#18,336
After going a month without publishing, the EID Journal released a large collection of articles yesterday, several of which deal with HPAI H5N1. Two in particular look at the potential for there being some degree of immunity against the bovine B3.13 H5N1 virus due to prior exposure to the 2009 H1N1 seasonal flu virus (or vaccine).
This is, admittedly, not a new idea (see Two More Preprints Suggesting Prior H1N1 Infection May Provide Some Cross-Protection Against `Bovine' HPAI H5N1), although as recently as last summer the CDC was warning (see July 14th H5N1 Update) that:
CDC analyzed sera (blood) collected from people of all ages in all 10 HHS regions. Blood samples were collected during the 2022-2023 and 2021-2022 flu seasons. These samples were challenged with H5N1 virus to see whether there was an antibody reaction. Data from this study suggest that there is extremely low to no population immunity to clade 2.3.4.4b A(H5N1) viruses in the United States.
Antibody levels remained low regardless of whether or not the participants had gotten a seasonal flu vaccination, meaning that seasonal flu vaccination did not produce antibodies to A(H5N1) viruses. This means that there is little to no pre-existing immunity to this virus and most of the population would be susceptible to infection from this virus if it were to start infecting people easily and spreading from person-to-person.
Unexpectedly, over the past year we've seen numerous mild, sometimes even subclinical, human infections with the bovine B3.13 genotype of H5N1. Unlike past subclades and genotypes, this `bovine' variant appears to be less virulent in humans.
- Last August, we looked at a preprint by NIAID researchers at the NIH facility in Hamilton, MT, which found the bovine B3.13 genotype doesn't replicate in human lung tissues as well - or produce as strong of an immune response - as an earlier, more pathogenic, H5N1 strain (A/Vietnam/1203/2004).
- More recently, in Nature: Pathogenesis of Bovine H5N1 Clade 2.3.4.4b Infection in Macaques, we saw evidence that the route of exposure may make a difference in its presentation.
If there is one thing we can say about H5N1 - with more than 100 genotypes in North America - is that it has a lot of moving parts. And what we say about one variant may not apply equally to another.
What we have seen across many different subclades of H5N1, is that it appears to have a preference for infecting younger individuals (see A Predilection For The Young). In China's 5 year battle against H7N9 - the opposite was true - with those under 40 being far less affected (see comparison chart below).
- Those born prior to the mid-1960s were almost certainly first exposed to Group 1 flu viruses (H1N1 or H2N2)
- Those born after 1968 and before 1977 would have been exposed to Group 2 (H3N2)
- After 1977, both Group 1 and 2 viruses co-circulated, meaning the first exposure could have been to either one.
While it is possible that the B3.13 subtype might produce a `kinder and gentler' pandemic than other variants, there are no guarantees that any future H5N1 pandemic would stem from that genotype, or that its virulence couldn't change over time.
Due to their lengths, I've just posted the links, abstracts, and a few excerpts from each study. Both are well worth reading in their entirety. I'll have a bit more after the break.
Effect of Prior Influenza A(H1N1)pdm09 Virus Infection on Pathogenesis and Transmission of Human Influenza A(H5N1) Clade 2.3.4.4b Virus in Ferret ModelXiangjie Sun, Jessica A. Belser, Zhu-Nan Li, Nicole Brock, Joanna A. Pulit-Penaloza, Troy J. Kieran, Claudia Pappas, Hui Zeng, Jessie C. Chang, Paul J. Carney, Brandon L. Bradley-Ferrell, James Stevens, Terrence M. Tumpey, Min Z. Levine, and Taronna R. Maines
Author affiliation: Author affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, USA
Abstract
Reports of human infections with an influenza A(H5N1) clade 2.3.4.4b virus associated with outbreaks in dairy cows in the United States underscore the need to assess the potential cross-protection conferred by existing influenza immunity. We serologically evaluated ferrets previously infected with an influenza A(H1N1)pdm09 virus for cross-reactive antibodies and then challenged 3 months later with either highly pathogenic H5N1 clade 2.3.4.4b or low pathogenicity H7N9 virus.Our results showed that prior influenza A(H1N1)pdm09 virus infection more effectively reduced the replication and transmission of the H5N1 virus than did the H7N9 virus, a finding supported by the presence of group 1 hemagglutinin stalk and N1 neuraminidase antibodies in preimmune ferrets. Our findings suggest that prior influenza A(H1N1)pdm09 virus infection may confer some level of protection against influenza A(H5N1) clade 2.3.4.4.b virus.
