Untangling the Fate of the Dengue Vaccine

It can't be emphasized enough the dengue fever is a deadly viral infection that exacts a considerable burden on the world. Any tool to diminish this impact would be welcomed by the world. This mosquito-borne virus has a unique aspect about its pathophysiology that makes it especially intriguing and difficult to develop a vaccine against. There are 4 types or strains of dengue virus (maybe five) that circulate and it has been shown that antibody-based immunity to one strain enhances the severity of subsequent infections with the other strains. This phenomenon is known as antibody-dependent enhancement and is what accounts for severe dengue. 

Because of this capacity of dengue, it is essential that any vaccine not induce antibodies that lead to enhancement of infection. The only dengue vaccine on the market to seemingly clear this hurdle was Sanofi Pasteur's Dengvaxia which has been licensed in several countries (but not the US). This vaccine, based on a yellow fever vaccine platform, is protective against 4 strains of dengue.

Dengvaxia has been in the news because of new longer term data showing that in those with no prior immunity to dengue, the vaccine increases the chances that infection will lead to severe disease. Perhaps vaccine induced antibodies -- in the absence of any naturally formed antibodies -- are enhancing. Interestingly, in the clinical trials of this vaccine an increased rate of hospitalization and severe dengue was noted in children less than 9 years of age which restricted its use to those above 9.  I wonder if this is because those younger than 9 are more likely to have escaped natural dengue infection and be liable to develop severe dengue due to vaccine-induced antibodies. Of course, some people may reach 9 years of age and escape natural infection and have a similar risk as those below age 9.

It may be that restriction of the vaccine to those with laboratory confirmed dengue -- irrespective of age -- will be the best way to salvage this vaccine as a tool to prevent severe dengue. However, adding a lab test will considerably increase the costs and logistical difficulty of deployment. This finding also makes it very difficult to market the vaccine to travelers, most of whom will not have any natural dengue antibodies.

While this negative finding is clearly a setback for Sanofi, the dengue vaccine field, and for the countries using the vaccine it should be seen as a validation for the rigor of post-licensure vaccine safety testing in which this signal was uncovered and openly publicized. This finding should not be misinterpreted as some way to bolster the veracity of the anti-vaccine movement (which I am sure is inevitable) and be used to smear other vaccines to which this finding is wholly inapplicable.

Vaccination is the Real Baptism: From the Mouth of SMILF

What is the difference between baptism and vaccination? That's a question that is raised in the latest episode of Showtime's SMILF. SMILF is a clever new comedy based upon the life of Frankie Shaw, who has multiple roles (star, writer, etc.) in the show. 

On first glance, readers might say that baptism is a mystical religious ritual and vaccination is a science-based medical practice that are completely different and they would be right. But Shaw, ingeniously, sets up a great juxtaposition. A couple of episodes back her character Bridgette, confronted with the threat of chickenpox in her unvaccinated child and realizing the child's biological father's opposition to vaccination (because he believes they are poison and government mind control), has the child surreptitiously -- and laudably -- vaccinated.

End of story...except for the baptism issue.

Bridgette, again very admiringly, is not religious and has not permitted her son to be baptized despite her mother's fervent Catholicism. When the child's father finds out about the vaccination and simultaneously is offered an opportunity to have the child baptized, he falsely creates an equivalency between the two actions and has the child baptized.

It's this false equivalency -- in the face of a gulf wider than the Red Sea--that is worth thinking about. Vaccination, in 2017, is performed because of the clear benefit it offers the individual being vaccinated against specific infections for which the risk is not neglibile. This benefit is evidenced by falling childhood mortality rates, rising lifespans, and the recession (and even the eradication) of vaccine-preventable diseases. Vaccination is performed because it is evidence-based, biologically-plausible, and has proved tremendously successful. 

Baptism, on the other hand, is none of this. It is performed to supposedly nullify the sin that every human is allegedly born with through no fault of their own. These "sinful" babies, if they fail to be baptized, are prohibited entry into a paradisiacal afterworld. To me, nothing can really be more cruel or calculatingly devious than to morally damn all humans by virtue of their being born and offer as the only solution a primitive ritualistic practice. Far from being a protective like vaccination, baptism is the opposite for it exposes one to the true poison of religious dogma that one is immersed in along with the "holy" water. 

The true baptism is one that is the culmination of the painstaking scientific inquiry and research that has allowed our species to tame some of the more dangerous members of microbial world.

Thanks to the talented Frankie Shaw for making this point so clearly, dramatically, and entertainingly. 

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.

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.

Understanding Vaccination Through the Lens of Inoculation: A Review of Defying Providence

When the history of vaccination is discussed it, naturally, begins with the path-breaking step taken by Edward Jenner in the late 1700s. Jenner’s use of cowpox to protect against smallpox—an action that would culminate in the eradication of smallpox from the planet under the aegis of DA Henderson—is often discussed without any knowledge of the context that conditioned the development of the first vaccine in history.

Dr. Arthur Boylston’s Defying Providence: Smallpox and the Forgotten 18th Century Medical Revolution provides that valuable context. Boylston’s book, which is the result of extensive research, adds much detail to the means of controlling smallpox that existed before vaccination – i.e. inoculation. Inoculation is often treated as a historical relic in the path towards vaccination and given short shrift by many and often damned as a means by which smallpox spread but it is much more than that, as Boylston shows.

Inoculation was an ancient practice that rose in prominence in England and Boston (under the direction of another Dr. Boylston) in the 1700s. It involved the intentional infection of someone with smallpox via a small cut in the skin. Such artificial cases allowed an often minor infection to ensue conferring immunity against natural infection. Make no mistake, the artificial infection was true smallpox and, in rare instances, could kill and also had the ability to spread. However, it is crucial to not drop the context in which it was used – a time in which smallpox was a major killer in which risk-benefit ratios strongly favored the use of inoculation.

Boylston’s book provides a much-needed history of how this practice gained in acceptance, how the evaluation of its efficacy led to the foundations of evidence-based medicine, and how a specific phenomenon led to Jenner’s innovation. 

The phenomenon of those who had cowpox being protected from smallpox is cloaked in the myth of the fair complexion of the milkmaid but the actual truth is much more interesting scientifically.

Cowpox was an affliction known to farmers and the inability of an inoculation to take (i.e. produce a case of mild smallpox) in those with cowpox began to be known before Jenner. Jenner and others reasoned that because of the resistance to inoculation, cowpox might be protective against smallpox infection. In effect, Jenner sought to substitute vaccination (with cowpox) for inoculation, seeing if artificial cowpox would work the way natural cowpox did with respect to smallpox protection. Vaccination was a relatively safer alternative to inoculation and could not spread smallpox. The resistance to Jenner’s vaccination that occurred upon introduction can be seen not just as a reaction against the use of material from a cow but also hesitancy to discard inoculation, which had been a major component of smallpox control until then.  Indeed inoculation, as the title of the book makes explicit, allowed humans to defy Providence and take charge of the trajectory of their lives by protecting themselves from smallpox.

Dr. Boylston deserves much credit for writing this important history and illuminating the origins of vaccination—another means to defy Providence—by giving much due credit to inoculation and the inoculators.