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| Credit NIAID |
#15,344
For as along as I've been blogging on infectious diseases, there have been optimistic predictions that we are only 5 years away from having the holy grail of vaccinology; a universal flu vaccine.
Since I get a flu shot every year, I'm understandably hopeful this can be accomplished. But despite a full court press by the NIH - and many other scientific institutions over the past 15 years - we appear to be still 5 or more years away from having a `universal' flu vaccine.
A little over two years ago, in J.I.D.: NIAID's Strategic Plan To Develop A Universal Flu Vaccine, we looked at the National Institute of Allergy and Infectious Diseases' short term goals.
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| Credit NIAID |
Not quite what most people think of when you say `universal flu vaccine', but still a considerable improvement over what we have right now. But even with scaled down expectations, success has been elusive.
Part of the problem has been that influenza viruses, and our human immune system, don't always react the way we expect them to.
A long standing assumption is that once you are naturally infected with a specific influenza virus, you will carry lifelong - or at least long-lasting - antibody titers that are protective against that specific virus.
Similar, but potentially less long-lasting effects are also expected from vaccination. This `acquired immunity' is also expected to extend to antigenically similar viruses, although things get much murkier once even minor changes to the virus are introduced.
In the spring of 2019, in a fascinating research study conducted by researchers at the NIH and NIAID (see C.I.D.: Influenza A Reinfection in Sequential Human Challenge), we saw that this wasn't necessarily so.
In that study, researchers exposed a small group of healthy volunteers to a specific H1N1 virus, and recorded their subsequent infections and immune responses.
A year later, they repeated this virus challenge on the same group (n=7) with the exact same virus, expecting their residual immunity would protect them. To their surprise they found that at least 3 - and possibly 5 - of the 7 were reinfected with the exact same flu strain.
While the study cohort was small, the results led the researchers to write in their conclusion:
The data presented in this report demonstrate that sequential infection with the identical influenza A virus can occur and suggest it may not be rare. These data raise questions about immune memory responses in an acute superficial respiratory mucosal infection and their implications in development of broadly protective influenza vaccines. Further investigation of these observations is warranted.
There are other potential stumbling blocks, including ADE (Antibody Dependent Enhancement), and OAS (Original Antigenic Sin), both of which can produce paradoxical, and potentially dangerous immune responses among those who are either vaccinated, or previously exposed to a similar virus.
OAS has been described in relation to influenza viruses, Dengue Fever, and HIV. You can find a terrific background piece on OAS from 2009 by Robert Roos in my blog entitled CIDRAP On Original Antigenic Sin.
And if mistakenly sending the wrong antibodies into the fray isn’t bad enough, sometimes non-neutralizing antibodies can actually enhance a virus’s ability to enter a host’s cells via a process called ADE or Antibody-dependent enhancement.
Issues surrounding OAS and ADE (Antigenic Dependent Enhancement appear to have played a role in 2017's Dengue vaccine debacle (see Philippines: FDA Withdraws Dengvaxia® Vaccine - Sanofi Quantifies Risk), and may influence the impact of other vectorborne diseases (PLoS Currents: Another In Vitro Study Suggests Previous Dengue Exposure May Exacerbate Zika Severity).
Some recent studies have cautioned that some approaches to making universal flu vaccines may risk inducing an ADE response as well, including
To this impressive list of challenges, we can add another - the ability of some influenza viruses to mutate rapidly and evade the vaccine - as explained by the following study and press release - from the Scripps Research Institute.
Different genetic barriers for resistance to HA stem antibodies in influenza H3 and H1 viruses
Nicholas C. Wu1,*, Andrew J. Thompson2,*, Juhye M. Lee3,4,5, Wen Su6, Britni M. Arlian2, Jia Xie7, Richard A. Lerner7,8, Hui-Ling Yen6, Jesse D. Bloom3,4,9, Ian A. Wilson1,8,†
Science 19 Jun 2020:
Vol. 368, Issue 6497, pp. 1335-1340
DOI: 10.1126/science.aaz5143
The study is sadly behind a paywall, but we have press release giving us many of the pertinent details. I'll have a short postscript when you return.
