Influenza vaccine ‘desperately’ needs improvement

The current seasonal influenza vaccine is not perfect, but experts agree that it remains the best available tool for fighting influenza — at least for now.

“We wish it were better,” CDC Director Thomas R. Frieden, MD, MPH, said during the National Foundation for Infectious Diseases’ annual influenza news conference in Washington, D.C., “but if the match is good, it will cut your risk of flu by at least a half, and that’s far better than anything else you can do to protect yourself.”

Photo courtesy of Mount Sinai Health System.

Last season's influenza vaccine was 47% effective, according to CDC numbers. Effectiveness was far lower in 2014-2015, however, when the vaccine did not line up as well with circulating influenza viruses. Researchers believe a poor matchup like this can be avoided with a better vaccine, so they have been exploring ways to make one, including taking aim at parts of the virus that are not as susceptible to mutation as the one targeted by current vaccines.

If successful, experts believe a so-called “universal” influenza vaccine could protect patients against all strains of the virus for decades — maybe even a lifetime. It could mean a world without seasonal epidemics and global pandemics of influenza, which remain among the world’s biggest infectious disease threats.

Other experts think the bar should be set lower, but agree that the vaccine needs improvement.

“This is a vaccine that desperately needs to be redone,” Michael T. Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota and one of the authors of a 2012 report about the need for better influenza vaccines, told Infectious Diseases in Children. “Influenza is a serious disease that desperately needs to be addressed both from a seasonal flu status and pandemic status.”

Infectious Diseases in Children spoke with several influenza experts about the successes and failures of the vaccine and what can be done to make it better.

Influenza remains biggest threat to public health

The 1918 influenza pandemic killed approximately 50 million people worldwide. If a similar pandemic happened today, more people would die in just a few months than AIDS has killed in 30 years, Osterholm said.

“This should be our public health threat No. 1,” he said. “This is it.”

Influenza pandemics have struck three more times since 1918, the last one occurring in 2009 when a new influenza A (H1N1) “swine flu” replaced the old epidemic “Spanish flu” strain and killed as many as 18,300 people in the United States. Unlike seasonal epidemics, which mainly occur in winter in most parts of the world, pandemics can go on for a year or more and occur when novel animal influenza viruses mutate and begin infecting humans.

Peter Palese, PhD, professor of microbiology and infectious diseases and chair of the department of microbiology, and his colleagues, Florian Krammer, PhD, associate professor in the department of microbiology, and Adolfo Garcia-Sastre, PhD, professor of microbiology and medicine, all in the Icahn School of Medicine at Mount Sinai in New York, have led research into finding a universal influenza vaccine. Palese was the first to genetically map influenza A, B and C viruses, which infect humans, and identified the mechanisms of neuraminidase inhibitors, which are used as antiviral drugs to fight influenza.

In 2005, Palese was part of a research team that reconstructed the 1918 pandemic influenza virus in a lab, providing new information about why it was so virulent and how it killed so many people. Seasonal influenza is deadly as well, killing up to tens of thousands of people in the U.S. in a single year.

Palese agrees with Osterholm that finding a better approach to fighting influenza should be at the top of the world’s public health goals.

“This is why we are spending our lives on it,” Palese said.

Click the image to enlarge.

‘Spotty’ record of current vaccine

The most compelling argument for a better influenza vaccine can be found in the data. Since 2004-2005, the effectiveness of the vaccine has ranged from 10% to 60%, according to the CDC. This means that, during the best year, getting the vaccine decreased a person’s chances of an influenza-related doctor’s visit by 60%.

In 2014-2015, the vaccine’s H3N2 component did not match a majority of the circulating influenza A (H3N2) viruses — the most prevalent subtype — leading to an overall vaccine effectiveness of just 19%, according to researchers. The protection for influenza A (H3N2) was 6%, not statistically different than 0%.

“The current vaccines have an at-best spotty track record for protection and, in fact, may very well end up being not protective at all in many cases,” Osterholm said.

