Influenza, a virus notorious for its rapid mutation and ability to evade the immune system, continues to pose a significant global health challenge. Traditional vaccines often struggle to keep pace with these changes, leading to mismatches with circulating strains and reduced effectiveness. This has spurred intense research into monoclonal antibodies (mAbs) engineered for broad-spectrum influenza protection, aiming to create "universal" therapies and vaccines.
Recent breakthroughs highlight the potential of engineered mAbs to neutralize a wide array of influenza A and B viruses. Scientists are focusing on several key strategies:
Targeting Conserved Viral Regions: A major focus is designing antibodies that target highly conserved regions of the influenza virus, particularly the hemagglutinin (HA) protein. The HA protein has a "head" region, which is highly variable and the primary target of current vaccines, and a "stem" region, which is much more conserved across different influenza strains.- HA Stem Antibodies: Broadly neutralizing antibodies (bnAbs) that target the HA stem have shown significant promise. These antibodies can prevent the virus from fusing with host cells, a critical step in infection. Research published in January 2025 highlighted the discovery and ongoing clinical studies of several HA stem-targeting bnAbs, such as FI6, which can bind to all 16 influenza A HA subtypes. Other notable mAbs in clinical development include MEDI8852 and VIS-410, which have demonstrated potent therapeutic effects in preclinical and clinical trials, respectively. MHAA4549A is another HA stem-targeting antibody that has shown to be well-tolerated and effective in reducing viral shedding in human challenge trials.
- HA Head Antibodies Targeting Conserved Sites: While the HA head is generally variable, studies have identified conserved regions within it, such as the receptor-binding site (RBS). Antibodies targeting these conserved epitopes, like CH65 and S139/1-derived antibody fragments, can neutralize multiple H1N1 strains. Recent research has also identified novel epitopes hidden in the HA trimeric interface that can be targeted by broadly neutralizing antibodies.
- Neuraminidase (NA) Targeting: The viral neuraminidase (NA) is another glycoprotein on the influenza virus surface. It is less abundant than HA but also a target for the immune system. Recent discoveries of protective antibodies recognizing conserved epitopes on NA from diverse influenza A and B viruses have renewed interest in NA as a vaccine target. Some mAbs targeting NA have shown therapeutic efficacy even when administered up to 72 hours after infection in animal models.
- Multidomain Antibodies and Nanobodies: Novel antibody engineering techniques are being employed to enhance potency and breadth. These include creating multidomain antibodies that can bind to multiple viral targets or epitopes simultaneously. Camelid single-domain antibodies (VHHs or nanobodies) are also being explored due to their small size, stability, and ability to access otherwise hidden epitopes. Gene transfer encoding fusion proteins of these engineered antibodies has shown cross-protection against both influenza A and B viruses in animal studies.
- IgM and IgA Engineering: Scientists are also exploring different antibody formats. For instance, engineered IgM antibodies, due to their large size and multiple binding sites (multivalency), can effectively cover the viral surface and prevent receptor engagement. This multivalency can also help overcome viral escape mutations. Similarly, polymeric IgAs (pIgAs), particularly tetrameric IgAs found in the nasal mucosa and induced by intranasal vaccination, have shown enhanced broad protection against influenza.
- Fc Domain Engineering: Modifying the Fc domain of antibodies can enhance their effector functions, such as antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC), leading to more effective viral clearance.
- Computational and Structure-Based Design: Advanced computational tools and a deeper understanding of antibody-virus interactions at a structural level are enabling the rational design of antibodies with improved affinity and breadth. This includes structure-based combinatorial approaches to engineer universal antibody fragments.
Despite these advancements, challenges remain. The high cost of mAb production and delivery, particularly in low- and middle-income countries, is a significant hurdle. Ensuring long-lasting protection and overcoming potential viral escape mutations are ongoing research priorities. Furthermore, the potential for antibody-dependent enhancement (ADE) of disease, while not extensively reported for influenza bnAbs, is a consideration that requires careful monitoring in clinical development.
The development of broadly neutralizing antibodies is a cornerstone of the strategy to achieve universal influenza protection. These engineered molecules, whether delivered as passive immunotherapy or elicited through advanced vaccine designs, hold the promise of transforming influenza prevention and treatment, offering longer-lasting immunity and better preparedness for seasonal epidemics and future pandemics. The ongoing innovation in antibody engineering, coupled with new vaccine platforms, is paving the way toward a future where influenza's threat is significantly diminished.