Flu Season Might Soon Pass, for Good

Winter is coming and with it comes that unwelcome but persistent visitor, influenza, also known as the flu. Some of us will heed the medical establishment’s urgings and dutifully head down to our local clinic to get a shot. Others will not, whether due to lack of access or because the ever-mutating nature of the virus means our four-strain vaccines are a game of chance, at best.

For this reason, the promise of a universal vaccine, one that will be able to grant immunity despite the mutating nature of the virus, has long been the holy grail of flu researchers and public health institutions. A year from now, at the end of 2020, we might get there for the first time, thanks to an Israeli company called BiondVax Pharmaceuticals Ltd. that is currently holding phase 3 clinical trials for its universal influenza vaccine. The flu is a universal experience. At least once in a person’s life, they experience the misery of a runny nose, complemented by a fever, joint and muscle pain, a sore throat, a cough, and a general sense of exhaustion. For most of us it tends to fly under the radar, an annoying but relatively harmless caller that comes back once or twice a year, incapacitates a few of our acquaintances for several days, and leaves just the way it came. But for high-risk groups—the very young, the old, and those with compromised immune systems or chronic health problems—influenza is a real danger and complications can include pneumonia and exacerbation of existing conditions like asthma.

In 1918, the Spanish Flu spread like wildfire throughout the globe, infecting some 500 million people according to current estimations. Though mortality was difficult to record and many deaths were likely obscured by World War I, experts today believe it killed between 50 million and 100 million people, three to five percent of the global population at the time and more than the death toll caused by both world wars combined.

But the risks are not limited to the distant past and even with current medical resources a flu pandemic can still sweep a multitude of fatalities. Most recently, in 2009, swine flu swept the world, killing almost 300,000 people, according to updated estimations.

To understand the unreliable nature of current vaccines, one needs to understand the flu virus. Though there are four types of influenza, A and B are the types that cause seasonal illnesses in humans, which is why vaccines cover two subtypes of influenza A and both subtypes of influenza B.

Influenza A accounts for 80% of flu cases, according to Tamar Ben-Yedidia, the chief technology officer of BiondVax. Influenza A viruses are also the least stable, with the most mutations, she said, which is why they cause pandemics and why the World Health Organization is focusing on influenza A for its universal vaccine efforts. “To date, there has not been an influenza B virus that caused a pandemic,” Ben-Yedidia said in a Monday interview with Calcalist.

Influenza A is classified according to two proteins located on the virus’ outer surface, hemagglutinin, abbreviated as H, and neuraminidase, abbreviated as N. The former has 18 subtypes while the latter has 11, but within those subtypes there is a great variety of strains. The H protein, which is made of a head and a stalk, is what enables the virus to enter the cells.

Each influenza vaccine is developed to combat only the four strains identified to be the most virulent for a specific flu season. Current vaccines, which use inactivated or weakened viruses incubated in hen eggs, induce antibodies that target the head of the H protein, which is subject to rapid change and mutation, sometimes rendering a vaccine ineffective even within the several months it takes to produce. Companies that attempt to develop a universal vaccine, which needs to confer immunity over several seasons and multiple strains and mutations, are therefore looking at a different way to target the virus. Though such a vaccine is being attempted by several companies and teams, BiondVax appears to be the closest to actually bringing one to market.

Jerusalem-based BiondVax was co-founded in 2003 by CEO and president Ron Babecoff. In 2004, he recruited Ben-Yedidia from the Weizmann Institute of Science, where she did her PhD under noted biochemist and immunologist Ruth Arnon. Under Arnon, Ben-Yedidia worked on developing peptide-based vaccines, with a focus on influenza.

“The immune system has two arms—one is responsible for producing the antibodies and the other is the cell mediated immunity,” Ben-Yedidia explained. “Once the pathogen reaches the blood, the antibodies grab it, neutralize it, and prevent it from entering the cells and causing disease.” That is how current flu vaccines work. But a virus is a parasite, and most of its lifespan is spent inside the cells, where the antibodies can’t reach it—but the cell mediated immunity arm can, she said. “Each infected cell displays virus parts on its surface, as a sort of a red flag, causing the cellular arm of the immune system to attack and kill it, and the immune cells also release substances that have an antiviral effect,” she said. And the cell mediated immunity arm can be taught to recognize the infected cells and stop the disease from advancing before they reach critical mass, she added.

