Immune health: New, novel ingredients are on the scene. Can they take on the market’s old guard?

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When health-focused consulting agency SPRIM recently surveyed¹ more than 1,000 North American consumers about immune function and maintenance, it found not only that 57% of respondents professed concern over immune health thanks to COVID-19, but that fully 61% of those who’d purchased a supplement in the preceding 12 months either began doing so or increased their purchase frequency specifically to boost immunity in the pandemic’s wake.

None of which should surprise any supplement-industry insider who’s witnessed—often with unabashed glee—the shot in the arm that COVID-19 gave the immune-support sector. Nor should it come as a surprise that those same survey respondents ranked vitamin C, vitamin D, B-complex vitamins, zinc, and probiotics tops amongst their preferred immune-support ingredients.

But what’s surprising is the fact that despite the big-five’s dominance, a whole host of emerging actives—some familiar; others less so—are vying for ground in the crowded immune-support category. And some of them even have the clinical clout to colonize it.

Symbol of Our Age

Angie Rimel, marketing communications manager, Gelita (Eberbach, Germany), hits the nail on the head when she observes that “the immune system has become a symbol of our age.”

But immunity’s impact—and the interest it’s attracted—is anything but symbolic.

“The pandemic propelled explosive growth in the immune-health supplement market,” notes Maria Stanieich, marketing manager, Kyowa Hakko USA (New York), with domestic sales nearing $6 billion and growth topping out at 72.3% in 2020 alone, according to Nutrition Business Journal’s 2021 Condition Specific Report.

“And while growth is eventually expected to return to pre-pandemic rates,” Stanieich acknowledges, “spending on immune-health products will continue to increase.” After all, SPRIM’s immune-support survey found that 83% of participants who take immune-support supplements do so daily—and buy more when they run out.

That loyalty has transformed immune support from a seasonal concern to “a year-round category as consumers seek to maintain health and wellness post-pandemic,” Stanieich concludes. “Today’s consumers are making immune health a daily priority, banking on the long-term benefits of building a strong, resilient immune system.”

New Opportunities

But as is the case in every commercial market these days—from personal tech to online-dating—consumers aren’t content with the same old options. And for that reason, “There’s evergreen interest in new immune-support ingredients, both from consumers and from brands,” observes Benny Antony, PhD, joint managing director, Arjuna Natural Pvt Ltd. (Kochi, India).

Indeed, says Mike Weiser, PhD, senior director of innovation and R&D, PanTheryx (Phoenix, AZ), “Scientific breakthroughs and new clinical research are happening every day, and new ways of approaching immune health—especially through nutraceuticals—present promising opportunities.” No wonder he and his colleagues “feel strongly that white space exists for novel immune-support supplements,” he says.

But can that white space coexist within the territory that legacy immune ingredients have already claimed? Greg Ris, vice president, sales, Indena USA Inc. (Milan), thinks so. Ingredients with high consumer awareness around immune support may have enjoyed the amplest pandemic-related sales surge, he admits, but the attention and investment immunity’s attracted open up “new opportunities that make this an ideal time for innovation, and that will help grow awareness for new immune ingredients and the market overall.”

Crossing Categories

Sometimes those new ingredients appear in unanticipated places, too. As Antony puts it, “Active compounds can have multiple benefits.” So while an ingredient may gain initial traction for a “first-case use,” he says—be it joint health, digestive support, or energy—“as knowledge progresses, research throws up new avenues.” And those avenues can lead to immunity.

Weiser agrees. What’s more, he says, “There’s opportunity to innovate with new ingredients that target multiple health systems, since immunity connects tightly with, for example, gut health. This means that ingredients that support a healthy gut can have downstream effects on immunity. With this multifunctional approach, brands can build products that truly support overall health and wellness.”

And if an ingredient already has a favorable reputation for one health condition, it’s a good bet that consumers will trust it for immunity. “General familiarity definitely helps with consumer acceptance when promoting an ingredient for new applications like immunity,” Ris maintains. “It’s much easier for ingredients with high consumer awareness to generate buy-in for new health claims.”