Currently, selecting which viruses will be in the seasonal influenza vaccine is a bit of a guessing game that involves picking strains that research has shown are most likely to circulate. In the Northern Hemisphere, WHO makes its recommendations for the vaccine in February. Last year, the FDA adopted WHO’s recommendations unanimously in March for a trivalent vaccine containing two influenza A viruses and one influenza B virus, and a quadrivalent vaccine containing two A and two B viruses. Some seasons, as in 2014-2015, antigenic drift leads to a mismatch between a component in the vaccine and a circulating strain.

Frieden said the current vaccine has been a good match for the viruses that have been seen so far this season, but noted that it is too early to predict what the coming months will bring.

“Flu is unpredictable,” he said. “We know there’ll be a season, but when it is and which flu strain predominates, only time will tell.”

There are two new vaccine choices this season: a four-component influenza shot (Flucelvax Quadrivalent, Seqirus) licensed for use in patients aged 4 years and older that uses virus grown in a cell culture instead of an egg, and a vaccine that includes an adjuvant for adults aged 65 years and older (Fluad, Seqirus). But children between the ages of 2 and 17 years will not have the option of getting the live-attenuated influenza vaccine (LAIV) — offered as the nasal spray FluMist (MedImmune) — after research showed that it was ineffective for the past 3 years. The CDC Advisory Committee on Immunization Practices (ACIP) voted to not recommend its use, raising concerns that vaccination coverage will drop in this age group.

Influenza vaccination coverage among children aged between 6 and 23 months was 75% during the 2015-2016 season, according to the CDC — higher than in any other group. One reason for this is because children that young make more frequent visits to the doctor and have more opportunities to get immunized, according to Patricia Whitley-Williams, MD, division chief and professor of pediatrics in the Robert Wood Johnson Medical School at Rutgers University.

In fact, children aged between 6 and 23 months were the only age group to exceed the national public health goal of 70% coverage. (The CDC noted a concerning decline in vaccination rates for older Americans.) After the ACIP recommended against using the LAIV, manufacturers increased production on the other vaccines, but Frieden said he hoped the spray would be available again soon. Canada and the United Kingdom said they would use the nasal spray vaccine following separate studies showing that it was still effective. Like Frieden, Whitley-Williams lamented the loss of that option in the United States.

“If there is a way to find out what went wrong with the nasal spray, obviously parents would have a choice for children above 2 years of age,” she said. “It’s important to continue to look at that issue and hopefully in future seasons it might be reintroduced.”

The CDC recommends that everyone aged 6 months and older receive an influenza vaccine every year, but one study published in March showed that repeated vaccinations may have had a negative effect on the vaccine’s performance in 2014-2015. Among those who were not vaccinated the previous season, the vaccine’s effectiveness against the H3N2 strain was shown to be 53% — much higher than for those who had been vaccinated the previous season.

The same study showed it was possible that getting vaccinated in all three seasons between 2012-2013 and 2014-2015 had a negative effect, increasing a person’s chances of getting influenza.

“There are so many questions that are still to be answered about our current flu vaccines. We don’t know how long it lasts. There’s a lot of dogma about it. Will it last even more than a season? Will it last more than a couple months? We don’t know,” Osterholm said. “Some suggest the impact of it may be less than 92 to 100 days if it does last. That’s the challenge we have.”

But influenza is contagious, and getting the seasonal vaccine is still the best way to decrease the risk for death and hospitalization related to influenza, particularly in high-risk groups, Whitley-Williams said. According to the CDC, vaccine coverage for the entire U.S. was estimated to be under 46% last season.

“Even if we have the most effective vaccine, people still need to get vaccinated,” she said. “I think that’s where the effort should be.”

The CDC said vaccine manufacturers estimate that 168 million doses of injectable vaccine will be available for the 2016-2017 influenza season. Whitley-Williams said people should look at the vaccine the same way they do a seatbelt.

“I think everybody realizes that if you wear a seatbelt, you have a chance, even if you’re in a serious accident,” she said.

