The numbers and science behind H5N1’s spread, the technologies and fears about HPAI vaccination 4 big questions on HPAI

Avian influenzas are not a new phenomenon. Indeed, they predate the existence of industrialised agriculture: “fowl plague” outbreaks affected both Europe and America in the 19th and early 20th centuries. Low pathogenic avian influenza is found around the world, and occasionally, these low pathogenic strains have mutated into highly pathogenic avian influenza (HPAI).

To quote an explanation by Nienke Beintema of Wageningen World1: “Initially, highly pathogenic variants tended to cause problems only locally. They were so deadly that wild birds that caught them never got very far. But around the turn of the [21st] century, a highly pathogenic variant that was able to hitch a ride with migratory birds emerged on poultry farms in Asia.” Throughout the last 20 years, this lineage of H5 avian influenza became multi-country, and then transcontinental.

However, despite the fact that the modern poultry production industry has been dealing with H5 (and sometimes H7) HPAI for two decades now, the experience over the last two years or so has been unlike anything anyone has ever seen. HPAI, mostly H5N1 clade 2.3.4.4b, has left a growing trail of devastation. Today, we try and grapple with how dramatically the numbers of affected birds have risen and understand what factors might be driving that. Then we examine the vaccine development landscape, looking at the different technologies and understanding the obstacles which have kept parts of the world from the widespread use of vaccination as a tool against HPAI.

Just how bad has HPAI been compared to previous years?

Various authorities measure HPAI’s impacts differently, but the numbers are sobering.

Members of the World Organisation for Animal Health (WOAH, formerly the OIE) are supposed to notify the organisation if HPAI is detected in their territories. Data from its information system WAHIS records 167.8 million birds killed and disposed of from HPAI in 2022. Here’s how that compares to previous years with particularly bad levels of HPAI:

• 2021: 60 million killed and disposed of.

• 2020: 23.6 million killed and disposed of.

• 2016: 39.2 million killed and disposed of.

In Europe, which tracks its HPAI by seasons rather than by the calendar year, the 2021/2022 epidemic was the largest ever recorded. The European Food Safety Authority (EFSA) officially recorded “a total of 2,467 outbreaks in poultry, 47.7 million birds culled in the affected establishments…and 3,573 HPAI virus detections in wild birds with an unprecedent geographical extent reaching from Svalbard islands [inside the Arctic circle] to South Portugal and Ukraine, affecting 37 European countries.”2 We’ve also seen at least 10 million culled so far over the 2022-2023 outbreak.3 Before this, comparatively bad years for Europe were:

• 2020-2021: 22.4 million affected poultry birds in the regular “season”, and another 0.5 million over the summer months before the following “season” started.4,5

• 2016-2017: 13 million domestic birds reported in the Animal Disease Notification System as having died of or been culled due to the HPAI epidemic from 2016 through April 2017. EFSA records this as “a number that is already 10 times greater compared with the 2005-2006 epidemic.”6

In the US, which has kept a running tally since the current round of A(H5) viruses first appeared in the country in January 2022, the number of birds on affected premises was around 58.6 million at the time of publication7. Every one of the states had observed bird flu in its wild birds. For comparison, in the US, the 20142015 outbreak saw about 50 million birds in total which were depopulated or died of the disease.8

Beyond the cull numbers, we are also now looking at an HPAI threat which is less constrained by season and which has a greater geographical reach than ever before.

ENDEMIC, YEAR-ROUND INFECTION

Unfortunately, HPAI no longer seems to be disappearing during the summer months as it has generally been expected to, with EFSA also noting that “HPAI outbreaks were still observed in poultry from June to September with five-fold more infected premises than observed during the same period in 2021 and mostly distributed along the Atlantic coast.”2

Meanwhile, in the US, the previous outbreak was a threat to commercial flocks for about six months, between January and June 2015, according to APHIS’s 2016 Final Report of the outbreak8, whereas the current outbreak continues to rage 14 months after HPAI’s appearance in the US, including infections over the summer as well.

DR. DAVID SWAYNE

Now In South America

In Q4 2022, H5N1 reached South America for the first time, a milestone for a critically important poultry exporting region which had not yet faced the virus. As of mid-March, 8 South American countries had declared outbreaks to WOAH. Several of their North and Central American neighbours have also been affected.

What’s making HPAI so bad now?

The answer to that appears to be wild birds.

Just like the move into migratory birds was what helped highly pathogenic avian influenza become a global phenomenon, it looks like a significant part of the story of the last few years are evolutions of the virus which allow it to infect more species and/ or to transmit more easily between birds. “The current clade of H5N1 virus, called clade 2.3.4.4b, appears well-adapted to spread efficiently among wild birds and poultry in many regions of the world,” observed Dr. Tim Uyeki, Chief Medical Officer of the Influenza Division at the US’s Centers for Disease Control and Prevention (CDC), in a publication on February 20239. Meanwhile, an April 2022 piece in Science10 quoted other US experts’ suspicions that the virus spreads more easily than previous strains, and noted that a mere five months after HPAI’s return to North America in November 2021, it had already been noted in twice as many wild bird species.

That is more than just an interesting (if gruesome) bit of trivia. Instead, it is at the heart of how commercial poultry operations are now getting infected by HPAI, according to Dr. David Swayne, a leading expert in avian influenza who spent 28 years at the USDA-ARS Southeast Poultry Research Laboratory, retiring as its director at the end of 2022, in a conversation with Feedinfo this February. As he explained, molecular analysis of the viruses circulating in the Midwest in during the last HPAI epidemic in the US in 2014-15 showed that, after having been introduced to the area, the dynamics of its spread were different: “it was primarily being spread from premise to premise, and not by introductions of wild birds…but today it’s mainly environmental contamination from wild birds, and there’s very little of that farm-to-farm spread, and there’s really very little evidence of backyard poultry to commercial poultry spread, or vice-versa.”