Special Delivery

Consider quercetin. While the compound is no stranger to supplements, Ris says that Indena’s Quercefit Phytosome form of the ingredient “has emerged” as an immunity aid.

The reason, he explains, lies in the company’s unique phytosomal delivery system, which improves quercetin’s bioabsorption. And several company-supported studies do document its benefits in immune systems exposed to infectious COVID-19 environments.

“This may indicate support for the body’s physiological response in such conditions,” Ris surmises. He points to one recently published human pharmacokinetic study² showing that Quercefit optimized quercetin plasma levels after only one administration compared to quercetin not formulated as a phytosome. “This supports Quercefit’s efficacy in health conditions linked to senescence, oxidative stress, inflammation, and, of course, the immune response, as shown in human studies,” Ris says.

Interrupting Inflammation

Like quercetin, omega-3 fatty acids are also supplement stalwarts and, adds Bill Harris, president, Fatty Acid Research Institute (FARI; Sioux Falls, SD), “some of the most-studied substances in history.” And also like quercetin, they’re attracting notice for their immune effects.

Namely, says Harris, “They’re crucial in priming the immune system in the face of extraordinary health challenges—including COVID-19—and this assertion isn’t based on anecdotes, but on human and basic-science evidence.”

It’s also based on the immunity-inflammation relation. As Harris explains, “Inflammation is often the result of an overactive immune system; while the body needs a certain amount of inflammation to survive, too much will send the immune system into a downward spiral.”

A manifestation of this spiral arrived in the infamous “cytokine storms” that strike patients with serious COVID-19 disease and result from an overactive immune system’s uncontrolled and overwhelming release of pro-inflammatory mediators. The response unleashes so much unbridled systemic inflammation, Harris says, that severe illness and death are often, in part, “mediated by this rampant cytokine storm.”

Omega-3s, he continues, “may present an attractive approach to preventing and mitigating severe outcomes by resolving the cytokine storm.”

They do so as building blocks for a family of compounds called specialized pro-resolving mediators, or SPMS—“powerful substances,” Harris says, that quell inflammation at the source and spark healing. Omega-3s also prevent initiation of the inflammatory response by subtly changing the cell membrane’s architecture such that the cells become less susceptible to potential inflammatory events, he adds.

A pilot study³ published in January 2021 explored the association between the Omega-3 Index (the measure of a person’s blood levels of omega-3s EPA and DHA) and risk for COVID-19 death in 100 patients and found that those with an index above 5.7% had roughly a 75% lower risk for death than did patients with a lower index. “This was the first study to directly test the hypothesis that omega-3 fatty acids could benefit COVID-19 patients, and a second 2021 study⁴ from Chile confirmed these findings,” Harris says. “So if consumers don’t often associate omega-3 EPA and DHA with immunity, that will soon change given the amount of evidence that continues to support this benefit.”

Maintaining Homeostasis

Researchers at Unigen Inc. (Tacoma, WA) were also puzzled by COVID-19’s progression and catastrophic cytokine storms, and in early 2020 the company shifted much of its R&D work toward investigating immunity and respiratory health as a means of understanding them better.

As Qi Jia, PhD, Unigen’s CEO and chief science officer, recalls, “We knew that SARS-CoV-2’s most detrimental damage comes from an overstimulation of the immune response called a cytokine storm.” Yet the team also saw how the pandemic underscored the importance of vigorous antibody production for fighting the virus.

So while “traditional thinking” suggested suppressing the immune system’s production of pro-inflammatory cytokines to turn back the disease’s progression, doing so ran the risk of suppressing antibody production under vaccination, Jia continues. “This complicated immune dilemma called for a novel approach to maintaining immune homeostasis while also addressing immune senescence and ‘inflammaging,’” he concludes.

