Influenza Vaccination: What’s New with the Flu?

THIS PAST YEAR, the U.S. Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee unanimously voted to adopt the World Health Organization’s (WHO) recommendations to make two changes to the 2016-2017 influenza vaccine based on global surveillance of circulating influenza strains, and on an evaluation of the effectiveness of the Northern Hemisphere vaccine for the 2015-2016 season.¹ Of the 146.4 million doses of flu vaccine distributed in the 2015-2016 season, there was an overall effectiveness rating of 59 percent, according to the Centers for Disease Control and Prevention (CDC). Strain-specific effectiveness ratings included a 51 percent rate for the A(H1N1) component and 76 percent effectiveness against B strains.²

Efforts to produce more effective vaccines to protect against influenza are ongoing, as are more effective methods of producing vaccines to make them available more quickly and in greater quantity. However, despite these changes, an unwillingness on the part of many to get immunized continues to put society at risk.

Understanding the Recommended Updates

Viral strains change and mutate each year, and as a result, vaccine formulations are customized for each flu season. Annually, more than 100 national influenza centers in over 100 countries conduct ongoing influenza surveillance to gather data for analysis. The surveillance involves receiving and testing thousands of influenza virus samples from patients with suspected flu illness. The laboratories then send representative viruses to five WHO Collaborating Centers for Reference and Research on Influenza, including locations in Atlanta, Ga., London, U.K., Melbourne, Australia, Tokyo, Japan, and Beijing, China.³ WHO then consults with each center’s experts to review the generated data and make recommendations for the composition of the influenza vaccine for the coming season. In March, it was announced that, based on its advisory group’s in-depth analysis of the most recent circulating viruses, WHO recommends changing one strain for the Northern Hemisphere’s 2016-17 flu season, and changing the order of the B strains. Based on the WHO recommendations, the vaccine formulation being distributed for the Northern Hemisphere’s influenza season beginning in the fall of 2016 includes an A/California/7/2009 (H1N1) pdm09-like virus, an A/Hong Kong/4801/2014 (H3N2)-like virus and a B/Brisbane/60/2008-like virus for the trivalent influenza vaccine, as well as a B/Phuket/3073/2013-like virus for the quadrivalent influenza vaccine.

Growing the Next Great Vaccine

Each year, flu vaccine manufacturers make about 155 million doses of flu vaccine for the U.S. market alone, growing the virus in chicken eggs. Usually, the doses, which are designed to protect against strains that experts have predicted the previous February, are ready in time and in sufficient quantity.

However, it’s widely known that the current system has its flaws. For instance, if the strain that appears during flu season varies from the one experts forecast, the vaccines might not be effective. The appearance of H1N1 swine flu in 2009-2010, for example, took experts by surprise, and the flu was already on its second wave before a new vaccine was ready. During that outbreak, an estimated 61 million people in the U.S. got swine flu and 12,500 died.⁴ The search for new and faster methods of formulating the flu vaccine has been ongoing, and many manufacturers have begun looking at the viability of using plants in pharmaceutical production.

The use of plants to produce lifesaving pharmaceuticals captured global attention recently when it was revealed that the Ebola drug ZMapp is produced in the leaves of tobacco plants. Based on that success, it looks like the next big market for plant-based biopharmaceuticals will likely be influenza vaccines. Experts say making vaccines from plants is faster and cheaper than the established method of using chicken eggs; while one chicken egg can produce one or two doses of flu vaccine, one tobacco plant can produce 50 at a fraction of the cost.⁵

Timing is also a key advantage of the proposed plant-based vaccines. Leading producers currently need as much as six months to produce flu vaccine once scientists identify the dominant strains expected to circulate during flu season. Vaccine production from tobacco plants at manufacturers like Caliber Biotherapeutics in Bryan, Texas, could reportedly be available within a matter of weeks, and some are saying it could be a game changer. “Seven to 10 years from now, plants might be the dominant vaccine-production system,” said Brett Giroir, MD, CEO of Texas A&M Health Science Center in Bryan. Texas A&M has one of three U.S. facilities tasked by the government to be ready to produce and deliver 50 million doses of flu vaccine in a 12-week time span, and is working with Caliber toward that goal.

A tobacco-based virus-like particle (VLP) influenza vaccine is also being developed by Japan’s Mitsubishi Tanabe Pharma. The technology used to create the vaccine, which involves implanting influenza genetic material into tobacco leaves, enables vaccine production in four weeks, six times faster than egg-based methods. Currently in Phase III studies, the vaccine is expected to be launched in the U.S. for the 2018–19 flu season.⁶ Achilleas Livieratos, PhD, GlobalData’s analyst covering infectious diseases, says “Mitsubishi Tanabe’s pipeline tobacco product is one of a number of VLP influenza vaccines set to take over from the traditional kind, as they represent an exciting emerging vaccine class that can generate effective and longer-lasting protection, while also being amenable to a diverse array of production methods.”⁶

If Mitsubishi Tanabe’s product, or one like it, is approved, GlobalData expects a novel vaccine that boasts a rapid, plant-based manufacturing process to have a significant impact on the seasonal influenza vaccine landscape.