“All influenza strains have something in common, and if we teach the immune system to fight that commonality it will recognize every flu virus that arrives and be able to deal with it,” Ben-Yedidia explained the rationale behind all attempts to develop a universal vaccine.

During her years at Weizmann and later at BiondVax, they identified nine conserved epitopes—the part of an antigen that the immune system recognizes—inside several proteins of the influenza virus, Ben-Yedidia explained. The final vaccine, currently in phase 3 clinical trial, combines those conserved epitopes into one protein that can then be used to invoke a much more expansive response towards the virus. As it is not incubated in eggs but rather created in a lab using engineered E. coli bacterium, it both shortens the time needed to create the vaccine and solves a lot of logistical problems, making the process a lot more of an industry standard.

“Since we have one vaccine, one formulation, we broke the connection between the vaccine and the season or a specific strain,” Babecoff said. “We could manufacture all year, we could stockpile, which is something you cannot do with the current vaccines, which change by definition. You turn it into an industrial product and hand the reins over to the health organizations, who will now be able to decide on orderly vaccination campaigns according to age or geography, for example.”

This brings to mind the words of Keiji Fukuda, then the interim assistant director-general for Health, Security, and Environment for the World Health Organization, when he spoke about the creation of a vaccine for the 2009 pandemic. “In terms of capacity, there is much greater vaccine capacity than there was a few years ago,” he said during a briefing about the rising number of cases being reported by countries, “but there is not enough vaccine capacity to instantly make vaccine for the entire world's population for influenza.”

Nasdaq-listed BiondVax received investments from both government bodies and private companies and funds over the years. Marius Nacht—co-founder of cybersecurity company Check Point Software Technologies Ltd.—and his life sciences venture capital firm aMoon own a 42.5% stake in the company, according to Babecoff. The Israeli government’s tech investment arm, the Israel Innovation Authority, made a $5 million investment and the European Investment Bank committed 24 million euros for the current trials.

“When I initially wrote the first business plan, I said ‘$4 million, let’s say three years for phase 1-2, and then big pharma will come and pick it up’,” Babecoff said Monday. “In the meantime we raised $100 million, most of which we spent on trials, it has been almost two decades, and there is a giant unknown in the room—where is big pharma? It is an almost $5 billion market that grows by 6%-7% each year, and there is a flu season every year, it is not like ebola that flares up only occasionally. And big pharma is not in the game. We know the current vaccines are effective around 40% of the time in the general population, for the elderly it is less than 20%.” These odds make people question whether they should even get the vaccine, he said. “My dad, who is 83, does not get vaccinated. He says, ‘why should I, when next year I will need to do it again?’“

When BiondVax started early stage clinical trials, it saw their formulation evoked a certain reaction to influenza, but because their vaccine candidate relied on a cell mediated immune response and not an antibody response as all approved vaccines do, they ran into a regulatory problem, Babecoff said.

The problem, Ben-Yedidya realized, was that the vaccine caused a certain effect in the body that was different from that of the standard vaccine, so, existing regulation did not cover it, Babecoff explained. The solution was to use the standard vaccine as a way to establish that subjects were protected. The trial subjects were divided into two groups, one that received BiondVax’s vaccine, and a control group that received a placebo. Both groups also received the standard seasonal influenza vaccine. Across almost all trials and strains, the group that received BiondVax’s vaccine had more people that were considered protected, according to the regulation, Babecoff said,

The U.S. Food and Drug Administration (FDA) was somewhat flabbergasted, Babecoff recalled. “They said it was unprecedented and that we should continue. But because we ran the phase 2 trials combined with a standard vaccine they wanted us to partner with one of the vaccine manufacturers.”

