3 March 2023 Episode 320 Avian Flu epidemiology and vaccination

Episode 320: Epidemiology of avian flu and more on vaccination

Dear colleagues,

Based on some reports and papers, I will try to depict the present epidemiology of avian flu in birds and people in Europe and the world and assess the epi or pandemic risk, taking into account that there is also still swine flu.

In a second part, the controversy on vaccinating poultry will be discussed, as well as the various vaccination platforms suitable for poultry.  

Ep 320-1:  Report from ECDC Dec 2022

Bird cases of highly pathogenic avian flu = mainly H5N8 and H5N1 in Europe 2016- end 2022

Total = 14, 629                                                                                                 Wild birds = 8,389   Domestic = 6,240

 

Distribution according to virus (shift from H5N8 to H5N1) and bird type

 

Origin and composition of the presently circulating H5N1 virus bearing the 2.3.4.4b HA gene in 2020.

 

 

The eight bars represent the eight gene segments (from top to bottom: PB2, PB1, PA, HA, NP, NA, M, and NS

 

As can be seen, this 2.3.4.4b AIV got its H5 and M segment from Russia; its NA, PA and NS from two different Belgian H1N1 strains, while the PB1, PB2 and NP originate from a Mongolian and a Chinese H8N3 strains

 

Present geographical distribution (Sept 2022-Dec 2022)

 

 

Clearly since Sept 2020, the virus has shifted from H5N8 to H5N1

Considering only HPAI outbreaks in poultry, so far ~58.3 million of birds have been died or culled in the HPAI-affected establishments since October 2021.

Situation worldwide in birds in Sept-Dec 2022: Clear-cut increase in the Americas!

 

Human cases 2003 – end Nov 2022 in the world

1. High pathogenic H5N1 = 868 case fatality = 53 %

 

 

2. High pathogenic H5N6 n= 82 in China and Laos: case fatality ratio = 42 %

 

3. Low pathogenic H9N

 

Clearly, mainly children under 10 who developed only mild symptoms

 

SOME OBSERVATIONS and CONCLUSIONS on situation Sept-Dec 2022

Observations :

1. Presently, there is high infection pressure due to the continuous circulation of HPAI A(H5N1) virus in the wild reservoir has led to frequent introductions of the virus into poultry populations across Europe.   Situation rather stable in Africa, Asia and Russia, but increasing in the Americas
2. All the HPAI A(H5Nx) viruses characterised since October 2020 in Europe belong to clade 2.3.4.4b:  they belong to eleven genotypes, three of which have circulated in Europe during the summer months, while eight represent new genotypes, likely evolved through reassortment events, most likely occurred locally.

 

3. Presence of H5N1 in mammals:

• A mink farm in Spain (with a polymerase mutation in PB1 which favors growth in humans
• A fox in Belgium
• An amour leopard in USA

 

4. Human infections

• Spain two H5N1 in Spain
• China: one H5N1 + one H5N6 + one H9N3
• Vietnam: one H5N?

Conclusions:

• For poultry: The biosecurity measures implemented along the poultry production chain do not seem effective in preventing all introductions of the HPAI A(H5N1) virus into poultry establishments.
• The viruses characterized to date retain a preference for avian-type receptors; mutations associated with mammalian adaptation have only been sporadically identified in the analysed viruses from avian species, but they are frequently acquired upon transmission to mammals

Nevertheless:

• The risk of infection for the general human population in the EU/EEA is assessed as low, and for occupationally exposed people low to medium with high uncertainty due to the high diversity of circulating avian influenza viruses in bird populations

 

Ep 320-2: M-A Widdowson in JID 2017 provided a nice overview of the threat of zoonotic influenza

Zoonotic influenza is increasingly reported since the nineties across the world. 

 

Most outbreaks are limited and with low case fatality, with the exception of the well-known 1997 H5N1(worldwide)  and the 2013 H7N9 (mainly China).  Nevertheless the smaller outbreaks of H5N6 in 2014 and H7N9 in 2017 also showed a high CFR.  

