Might it be possible to develop a vaccine that works on every strain of influenza, rather than going through a seasonal exercise of vaccination every year? Or at least many strains, rather than just a few? In today's research materials, scientists discuss a possible approach, identifying a novel part of the influenza virus to target, a part of the viral structure that may mutate less readily than the usual vaccine targets. Viruses mutate aggressively when they infect large population, a challenge to both vaccination and natural immunity. The immune system recognizes small parts of a virus, epitopes, and the epitopes most readily recognized are those that mutate to form new strains. This is why we are presently stuck with (a) the yearly death toll inflicted by influenza variants, and (b) the small chance of a much worse variant showing up at some point to produce an outcome to rival the 1918 pandemic.
The burden of infectious disease falls most heavily on the old. An age-damaged immune system responds poorly to many types of vaccination, and is in any case far less capable of mounting a defense against pathogens of all varieties, even given vaccination. Vaccination clearly helps in the case of influenza, but old people are remain vulnerable and exhibit the highest mortality as a result of infection. Arguably far greater effort in research and development should be directed towards the rejuvenation of the immune system rather than better vaccines: regrowing the thymus; regeneration of lymph nodes; restoring youthful hematopoietic function; and clearing damaged and misconfigured immune cells.
In a typical year, influenza affects more than 20 million people in the United States and leads to more than 20,000 deaths. Vaccines against influenza typically coax the immune system to generate antibodies that recognize the head of hemagglutinin (HA), a protein that extends outward from the surface of the flu virus. The head is the most accessible regions of HA, making it a good target for the immune system; unfortunately, it is also one of the most variable. From year to year, the head of HA often mutates, necessitating new vaccines.
Researchers have designed experimental influenza vaccines to be more universal, spurring the body to create antibodies against the less-variable stalk region of HA. In the new study, a collaborative team of scientists characterized 358 different antibodies present in the blood of people who had either been given a seasonal influenza vaccine, were in a phase I trial for an experimental, universal influenza vaccine, or had been naturally infected with influenza. Many of the antibodies present in the blood of participants were antibodies already known to recognize either the HA head or stalk. But a collection of new antibodies stood out; the antibodies bound to the very bottom of the stalk, near where each HA molecule is attached to the membrane of the flu virion.
Researchers named this section of HA the anchor, and began studying it further. In all, the scientists identified 50 different antibodies to the HA anchor, from a total of 21 individuals. The antibodies, they discovered, recognized a variety of H1 influenza viruses, which account for many seasonal flu strains. Some of the antibodies were also able to recognize pandemic H2 and H5 strains of influenza in lab tests. And in mice, the antibodies successfully protected against infection by three different H1 influenza viruses.
Broadly neutralizing antibodies (bnAbs) targeting epitopes of the influenza virus hemagglutinin (HA) have the potential to provide near universal protection against influenza virus infection. However, viral mutants that escape bnAbs have been reported. The identification of bnAb classes that can neutralize viral escape mutants is critical for universal influenza virus vaccine design. Here, we report a distinct class of bnAbs targeting a discrete membrane-proximal anchor epitope of the HA stalk domain. Anchor epitope-targeting antibodies are broadly neutralizing across H1 viruses and can cross-react with pandemic-threat H2 and H5 viruses. To maximize protection against seasonal and pandemic influenza viruses, vaccines should aim to boost this previously untapped source of bnAbs that are widespread in humans.