The current approach to seasonal and pandemic flu is akin to a game of Whack-a-Mole. Scientists do their best to anticipate the most likely culprits from a constantly evolving cast of viral characters, hoping that their efforts will land effectively in the coming flu season.
Predictions of which influenza strains will be circulating each year are made more than six months before the onset of flu season—and even if projections are accurate, unexpected strains can and do arise, rendering that year’s vaccine minimally effective. The best-case scenario results in delivery of seasonal flu vaccines with an average 30%–60% efficacy—not exactly an inspiring score.
Given what we know about the 1918 pandemic, combined with current knowledge derived from the COVID-19 crisis, it is obvious that vaccine development needs to strategize for broad and enduring efficacy. Knocking out all strains of the targeted virus with one swift strike—a universal vaccine—is the necessary approach.
At EnGen Bio, we believe the development of a universal vaccine for type A flu is in sight. Even prior to the emergence of COVID-19, we have been pursuing a universal immune strategy against type A influenza (the most common and deadly form of seasonal and pandemic flu in both humans and animals), and we have discovered what we believe to be the Achilles’ heel of all type A influenza viruses. It potentially offers broad immunity against 100% of flu pandemics, 100% of animal influenzas and 80% of seasonal flu cases.
The idea of a universal flu vaccine is not entirely novel. Several companies and institutions, including Novavax, NIH, J&J and GlaxoSmithKline, are pursuing universal flu vaccine strategies. To date, the most advanced approaches target a specific protein called hemagglutinin (HA). Unfortunately this protein is hypervariable (meaning it rapidly changes when viral strains mutate or re-assort), leaving recipients vulnerable to infection by newly arising strains, which are no longer recognized by the body’s immune system. They have homed in on a stem segment of the HA protein that, while less variable, is still prone to mutation, and the implications are obvious from an evolutionary biology standpoint: Variation opens the door for evolution. And from a drug efficacy standpoint, that means new formulations of the vaccine will always be required, thereby also foiling any hopes for herd immunity.
Other companies (for example, EpiVax and BiondVax) have attempted to develop subunit vaccines made up of several well-conserved flu components, in hopes of inducing both arms of the immune system, the “innate” and the “adaptive.” In its simplest conception, the innate immune system is our body’s front line of attack against invading pathogens, while the adaptive immune system comprises the immune cells and molecules that have learned to identify and attack specific pathogens. So far, these other strategies do not meet the criteria for universality, as they target a mix of influenza proteins that vary from strain to strain, and fail to elicit both innate and adaptive immune responses. The most advanced of these solutions, from BiondVax, just failed phase 3 clinical trials, proving to be safe but ineffective at reducing flu illness and severity.
Our research points to an abundant, viral protein region called an “epitope,” which, because of its context within the viral genome, likely cannot mutate significantly without destroying viral viability. As strong evidence of this, looking all the way back to the 1918 Spanish flu virus, sequence variants at only four non-essential positions within the epitope can be found among the tens of thousands of M1 sequences contained in the NCBI database. The epitope is displayed on the surface of the virus, leaving it exposed to the body’s defenses. When a particular antibody specificity is bound to any of these known variants of the epitope, the viruses are inactivated, rendering them incapable of causing illness. Therefore, it should function universally for type A strains, including all flu pandemics.
This exposed epitope is not particularly immunogenic in the context of the whole virus. However, when one of the epitope variants is used in isolation as an immunogen in a test vaccine, it produces serum from the test animals rich in neutralizing antibodies, equally effective against all four positional variants.
If you picture HA-based vaccines being focused on finding one solution for thousands of problems, our discovery reduces the equation to only four variables, which greatly decreases the complexity of the problem we are trying to solve. Rather than hoping to find one key that opens thousands of doors, we need only one universal key that works on four doors.
Our data suggests that a vaccine based on this discovery could offer long-term efficacy, which means that patients could see lasting results from one or two injections—with possible lifetime immunity—eliminating the need for production and distribution of seasonal vaccines.
We have learned from COVID-19 that, once a pandemic hits, it is already too late to identify, manufacture and distribute a solution. A universal vaccine for influenza could be administered prior to need, potentially issued alongside standard childhood vaccinations such as measles/mumps/rubella and varicella. And a shelf-stable delivery method would enable safe storage and distribution worldwide. Even if protection is not as long as we anticipate, and more frequent boosters are required, there will be no failed predictions by WHO on strain selection for that year. There will also be no flu vaccine shortages, because the vaccine can be produced well in advance for each season.
We at EnGen Bio believe the aim should not simply be to develop the next vaccine, but to create a future where type A influenza has become a thing of the past.
