Strains of a common subtype of influenza virus, H3N2, have almost universally acquired a mutation that effectively blocks antibodies from binding to a key viral protein, according to a study from researchers at Johns Hopkins Bloomberg School of Public Health. The results have implications for flu vaccine design, according to the researchers. Current flu vaccines, which are “seasonal vaccines” designed to protect against recently circulating flu strains, induce antibody responses mostly against a different viral protein called hemagglutinin.
The new mutation, described in the study published online in PLoS Pathogens, was first detected in the 2014–2015 flu season in some H3N2 flu strains, and evidently is so good at boosting flu’s ability to spread that it is now present in virtually all circulating H3N2 strains. Recent flu seasons, in which H3N2 strains have featured prominently, have been relatively severe compared to historical averages.
The mutation alters a viral protein called neuraminidase, and the researchers found in their study that this alteration paradoxically reduces the ability of flu virus to replicate in a type of human nasal cell that it normally infects. However, the researchers also found evidence that the mutation more than compensates for this deficit by setting up a physical barrier that hinders antibodies from binding to neuraminidase.
The goal of the study was to understand better the workings of the new H3N2 mutation. Scientists have known that it alters the flu virus’ neuraminidase protein in a way that provides an attachment point, close to neuraminidase’s active site, for a sugar-like molecule called a glycan. But how the presence of a glycan at that location on the neuraminidase protein improves the virus’s ability to infect hosts and spread has not been clear.
Researchers compared the growth, in laboratory cells, of typical H3N2 strains that have the glycan-attachment mutation to the growth of the same flu strains without the mutation. They found that the mutant versions grew markedly more slowly in human cells from the lining of the nasal passages—a cell type that a flu virus would initially infect. The researchers found the likely reason for this slower growth: the glycan-attracting mutation hinders the activity of neuraminidase. The protein is known to serve as a crucial flu enzyme whose functions include clearing a path for the virus through airway mucus and enhancing the release of new virus particles from infected cells.
It was not entirely unexpected that the addition of a moderately bulky glycan molecule near the enzyme’s active site would have this effect. But it left unexplained how that would benefit the virus. The scientists solved the mystery by showing that the glycan blocks antibodies that would otherwise bind to or near the active site of the neuraminidase enzyme.
Neuraminidase, especially its active site, is considered one of the most important targets for the immune response to a flu infection. It is also the target of flu drugs such as Tamiflu (oseltamivir). Thus, it makes sense that a mutation protecting that target confers a net benefit to the virus, even if it means that the neuraminidase enzyme itself works less efficiently. The researchers have been following up their findings with studies of how the new mutation affects the severity of flu, how it has spread so rapidly among H3N2 strains, and how these altered flu strains have adapted with further mutations.
