Neuraminidase Protein Could be a Target for New Influenza Treatments and Vaccines

The variability of the influenza virus across seasons and strains has long impeded efforts at long-term prevention. Current seasonal influenza vaccines induce strain-specific immune responses which depend on how well they match virus strains in circulation, providing incomplete protection against pandemic or emerging viruses. This has led to efforts to produce a universal or cross-strain influenza vaccine.

Results from a new study published in Science suggest that antiviral treatments and antibody-guided vaccines with a new target, the virus-coat glycoprotein neuraminidase (NA), could yield cross-strain results. Investigators found that 3 human monoclonal antibodies (mAbs) isolated from a donor sick with H3N2 bind “with exceptional breadth” to multiple different influenza A and B virus neuraminidases.

Current vaccines target the mutable hemagglutinin, a protein involved in binding the influenza virus to target cells. These seasonal vaccines are effective, but their target—the immunodominant globular head of the protein—is highly variable between strains. Antibodies which target the stalk of the hemagglutinin have been shown to have greater breadth, but vaccines focused on this area are still early in development.

In this study, investigators isolated 45 mAbs from the volunteer sick with H3N2 influenza. Of the 45 mAbs, 3 bound to NA proteins of the H3N2 strain. The 3 mAbs identified were 1G04, 1E01, and 1G01. The same mAbs were then found to bind to NA proteins from multiple other types of influenza viruses.

According to investigators, the 3 mAbs “displayed broad binding to recombinant N2 NA (group 2) from seasonal and avian influenza viruses. Furthermore, 1G04 showed some cross-reactivity to N3 and N6 (group 2) and N1, N5, and N8 (group 1), as well as weak binding to influenza B NA. 1E01 showed a broader binding pattern that included group 1 NAs (N1, N5, and N8) and group 2 NAs (N3, N6, N7, and N9), as well as strong binding to influenza B NA from the B/Victoria/2/87 lineage and weak binding to the NA of the B/Yamagata/16/88 lineage. Finally, mAb 1G01 showed the broadest binding activity that covered all group 1 NAs (N1, N4, N5, and N8) and group 2 NAs (N2, N3, N6, N7, and N9), as well as NAs from both influenza B virus lineages.”

Next, 1G04, 1E01 and 1G01 were assessed for their ability to prevent influenza virus from infecting mammalian cells. Investigators found that the 3 mAbs inhibited multiple kinds of NA proteins from different influenza strains. The mice were protected from both morbidity, measured as weight loss, and mortality in a manner consistent with the discovered reactivity patterns. The therapeutic potential of the mAbs was also assessed. Mice were given a lethal dose of H3N2 virus and treated 48 or 72 hours after infection. Investigators found that the mice given lethal doses of H3N2 who were treated with a low mAb dose of 5mg/kg survived.

The study authors wrote that “because of the extensive breadth of these mAbs, they could potentially be used as antivirals for treatment of seasonal, pandemic, and zoonotic influenza virus infection in humans. In addition to the potential of these mAbs as therapeutics, they might also be useful for antibody-guided vaccine design.” They further concluded that “the discovery of these mAbs raises the hope that similar antibodies can be induced in the population if the right vaccination regimen is administered.”

This research was supported by the National Institutes of Allergy and Infectious Diseases, part of the National Institutes of Health.