There aren’t many players in the flu vaccine market. The largest is Sanofi Pasteur—which controls around 40% of the market, according to Babecoff— while CSL controls around 20%. GlaxoSmithKline is another major player. “We ran around for maybe two years, knocking on doors,” he said. “They did not want to partner with us. I can understand why—it could hurt the image of their own product, which now suddenly needs help. They really did not want to. It held us back for a while.”

Phase 3 trials, the last stage before regulatory submission and then marketing, are extremely expensive. For BiondVax, the break occurred when it managed to secure an investment from the European Investment Bank, under Horizon 2020, the European Union's research and innovation program. The company used part of the funding to relocate from Israeli central town Ness Ziona to larger offices at the Jerusalem Bio Park, expand its team to 22 people, and start building a facility capable of manufacturing a commercial amount of vaccine doses.

For its phase 3 double-blind placebo-controlled trials, BiondVax recruited around 12,400 participants, half of them between the ages of 50 and 65 and the rest, considered a high-risk group, are over 65. The trials are being conducted in 83 hospitals across seven Eastern European countries, including Poland, Bulgaria, and Georgia. Vaccinations started in July, and all participants had to sign an informed consent form committing to not recieving a seasonal vaccination this year. Local standard vaccination rates vary between 2% and 5% of the population, according to Babecoff.

“These are all countries that do not offer the standard vaccine as part of their state healthcare plan,” Ben-Yedidia explained why the regulatory go-ahead was given despite this stipulation. Vaccinating is recommended by the healthcare systems in these countries, but it is not paid for by the state, so most people basically have no way to get the vaccine, as it is rather expensive, she said. So we offer them—it is true that we don’t know if the vaccine is effective, but there is a chance it is. The system is also very clean, people either receive our vaccine or they don’t receive any vaccine at all,” she said,

The Northern Hemisphere is now entering flu season. Throughout the winter, local caregivers from one of the 83 hospitals participating in BiondVax’s trial will collect samples from participants who report flu symptoms and send them to the Israeli Ministry of Health’s virology lab in Tel HaShomer, which is part of a global World Health Organization network of labs that monitor influenza. All samples will be checked for the presence of the virus. In the fourth quarter of 2020, it will be revealed how many of the control group contracted flu compared to the vaccine group.

“Our expectation is that the control group will have the same infection rate seen in the general population, and the vaccinated group will have no sick people, or very few sick people,” Ben-Yedidia said. If this will be the case, it will essentially be the first time a universal flu vaccine proves its effectiveness and can reach the market, she said. It should be noted that Both Ben-Yedidia and Babecoff repeatedly cautioned throughout the interview that the trial could still be unsuccessful. Though they are currently the most advanced company in the field, phase 3 trials can, and do, fail all the time. If the trial is successful, though, and the results will enable BiondVax to proceed with regulatory submission and with the new drug application in the EU, the first universal flu vaccine could hit pharmacies as soon as 2023, according to Babecoff, ahead of the World Health Organization’s target of 2027.  

BiondVax is now also in the process of completing the set up of its Jerusalem manufacturing plant and the upscaling of its manufacturing process, necessary steps for regulatory approval. While the facility will have the capacity to manufacture 20 million doses a year—perhaps even 40 million working double shifts, according to Babecoff—around 500 million flu vaccine doses are sold annually around the world, with the potential being much greater if more people opt for vaccination. If they get there, then BiondVax will probably increase production either through partnerships or licensing, he said, though it is still too soon to consider it.

The company’s decision to set up an Israeli manufacturing facility was not just a matter of wanting to support the local economy or wanting it to be close to home, though. “We remember what happened in 2009,” Babecoff said. “Israel waited in line, asked for vaccines and there were none.” Everyone was looking out for number one, he said. The U.K. manufactured its own vaccines because it has a facility in Liverpool, France manufactured its own because it has a facility in Lyon, and Israel did not have one, he added.

“I think having a facility for manufacturing influenza vaccinations here in Israel is very important,” Babecoff said, “because we do not know when the next pandemic will occur. We just know that it will.”