Ep 320-3:  CDC March 2023: Risk assessment of Influenza A viruses of animal origin for humans USA perspective

According to this report, the highest “emergence” risk for epidemics comes from two swine IAV H1N1 and H3N2, followed by H7N9 and H9N2 avian IAV, while infamous H5N6 clade 2.3.4 4b avian virus is further down the line (see Table on p.2)

 

Ep 320-4: Jianzhong Shi Emerg Infect Microbes 2023 gives the Chinese perspective:

• Attention for both H5 and H7 AIV (which are the two major types that have spilled over the humans.

 

• Proposing that vaccination of poultry could be an effective control measure (not applied in Europe)

Situation in poultry

1. H5 AIV epidemics and loss since 2005

 

 

 

2. H7 AIV outbreaks and loss since 2005

 

Situation in humans

1. Infections with H5 AIV since 2003

 

2. Infections with H7 AIV since 1959

 

Curtailing human infections with H7N9 by introduction of poultry inactivated vaccination in poultry

 

Authors conclusions:

H5 and H7 subtype avian influenza viruses have caused severe problems:

•  to the global poultry industry with more than 389 million domestic birds dying or being destroyed since 2005.
• to public health and have caused 2634 human cases with over 1000 fatalities.

Vaccines have been used in poultry to successfully prevent highly pathogenic influenza virus infection in China.

 

H5N1 viruses clade 2.3.4.4b HA gene are widely circulating in wild birds and causing problems in domestic poultry

in numerous countries around the world. To improve animal welfare, reduce economic damage, and reduce human infections, vaccination should be immediately and seriously considered as a control strategy

 

 

Ep 320-5: Why is poultry vaccination not applied in Europe and could policies change? 

 

Sarah Mikesell reports on a paper from “Wageninen World”, wherein Profs Mart De Jong (Quantitative Veterinary Epidemiology), Nancy Beerens  (Bird Flu Reference Laboratory ) and Henk Hoogeveen (Animal Health Management) explain the challenges and possible solutions: 

 

Problems:

• It is not clear whether the traditional “inactivated vaccines” protect against transmission and, for the same reasons as human flu vaccines their effect on infection and disease could be variable, because “mismatches” between the expected viral strain and the actually occurring one.
• ‘Within Europe, countries only trade in non-vaccinated poultry and meat,' De Jong says, 'because vaccinated birds are diagnostically difficult to distinguish from infected ones.’ For this reason, there is no international market for vaccinated birds, so poultry farmers do not want to vaccinate, and pharmaceutical companies therefore do not invest in making really good bird flu vaccines.
• There is also a problem of timing for broilers:….it takes several weeks before an animal is optimally protected. So it’s of little use for broilers: they are sent for slaughter after six or seven weeks, according to Hoogeveen.
• There is increasing public resistance to mass culls and the confinement of all poultry every winter

 

Ways out?

• This situation could change with new vaccines for the better: . New types of vaccines are often based solely on the haemagglutinin (HA) protein, a protein that is characteristic of the virus variant in question and is found on the outside of the virus particle. In animals vaccinated with these vaccines, antibodies will only be present against this HA protein. Beerens: 'If you find antibodies against other viral proteins in a blood test, then you know that an infection is present.’
• The government can push for changes to European trade agreements, so that vaccination does get accepted and progress can be made on developing better vaccines, improving their administration, and differentiating between infected and vaccinated animals. (Hoogeveen)
• ‘As far as I’m concerned, they can make vaccination compulsory in Europe, or subsidize it, or both. Make sure that vaccination becomes part of the cost structure. Then manufacturers will take the initiative to develop better vaccines.’ (Hoogeveen)

Ep 320-6: Jidang Chen Front Immunol 2021 Novel Concepts for Influenza viruses

 

This overview is complementary to Ep 319-2, -3, -4, where we discussed the application of mRNA vaccines.  

 

More traditional approaches

 

 

 

Split-virion influenza vaccines are prepared from inactivated whole influenza vaccines.

The viral envelope is disrupted:

•  nucleic acids and large molecular weight proteins of the virus are discarded,
• active antigenic components (HA and NA) and part of M and NP proteins are preserved.

