Highly pathogenic avian influenza (HPAI) A(H5N1) virus, commonly known as bird flu, has been causing significant concern due to its widespread outbreaks in various animal populations, including dairy cattle in the United States. While the current risk to the general public remains low, the possibility of H5N1 evolving to facilitate sustained human-to-human transmission raises serious public health concerns. This article aims to analyze the potential case fatality rate (CFR) if H5N1 from cattle infections in the US were to achieve sustained human-to-human spread, considering the effects of mutations found in the circulating cattle clades, including B3.13 and the newly discovered D1.1 in Nevada.
The information presented in this article is based on a comprehensive review of scientific literature, including research papers, technical reports, and expert opinions. Databases such as PubMed, Google Scholar, and websites of public health organizations like the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) were consulted to gather relevant information.
The emergence of HPAI A(H5N1) infections in dairy cattle in the United States was first detected in March 2024 1. The virus responsible for these infections, belonging to the 2.3.4.4b clade and designated as genotype B3.13, has caused outbreaks in over 900 dairy herds across 16 US states as of December 2024 2. While B3.13 has shown a lower virulence in humans compared to other H5N1 strains, the recent discovery of the D1.1 genotype in Nevada dairy herds adds another layer of complexity to the situation 3.
Analysis of B3.13 viruses reveals critical mutations in the hemagglutinin (HA), M1, and NS genes, but a lack of critical mutations in the PB2 and PB1 genes, which are known to enhance virulence or adaptation to mammals 1. However, studies have shown that B3.13 viruses have rapidly accumulated adaptations in polymerase genes, enabling better replication in bovine cells and other mammalian species, including humans and pigs 2. These adaptations include mutations such as PB2 M631L, PB2 E362G, and PA L219I, which have been previously reported to enhance the replication of avian influenza viruses in mammals 2.
The NS gene of influenza A viruses also plays a crucial role in viral virulence. It encodes the non-structural protein 1 (NS1), which interferes with the host's immune response, allowing the virus to replicate more efficiently. Studies have identified specific mutations in the NS1 protein that can affect the virulence of H5N1 viruses 5. For example, the NS1-92E mutation has been associated with increased virulence in pigs 5.
Despite these adaptations, human infections with B3.13 have generally been mild, with symptoms like conjunctivitis and fever 6. This suggests that B3.13 may be less likely to cause severe disease in humans compared to other H5N1 strains. However, the virus has caused severe illness and mortality in other animals, such as cats, raising concerns about its potential to evolve further 6.
The D1.1 genotype, previously circulating in North American wild birds and poultry, has now been detected in Nevada dairy herds 3. Unlike B3.13, D1.1 has been associated with severe respiratory illness in humans 3. Notably, a teenager in British Columbia and a senior in Louisiana experienced severe illness after being infected with D1.1, with the latter case resulting in death 7.
Studies have identified specific mutations in the HA gene of D1.1 viruses isolated from severely ill patients, suggesting potential adaptation to the human respiratory tract 8. These mutations, including E186D and Q222H in the H5 hemagglutinin gene, warrant further investigation to assess their impact on viral transmissibility and pathogenicity 9. Additionally, the HA N193D substitution has been shown to enhance the virulence of H5N1 in mammalian hosts 10, raising concerns about the potential for increased virulence in humans infected with D1.1.
Furthermore, analysis of D1.1 viruses from infected cats revealed unique mutations, including T143A in the HA gene and F314L and L342Q in the PA protein 11. These mutations may affect infectivity, immune evasion, polymerase activity, and virulence, suggesting potential adaptation of the virus to mammalian hosts.
Comparing the mutations in B3.13 and D1.1 to those found in past human-adapted H5N1 strains can provide valuable insights into their potential for human-to-human transmission and virulence. While B3.13 lacks some of the key mutations associated with increased virulence in mammals, such as PB2 E627K, it has acquired other mutations that enhance its replication in mammalian cells 1. This suggests that B3.13 may be on an evolutionary trajectory towards increased adaptation to mammals, including humans.
D1.1, on the other hand, has shown evidence of mutations that could potentially enhance its ability to infect and spread among humans. The mutations observed in the HA gene of D1.1 viruses from severely ill patients raise concerns about its potential to become more transmissible and virulent in humans 8.
The primary mode of H5N1 transmission to humans is through direct contact with infected birds or contaminated environments. However, the recent outbreaks in dairy cattle have raised concerns about potential transmission through consumption of contaminated unpasteurized milk or raw meat 12. It is important to note that pasteurization effectively kills the virus, making commercially available cow's milk safe for consumption 13. However, consuming unpasteurized milk or undercooked meat from infected animals could pose a risk of infection.
