The New Formula for Stronger, Longer-Lasting Vaccines

Vaccines work pretty well. But with a little help, they could work better.

Stanford researchers have developed a new vaccine helper that combines two kinds of adjuvants, ingredients that improve a vaccine’s efficacy, in a novel, customizable system.

In lab tests, the experimental additive improved the effectiveness of COVID-19 and HIV vaccine candidates, though it could be adapted to stimulate immune responses to a variety of pathogens, the researchers said. It could also be used one day to fine-tune vaccines for vulnerable groups like young children, older adults, and those with compromised immune systems.

“Current vaccines are not perfect,” said lead study author Ben Ou, a PhD candidate and researcher in the lab of Eric Appel, PhD, an associate professor of materials science and engineering, at Stanford University, Stanford, California. “Many fail to generate long-lasting immunity or immunity against closely related strains [such as] flu or COVID vaccines. One way to improve them is to design more potent vaccine adjuvants.”

The study marks an advance in an area of growing scientific interest: Combining different adjuvants to enhance the immune-stimulating effect.

The Stanford scientists developed sphere-shaped nanoparticles, like tiny round cages, made of saponins, immune-stimulating molecules common in adjuvant development. To these nanoparticles, they attached toll-like receptor (TLR) agonists, molecules that have become a focus in vaccine research because they stimulate a variety of immune responses.

Ou and the team tested the new adjuvant platform in COVID and HIV vaccines, comparing it to vaccines containing alum, a widely used adjuvant. (Alum is not used in COVID vaccines available in the United States.)

The nanoparticle-adjuvanted vaccines triggered stronger, longer-lasting effects. 

Notably, the combination of the new adjuvant system with a SARS-CoV-2 virus vaccine was effective in mice against the original SARS-CoV-2 virus and against Delta, Omicron, and other variants that emerged in the months and years after the initial outbreak. 

“Since our nanoparticle adjuvant platform is more potent than traditional/clinical vaccine adjuvants,” Ou said, “we expected mice to produce broadly neutralizing antibodies and better breadth responses.”

100 Years of Adjuvants

The first vaccine adjuvants were aluminum salts mixed into shots against pertussis, diphtheria, and tetanus in the 1920s. Today, alum is still used in many vaccines, including shots for diphtheria, tetanus, and pertussis; hepatitis A and B; human papillomavirus; and pneumococcal disease.

But since the 1990s, new adjuvants have come on the scene. Saponin-based compounds, harvested from the soapbark tree, are used in the Novavax COVID-19 Vaccine, Adjuvanted; a synthetic DNA adjuvant in the Heplisav-B vaccine against hepatitis B; and oil in water adjuvants using squalene in the Fluad and Fluad Quadrivalent influenza vaccines. Other vaccines, including those for chickenpox, cholera, measles, mumps, rubella, and mRNA-based COVID vaccines from Pfizer-BioNTech and Moderna, don’t contain adjuvants. 

TLR agonists have recently become research hotspots in vaccine science. 

“TLR agonists activate the innate immune system, putting it on a heightened alert state that can result in a higher antibody production and longer-lasting protection,” said David Burkhart, PhD, a research professor in biomedical and pharmaceutical sciences at the University of Montana in Missoula, Montana. He is also the chief operating officer of Inimmune, a biotech company developing vaccines and immunotherapies.

Burkhart studies TLR agonists in vaccines and other applications. “Different combinations activate different parts of the immune system,” he said. “TLR4 might activate the army, while TLR7 might activate the air force. You might need both in one vaccine.”

TLR agonists have also shown promise against Alzheimer’s disease, allergies, cancer, and even addiction. Inimmune’s experimental immunotherapy using TLR agonists for advanced solid tumors has just entered human trials, and the company is looking at a TLR agonist therapy for allergic rhinitis. 

Combining Forces

In the new study, researchers tested five different combinations of TLR agonists hooked to the saponin nanoparticle framework. Each elicited a slightly different response from the immune cells. 

“Our immune systems generate different downstream immune responses based on which TLRs are activated,” Ou said.

Ultimately, the advance could spur the development of vaccines tuned for stronger immune protection.

“We need different immune responses to fight different types of pathogens,” Ou said. “Depending on what specific virus/disease the vaccine is formulated for, activation of one specific TLR may confer better protection than another TLR.”

According to Burkhart, combining a saponin with a TLR agonist has found success before.

Biopharma company GSK (formerly GlaxoSmithKline) used the combination in its AS01 adjuvant, in the vaccine Shingrix against herpes zoster. The live attenuated yellow fever vaccine, given to more than 600 million people around the world and considered one of the most powerful vaccines ever developed, uses several TLR agonists. 

The Stanford paper, Burkhart said, “is a nice demonstration of the enhanced efficacy [that] adjuvants can provide to vaccines by exploiting the synergy different adjuvants and TLR agonists can provide when used in combination.”

Tailoring Vaccines

The customizable aspect of TLR agonists is important too, Burkhardt said. 

“The human immune system changes dramatically from birth to childhood into adulthood into older maturity,” he said. “It’s not a one-size-fits-all. Vaccines need to be tailored to these populations for maximum effectiveness and safety. TLRAs [TLR agonists] are a highly valuable tool in the vaccine toolbox. I think it’s inevitable we’ll have more in the future.”

That’s what the Stanford researchers hope for.

They noted in the study that the nanoparticle platform could easily be used to test different TLR agonist adjuvant combinations in vaccines.

But human studies are still a ways off. Tests in larger animals would likely come next, Ou said. 

“We now have a single nanoparticle adjuvant platform with formulations containing different TLRs,” Ou said. “Scientists can pick which specific formulation is the most suitable for their needs.”