During the 2009 H1N1 influenza pandemic, vaccines for the virus became available in large quantities only after human infections peaked. To accelerate vaccine availability for future pandemics, we developed a synthetic approach that very rapidly generated vaccine viruses from sequence data. Beginning with hemagglutinin (HA) and neuraminidase (NA) gene sequences, we combined an enzymatic, cell-free gene assembly technique with enzymatic error correction to allow rapid, accurate gene synthesis. We then used these synthetic HA and NA genes to transfect Madin-Darby canine kidney (MDCK) cells that were qualified for vaccine manufacture with viral RNA expression constructs encoding HA and NA and plasmid DNAs encoding viral backbone genes. Viruses for use in vaccines were rescued from these MDCK cells. We performed this rescue with improved vaccine virus backbones, increasing the yield of the essential vaccine antigen, HA. Generation of synthetic vaccine seeds, together with more efficient vaccine release assays, would accelerate responses to influenza pandemics through a system of instantaneous electronic data exchange followed by real-time, geographically dispersed vaccine production.
Ed Rybicki's insight:
So let's be clear: they made the vaccine SEED in 4 days, NOT the vaccine! One would still then have to scale up production in mammalian cells - which is not trivial.
The 2009 swine-origin H1N1 influenza, though antigenically novel to the population at the time, was antigenically similar to the 1918 H1N1 pandemic influenza, and consequently was considered to be [ldquo]archived[rdquo] in the swine species before reemerging in humans. Given that the H3N2 is another subtype that currently circulates in the human population and is high on WHO pandemic preparedness list, we assessed the likelihood of reemergence of H3N2 from a non-human host. Using HA sequence features relevant to immune recognition, receptor binding and transmission we have identified several recent H3 strains in avian and swine that present hallmarks of a reemerging virus. IgG polyclonal raised in rabbit with recent seasonal vaccine H3 fail to recognize these swine H3 strains suggesting that existing vaccines may not be effective in protecting against these strains.
Vaccine strategies can mitigate risks associated with a potential H3N2 pandemic in humans.
Ed Rybicki's insight:
No-one think of H3N2...except, as it happens, these folk - who have shown quite convincingly that circulating strains of H3N2 in birds and pigs would be quite capable of avoiding vaccine-conferred immunity, and potentially of causing a pandemic, if they reassorted with human-infecting viruses.
I can't help but feel that there are several ticking influenza pandemic time bombs out there...H5N1, H7N9, and now H3N2.
Medicago Inc. (TSX: MDG; OTCQX: MDCGF), a biopharmaceutical company focused on developing highly effective and competitive vaccines based on proprietary manufacturing technologies and Virus-Like Particles (VLPs), today announced that it has successfully produced a new VLP vaccine candidate for the H7N9 virus that is responsible for the current influenza outbreak in China.
Influenza in birds graphic from Russell Kightley Media
Ed Rybicki's insight:
I keep saying, you gotta go green...and Medicago do, and have for H7N9.
Quicker than anyone else, evidently. Truly impressive for plant production technology!
TORONTO — Making a vaccine to protect against the new bird flu virus that has emerged in eastern China could prove to be problematic, influenza experts acknowledged yesterday.
Ed Rybicki's insight:
"...clinical trials of vaccines made to protect against other viruses in the H7 family have shown the vaccines don't induce much of an immune response, even when people are given what would be considered very large doses."
This is a little worrying - and possibly a spur to making universal vaccines!
GlaxoSmithKline’s quadrivalent influenza vaccine has been granted marketing authorisation in Germany and the UK. The four-strain vaccine is the first to be approved in a European country for active immunisation of adults and children from three years of age for the prevention of influenza disease caused by the two influenza A and two influenza B virus subtypes contained within the vaccine.
I am TRYING to write an eBook on influenza, which stubbornly refuses to be finished - as part of a sabbatical project, which finished in December 2010. So, like my History of Virology, I am triall...