Thus, Unigen combed its PhytoLogix botanical library for bioflavonoids that could square the homeostasis circle, and what they found led to the development of Attenutin, a trademarked formulation comprising bioflavonoids from the roots of Scutellaria baicalensis—a.k.a. Chinese skullcap, a staple of traditional Chinese medicine—and the heartwood of Acacia catechu.

The formulation is clinically shown to support both innate and adaptive immunity while also maintaining healthy levels of cytokines and the antibodies IgA and IgG. What’s more, it preserves macrophage phagocytosis activity and maintains healthy levels of HMGB1, which Jia describes as an alarmin protein and biomarker “proven to support and protect the immune function of the respiratory system.” The product’s ability to increase glutathione peroxidase levels highlights a strong antioxidant function, too.

Not content with Attenutin, Unigen also tested blends of immune-regulatory polysaccharides and polyphenols for their homeostatic effects and ultimately standardized a formulation of Aloe vera leaf gel powder, Poria cocos sclerotium extract, and rosemary leaf extract and launched it as Symetrian.

Clinical results indicated that the product promotes production of circulating γδT cells, a subgroup of T cells bearing T-cell receptors (TCRs) with γ and δ chains, and a set of cells that act as a bridge between innate and adaptive immunity. By goosing circulating levels of these TCRγδ+ γδT cells, Jia says, Symetrian may exert “heightened immune surveillance at portals of entry.”

“In a clinical trial⁵”—currently pending publication—“of rapid immune modulation,” he continues, “a single oral dose showed progressive activation of lymphocytes—NKT cells, NK cells cytotoxic T cells, and γδT cells—in the blood over a three-hour period where the percent changes in activation proved to be statistically significant against placebo.” And like Attenutin, Symetrian also exhibits antioxidative capacity by elevating glutathione peroxidase levels.

In sum, Jia believes that viewing immune support as a homeostatic problem to solve “is the new, and more relevant, main concept for any immune product to follow, rather than acting solely through traditional ‘stimulation’ or ‘suppression.’”

Back in Balance

Antony is of like mind. “Immunity is a double-edged sword,” he notes. “Activation alone can lead to autoimmune disorders. So what’s required is modulation and balance among immune markers, and we’ve proven we can achieve this in humans with our Shoden ashwagandha extract.”

The company explored the adaptogen’s effects on HIV-positive patients, for whom a common blood test used to monitor immune function measures the ratio of “helper” CD4 immune cells to “killer” CD8 cells. (The former help initiate the immune response while the latter kill the body’s infected cells.) Though this ratio ranges from 1.4:1.0 to 1.8:1.0 in “normal individuals,” Antony says, in those with viral infections—particularly HIV—it trends lower.

Arjuna found that upon administration of Shoden, CD4 and CD8 levels increased while still maintaining a ratio slightly above the lower limit, “which shows that it can be used safely in autoimmune diseases caused by a reduction in total population of CD4 and CD8 cells, or caused by severely altering its ratio,” Antony says.

And a little goes a long way, he adds, which should please formulators. “The battle for real estate in the capsule and tablet market favors potent products that have effects at lower doses,” he argues. “This is where ingredients like Shoden—with proven benefits at a dose of just 60 mg—become even more effective.”

Gut Reactions

Given that ashwagandha is already on consumers’ radars for benefits around mood, sleep, cognition, and even memory, its star can only rise should further evidence bolster its immune effects.

A similar case can be made for colostrum, too, Weiser proposes, as a long history of randomized-controlled trials underscores its role in promoting not just digestive health but, increasingly, immune health, too.

And it makes sense: As a breastfed infant’s first food, colostrum provides “the initial immunity shield that transfers passive immunity to the baby and delivers nutritional components that support the baby’s own immune defenses—otherwise known as the innate immune system,” Weiser explains. And as a prebiotic that nurtures healthful Bifidobacterium and Lactobacillus species in an infant’s developing intestinal microbiota, colostrum also offers “an added defense against pathogens,” he continues.

