If flu vaccines produced more plasma cells from bone marrow (pictured here) that live long lives, immunity would last much longer.
Gopal Murti / Scientific Source
By Jon Cohen
The annual flu vaccine saves lives and saves many people from serious illness, which is why governments and employers promote and subsidize its use. But it is hardly an ideal vaccine, and offers so-so protection that fades quickly. A new, unique kind of study, published today in Science, helps explain these deficiencies: A key cell type hidden in bone marrow that begins rapidly in activity within a few months disappears after vaccination, researchers found. The discovery could lead to new strategies to increase the durability of the vaccine.
The best vaccines – such as those for measles, rubella and diphtheria – provide almost 100% protection for life. However, influenza vaccines often do not exactly match the rapidly evolving influenza virus, so their effectiveness changes every year: In the United States between 2009 and 2019, it ranges from a low of 19% to a high of 60%. And protection disappears quickly: If you live in a temperate region of the world and receive the shot in early fall, immunity may disappear before the end of that winter.
To better understand the sustainability problem, Rafi Ahmed, an immunologist at Emory University School of Medicine, hopped into a type of B-cell that lives in the bone marrow and whose role Ahmed helped discover in 1996. B-cells make antibodies that can attach to and eliminate viruses. Ahmed focused on a type of B-cell called bonomer plasma cells (BMPCs), which continuously produce antibodies after an infection or vaccination. So-called B-cells also produce antibodies and are made in the same way, but unlike BMPCs, they do not pump out the protective proteins. Instead, as the name suggests, memory B cells that are trained to recognize a specific virus are only put together when they are re-exposed there. It takes them several days after an infection to produce high levels of antibodies – a disadvantage in flu, which can quickly cause illness.
To the surprise and dismay of many, Ahmed’s group in 1996 showed that some BMPCs could live for many years, which meant that they could, in theory, be granted long-term immunity. Whether influenza vaccines trigger high levels of BMPCs and if so, whether the cells are the long-lived variety, however, was a mystery.
Ahmed and colleagues examined the bone marrow and blood of 53 volunteers between the ages of 20 and 45 years in the weeks and months before and after flu vaccines. (Some people have experienced more than one flu season.) The study was not fun for the participants: Removing fluids from a bone is a challenging and painful procedure in which the pelvis is removed with a special needle. “The logistics … were very difficult, and I think no one will ever try to do the same thing again,” says Ahmed.
Rino Rappuoli, chief scientist at GlaxoSmithKline Vaccines, says he knows of no other study that has sampled bone marrow research. “Rafi’s work is amazing and pioneering,” Rappuoli says.
The researchers found spikes of BMPCs specific for flu 4 weeks after immunization. But after 1 year, the new cells were virtually gone. Rappuoli and others here are not particularly surprised, but marvel at the evidence. “It simply came to our notice then [blood] antibody titers and decreasing protection in humans after receiving the flu vaccine, ”says Adam Wheatley, an immunologist at the University of Melbourne. “It’s a really nice piece of work.”
The study “helps define the landscape” of the poor sustainability of the flu vaccine, says Mark Slifka, an immunologist at Oregon National Primate Research Center who completed his Ph.D. with Ahmed more than 20 years ago but was not involved in this work. “They bite off the stone in terms of understanding why the immune response is short-lived,” Slifka says.
But Slifka thinks that the BMPC population stimulated by vaccines probably has a small proportion of cells with long-lived animals, undetected in this study, that could provide more lasting protection. The way to increase their presence is to improve the system so that it generally creates more BMPCs, he says. One possible way to do this is with adjuvants, additives to vaccines that act as irritants, and boost the immune response. It may also help to increase the amount of viral proteins in the vaccine, he says.
The first flu vaccines, developed in the 1940s, used adjuvants. They contained killed flu viruses mixed it with a water-in-oil emulsion called “imperfect Freund’s.” But the adjuvant caused ulcers at the injection site, so it was dropped from later vaccines. To further reduce unusual reactions, researchers also stopped injecting the highly killed virus, replacing it only with the surface proteins from the virus. The resulting vaccines had fewer viral proteins and no immune-stimulating agents. These faxes, widely used today, cause far fewer side effects – but they came at a steep cost, says Slifka, who last year published a review article that hammered into these points. “We have damaged the immunogenicity and sustainability of the response.”
But for the past 2 decades, improved adjuvants have found their way into licensed fax machines. A refurbished flu vaccine containing an oil-in-water supplement – the water protects the oil and makes it safer – has been used in Italy since 1997 and was approved by European and American regulators respectively in 2000 and 2015. But whether it is capable to trigger long-term BMPCs is unclear. No one in Ahmed’s study received this product – when the project began, it was not even a license in the United States – which is “unfortunate,” Rappuoli says.
“It’s completely crazy” that impact vaccines most commonly used do not include adjuvants, Ahmed says. “I hope things will change in the world of flu vaccines, and 10 years from now you will not be getting vaccines with non-adjuvants. This has taken years. It is difficult to change the sector. ”
