed, that is what I thought until I studied this vaccine in more detail and realized that its superior perfomance was due to something that nullifies the above argument.

Its advantage is its ability to ward off the tricky-to-grow H3N2 A strain included in both 3 and 4 strain vaccines; not the extra B that is included in quadrivalent vaccines. Remember, since Flublok is a recombinant vaccine there's no growing in chicken eggs and, consequently, no mutations that occur during growth creating a difference between what strain was used to construct the vaccine and what ultimately hatches at the end (such differences are likely a cause of diminished protection seen with the routine vaccine). Additionally, Flublok contains 3 times the amount of antigen per strain than the ordinary vaccine which also may play a role in its potency as does its ability to stimulate antibodies that are more broadly protective (against the hemagglutinin stalk in addition to the globular head). Overall, this approach has very high biological plausibility and I anticipate clinical studies will soon be published that definitively confirm these findings.

Flu is the big beast, the infectious disease I fear most. This flu season I might try the vaccine of the future.

Flu: Always Trying to Avoid Partying like It's 1918

That a 57 year old man died from influenza should come as no surprise, even if that man is named Prince. While it is not confirmed that Prince actually succumbed to true influenza—people use the word “flu” for a variety of conditions--his tragic loss should serve as a reminder that influenza is not a benign illness but a major infectious disease killer responsible for the deaths of thousands of Americans yearly.  Just hours before Prince’s death was announced to the world, a friend of mine was baffled over the death of a young police officer in my own county from influenza.

People die from influenza when it progresses to severe pneumonia blocking the ability of the lungs to deliver oxygen to the bloodstream. This phenomenon can occur with primary viral pneumonia caused by influenza or via a secondary bacterial pneumonia. Also, those with severe illness who are hospitalized are at risk for downstream complications of that hospitalization such as kidney failure or pulmonary embolism, for example.

As of this writing it is unclear what the circumstances of Prince’s death were and the nature of his illness, but it is said he was battling flu for weeks leading me to speculate he may have had a secondary complication of some sort.

While this year’s flu season has been late-peaking and relatively benign (thanks, in part, to a well-matched flu vaccine), there have been many severe cases around the nation. In its latest weekly report (covering through April 9) on flu the CDC relates that 7.5% of deaths reported in the 122 Cities Mortality Reporting System were due to pneumonia/influenza – above the threshold value expected for this time of year. Additionally, 10 pediatric deaths were reported for that same week.

This is what it sounds like when flu kills.