Nature: Review of Cross-Species Transmission of HPAI H5 & Recommendations For development of Vaccines

#17,499

While no one can predict the future trajectory and impact of HPAI H5 with any certainty, its rapid evolution and remarkable intercontinental spread - which accelerated following a reassortment event in summer of 2016 - has many scientists understandably concerned.  

Over the past 7 years we've seen HPAI H5 clade 2.3.4.4 switch from H5N8, to (briefly) H5N6, and now (primarily) to H5N1, and expand into at least 8 subclades (A-H).

The virus has also traveled down the full length of the African Continent (2017), crossed the Atlantic and become endemic in both North & South American birds (2021), and has spilled over into a remarkable number of mammalian species (see below).

While confirmed human cases remain low, surveillance, testing, and reporting remains limited around the globe (see UK Novel Flu Surveillance: Quantifying TTD), and in some places, practically non-existent. 

This coming week (June 20th) the CDC will hold a webinar for clinicians (see CDC Webinar (Jun 20th): What Providers Need to Know about Zoonotic Influenza) on recognizing, treating, and reporting novel flu infections. 

For those desirous of a long (and technical) read this Sunday morning, we've got a review article - published by Nature - on the history, and recent changes in the genetics, of HPAI H5 along with recommendations for the development of vaccines, mAbs, and antivirals for use against this potential threat. 

Due to its length, I've only reproduced the link, abstract, and some excerpts. You'll want to follow the link to read it in its entirety.  I'll have more when you return. 

Potential cross-species transmission of highly pathogenic avian influenza H5 subtype (HPAI H5) viruses to humans calls for the development of H5-specific and universal influenza vaccines

Pan Huang, Lujia Sun, Jinhao Li, Qingyi Wu, Nima Rezaei, Shibo Jiang & Chungen Pan

Cell Discovery volume 9, Article number: 58 (2023) Cite this article

Abstract

In recent years, highly pathogenic avian influenza H5 subtype (HPAI H5) viruses have been prevalent around the world in both avian and mammalian species, causing serious economic losses to farmers. HPAI H5 infections of zoonotic origin also pose a threat to human health. Upon evaluating the global distribution of HPAI H5 viruses from 2019 to 2022, we found that the dominant strain of HPAI H5 rapidly changed from H5N8 to H5N1. A comparison of HA sequences from human- and avian-derived HPAI H5 viruses indicated high homology within the same subtype of viruses. Moreover, amino acid residues 137A, 192I, and 193R in the receptor-binding domain of HA1 were the key mutation sites for human infection in the current HPAI H5 subtype viruses. The recent rapid transmission of H5N1 HPAI in minks may result in the further evolution of the virus in mammals, thereby causing cross-species transmission to humans in the near future. This potential cross-species transmission calls for the development of an H5-specific influenza vaccine, as well as a universal influenza vaccine able to provide protection against a broad range of influenza strains.

Introduction

Avian influenza is an infectious disease that affects poultry and wildfowl. It is caused by highly pathogenic avian influenza (HPAI) or low pathogenic avian influenza (LPAI) viruses, which belong to the Orthomyxoviridae family and have a single-stranded negative-sense RNA genome. Avian influenza viruses (AIVs) are mainly classified on the basis of their surface proteins, hemagglutinin (HA) and neuraminidase (NA). HA protein on the surface of the virion, the main antigenic site in vaccine design, causes erythrocyte agglutination in vitro and in vivo1. Over the years, outbreaks of HPAI H5 subtype viruses in poultry have caused huge economic losses to the farming industry. In 2022, more than 25 million poultry and wild birds were infected with HPAI H5 worldwide, resulting in 5.28 million deaths (https://wahis.woah.org/).

Recently, HPAI H5 has caused more sporadic cases, or even outbreaks, in mammals, including minks, otters, foxes, and sea lions2,3,4. With possible further mutations in avian and mammalian species, HPAI H5 has a strong potential to cause human infection and trigger a global pandemic. Therefore, it is essential to develop an H5-specific vaccine, as well as a universal influenza vaccine, to fully cover a broad range of influenza strains.

          (SNIP)

While small-molecule compounds, peptides, and antibodies have been developed for influenza antiviral therapy, the constant mutation of the virus and its ability to evade immune response confound these efforts. Therefore, drugs and vaccines must be regularly updated to address the emergence of new strains. In response, scientists are trying different methods to develop universal vaccines against multiple subtypes of influenza viruses. HA is the main immunogen for vaccine design and mainly induces antibodies against the RBD region at the spherical head of HA, which is also highly prone to mutation. However, some cross-protective antibodies against highly conserved HA stalk may also be induced104. Emerging vaccine platforms and new vaccine adjuvants also provide pathways toward improving vaccine efficacy. Although not emphasized in this review, the potential of cross-reactive T cell-based responses for influenza vaccine design cannot be ignored.