(SNIP)
Our experimental evidence from the ferret model underscores the potential role of cross-reactive HA stalk and NA antibodies in reducing disease severity and transmission after H5N1 virus infection. However, future studies of larger group sizes are warranted, as are studies investigating how antibodies targeting internal influenza virus proteins, such as NP, or cellular immunity, contribute to cross-protection. In addition, a single seasonal virus infection in naive ferrets cannot fully recapitulate the complexity of human IAV immune history. Future studies involving ferrets vaccinated with different types of influenza vaccines or repeatedly exposed to seasonal viruses more closely mirroring the varied infection histories in humans will help provide deeper insights into cross-immunity elicited across different IAV subtypes. Furthermore, inclusion of multiple zoonotic strains to assess relative contributions of nonspecific effects in preimmune animals, as demonstrated here by performing tandem challenge studies and serology assessments with both H5N1) and H7N9 viruses, is a practice not typically used in the field yet shown to be a key provider of essential contextual information.
In conclusion, our results showed that prior pH1N1 virus infection more effectively reduced the replication and transmission of H5N1 virus than it did H7N9 virus in a ferret model. Those results suggest that pH1N1 virus immunity may confer some level of protection against H5N1 clade 2.3.4.4.b virus in humans.
Valerie Le Sage
Abstract
The emergence of highly pathogenic avian influenza A(H5N1) virus in dairy cattle herds across the United States in 2024 caused several human infections. Understanding the risk for spillover infections into humans is crucial for protecting public health. We investigated whether immunity from influenza A(H1N1)pdm09 (pH1N1) virus would provide protection from death and severe clinical disease among ferrets intranasally infected with H5N1 virus from dairy cows from the 2024 outbreak.We observed differential tissue tropism among pH1N1-immune ferrets. pH1N1-immune ferrets also had little H5N1 viral dissemination to organs outside the respiratory tract and much less H5N1 virus in nasal secretions and the respiratory tract than naive ferrets. In addition, ferrets with pH1N1 immunity produced antibodies that cross-reacted with H5N1 neuraminidase protein. Taken together, our results suggest that humans with immunity to human seasonal influenza viruses may experience milder disease from the 2024 influenza A(H5N1) virus strain.
(SNIP)
In conclusion, we found ferrets with immunity to pH1N1 virus exhibited reduced H5N1 virus replication and dissemination, had less mortality and fewer disease symptoms from H5N1 infection, and expressed H5N1 cross-reacting antibodies to the NA protein. Those results suggest that immunity to heterotypic influenza viruses may explain the mild symptoms observed during 2024 H5N1 infection of dairy and poultry farm workers. Although human H5N1 infections from the 2024 outbreak resulted in mostly mild illnesses, additional research addressing the effects of prior influenza immunity on the pathogenesis and transmission of H5N1 could shed light on the 2024 outbreak strain and inform pandemic risk plans.
(Continue . . . )
Yesterday, in Emerg. Microbes & Inf: Oseltamivir Resistant H5N1 (Genotype D1.1) found On 8 Canadian Poultry Farms, while the headline was the spread of antiviral resistant variants of the D1.1 genotype, it also included news of a new reassortment - a replacement of the NA - with a new, North American N1 gene.
The authors wrote:
The origin of the current panzootic A(H5N1) HPAI was due to a reassortment event involving the HA segment of clade 2.3.4.4b A(H5N8) HPAI and the NA segment from a LPAI virus circulating in European wild birds. Since then, similar events have been rare, as the only reported reassortment involving the surface protein encoding segments of an H5N1 clade 2.3.4.4b virus was an isolated event in Japan in 2022[12].
Here we report the first detection of a reassortant H5 clade 2.3.4.4b virus with a North American wild bird lineage N1 subtype in Canadian poultry. This virus is estimated to have emerged in Canada at the end of September, 2024 (TMRC: 2024-09-26, 95% HPD: 2024-09-01 - 2024-10-14), shortly before its first detection in British Columbia poultry on October 21, 2024 (Figure 1B).
Stay tuned. The H5N1 virus continues to evolve, as will its threat over time.