Another potential route of transmission is through contaminated pet food. Cases of H5N1 infection in pets, particularly cats, have been linked to contaminated raw meat pet food products 14. Safe handling and storage of pet food are essential to minimize the risk of transmission to both pets and humans.
Reassortment, the process of genetic mixing between different influenza viruses, poses a significant risk for the emergence of novel influenza strains with pandemic potential. Co-infection of humans with H5N1 and human influenza viruses, such as H3N2 or the pandemic H1N1, could lead to the generation of reassortant viruses with altered virulence and transmissibility characteristics 14.
Studies have shown that reassortment between avian H5N1 and human influenza viruses can occur readily in vivo, particularly in the upper respiratory tract 16. While most reassortant viruses generated in laboratory settings have not shown a significant increase in transmissibility, the possibility of reassortment events leading to the emergence of a highly transmissible and virulent H5N1 strain cannot be ignored 17.
The recent detection of H5N1 in backyard pigs in the US, specifically the D1.2 genotype, further highlights the potential for reassortment 12. Pigs are considered "mixing vessels" for influenza viruses because they can be infected with both avian and human influenza viruses, increasing the likelihood of reassortment events.
Preventing the spread of H5N1 and mitigating the risk of a human pandemic requires a multi-faceted approach. One crucial aspect is the use of personal protective equipment (PPE) for those with occupational exposure to potentially infected animals. However, studies have shown that PPE use among farmworkers is not universal, increasing the risk of infection 18. Public health authorities should emphasize the importance of proper PPE use and ensure its availability to those at risk.
The circulation of H5N1 in US cattle has significant public health implications. The potential for the virus to evolve and acquire the ability for sustained human-to-human transmission could lead to a pandemic with devastating consequences. The economic impact of such a pandemic could be substantial, with disruptions to agriculture, trade, and travel. Healthcare systems could be overwhelmed by a surge in cases, potentially leading to shortages of medical resources and increased mortality.
Furthermore, the ability of H5N1 to infect a wide range of mammalian species raises concerns about the virus establishing itself in a new reservoir, increasing the risk of human exposure and making eradication more challenging 12.
Estimating the CFR of a hypothetical human-to-human transmissible H5N1 virus derived from cattle infections is challenging due to the complex interplay of viral and host factors. However, considering the available data on the virulence of B3.13 and D1.1, along with historical data on H5N1 CFRs, we can make some tentative assessments.
Historically, H5N1 viruses have exhibited high CFRs in humans, ranging from 30% to over 60% 5. However, it's important to note that these estimates are based on a limited number of cases with varying levels of healthcare access and treatment.
If B3.13 were to acquire mutations that enable sustained human-to-human transmission, its CFR might be lower than that of previous H5N1 strains due to its apparent lower virulence in humans. However, the possibility of reassortment with human influenza viruses or the acquisition of further virulence-enhancing mutations could significantly alter its CFR.
D1.1, with its demonstrated ability to cause severe illness in humans, poses a greater concern in terms of potential CFR. If this strain were to become transmissible among humans, its CFR could be comparable to or even higher than that of historical H5N1 strains.
The first severe H5N1 case in the US, caused by the D1.1 genotype, highlights the potential for severe illness and death associated with this strain 19. This case, along with the case of the severely ill teenager in British Columbia, underscores the need for increased vigilance and preparedness.
Effective surveillance and monitoring are crucial for early detection of H5N1 cases, tracking the evolution of the virus, and identifying potentially dangerous mutations. Genomic surveillance plays a vital role in this process, allowing researchers to monitor changes in the viral genome and assess the risk of increased transmissibility or virulence 8.
One challenge in surveillance efforts is the potential for asymptomatic H5N1 human cases 13. Asymptomatic individuals can still shed the virus and contribute to its spread, making it difficult to track and control outbreaks.
The ongoing circulation of H5N1 in US cattle, with the emergence of both B3.13 and D1.1 genotypes, poses a significant public health threat. While human infections with B3.13 have generally been mild, the virus's ability to infect a wide range of mammalian species and its ongoing evolution raise concerns about its future pandemic potential. The emergence of D1.1 in dairy cattle and its association with severe human illness has further heightened these concerns.
The potential for these viruses to evolve and acquire the ability for sustained human-to-human transmission, potentially through reassortment with human influenza viruses, necessitates continued research, surveillance, and public health preparedness. Genomic surveillance is crucial for monitoring the evolution of H5N1 and identifying potentially dangerous mutations. Public health authorities should strengthen surveillance efforts, promote biosecurity measures in animal populations, and develop effective strategies to mitigate the risk of a potential H5N1 pandemic.
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