A #monoclonal anti-hemagglutinin stem #antibody modified with #zanamivir protects against both #influenza A and B viruses

Significance

Anti-influenza therapeutics remain essential for the control of influenza infections, which may require hospitalization for the most severe cases. Hemagglutinin (HA) and neuraminidase (NA), the two membrane glycoproteins of the influenza virus, play crucial roles in the viral replication cycle. While many monoclonal antibodies and small-molecule inhibitors target HA or NA, each faces limitations tied to their individual properties. We developed an antibody–drug conjugate (ADC) by covalently linking the NA inhibitor zanamivir to MEDI8852, an HA stem-specific monoclonal antibody. The MEDI8852–zanamivir conjugate targets both HA and NA and offers robust and long-lasting protection in mice against lethal infections with influenza A and B viruses. This approach represents an addition to anti-influenza therapy.

Abstract

Influenza remains a significant public health threat. Both monoclonal antibodies and small-molecule inhibitors can target the influenza surface glycoproteins hemagglutinin (HA) or neuraminidase (NA) for prevention and treatment of influenza. Here, we combine the strengths of anti-influenza antibodies and small molecules by site-specific conjugation of the NA inhibitor zanamivir to MEDI8852, an HA-specific fully human monoclonal antibody. MEDI8852 targets the conserved stem region of HA and inhibits HA-mediated fusion of the viral and host cell membranes. Elimination of virus-infected cells involves Fcγ receptor–mediated effector functions. The efficacy of MEDI8852 is limited to influenza A viruses. Zanamivir, on the other hand, binds to the active site of NA in both influenza A and B viruses to inhibit NA activity and virus release. However, because of its small size, zanamivir has a short half-life and requires repeated dosing at high concentrations. We produced a MEDI8852–zanamivir antibody–drug conjugate (ADC) that engages Fc-mediated effector functions and benefits from neonatal Fc receptor (FcRn)-mediated recycling. The MEDI8852–zanamivir conjugate extends the circulatory half-life of zanamivir, targets both influenza HA and NA, and shows enhanced antibody-dependent cellular cytotoxicity (ADCC) compared to MEDI8852 alone. The MEDI8852–zanamivir conjugate protected mice from a lethal (10 × LD50) challenge with influenza A and B viruses at a dose similar to that required for broadly neutralizing anti-NA antibodies, with the added advantage of simultaneously targeting NA (influenza A and B) and HA (influenza A).

Source: Proceedings of the National Academy of Sciences of the United States of America, https://www.pnas.org/doi/10.1073/pnas.2424889122

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#Neuroinvasive #Oropouche virus in a patient with #HIV from extra-Amazonian #Brazil

{Excerpt} A novel reassortant Oropouche virus (OROV) lineage (with medium [M], large [L], and small [S] RNA segments : M1L2S2) has driven Brazil's largest and most geographically widespread OROV epidemic , expanding beyond the endemic Amazon basin to establish local transmission across multiple Brazilian states and other previously unaffected Latin American countries . The rapid spread of this lineage underscores its evolutionary potential and reinforces its significance as a public health threat .1 Similar to chikungunya and Zika viruses, expanding arboviruses can exhibit unexpected clinical and epidemiological shifts , including vertical transmissions , neuroinvasive effects, and potentially fatal outcomes.2–4 Although OROV typically causes self-limited febrile illness, accumulating clinical and experimental evidence suggests neurotropic potential .5 This Correspondence describes the first confirmed case of neuroinvasive OROV infection caused by the emergent M1L2S2 lineage in ext...

Stability of #influenza viruses in the #milk of #cows and #sheep

Abstract In late 2023, H5N1 high pathogenicity avian influenza (HPAIV) started circulating in dairy cattle in the USA . High viral titres were detected in milk from infected cows , raising concerns about onwards human infections . Although pasteurisation was shown to effectively inactivate influenza viruses in milk, unpasteurised milk still poses a risk of infection, both from occupational exposure in dairies and from the consumption of raw milk. We therefore assessed how long influenza viruses could remain infectious for in milk without heat inactivation. We examined the stability of a panel of influenza viruses in milk , including a contemporary H5N1 HPAIV and a variety of other influenza A and D viruses. We incubated viruses in cows' milk under laboratory conditions : at room temperature to simulate exposure in dairies and at 4°C to simulate exposure to refrigerated raw milk. Following an isolated report of H5N1 viral RNA being detected in milk from a sheep in the UK , we also c...

#Evidence of #Viremia in Dairy #Cows Naturally Infected with #Influenza A {#H5N1} Virus, #California, #USA

Abstract We confirmed influenza A virus (IAV) by PCR in serum from 18 cows on 3 affected dairy farms in California, USA . Our findings indicate the presence of viremia and might help explain IAV transmission dynamics and shedding patterns in cows. An understanding of those dynamics could enable development of IAV mitigation strategies. Source: US Centers for Disease Control and Prevention, https://wwwnc.cdc.gov/eid/article/31/7/25-0134_article ____

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