Many flu strains may be capable of mutating to escape universal-vaccine antibodies.June 23, 2020LA JOLLA, CA—Some common strains of influenza have the potential to mutate to evade broad-acting antibodies that could be elicited by a universal flu vaccine, according to a study led by scientists at Scripps Research. The findings highlight the challenges involved in designing such a vaccine, and should be useful in guiding its development.In the study, published in Science, the researchers found evidence that one of the most common flu subtypes, H3N2, can mutate relatively easily to escape two antibodies that were thought to block nearly all flu strains. Conversely, they found it is much more difficult for another common subtype, H1N1, to escape from the same broadly neutralizing antibodies.One of the main goals of current influenza research is to develop a universal vaccine that induces broadly neutralizing antibodies, also known as “bnAbs,” to give people long-term protection from the flu.“These results show that in designing a universal flu vaccine or a universal flu treatment using bnAbs, we need to figure out how to make it more difficult for the virus to escape via resistance mutations,” says the study’s senior author Ian Wilson, DPhil, Hansen Professor of Structural Biology and Chair of the Department of Integrative Structural and Computational Biology at Scripps Research.The promise of a universal vaccineInfluenza causes millions of cases of illness around the world every year and at least several hundred thousand fatalities. Flu viruses have long posed a challenge for vaccine designers because they can mutate rapidly and vary considerably from strain to strain.The mix of strains circulating in the population tends to change every flu season, and existing flu vaccines can induce immunity against only a narrow range of recently circulating strains. Thus, current vaccines provide only partial and temporary, season-by-season protection.Nevertheless, scientists have been working toward developing a universal flu vaccine that could provide long-term protection by inducing an immune response that includes bnAbs. Over the past decade, several research groups, including Wilson’s, have discovered these multi-strain neutralizing antibodies in recovering flu patients, and have analyzed their properties. But to what extent circulating flu viruses can simply mutate to escape these bnAbs has not been fully explored.In the study, first-authored by postdoctoral research associate Nicholas Wu, PhD, and staff scientist Andrew Thompson, PhD, the team examined whether an H3N2 flu virus could escape neutralization by two of the more promising flu bnAbs that have been discovered so far.Known as CR9114 and FI6v3, these antibodies bind to a critical region on the virus structure called the hemagglutinin stem, which doesn’t vary much from strain to strain. Because of their broad activity against different flu strains, they’ve been envisioned as antibodies that a universal flu vaccine should be designed to elicit, and also as ingredients in a future therapy to treat serious flu infections.Using genetic mutations to methodically alter one amino acid building-block of the protein after another at the stem site where the bnAbs bind, Wu and colleagues found many single and double mutations that can allow H3N2 flu to escape the antibodies’ infection-blocking effect.The team also found a few instances of these “resistance mutations” in a database of gene sequences from circulating flu strains, suggesting that the mutations already happen occasionally in a small subset of ordinary flu viruses.Escape skills vary by flu strainAlthough experiments and analyses suggested that H3N2 viruses are broadly capable of developing resistance mutations, the same was not true for H1N1 viruses. The researchers tested several H1N1 viruses and found that none seemed able to mutate and escape, except for rare mutations with weak escape effects. The H3N2 and H1N1 subtypes account for most of the flu strains circulating in humans.The researchers used structural biology techniques to show how differences in the hemagglutinin stem structure allow H3N2 flu viruses to develop resistance mutations to the two stem-binding antibodies more easily than H1N1 viruses.“If it’s relatively easy for H3N2 to escape those bnAbs, which are the prototype antibodies that a universal flu vaccine should induce, then we probably need to think more carefully and rigorously about the design of that universal flu vaccine against certain influenza subtypes,” Wu says. “The good news is that a universal flu vaccine should at least work well against the H1N1 subtype.”The researchers now plan to conduct similar studies with other flu subtypes and bnAbs. They say that in principle, a vaccine eliciting multiple bnAbs that attack different sites on flu viruses or are more accommodating to changes in the virus could help mitigate the problem of resistance mutations.“Different genetic barriers for resistance to HA stem antibodies in influenza H3 and H1 viruses” was authored by Nicholas Wu, Andrew Thompson, Juhye Lee, Wen Su, Britni Arlian, Jia Xie, Richard Lerner, Hui-Ling Yen, Jesse Bloom, and Ian Wilson.Support for the research was provided by the Bill and Melinda Gates Foundation (OPP1170236), and the National Institutes of Health (K99 AI139445, F30 AI136326, R01 AI127893, R56 AI127371, R01 AI114730).
(Continue . . . )
Not surprisingly, it is H3N2 - the longest running - and arguably fastest mutating, and most agile seasonal flu subtype to emerge in modern times (see The Enigmatic, Problematic H3N2 Influenza Virus) that poses the greatest challenge.
H3N2 first appeared 52 years ago (1968) as a pandemic strain, and supplanted the short-lived H2N2 virus (which sparked the 1957 pandemic). It then survived challenges by the return of H1N1 - after a 20 year absence - in 1977, and similarly managed to hold on when the 2009 H1N1 pandemic strain emerged.
While long in the tooth, H3N2 is a survivor - in large part because there are so many genetically distinct, yet biologically `fit' - clades circulating around the world.
While the challenges to creating a universal flu vaccine are many and varied, the dividends from creating a `universal' flu vaccine are potentially huge. If developed, it might even stave off - or blunt - the next influenza pandemic.
It would really help a lot, though, if H3N2 would begin acting its age and retire.