Meanwhile, across the pond, HPAI has now probably become a permanent fixture in Europe as well. “The observed persistence of HPAI (H5) virus in wild birds since the 2020-2021 epidemic wave indicates that it may have become endemic in wild bird populations in Europe, implying that the health risk from HPAI A(H5) for poultry, humans, and wildlife in Europe remains present year-round, with the highest risk in the autumn and winter months,” stated the ECDC in June 202211 .

Beyond increasing its spread, having endemic HPAI in Europe has also contributed to a worsening of the disease’s economic impact. Effectively, whereas HPAI in Europe had previously been something of a cold-season phenomenon, it is now cropping up even during the summer. This means that exporters are finding themselves with less and less of a window during which the absence of HPAI allows their poultry products to be accepted by wary importers, as representatives from AVEC (the association of poultry processors and the poultry trade in EU countries) told Feedinfo.

Ultimately, though, there remains much to be learned about all of these aspects of this disease, as noted by Offlu, a network of expertise on animal influenza associated with WOAH and the FAO. In a document published this March12, it identified “gaps in knowledge that remain unresolved regarding the current epidemic including, but not limited to:

• What are the roles of different species of wild bird in long distance spread, and local transmission and maintenance of the current H5N1 virus?

• What are the underlying factors associated with an increased range of wild bird species affected and their relevance for future disease epidemiology?

• What specific viral factors allow the expanded geographical spread and continued circulation causing outbreaks in the northern hemisphere summer (unlike 2014-15 strains)? […]

• Will the H5N1 HPAI viruses circulating in wild birds remain enzootic or will they self-extinguish as has been the case with HPAI viruses that have crossed over and spread in wild birds in the past (e.g. virus in wild birds in North America in 2014-2015 and in Europe from 2005 to 2008)?

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Highly Pathogenic Avian Influenza

What’s the state of HPAI vaccine development?

Several vaccines against bird flu exist, and have been deployed over the last two decades in a variety of countries, from China to Mexico. The technology behind these existing vaccines largely falls into two categories, although there are some looking to apply emerging vaccine technologies to the problem as well. The two most prominent technologies are discussed briefly below:

“Hang on, I thought that vaccine x was licensed in the US, but now I understand that they’re not using HPAI vaccines in their domestic poultry flock. What’s As Dr. Swayne explained, the authorization process for animal vaccines in the US can be thought of as having two parts (although that is an oversimplification). The first is registration or licensing, for which the Center for (CVB) requires proof that the vaccine is safe and efficacious. And the second is authorization for use. For endemic diseases, this authorization is already in place; however, for HPAI, it is not. Therefore, there is no contradiction in the fact that a vaccine might be authorized in the US, but not

Inactivated vaccines, also called “killed vaccines”, are estimated to represent over 95% of the 113 billion doses of HPAI vaccine used between 2002 and 2010, according to research Swayne co-authored which was cited by the OIE Terrestrial Manual 2021 13 (the other 5% being recombinant vaccines, explained below).

Inactivated vaccines are an “old, established technology” widely used for diseases such as infectious bronchitis or Newcastle disease, as Feedinfo learned from Dr. Swayne directly in an interview.

Nonetheless, it is a category with recent innovations which are particularly interesting to the question of HPAI vaccination, including the development of reverse genetics to make new seed strains for the vaccines. In Dr. Swayne’s words, “by using reverse genetics you can design that hemagglutinin [the H protein in an influenza virus such as H5N1], so it would match the high pathogenic [avian influenza strain that was circulating locally].” Having a good match like this improves the ability of the vaccine to protect against the virus, and also lengthens the amount of time the vaccine can be used before new strains evolve for which the vaccine’s protection is no longer sufficient.

Beyond this, there are also a few other points to note about this technology. These vaccines are inactivated, which simplifies the question of assessing the potential risk to the environment from their use – as the viral ingredient of the vaccine is dead, it cannot mutate in the field. They can also be used in practically any species of bird; Dr. Swayne pointed out that territories worried about the exotic birds held in their zoos have used inactivated vaccines to protect them.

However, there is an important caveat. While this is a technology that might help protect long-living birds such as layers, breeders, or turkeys, inactivated vaccines can only be deployed after the birds’ immune systems have reached a certain level of maturity. This makes it impractical for broiler production; in settings where birds’ lifespans are measured in weeks, a technology that could not provide protection for several of those weeks is not worth the investment.

VIRAL-VECTORED RECOMBINANT VACCINES

Still, there are existing technologies which can be used much earlier in the bird’s lifespan: viral vector vaccines. In these vaccines, another poultry virus such as turkey herpesvirus (HVT), fowlpox, or Newcastle disease is modified to express proteins of the disease you want to vaccinate against — in this case, HPAI. “Their huge advantage is that they can be used in the hatchery, at one day of age, or [even before], actually injecting it into the egg while it’s developing,” explained Dr. Swayne.

While these represent a much smaller portion of the vaccines that have historically been used against avian influenzas, vector vaccines are worth discussing because of recent technological developments in Europe. In mid-March, the Dutch Ministry of Agriculture announced that a study it had commissioned had found two vaccines against H5N1 HPAI had proven effective in chickens in an experimental trial under controlled conditions conducted by Wageningen Bioveterinary Research. The vaccines protected the chickens against both symptoms of the disease and