The Constant Evolution of Influenza Complicates Long-Term Immunity
The influenza virus undergoes continuous changes due to two key processes:
- Antigenic drift – gradual mutations in the viral proteins hemagglutinin and neuraminidase, which enable the virus to evade the immune response.
- Antigenic shift – abrupt genetic changes that can lead to the emergence of new strains with pandemic potential.
As a result of these changes, influenza vaccines must be updated annually. Seasonal vaccines protect only against circulating strains (H1, H3, B) and are ineffective against novel pandemic-potential viruses such as H5Nx or H7Nx.
Avian influenza H5Nx is widespread among wild and domestic birds and can infect humans if it acquires mutations that enhance its binding to human sialic acid receptors. While no human-to-human transmission of H5Nx has been reported, experiments in ferrets suggest that only a few mutations in the HA gene are needed to enable airborne transmission. Additionally, genetic reassortment between avian and human influenza viruses could lead to the emergence of new pandemic strains.
Antibodies Targeting H5 Hemagglutinin
Hemagglutinin (HA) is an influenza virus protein initially synthesized as a single polypeptide chain and later cleaved by host proteases into two subunits: HA1, which mediates receptor binding, and HA2, which facilitates viral entry into host cells.
Following infection or vaccination, the immune system primarily generates antibodies against the HA head, which is highly variable. These antibodies block viral attachment to host cells and confer protection.
MIT, Harvard, and Cambridge researchers investigated how human naïve B cells (which have not previously encountered the antigen) respond to the hemagglutinin of avian influenza H5. They compared these responses with B cells capable of recognizing H5 and circulating H1N1 viruses. The study revealed that naïve B cells specific for H5 are more prevalent than those cross-reactive to both H5 and H1. Naïve antibodies these cells produce bind to vulnerable sites on H5 HA like antibodies generated after infection or vaccination.
Naïve Antibodies Interact with a Broad Spectrum of H5 Hemagglutinins
The researchers identified two types of naïve antibodies: those specific to the H5 HA head and those cross-reactive to both H1 and H5. Key amino acid residues involved in antibody binding to HA are conserved among different H5 strains. Approximately 95% of antibodies recognizing H5 VN04 were also bound to the closely related A/Indonesia/5/2005 strain. However, as amino acid sequence divergence increased, the ability of antibodies to recognize HA declined.
Around 25% of naïve antibodies interacted with conserved regions of HA across different H5 strains. Despite the high sequence similarity in the HA stalk domain of H5 viruses, cross-reactivity between H1 and H5-specific antibodies was limited, suggesting that these antibodies are sensitive to minor amino acid variations in HA that do not necessarily affect the HA head.
Naïve Antibodies Against H5 HA Can Neutralize the Virus
Of the 26 antibodies tested, nine (~35%) demonstrated neutralizing activity at a 100 µg/mL concentration. Most of these antibodies were specific to the HA head, with a strong correlation between binding affinity and neutralization efficacy.
The three highest-affinity antibodies exhibited inhibitory concentrations (IC50) ranging from 0.34 to 35.3 µg/mL. Unlike antibodies generated after infection or vaccination, these naïve antibodies may provide immediate protection upon first exposure to emerging H5Nx strains, contributing to pandemic prevention.
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Reference
Human naïve B cells recognize prepandemic influenza virus hemagglutinins
