ByEmily Sohn
Published February 21, 2024
French veterinarian Gaston Ramon was researching diphtheria vaccines in the 1920s when he noticed something unusual. Adding breadcrumbs, tapioca, and other seemingly random ingredients made the vaccines work better.
Ramon used the word adjuvants to describe these additives, based on the Latin word adjuver, which means “to help.” Today, there are more than half a dozen of them in use for various vaccines, and scientists continue to refine their understanding of how these helpers work to take the reins of the immune system and optimize inflammation. The research, experts say, might be the key to a new generation of vaccines that fight off more diseases for longer periods of time.
Vaccines already work by stimulating the inflammatory processes necessary to fight off infections, says Bali Pulendran, an immunologist at Stanford University in Palo Alto, California. Adjuvants take the process a step further, helping our bodies produce enough of the right type of inflammation but not too much of it. “You need just that Goldilocks zone—not too hot, not too cold, but just the right kind of inflammation of the right level and in the right place,” Pulendran says. “That’s where adjuvants can do their magic.”
Controlled burn
The basic idea of a vaccine is to mimic the disease you want to protect against so that the immune system will respond in a specific way, says Larry Corey, an expert in virology, immunology, and vaccine development at the Fred Hutchinson Cancer Center in Seattle. Many vaccines do this with a killed version of a germ, a weakened version of a germ, or a toxic product of the germ that is packaged into a shot. Once injected, usually in the arm, the shot starts to trigger the immune system as soon as the offending agent, known as an antigen, enters the body. For an antigen that is new to the body, it takes two weeks to mobilize a measurable response.
The immediate reaction to a foreign antigen is called the innate immune response, and it involves specialized cells, such as dendritic cells and monocytes, which emit cytokines, prostaglandins, and other proteins that induce inflammation, Corey says. Symptoms of that immediate inflammation can include pain and swelling that may make your arm red and sore. In some cases, people also feel sick for a day or two.
In the meantime, immune cells carry the vaccine antigen to nearby lymph nodes, setting off a more lasting, “adaptive” immune response, during which yet more specialized cells, such as T cells and B cells, produce antibodies and develop a memory for the antigen. After they have been programmed, memory cells retreat to the bone marrow and lymph nodes, where they lay in wait until a similar invader appears again. The adaptive response is what leads to protection that can last for months to decades, Corey says.
Both the innate and adaptive immune responses rely on inflammatory processes, and vaccines are designed to try and induce just the right amount of it. “Vaccination is a form of inflammation,” says Corey. “You’re trying to elicit an immune response against the foreign antigen in a controlled way so you don’t get sick.”
Help needed
Some vaccines do a good job of inducing immunity simply by showing the immune system part of the pathogen being targeted; the meningococcal vaccine targeting meningitis is one example. But some diseases are particularly hard to develop vaccines for. HIV, for example, employs multiple strategies to avoid recognition by immune cells and downplay their response. Influenza and SARS-CoV-2 evolve variants that can evade immune recognition. The malaria parasite has a complicated life history with still poorly understood impacts on the immune system.
To develop vaccines for these and other elusive pathogens, scientists are tapping into the intricacies of the immune system—many of them still not completely understood. For the ever-evolving SARS-CoV-2 and influenza viruses, for example, some researchers are working on universal vaccines that would recognize the parts of antigens that remain stable even as other parts mutate to produce new strains.
Adjuvants are a major part of the effort to harness inflammation with vaccines, based on work dating back to Ramon’s era. The Frenchman’s discovery began with what was a routine procedure at the time. For decades, scientists had been injecting a toxin made by the diphtheria bacteria into horses to elicit an immune reaction. They would then extract the horse’s blood, which was now filled with antibodies, and use the serum to treat people who were sick with diphtheria.
Ramon noticed that when horses developed infections around the site of the vaccine injection, they produced a more powerful anti-diphtheria serum. Soon he was adding breadcrumbs and other items to shots to try and spur the same inflammatory reaction and aid immunity.