→ concentrate and increase active antigenic proteins to

• stimulate maximum antibody production effects while
• greatly reducing unnecessary side effects from the virus particle

 

Subunit Influenza Vaccine: purified or recombinant HA and NA e.g. Influvac and Agrippal

 

Virosomes are reconstituted influenza virus envelopes consisting of HA, NA and viral phospholipids: could stimulate T cell responses, if sufficiently adjuvanted.  E.g. Epaxal® and Inflexal®

 

 

VECTOR-BASED VACCINES

 

1. General principle (based on Adeno-vectors)

 

 

 

2. Vector types in development

 

 

Adenovirus: well advanced as a mucosal vaccine for Influenza, but the side effects from Adeno-based COVID vaccines may negatively impact on further development

 

Arenavirus: include lymphocytic choriomeningitis virus (LCMV), Lassa virus (LASV), Junin virus (JUNV), Machupo virus (MACV), Pichinde virus (PICV) among others.  Several of these are human pathogens. LCMV has been used as vector but might have neurological issues, PICV is safer.  There is preclinical development with Influenza HA and/or NP(nucleoprotein) in PICV vector with positive results in mice.

 

Newcastle Disease Virus: (NDV = paramyxovirus) is a pathogen for poultry but not for humans: both Newcastle disease and avian influenza are important infectious viral diseases that seriously endanger the poultry industry. Thus, preventing both of these diseases through vaccination is of particular interest

• Infects respiratory epithelium, thus stimulating mucosal immunity.
• Can easily be manipulated to express foreign antigens
• Replicates only in cytoplasm, thus no genetic risk   
• Grows well in chicken embryos, allowing mass production
• Large-scale immunization, such as spraying and/or adding the vaccine into drinking water feasible

→ seems ideal format also to immunize broilers, but there can be a negative effect on induction of immunity because of maternal antibodies against NDV.

 

Baculovirus vector expression system BEVS-based vaccines have 7 commercialized products approved for human use, among which are human papillomavirus vaccine, influenza vaccine, prostate cancer vaccine, and lipoprotein lipase deficiency vaccine.   Influenza-Flublok has been licensed for use in humans.

Herpes virus:  Herpes Virus of Turkeys (HVT) has been used expressing the HA protein of H5 subtype AIV, such as Vectormune® A: it provides effective immune protections for turkeys and domestic ducks against H5 subtype HPAIV.  Another construct significant protective effect in chickens after H5N1 and H5N2 HPAIV challenges that could achieve the survival rate of the animals by 80%-95%.

Some disadvantages:

• high level of pre-existing anti-vector immunity, requiring relative longer time to provide full protection by in ovo route;
• potential risk caused by lifelong infections in hosts cells can be an impediment

 

 

SOME GENERAL CONCLUSIONS

 

1. Avian Influenza remains a continuous massive threat for the domestic birds, but the threat to humans is comparatively low.  At present, it is more likely that a zoonotic epidemic or pandemic would originate from swine influenza virus.  With our present knowledge, however, we cannot predict what will be the animal source of the next epi/pandemic. Surveillance of all possible sources remains important.
2. In order to control AIV in domestic birds, Europe and North-America stick to massive culling of animals, based on a mix of public health and economic interests, but the question is whether this policy is sustainable and ethically correct. China has started with poultry vaccination since almost a decade with apparently favorable results. 
3. Many vaccine platforms are under development.  While mRNA has gained a lot of interest, it is probably  still too expensive and complicated to use in  poultry. Some vector based approaches are well advanced for poultry,  including Adeno, Newcastle Disease Virus and Herpes Virus of Turkey.   
4. Although these novel approaches are more immunogenic than inactivated virus and other traditional methods (split vaccine, subunit …) the basic problem remains that the virus changes all the time (especially the head of HA), resulting in the risk of “vaccine mismatch”, irrespective of the platform.  There is continuous progress towards a broad or universal flu vaccine, but it has not yet been realized.       

 

Best wishes,

 

Guido