A story is told of a well-known scientist, who on the way yet another speaking engagement, suggested to his chauffeur that he was tired and didn’t want to lecture. The chauffeur suggested that since he had heard the speech so many times, he could deliver it instead, and the scientist could relax. The esteemed scientist agreed. As they entered the lecture hall, the scientist took the chauffeur’s hat and coat, and sat in the back, as the chauffeur brilliantly delivered the speech. He even managed to answer some basic questions that the scientist frequently received. But finally, someone in the crowd asked a detailed and highly technical question. The chauffeur, flustered but not wanting to break his cover, replied, “Why, the answer to that question is so simple, even my chauffeur could answer it!”
Now, while I’m not a chauffeur, I most recently performed research in Don Low’s microbiology lab at the University of Toronto in 1998, far back in the pre-digital pipette era.
Despite the twenty years that have passed, I believe that at least one lesson I learned from the lab remains true today: Scientific research nearly always takes longer than expected. And so, while we originally expected BiondVax’s Chief Scientist Tamar Ben-Yedidia, and our UNISEC consortium colleague Eelko Hak, both accomplished scientists, would use this time to share final results from our Phase 2b trial, despite everyone’s herculean and best efforts, the results aren’t quite yet ready. In a few minutes, I will share available data from the trial.
But before that, with your permission, I think it’s appropriate to take a step back to consider the wider context of our efforts as we gather here in Lausanne to discuss the latest in flu vaccine innovations.
For thousands of years, human population levels were relatively stable, showing only moderate growth. However, in the past 200 years the rate of growth began to exponentially increase. In 1900, we were about 1.6 billion. Today, we are well over 7 billion. The remarkable and relatively recent growth in human population may be largely attributed to three factors: Clean water, nutrition, and vaccination.
Similarly, as vaccination rates have increased, global infant mortality has declined. For local relevance, in 1900, nearly 20% of Swiss children did not survive to their 5th birthday [ref]. Today, over 96% survive – still tragically far from perfect, but certainly a vast improvement! Overall, global infant mortality has been roughly halved just in the past 15 years!
This Forbes infographic, based on American CDC data, highlights the reduction in cases of infectious illnesses in the USA before vaccines were available, and after vaccination was widespread. Polio and Small Pox are no more. Tetanus, Rubella, Diptheria, Measles, Mumps and more have been significantly reduced.
But if you look closely, you’ll note that influenza isn’t included on the list, even though flu vaccination coverage has significantly increased in the US, as it has in most of the industrialized world. I would imagine all of you understand why flu isn’t yet on the list, but I would argue that we are not doing enough to communicate the significant challenges of flu vaccines to the general public. Up to 500,000 people die each year from the flu. It is the 8th leading cause of death in the USA. According to CDC data, today’s flu vaccines are, on average, only about 40% effective. And in the most vulnerable populations, including people over 65 years of age, flu vaccine effectiveness is as low as 9%! And so despite rising vaccination rates, the flu continues to cause illness, hospitalizations, financial and social costs.
Furthermore, despite vastly improved monitoring, it takes months to react to new pandemic strains. For example, in 2009, the WHO declared a pandemic in June, but it took over 5 months until vaccines were distributed! Our governments are spending millions stockpiling vaccines for the next pandemic, but we have no idea if the stockpiled vaccines will actually match the new strain!
Flu vaccines are generally made the same way they’ve been made for a hundred years. We make an educated guess about what the next season’s circulating strains will be, then spend months manufacturing the matching strain-specific vaccine in eggs. This vaccination approach can be highly effective against pathogens that don’t significantly mutate. But it is unreliable and often ineffective for pathogens like influenza and HIV that frequently and unpredictably mutate.
Today, we’re threatened by new circulating Avian strains – H5N6, H5N8, H7N9.
We are not adequately prepared. With current vaccines, we’re simply one-step behind –
There’s clearly a need for a new approach for flu vaccines. An approach that is proactive, to eliminate the guess work regarding what the next season’s circulating virus will be.
BiondVax’s approach is one of the most advanced. The idea was formulated in the 1990’s by Professor Ruth Arnon of the Weizmann Institute of Science. She proposed what was then a radical idea: Instead of making vaccines that specifically target existing flu strains, why not examine all known flu strains to identify widely conserved influenza virus peptides.
Professor Arnon hypothesized that widely conserved peptides in an otherwise frequently mutating virus are likely to be essential to the flu’s vitality. Without these parts, it would lack a vital function; These conserved parts must be inherent to making a flu virus a flu virus!
Of the conserved peptides Professor Arnon and her team identified, they selected elements that are immunogenic –that induce both B-cell (antibodies) and T-cell (CMI) responses. Nine of those immunogenic conserved peptides – epitopes – were joined in a recombinant protein, known today as Multimeric M-001, which is BiondVax’s universal flu vaccine candidate.
We have completed 5 human Phase 1/2 and 2 clinical trials, in a total of 479 participants. All trials have shown M-001 to be safe and immunogenic.
BiondVax is currently eagerly awaiting results from a Phase2b trial conducted in collaboration with our colleagues at the EU’s UNISEC consortium. The 219 trial participants completed their final visit this past September.