But if colostrum is good for infants, is it good for adults? Weiser says that it is, pointing to bovine colostrum as a source of 250-plus immune-supporting components, including immunoglobulins for passive, innate, and adaptive immune support; cytokines that modulate immune-response intensity; oligosaccharides to block intestinal pathogen binding sites and support the gut microflora; and immune factors like lactoferrin and lysozyme, both of which possess powerful antiviral and antibacterial properties.

All told, Weiser believes colostrum’s bona fides make it “worth watching” as a standalone supplement and in combination formulations—think probiotics, he says—that “create truly novel immune-health products.”

Such formulations might eventually pair colostrum with postbiotics, too—“the latest ‘biotics’ category to see a lot of interest and growth in the marketplace” and one with intriguing immune potential, Stanieich says.

For example, Kyowa Hakko’s Immuse LC-Plasma postbiotic activates plasmacytoid dendritic cells (pDCs)—“the key leader of the immune system,” Stanieich says—to support immune health at the cellular level. “It stands out as a science-based food and dietary ingredient with a novel mechanism of action for more comprehensive immune support,” she claims.

And with 29 studies, including 14 human clinical trials, behind it, the postbiotic is the sort of scientifically substantiated ingredient that Stanieich believes “will support consumers’ acceptance of new immune ingredients while providing brands the support they need to incorporate it into formulations.” Vegan, allergen-free, and self-affirmed GRAS, it’s “stable in a wide variety of applications, including tablets, capsules, and gummies,” she adds.

Collagen Connection

While connective tissue may not be an obvious first line of defense against outside assault, the Gelita team sees uncharted immune-sector territory for ingredients that, like collagen, support connective tissues.

In fact, says Rimel, now that the first wave of interest in traditional immune-support ingredients has subsided, “Protein is emerging as a critical nutrient, and collagen peptides have great potential in the next generation of immunity products.”

Consumers already know collagen as a building block for skin, bones, joints, and more, she says, but “less known is that the collagen-rich extracellular matrix performs several metabolic functions, including immunologic ones”—a connection “that nobody was talking about,” but that Gelita doggedly explored. So when the rush to offer immune-support products took off during the pandemic, the company seized the chance to promote Immupept bioactive collagen peptides as candidates.

The move helped advance the understanding that specific bioactive collagen peptides benefit immune health “in a holistic way,” Rimel says, “creating a new generation of immunity products with collagen at their core.” Even better, the ingredient plays well with other actives, including vitamins and probiotics, and clinical studies show efficacy at low doses.

“Collagen is much in demand to support healthy skin,” Rimel says, “but it really does show promise in bridging the gap to support immune health through the relationship between collagen-rich connective tissue and healthy immune function.”

And that’s no small asset in a competitive market. But, as Rimel opines, perhaps a novel immune supplement’s success hangs “less on competition and more on how big the immune sector is. All the complex solutions being developed will benefit the whole sector in so many ways. So rather than watching for which ingredient is best, the key may to be combine the right ingredients for the best holistic approach.”

References

1. White paper. “Immune Support Supplement Category Market Insights.” SPRIM. Published December 2021.
2. Rondanelli M et al. “Promising effects of 3-month period of quercetin phytosome supplementation in the prevention of symptomatic COVID-19 disease in healthcare workers: A pilot study.” Life, vol. 12, no. 1 (2022): 66
3. Asher A et al. “Blood omega-3 fatty acids and death from COVID-19: A pilot study.” Prostaglandins, Leukotrienes, and Essential Fatty Acids. Published online January 20, 2021.
4. Zapata BR et al. “Omega-3 Index and clinical outcomes of severe COVID-19: Preliminary results of a cross-sectional study.” International Journal of Environmental Research and Public Health, vol. 18, no. 15 (July 21, 2021): 7722
5. Registered study. Not yet published. “A study to compare the acute immune effects of a herbal blend compared to a placebo.” ISRCTN #14647763