Ed Rybicki's insight:
I will reprise this post, given a considerable recent spike in interest in it as the new H7N9 Shanghai bird flu starts. Hopefully to fizzle out, but you never know....
Incidentally, I have an almost-finished iBook (for iPad) on influenza: the first five respondents to this post can trial it for free!
Geographic variables play an important role in the study of epidemics. The role of one such variable, population density, in the spread of influenza is controversial.
Prior studies have tested for such a role using arbitrary thresholds for population density above or below which places are hypothesized to have higher or lower mortality. The results of such studies are mixed.
The objective of this study is to estimate, rather than assume, a threshold level of population density that separates low-density regions from high-density regions on the basis of population loss during an influenza pandemic. We study the case of the influenza pandemic of 1918--19 in India, where over 15 million people died in the short span of less than one year.
Pandemic recombinant influenza virus graphic from Russell Kightley Media
Ed Rybicki's insight:
This is an interesting paper, because it is one of the ONLY ones I have ever seen that analyses ANYTHING to do with the 1918 H1N1 pandemic, that comes from a developing country. Moreover, it makes what I think is possibly quite a valuable contribution to "health geographics", especially for high-denisty low-income populations.
I also note that 15 MILLION PEOPLE were estimated to have died in India ALONE: this is close to the old estimate for the WORLD total (20 million), which was revised upwards to 50-100 million after developing country stats were taken into account, in the late 1990s.
This analysis focuses on population density in regards to the influenza pandemic of 1918-1919. After extensive research and experimenting, researchers found that "districts on the low side of the threshold experienced rates of population loss (3.72%) that were lower than districts on the high side of the threshold (4.69%)". With the results from these experiments, geographers will be able to predict future pandemic patterns in population and how to stop virus at form spreading further. By determining techniques to stop the pandemic while observing the population density of the outbreak, they might be able to successfully stop the disease at its source. Personally, I see this as not only a medical break through, but a geographical innovation that allows us to study population density in a much more extensive fashion.
Animation of the mechanism of an influenza virus and how Crucell's antibodies target the HA1 proteins on the virus and prevent further spread of influenza.
Might be an advert, but it's one of the nicest animations of flu virus entry and neutralisation that I've ever seen. In fact, it's the ONLY one!
An important document - because it lays out in detail just what a high-level team that went to China found during their travels. And it is disturbing: the virus has 6 internal genes of H9N2, with the H7 HA and N9 NA - the first time the latter has been seen in humans. I note that H9N2 keeps popping up in humans, but is not so nasty: the H7N9, however, is a low pathogenicity virus in chickens, but severe in humans.
Dr Thomas P. Monath, Adjunct Professor at Harvard School of Public Health gives his presentation on ‘New vaccines needed for pathogens infecting animals and humans: One Health’.
Ed Rybicki's insight:
This is a very interesting presentation for a number of reasons - prime among which is the fact that a number of very influential international organisations and funders are taking the notion of "One Health" very seriously.
That is, the development of reagents and vaccines that can be used for agents that cause both animal and human diseases, such as avian influenza, Nipah and Hendra and Rift Valley fever viruses, and so on.
Great idea - and one we are trying to address with making such things in plants!
Infection with influenza virus leads to significant morbidity and mortality. Annual vaccination may prevent subsequent disease by inducing neutralizing antibodies to currently circulating strains in the human population. To escape this antibody response, influenza A viruses undergo continuous genetic variation as they replicate, enabling viruses with advantageous antigenic mutations to spread and cause disease in naïve or previously immune or vaccinated individuals. To date, the 2009 pandemic virus (A(H1N1)pdm09) has not undergone significant antigenic drift, with the result that the vaccine remains well-matched and should provide good protection to A(H1N1)pdm09 circulating viruses. In this study, we induced antigenic drift in an A(H1N1)pdm09 virus in the ferret model. A single amino acid mutation emerged in the dominant surface glycoprotein, hemagglutinin, which had a multifaceted effect, altering both antigenicity and virus receptor specificity. The mutant virus could not be isolated using routine cell culture methods without the virus acquiring additional amino acid changes, yet was fit in vivo. The implications for surveillance of circulating influenza virus are significant as current assays commonly used to assess vaccine mismatch, as well as to produce isolates for vaccine manufacture, are biased against identification of viruses containing only this mutation.