Currently, avian influenza vaccines are mandatory for poultry immunization. However, they are not included in routine human immunization but are only used as a preventive vaccination strategy during emergencies. HPAI H5 viruses are circulating in birds and have even caused outbreaks in mammals in recent years, thus raising concerns about HPAI H5 infections in humans. Heterologous prime–boost immunization strategies against H5N1 could induce broader cross-clade antibody responses. It is also worth considering priming with a universal vaccine and boosting with a specific vaccine against the current pandemic strain.

          (Continue . . . ) 

Huang, P., Sun, L., Li, J. et al. Potential cross-species transmission of highly pathogenic avian influenza H5 subtype (HPAI H5) viruses to humans calls for the development of H5-specific and universal influenza vaccines. Cell Discov 9, 58 (2023). https://doi.org/10.1038/s41421-023-00571-x

While vaccine manufacturing technology has come a long way - creating, testing, and deploying billions of doses of a safe and effective H5Nx vaccine in the opening months of an avian flu pandemic is still beyond our abilities.

Any vaccine would likely require two shots - 30 to 60 days apart - to convey significant immunity, and as we've seen previously (see Manufacturing Pandemic Flu Vaccines: Easier Said Than Done), vaccine production doesn't always go smoothly.

Readers with long memories may recall that 15 years ago (2008) - when H5N1 was still a regional threat (primarily in Asia & the Middle East), but infecting far more humans (see WHO chart below) - we saw similar discussions on possible pre-pandemic vaccine strategies (see UK: Considering A `Prime Directive' and Prepandemic Vaccine Strategies).

In 2010, as the 2009 H1N1 pandemic was winding down, Dr. Klaus Stohr, former head of the World Health Organization's global influenza program, floated the idea (see The Prime Of Our Lives) of including potential future pandemic strains in yearly seasonal flu shots to create some degree of pre-existing immunity. 

Essentially, this was done in Japan back in 2008, when their limited stockpile of H5N1 bird flu vaccine was about to expire. They decided to `store it’ in the arms of healthcare and public safety workers, rather than pour it down the drain (see Japan Begins Pre-Pandemic Inoculation Of Health Care Workers).

In a similar vein, in 2011 (see Nature: A Preemptive H2N2 Vaccine Strike?), researchers concerned over the possible return of H2N2 (last seen in the 1960s), suggested including an H2N2 strain in the yearly jab.  

That idea, like the others mentioned above, never gained traction. 

While the inclusion of an H5 component in flu vaccines to `prime' the population might help blunt the opening months of an H5N1 pandemic, a strain specific `booster' shot would almost certainly still be needed.   

The rub is, no one knows what the next emerging influenza virus is going to be (H2? H3? H5? H7? H9?). And our experience with the novel 2009 H1N1 pandemic has shown that having had an H1 vaccination (or exposure) in the past was no guarantee of immunity.

The other obstacle is - in this increasingly vaccine-hesitant culture - whether people would accept a pre-pandemic vaccine, or a seasonal jab with an added H5 component. 

H5N1 vaccines have performed poorly without the addition of adjutants, which tend to increase adverse reactions, and that might further discourage uptake of the vaccine. 

There are other potential problems as well, including those involving ADE (Antibody Dependent Enhancement), and OAS (Original Antigenic Sin), both of which can produce paradoxical, and potentially dangerous immune responses. 

For a deeper look at those issues you may wish to revisit Scripps Research: Study Suggests Some Flu Viruses May Be Less Susceptible To A `Universal' Flu Vaccine.

In addition to these many practical considerations, memories of an ill-fated vaccination campaign 47 years ago (see Remembering An Emergency Pandemic Vaccine Program That Went Awry) still haunt public health officials.

Me in 1976, giving Swine Flu Shots.

While a large scale pre-pandemic vaccination campaign might be beneficial, it would undoubtedly face serious headwinds - from the public - and from government and public health officials who would have to answer for any perceived shortcomings. 

That said, I would not be surprised to see specific sectors (healthcare, military, and other `essential' workers) offered a pre-pandemic jab (from existing stockpiles) if the threat levels should increase. 

Last month we saw Japan announce plans to Stockpile 10 Million Doses of H5N1 Vaccine for that very reason.  I would expect to see other countries follow suit.