BiondVax also expects an NIH-funded Phase 2 trial to begin soon in the USA.
Until now we’ve produced M-001 in our small in-house facility, so we’ve been working with a US-based CMO to upscale and optimize production for Phase 3 batches, and plans are also underway to build a mid-sized facility in Israel for Phase 3 and commercial batches.
As a small biotech company proposing an entirely new approach to flu vaccines, there are a number of obstacles to overcome, not least of which is the need to develop an acceptable regulatory pathway. As you know, current flu vaccines are HA-based – they target the frequently mutating hemagglutinin head protruding from the virus’ surface. And so the currently accepted correlate of protection for current flu vaccines is HAI. M-001 isn’t designed to target the flu’s variable regions, and so M-001’s impact can’t be directly tested with HAI.
As I believe will be discussed in the workshop later this afternoon, alternative correlates of protection need to be adopted for non HA-based vaccines. For now, in consultation with regulatory experts, BiondVax has developed a unique approach, which was recently published in Future Virology:
We propose a stepwise process for regulatory and marketing approval. As a first step, the universal vaccine will be tested in conjunction with existing HA-based vaccines. Regulatory approval and conditional marketing authorization will be granted based on safety assessments and improved hemagglutination inhibition antibodies (HAI) (as a marker for efficacy) for the vaccines used in combination. Permanent market authorization will be granted next, based on clinical efficacy data, accumulated during several years, and ultimately the new vaccine will be approved as a standalone vaccine.
Our regulatory plan lets us compare apples to apples, based on HAI. Our trials are generally designed as follows: One group receives a placebo, and one group our M-001. On their next visit, a few weeks later, we take the blood of all participants, in both groups, to look at the specific cellular response to M-001 as a standalone vaccine. Then the current HA-based flu vaccine is administered to all participants. A few weeks later, we again draw blood and compare the HAI response in both groups after receiving the current vaccine. We also look at the HAI response to non-vaccine strains.
Our pre-clinical and clinical trials have shown that, compared to the placebo group, more subjects receiving M-001 reach the level of protection according to HAI, the current regulatory marker.
We have completed 5 clinical trials. In all trials, M-001 was shown to be safe and immunogenic.
The 219-participant Phase 2b trial in collaboration with UNISEC was completed in 2016. The trial is looking at the impact of M-001 administered prior to an H5N1 pandemic vaccine. The data are still blinded, and so the distribution of adverse events between the total of 219 participants who completed the study in both the control and experimental groups is unknown. However I can report that, from all participants, only 3 moderate adverse events were considered to be possibly or probably related to the treatment and no related severe adverse events were reported.
This means we have demonstrated safety now in nearly 700 trial participants, ranging in age from 18 to 91 years old.
Our UNISEC colleagues are currently busily processing and analyzing immunogenicity data. We hope to have the results soon.
These charts (on the left) show results from clinical trials in older adults. As people over 65 years are the most vulnerable to flu infection illness, we believe it is particularly important for M-001 to be approved for use in this population as soon as possible. The light blue bars show the rate of seroconversion in participants only receiving current flu vaccines. The dark blue bars show the rate of seroconversion in the group that received M-001 first.
Data from our trials have shown M-001 to be immunogenic towards different flu strains, including both vaccine and non-vaccine strains.
Note that the vaccine, M-001, is one product. It is not used in combination with an adjuvant. Production in e.Coli rather than eggs enables us to cut production time from months to weeks. And I would like to emphasize that we have not only created a platform for faster flu vaccine production – keep in mind that the final product, M-001, does not change. It is a single formulation, “one for all” vaccine, designed to provide broad and lasting protection against all current and future seasonal and pandemic flu strains. This means it can be produced year-round, and stockpiled for proactive pandemic preparedness.
A few moments ago I noted the many infectious diseases that have been eliminated or massively reduced by vaccination. And I reviewed why flu is still not on that list, despite widespread vaccination. BiondVax has proposed a truly universal flu vaccine, and I’d imagine, naturally, that many of you are skeptical. But let me leave you with this extraordinary story that provides evidence of M-001’s potential. This story was published earlier this year in Vaccine journal:
In 2011, we administered M-001 to adults aged 65 plus in our BVX-005 trial. As is standard procedure, we preserved the participant’s sera after the trial. In 2014/15, a new epidemic strain, A/Swiss, emerged. It didn’t exist in 2011 when we drew and froze our trial participants’ sera. We thawed the sera of the 2011 participants and tested it against the new A/Swiss strain, and showed that FIVE times more participants in the group that received M-001 reached the level of seroprotection compared to the placebo! Antibodies were produced in advance, in 2011, that were protective against the new, 2014 epidemic strain!
This remarkable results provides more striking evidence that M-001 has the capacity to protect against future strains.
For all these reasons, we believe BiondVax’s vision, a flu vaccine providing lasting protection against current and future seasonal and pandemic flu strains leading to flu eradication, is achievable!
These words are a rough transcript of words delivered by Joshua Phillipson, BiondVax’s Business Development manager, on April 20, 2017 at the “Influenza Vaccine for the World” conference in Lausanne, Switzerland. The 3-day conference featured leading scientists, regulatory, and industry experts from North America, Europe, and APAC.