It’s the middle of the year, summer has just kicked off, and many of us are stocking up in preparation for our July 4th celebrations. Just around the corner are pool parties, dogs and burgers on the grill, and firework displays to light the balmy night red, white, and blue. With summer fun ahead, few of us are thinking about the woes of winter, the rains, the snow, or the sniffles. In fact, we can honestly say that thoughts of winter bugs were not even on our radar. Until we read about the fall armyworm – and that’s when everything changed…
The fall armyworm? Anyone ever heard of it? Unless you are an entomologist it’s doubtful, and we hadn’t either until the little green inchworm crossed our radar in an article about Africa. As if that continent’s history has not given it sufficient to deal with – from colonization to civil wars, apartheid to famine – Africa, the cradle of civilization, is facing potential devastation once again. This time from a two-inch long member of the order Lepidoptera, scientific name Spodoptera frugiperda – the larval incarnation of the fall armyworm moth.
Like locusts, the fall armyworms eat everything in their path…
In early 2017, vast swathes of southern Africa were laid waste by S. frugiperda which feasts on grasses, leafy crops, and small-grain crops such as maize. Like locusts, the fall armyworms eat everything in their path before moving, en masse and under cover of darkness, to the site of their next banquet. The bug is especially devastating because it eats the plant’s reproductive parts – in the case of corn, the cob itself. Already this year upward of 290,000 hectares of crops have been destroyed and it’s just getting started.(1) A tender creature that cannot survive freezing temperatures, the fall armyworm is native to Africa and the Americas and understandably is considered a dangerous pest.
But it could be that this annoying little creature may not be all bad. According to an article by Maggie Fox of NBC News, Caterpillar-Grown Flu Vaccine Protects Better Than Egg-Incubated Vaccine, modern technology may be about to transform the reputation of the caterpillar from fiend to friend. And to see why this is so significant, let’s take a look at a common, yet often fatal, condition – influenza.
In the U.S., influenza – the ‘flu’ – is a major killer. A respiratory condition that infects the nose, throat, and lungs, it manifests as a fever, cough, muscle aches, fatigue, and sometimes vomiting and diarrhea. It is spread both by bodily fluids – one sneeze can release more than half a million virus particles into the air – and by contact with surfaces that are infected. And it is stealthy: carriers are contagious for one day before onset of symptoms and up to between 5 and 7 days after becoming unwell. Although anyone can contract the illness, those at higher risk include seniors, those with endocrine disorders such as diabetes, those with heart disease or compromised immune systems, pregnant women, and children. Although antiviral drugs such as Tamiflu®, Relenza®, and Rapivab® are available and can help prevent the onset of post-flu conditions such as pneumonia, time is critical as they are most effective when started within two days of becoming sick. Perhaps because the treatment window is short, the Centers for Disease Control and Prevention (CDC) estimates that between 140,000 and 700,000 people are admitted to hospital annually for flu-related issues, of whom between 12,000 and 56,000 will die. In a multi-year analysis by that agency, ‘flu season’ was shown to run from approximately October through the end of May with cases spiking in February.(2) In summary, although it’s a common complaint, the flu – that scourge of the winter months – is anything but quotidian.
Modern anti-flu vaccines are a response to the 1918 flu pandemic that infected 500 million people worldwide and resulted in between 50 and 100 million deaths. To put this figure in context, it represented a loss of between 3% and 5% of the global population and shortened the average lifespan in the U.S. alone by 12 years. The particular strain of the virus, H1N1, was particularly aggressive insofar as it triggered in victims a cytokine storm. When healthy immune systems are attacked, cytokines summon first responders such as T-cells and macrophages to destroy the pathogens, but in a cytokine storm a loop results in which an excessive number of these responders are produced. In such overwhelming numbers, T-cells and macrophages can cause sufficient damage to organs to prove fatal. And this is what happened in the pandemic of 1918 and occasioned the renewed interest in vaccination.
According to the Daily Telegraph, GSK’s vaccine factory received ‘nearly 360,000 eggs per day’ to use in its vaccine preparation.
The history of immunization through vaccination is well known with Edward Jenner and Louis Pasteur in starring roles. But what may be less well known is how the different vaccines are created. Vaccines basically fall into one of four categories: live, attenuated (for example, Varicalla for chickenpox); inactive/killed (hepatitis A); toxoid (diptheria); and subunit/conjugate (pertussis).(3) Inactivated vaccines are created by destroying the pathogen chemically or via heat while leaving it intact for the immune system to recognize in future encounters. Toxoids are made from inactivated toxins for use against bacterial infection where disease is caused by toxins produced by the bacterium. An example of this would be tetanus, which is caused by the neurotoxin associated with Clostridium tetani. The less than prosaic names ‘subunit’ and ‘conjugate’ refer to vaccines that contain only fragments of the pathogen against which they have been formulated, sometimes working by presenting a specific protein as an antigen. But the most well known vaccine is the live/attenuated type, produced by introducing the virus to a series of cell cultures or animal embryos. Typically vaccine producers such as GlaxoSmithKline, the world’s largest manufacturer of vaccines, use chicken’s eggs to culture the virus, allowing it to replicate in chick cells. According to the Daily Telegraph, GSK’s vaccine factory received ‘nearly 360,000 eggs per day’ to use in its vaccine preparation.(4)
In culturing the virus it is “passaged’ through more than 200 embryos or cell cultures, each iteration allowing it to ‘learn’ how best to replicate in those cells. Correspondingly, however, since chick cells are different from human cells, the virus becomes weaker at replicating in a human cell medium. A vaccine derived from this method provokes an immune response but is physically unable to replicate sufficiently to cause illness.