The search for a universal vaccine

Creating a better influenza vaccine likely means changing which parts of the virus are targeted. Currently, vaccines are primarily directed at the most important protein on the surface of the virus, the hemagglutinin. Specifically, influenza vaccines target the globular head of the hemagglutinin — which binds the virus to human host cells — instead of the immunologically subdominant stalk. However, the head of the hemagglutinin mutates frequently, leading to antigenic drift over time and the almost yearly need to update the formula of the seasonal vaccine, a timely and expensive process.

“The problem with the flu is that the virus changes constantly,” Palese said. “After 3 years, 4 years, the virus is sufficiently different.”

So instead of targeting the head of the hemagglutinin, Palese and colleagues are developing a vaccine that, in effect, does something akin to what a trainer might tell a boxer during a fight: Work the body.

Specifically, Palese and colleagues believe a vaccine that targets both the stalk of the hemagglutinin and the neuraminidase protein will offer lasting protection against changing seasonal influenza viruses as well as pandemic strains because these parts of the virus are not as susceptible to mutation. According to Palese, the vaccine could offer protection for at least 20 years, but he hopes it will offer lifetime immunity. So far, such vaccines have been shown to work well in animals.

“But as you well know, mice are not men and ferrets are not humans,” Palese said.

Still, universal influenza vaccines are close to being tested on humans, according to Krammer.

“We’re not far from that,” he said in an interview.

Further, Krammer said he expects the vaccines will work better on humans than animals because animals are usually naive to influenza. However, forecasting when such a vaccine will be available to people is more difficult than predicting when it will be tested on them.

“I would say 10, 15 years,” Krammer said. “The average time that it takes to develop a vaccine from scratch is about 10 to 25 years, historically, so we’re on the short end of that.”

Not everyone feels the same way about how the vaccine should be improved. Osterholm believes the goal should be more modest than “universal” protection — a term he does not like. Instead, the aim should be a vaccine that protects for a longer period — perhaps a decade — and works against the most dangerous strains for humans. These include H1, H2, H3, H5, H7 and H9 — only six of the 18 H types of influenza.

“What we really need is a game changer flu vaccine, one that will cover those influenza A strains in particular that are likely to cause both seasonal flu and/or pandemic influenza,” he said. “And the bar for that vaccine may be lower than it would be for a universal flu vaccine. I think that’s a really important concept to get across.”

Some pharmaceutical companies prefer what are called broadly protective vaccines because they will not cost as much or take as long to develop, Krammer said. Such vaccines would last longer than one influenza season, protecting for 3 or 4 years.

“They might not protect us from a new pandemic, but they will work a little bit longer,” Krammer said. “But it’s a different idea. The idea of a universal influenza virus vaccine is that you would protect against not only human influenza viruses, but also against pandemic strains — all these viruses that are out there in avian species and in pigs that could jump into the human population and cause a pandemic. Some kind of broadly protective vaccine wouldn’t protect against those. You would need a universal vaccine. That’s the ultimate goal, but some people think’s it’s hard to reach.”

In the meantime, the search for a universal influenza vaccine has led to other scientific advancements, Krammer said. These include a better understanding of the human immune system in general through analysis of B cell responses, and an advanced understanding of antigen-antibody interactions in other fields of study, such as those dealing with filoviruses and arenaviruses.

“Also, there is crosstalk with the HIV field. We help them with certain aspects [and] they help us,” Krammer said. “There is a lot of movement right now, and the hunt for a universal influenza virus vaccine created a lot of insights into basic human immunology, and also helps with other translational aspects that are not connected to universal vaccine development.”

Obstacles in the way of a better influenza vaccine

According to Palese, developing a universal influenza vaccine is a gradual process that will need proper funding and changes to the drug approval process.

“We have tens of thousands of doses,” he said, “but they haven’t been put into people.”

There are many obstacles standing in the way of making a universal influenza vaccine available to humans, Krammer said, including proving that it works. Among those obstacles, it is unclear what kind of data regulatory authorities such as the FDA will require to prove that the vaccine is not only broadly protective, but that is also lasts a long time, according to Krammer.

“You can imagine that if you have a universal influenza vaccine, but it only works for a year, that’s not very useful,” he said.

For instance, the effectiveness of the universal vaccine being proposed by Palese, Krammer and others cannot be measured the same way that current influenza vaccines are measured, which is by calculating how much the hemagglutinin is inhibited.