Around the same time that Ramon was doing his research, British immunologist Alexander Glenny, also working with shots of diphtheria toxin, found that he could accentuate their effects in rabbits by adding aluminum salts. Aluminum was the first adjuvant used in licensed vaccines in the U.S. and the only one used in these vaccines for the next 70 years. It is still the most commonly used, Pulendran says, contained in billions of doses of vaccines given today.
Adjuvant biology got its next boost in the mid-1990s with the discovery of receptors on innate immune cells that, Pulendran says, are like “the sixth sense in the body” for their ability to recognize bits of invading pathogens, initiate an inflammatory response, and rev up the adaptive immune system. That finding allowed scientists to start targeting specific receptors, leading to the development of at least half a dozen more adjuvants. One is a colorless oil called squalene that is sometimes supplemented with Vitamin E or other ingredients and is used in an influenza vaccine called Fluad, which is approved for older adults. Another is a compound from the Chilean soapbark tree, which is added to the Shingrix vaccine for shingles.
Helpers of the future
Researchers have a better handle on how some adjuvants work than others, says Darrell Irvine, an immunologist at the Massachusetts Institute of Technology in Cambridge. Some are accidental, like Ramon’s discovery. For instance, the mRNA vaccines produced by Pfizer and Moderna use an ingredient called lipid nanoparticles, which appear to work like adjuvants through pathways that are only partially understood. Some adjuvants are chosen more intentionally. For an adjuvant in the Shingrix vaccine, on the other hand, scientists incorporated a molecule that is a component of some kinds of infectious bacteria.
“Your immune system is evolved to recognize that molecule and it creates a certain kind of inflammation when it sees that molecule,” Irvine says. “It’s sort of fooling your immune system, saying, ‘There’s something dangerous. It looks like bacteria. And you should mount an immune response.’”
Eventually adjuvants might be able to reprogram gene activity in immune cells to fight off many illnesses at once, not just the one being targeted by a specific vaccine, says Pulendran, who is working on the technique. Studies, including work in his lab, suggest it might be possible.
In a combination of studies in mice and people, for example, evidence suggests vaccination with the BCG vaccine for tuberculosis can protect against influenza, candida yeast infections, staph infections, and respiratory infections, and researchers are investigating whether it might help against COVID.
Based on that research, along with evidence about the inflammatory molecules associated with those responses, groups including Pulendran’s are developing adjuvants that, he says, aim to induce low levels of long-lasting antiviral immunity, like lingering embers that burn on low heat for weeks to months and create a heightened resistance to all sorts of invaders. “It’s a kind of virus-agnostic inflammation that could be beneficial in fighting against any infection,” he says. “They keep the smoldering fire of good inflammation at a tolerable level—not too bad, not too damaging.”
Promise for cancer
Work on adjuvants that control inflammation in finely tuned ways are opening the potential for developing vaccines that would protect against diseases previously outside the realm of possibility for vaccination, including cancers, Irvine says. Ongoing trials of mRNA vaccines for melanoma and pancreatic cancer suggest that adjuvants (in this case, the lipid nanoparticles), combined with proteins produced by a person’s own tumors, could help the body develop immunity against cancer. “We don’t have really effective therapeutic vaccines for cancer yet, but we may get there one day,” he says. “The recent data have people excited.”
Underneath all these efforts to build better adjuvants and protect people from diseases is a basic idea: In order to fight diseases, our bodies need to produce just the right amount of inflammation to battle the illness but not make us extremely sick. When our immune systems can’t strike the right balance on their own, perhaps we can engineer solutions that do it for them.
Adjuvants of the future are likely to evolve alongside the growing understanding of how inflammation works, experts say, and may help tackle the diseases that continue to plague humanity: HIV, malaria, cancers, new strains of influenza and SARS-CoV-2, and whatever else emerges.
“A lot of the research in vaccines nowadays is trying to think about: How do you get the right amount of inflammation, and how do you make it happen at the right place to help the immune response without making people feel like they’ve gotten infected with something?” Irvine says. “Further engineered adjuvants will probably be an important part of finding ways to make vaccines for some of the really challenging scenarios.”
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