And this is where it gets interesting in terms of our fall armyworm.
Culturing vaccines in chicken’s eggs is a slow process and, with a quickly mutating virus like influenza, speed is of the essence. And now, Protein Sciences Corporation, a company based in Meriden, CT, has found a way to accelerate the process by using viral DNA grown on a matrix of caterpillar cells. Protein Sciences uses a proprietary BEVS protein expression technology to produce recombinant proteins for use in vaccines, gene therapies, antigens, and antibodies. Granted a license by the U.S. Food and Drug Administration (FDA) to manufacture Flublok in partnership with the federal Biomedical Advanced Research and Development Agency, or BARDA, the future for Protein Sciences looks especially rosy. The FDA support package also granted the company exclusivity for twelve years, meaning that the agency will not approve any similar products before 2025.(5)
So how effective is this new vaccine?
According to the company it is little short of a revolution in influenza protection, a position apparently supported by a review just published in the New England Journal of Medicine. Since the vaccine is made without the traditional use of chicken’s eggs it is not subject to the mutations than can be introduced during the process of egg adaptation. A high antigen-content quadrivalent preparation, it contains three times the hemagglutinin protein (3×45 mcg versus 3x15mcg) and none of the additives often found in its traditional, inactivated counterpart. These additives, introduced during the manufacturing process, include antibiotics, allergens such as gluten and latex, and compounds such as formaldehyde or thimerosal, a preservative that contains mercury. And in a randomized study of 9,003 clinical subjects aged 50 or older, ‘People who were given Flublok Quadrivalent were over 40% less likely to develop culture-confirmed influenza.’(6) The trial pitted the quadrivalent, recombinant influenza vaccine (RIV4) against the more standard egg-grown quadrivalent, inactivated influenza vaccine (IIV4) during the 2014/15 flu season in which the A/H3N2 flu strain was dominant. To test the vaccine efficiency,nasopharyngeal swabs were taken from participants exhibiting flu-like symptoms. In addition, reverse-transcriptase polymerase-chain-reaction (RT-PCR) confirmed any diagnosis of infection. In those who received RIV4 the RT-PCR rate was 2.2% (96 cases from a sample pool of 4303 candidates) in contrast with the 3.2% infection rate (138 individuals from a pool of 4427 potential hosts) of those who received IIV4. To distill this to its essence, the incidence of influenza was 30% lower with RIV4 than with IIV4.(7) In a recent press release, Lisa Dunkle, MD, Chief Medical Officer of Protein Sciences, noted: “We demonstrated statistically significantly better protection by Flublok based on considerably fewer people contracting the flu after vaccination […This] represents a major step forward in combatting influenza on a global scale.’(8)
Within a contamination-controlled environment, bioreactors – vast vats of cells that produce protein – are used to formulate the recombinant vaccine.
So what is the secret of the vaccine? It’s hard to be definitive, but it does seem that the move from chicken’s eggs – traditionally used as the birds are highly susceptible to the flu – could be the key. Since the eggs allow the virus to thrive it has the opportunity to mutate which confers a potential advantage. But, with an insect cell matrix, this kind of upper hand is not possible. Within a contamination-controlled environment, bioreactors – vast vats of cells that produce protein – are used to formulate the recombinant vaccine. In comparison with its traditional counterpart, it is simple and quick to make – needing only three to six weeks to produce as opposed to the usual six months. And just a few small pieces of viral DNA from the hemagglutinin gene are needed to create the shot.
So does this spell the end of influenza on the global stage? Protein Sciences certainly seems to hope so. And it’s about more than just eradicating the sort of human misery and suffering the world faced in 1918. According to PRNewswire, the global market for influenza vaccines is anticipated to be worth more than $5 billion by 2021 – that’s four years before the moratorium on competitive products expires.(9) The largest market share for this product is right here in the U.S., with Asia, Europe, China, India, Brazil, and South Korea also making up large segments. And according to the report cited, Global Influenza Vaccines Market and Forecast to 2012 – Size, Share, Growth, and Analysis Trends, just seven brands of vaccine dominate – and share the profits of – this massive market. The seventh brand? Flublok.
Could one small caterpillar, a pest in many ways, be the key to us beating the viral odds?
Got flu? Perhaps the days when we’d call in sick to work, hole up with in bed with vitamin C supplements, fluids, and the latest best-seller are now firmly behind us. Perhaps we need never again return to French philosopher Voltaire’s concept of patient care in which the ‘art of medicine consists in amusing the patient while nature affects the cure.’ And perhaps the tragic and wholly unprecedented losses the world suffered at the turn of the twentieth century will never be repeated. Could one small caterpillar, a pest in many ways, be the key to us beating the viral odds? Next flu season may give us some answers…
Do you dread flu season? Do you always fall victim to the sniffles or do you consider yourself immune? We’d love to hear your stories of flu season – please enter them in the comments!