Influenza virus graphic by Russell Kightley Media
Ed Rybicki's insight:
There is a rather disturbing result in this paper: that is, that the mutation in the H1N1 HA that emerged in serial ferret transfers that was responsible for antigenic drift, resulted in a virus that could NOT be cultured by routine methods despite being quite happy in ferrets. In fact, adapting the virus to culture meant it accumulated MORE mutations, meaning the thing they got out by "current assays" was NOT the same thing that was causing disease.
This is worrying for a number of reasons, not least of which is that informed decisions on probable vaccine efficacy are made as a result of such assays - and the vaccines themselves, in some cases. And if what these decisions are based on is incorrect...?
Time for some better science here, people - like next-gen sequencing rather than isolation as a measure of what is causing disease!
Water birds, to an influenza researcher, are more than majestic swans and charming mallards. They are instead stealthy vectors of novel influenza viruses, some of nature’s bioterrorist agents, chauffeuring dangerous microbes from place to place without showing symptoms of infection themselves. Wild waterfowl are reservoirs for every imaginable combination of influenza viruses, though the vast majority of those viral cocktails don’t seem to infect humans.
Ed Rybicki's insight:
ALL birds are winged rats, then?? I love the actual title of the piece: "Nature’s Bioterrorist Agents". Not alarming in any way, oh, no....
Human influenza infections exhibit a strong seasonal cycle in temperate regions. Recent laboratory and epidemiological evidence suggests that low specific humidity conditions facilitate the airborne survival and transmission of the influenza virus in temperate regions, resulting in annual winter epidemics. However, this relationship is unlikely to account for the epidemiology of influenza in tropical and subtropical regions where epidemics often occur during the rainy season or transmit year-round without a well-defined season. We assessed the role of specific humidity and other local climatic variables on influenza virus seasonality by modeling epidemiological and climatic information from 78 study sites sampled globally. We substantiated that there are two types of environmental conditions associated with seasonal influenza epidemics: “cold-dry” and “humid-rainy”. For sites where monthly average specific humidity or temperature decreases below thresholds of approximately 11–12 g/kg and 18–21°C during the year, influenza activity peaks during the cold-dry season (i.e., winter) when specific humidity and temperature are at minimal levels. For sites where specific humidity and temperature do not decrease below these thresholds, seasonal influenza activity is more likely to peak in months when average precipitation totals are maximal and greater than 150 mm per month. These findings provide a simple climate-based model rooted in empirical data that accounts for the diversity of seasonal influenza patterns observed across temperate, subtropical and tropical climates.
Ed Rybicki's insight:
This is really quite a big deal: I blogged recently on the first paper that explored this notion in detail; here we see that paper vindicated, and new data presented.
It is interesting that the virus should have evolved to be spread in this way: in drier cold air in temperate climates, and in warm wet air in more tropical climes. It also very nicely explains seasonality in influenza transmission.
Interesting data. In tropical climes, I wonder if this phenomenon is associated with the overcrowding of shelters during intense rainstorms. A temporary increase in population density during these events would likely facilitate increased rates of person-person transmission.
When U.S. public health agencies acknowledge the limitations of the influenza vaccine – which they do much less often than they should – they tend to use a phrase like “less than perfect.” “Less than adequate” would capture the situation better.
Ed Rybicki's insight:
...but it's still an excellent idea to get vaccinated. ESPECIALLY in a bad flu season.
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So let's be clear: they made the vaccine SEED in 4 days, NOT the vaccine! One would still then have to scale up production in mammalian cells - which is not trivial.