Llama antibodies are different from ours. Our antibodies are a mix of two pairs of proteins, heavy and light, wrapped around each other. Llamas, camels, and sharks all use only a pair of heavy chains. Because they are smaller, they can wedge into molecular crevices that our larger antibodies can’t access. Perhaps that’s why scientists based at The Scripps Institute decided to use them as a basis for flu protection.
There are four types of influenza viruses, creatively termed A, B, C, and D. Influenzas A and B are responsible for seasonal epidemics in humans, and influenza A is the one that causes pandemics. Influenza A viruses are further divided into subtypes based on two proteins on the surface of the virus: hemagglutinin (H) and neuraminidase (N). There are 18 different hemagglutinin subtypes and 11 different N subtypes, leading to nomenclature like H3N1.
Current flu vaccines generate antibodies to the head of the hemagglutinin protein, which is highly variable. This is why we need to get a new shot every year: it ensures we make antibodies that bind to and counteract the strain in circulation that year. Broadly neutralizing antibodies that recognize all forms of hemagglutinin have been made and tested, but they don’t combat influenza B, and they don’t last for very long in our upper airways.
So researchers immunized llamas with a flu vaccine and extra hemagglutinin molecules and isolated four antibodies the llamas made, two against influenza A and two against influenza B. When they examined the structures of the antibodies bound to the hemagglutinin molecule, they saw that they bound to the stem of the molecule, which is conserved across flu subtypes. (The variable head of the molecule is targeted by current vaccines.) Moreover, each antibody contacted a different part of the hemagglutinin stem.
Each antibody neutralized a group of flu viruses, not just one; but the groups of viruses did not overlap. So the scientists made a composite antibody by fusing parts of different llama antibodies with a human antibody base (the parts are termed “nanobodies” and targeted two different regions on the hemagglutinin stem). In a test tube, the resulting fusion antibodies could neutralize flu strains that neither of their single constituents could alone. When given to mice intravenously a day before the mice were infected with flu, the fusion antibodies were protective against a panel of 60 different flu viruses. And when administered to the mice intranasally a month before infection, they were also able to confer protection.
“If the above preclinical findings translate to humans, an annual intranasal administration may provide passive protection for the entire influenza season and would be of particular benefit to the elderly and other high-risk groups,” they conclude. Granted, that is quite a big if. But the authors note that since the antibodies work quickly, they could also be used prophylactically at the start of a flu pandemic, and the same strategy might be applicable to other rapidly mutating pathogens.