“They would have to accept a new surrogate marker,” Palese said.

Interestingly, according to the CIDRAP report authored by Osterholm and colleagues, one of the barriers to developing a better vaccine is the perception that the current vaccine is good enough.

Palese agrees.

“Well, the good can sometimes be the enemy of something better. I think that is true,” he said. “The other thing is that the FDA is extraordinarily careful, extraordinarily risk-averse to new innovation efforts.”

The CIDRAP report calls for, among other things, better estimates of the effectiveness of influenza vaccines, a new model for developing and licensing new vaccines, and making the goal of improving the vaccine a national priority.

Osterholm said the report, which was based on a review of more than 12,000 peer-reviewed writings dating back to 1936 and interviews with nearly 100 experts, remains as relevant today as when it was published in 2012.

“All the analysis we did, that’s all still [relevant],” he said, “which is a sad commentary in and of itself. That’s 4 years ago we wrote that.”

Even if the universal vaccine is proven to be effective, it is not clear who will pay for it, but Palese thinks it should be a combination of public and private money. Osterholm and colleagues agree. In their report, they said the U.S. government must increase its support for the development of new influenza vaccines to fill the hole created by manufacturers who fear upsetting a relatively stable market.

Right now, only about $50 million to $70 million is spent globally each year to develop new influenza vaccines, Osterholm said.

“In comparison, we spend over $1 billion a year on HIV vaccines,” he said. “And I will not take any money away from HIV vaccines, but it gives you a relative comparison of importance.”

There also is the possibility that a new influenza vaccine, such as the one preferred by Palese and Krammer, will not always protect the way it is designed to. In the case of a universal vaccine targeting parts of the virus that do not mutate as easily, such as the stalk of the hemagglutinin, changes may occur over time, leading to less effective protection.

However, Palese thinks such mutations would take “much, much longer” to occur than they do in the head of the hemagglutinin, giving a universal influenza vaccine the potential for longer-lasting protection in people.

“Part of our medical profession is not convinced that this is necessary and should be done,” Palese said. “But we feel that we can do it. We wouldn’t do it unless we felt there was a real chance it will work in humans.” – by Gerard Gallagher

• References:
• CDC. Estimating seasonal influenza-associated deaths in the United States: CDC Study confirms variability of flu. http://www.cdc.gov/flu/about/disease/us_flu-related_deaths.htm. Accessed October 19, 2016.
• CIDRAP. The compelling need for game-changing influenza vaccines. 2012. http://www.cidrap.umn.edu/sites/default/files/public/downloads/ccivi_report.pdf. Accessed October 19, 2016.
• Chung JR, et al. Pediatrics. 2015;doi:10.1542/peds.2015-3279.
• Gagliani M, et al. J Infect Dis. 2016;doi:10.1093/infdis/jiv577.
• Krammer F and Palese P. Curr Opin Virol. 2013;doi:10.1016j.coviro.2013.07.007.
• Loeb M, et al. Ann Intern Med. 2016;doi:10.7326/M16-1513.
• Skowronski DM, et al. Clin Infect Dis. 2016;doi:10.1093/cid/ciw176.
• Tumpey TM, et al. Science. 2005;doi:10.1126/science.1119392.
• Zimmerman RK, et al. Clin Infect Dis. 2016;doi:10.1093/cid/ciw635.

• For more information:
• Florian Krammer, PhD, can be reached at florian.krammer@mssm.edu.
• Michael T. Osterholm, PhD, MPH, can be reached at (612) 626-6770.
• Peter Palese, PhD, can be reached at peter.palese@mssm.edu.
• Patricia Whitley-Williams, MD, can be reached at hansenmp@rwjms.rutgers.edu.

Disclosures: Frieden, Osterholm and Whitley-Williams report no relevant financial disclosures. Krammer and Palese report that Mount Sinai has submitted patents on a universal influenza virus vaccine. Krammer also reports that they receive funding from multiple other sources, including the NIH, PATH, the Bill and Melinda Gates Foundation, and the industry.