Addressing Complacent Public Perceptions

When asked about flu, any expert will tell you that the most predictable characteristic of the influenza virus is that it is unpredictable. This unpredictability — from the warnings of an upcoming severe flu season that never actually pan out, to the suddenly severe outbreak no one saw coming — has left an already skeptical public often willing to take their chances and forgo vaccination altogether. “Flu is pretty well-known, and people think they know what the symptoms are and when the flu season is, but overall, they don’t regard it as a serious disease,” said Brendan Flannery, PhD, a CDC epidemiologist. “They don’t realize that there are people who are at especially high risk for severe disease, and everyone should be vaccinated to help that high-risk group.”⁷

Kathleen M. Neuzil, MD, MPH, director of PATH’s Vaccine Access and Delivery in Seattle, and clinical professor of allergy and infectious diseases and global health at the University of Washington, agrees, adding that public perception of flu is something that physicians have struggled with. One reason, she said, may be that the word “flu” is often used in a generic sense to describe any similar illness. “This definitely works against us, and it’s something we have to explain to patients when we give them the flu vaccine,” Dr. Neuzil said. “There are other viruses that can make you feel bad this winter. What makes flu different is its high attack rates and severity. Those make it absolutely worth preventing.”⁷

WHO estimates between three million and five million cases of severe illness and between 250,000 and 500,000 deaths occur each year in the world due to influenza.⁸ Still, even if the health dangers associated with the flu are insufficient to stimulate an uptick in flu vaccinations, the economic costs affecting America’s pocketbook have the potential to sound the alarm. A total of 111 million lost workdays per year caused by the flu translates to a $7 billion loss in productivity. Direct medical costs associated with the flu average $10.4 billion annually, a significantly detrimental amount when you consider the current financial crises in healthcare systems. Additionally, the total yearly economic burden the influenza virus places on America is projected to exceed $87 billion.⁹

Given the potential personal and economic consequences, the question, then, is why do more than half of all Americans still fail to get an annual flu shot?² Studies suggest that if just 60 percent of America’s population were vaccinated annually, the threat of another flu pandemic could be completely extinguished.⁵ Although extensive time and energy have been funneled into flu education at the doctor-patient level, myths surrounding the efficacy and safety of the flu shot still play a significant role in deterring vaccination efforts. These misconceptions and excuses include:

• the widely circulated yet often refuted belief that the vaccine causes the flu (Influenza shots are made from either viruses that are inactivated and non-infectious, or from recombinant proteins that do not contain influenza viruses at all.);
• a phobia regarding needles (Other non-invasive methods of obtaining the vaccine such as a nasal spray or an intradermal needle injection are available for the needle-phobic); and
• the loudly asserted but officially debunked fear that the thimerosal preservative in some vaccines leads to autism (It is worth noting that thimerosal-free flu vaccines are also available for the unconvinced.).

Earlier this year, even Autism Speaks, a leading autism advocacy organization, came out in favor of vaccination. “Over the last two decades, extensive research has asked whether there is any link between childhood vaccines and autism,” the organization said in a statement. “Scientific research has not directly connected autism to vaccines. Efforts must be continually made to educate parents about vaccine safety. If parents decide not to vaccinate, they must be aware of the consequences in their community and their local schools.”¹⁰

Boosting Immunity: Improving Vaccine Effectiveness

Current CDC statistics report the 2015-16 influenza vaccine’s overall effectiveness at 59 percent.¹¹ While the percentage represents a good solid number, it may not be compelling enough to turn the tide of public apathy. As scientists search for ways to boost those numbers, a recent study suggests that timing rather than formulation may present an untapped opportunity to boost the efficacy of the flu shot.

British researchers have released the results of a study that claims getting vaccinated in the morning rather than the afternoon could increase the effectiveness of the flu vaccine. The randomized study, published in the journal Vaccine, included 276 men and women over age 65 who volunteered to be given the flu virus and were selected to get their flu shot either from 9 to 11 in the morning or 3 to 5 in the afternoon. The participants filled out questionnaires to assess health behaviors and socioeconomic status, gave a blood sample and were given the standard trivalent flu vaccine. A month later, they returned to give another blood sample. The researchers then compared anti-influenza antibodies in the two samples to measure the effect.¹² After controlling for differences in income, smoking, alcohol consumption, sleep duration and other health and behavioral characteristics, they found that for two of the three influenza strains contained in the vaccine, the response was significantly stronger in those vaccinated in the morning. For the third strain, morning or afternoon vaccination made no difference. “We know that there are fluctuations in immune responses throughout the day and wanted to examine whether this would extend to the antibody response to vaccination,” said the study’s author, Anna C. Phillips, PhD, a professor of behavioral medicine at the University of Birmingham.¹³

Chronobiology, the field of medical science that examines the way the body’s biological systems respond differently throughout the course of a day, is currently being used to study a number of vaccine responses in animals and humans. “Being able to see that morning vaccinations yield a more efficient response will not only help in strategies for flu vaccination but might provide clues to improve vaccination strategies more generally,” said Dr. Phillips.

The team plans to extend their research to investigate how the vaccination timing effect impacts individuals with existing conditions such as kidney disease and diabetes. If future results mirror those of the pilot study, the long-term impact on vaccination strategies could be significant, potentially boosting vaccination rates and ultimately saving lives.¹³

Speaking about the new research, Richard Pebody, MD, head of flu surveillance for Public Health England, said, “This is an interesting study and indicates more research is needed. Flu vaccine is the best protection we have against an unpredictable virus which can cause severe illness and deaths each year among at-risk groups, including older people, pregnant women and those with a health condition, even one that is well-managed.”¹²