Two Classic Adjuvants, One Powerful Punch: CpG 1018 and Alum Supercharge Immunity to an N2 Neuraminidase Flu Vaccine
For nearly a century, influenza vaccine design has been a love letter to a single molecule. Hemagglutinin, the lollipop-shaped surface protein the virus uses to dock onto respiratory cells, absorbs almost all of the attention — and almost all of the antibody response — that seasonal immunization produces. The virus’s other major surface protein, neuraminidase, has long been relegated to a supporting role. A new study published in npj Viruses argues that this hierarchy deserves to be shaken up, and it offers a disarmingly practical way to do so: pair a neuraminidase-based vaccine with a combination of two of immunology’s most familiar adjuvants, CpG 1018 and alum. According to the research, the duo does not simply add its effects together. Working in concert, the two adjuvants synergistically amplify both systemic immunity — the antibodies circulating in blood and tissues — and mucosal immunity, the specialized defenses guarding the moist surfaces of the airway where influenza virus first makes landfall.
Neuraminidase is the enzyme the virus cannot live without. Once hemagglutinin has let a virion slip into a cell and the pathogen has copied itself, it is neuraminidase that clips the sialic acid receptors holding newborn particles tethered to the cell surface, freeing them to infect again. Antiviral drugs such as oseltamivir exploit precisely this dependence, which is one reason vaccinologists have argued for decades that antibodies against neuraminidase — antibodies that do not usually block infection outright but throttle viral replication — should translate into milder illness, shorter disease duration, reduced viral shedding and less transmission. Human challenge studies and large observational cohorts have indeed linked higher neuraminidase-inhibition titers with meaningful protection, particularly against severe disease. Neuraminidase also carries a structural dividend: its stalk domain, beneath the catalytic head, is considerably more conserved than the relentlessly drifting head of hemagglutinin, making it an attractive anchor for vaccines that must survive antigenic drift. The N2 subtype carries special historical weight, having entered humans during the 1957 “Asian flu” H2N2 pandemic and circulated, via the 1968 H3N2 reassortment, ever since.
Why, then, has neuraminidase languished? Part of the answer is manufacturing and measurement. Standard seasonal vaccines are quantified by their hemagglutinin content, a convention that leaves the amount and integrity of neuraminidase in each dose poorly controlled, and purified NA is a fragile, tetrameric enzyme that has historically been difficult to produce and stabilize at scale. Dedicated neuraminidase vaccines have therefore often delivered weaker immune responses than the field would like, and a consensus has grown that if NA is to carry more of the protective burden, it will need help from potent, well-characterized adjuvants. That is the gap the new study set out to address, and it chose its tools with an eye toward translational realism: rather than inventing novel immunostimulants, the team leaned on molecules with existing regulatory track records, asking whether familiar chemistry could be coaxed into unfamiliar performance.
The study’s central players are anything but exotic. Alum, the aluminum-salt colloid that has anchored licensed vaccines since the 1930s, is the workhorse of the adjuvant world: it binds antigen into particles that phagocytes readily engulf, prolongs antigen persistence at the injection site and reliably drives strong antibody responses — though it skews immune signaling toward Th2 pathways and is notoriously feeble at rousing the cellular arm of antiviral defense. CpG 1018, by contrast, is a synthetic, nuclease-resistant strand of DNA engineered to imitate bacterial genomes. Its unmethylated CpG motifs are seized by Toll-like receptor 9, an innate immune sensor buried in the endosomes of plasmacytoid dendritic cells and B cells, igniting the MyD88 signaling cascade, unleashing type I interferons and inflammatory cytokines and pushing the overall response toward a Th1, antiviral character. CpG 1018 has already proven itself in the licensed hepatitis B vaccine Heplisav-B and, in combination with alum, in Valneva’s inactivated whole-virus COVID-19 vaccine. What the research team now reports is that when both adjuvants are mounted around an N2 neuraminidase antigen, the immune outcome exceeds the sum of its parts.
Modern adjuvant development has increasingly embraced exactly this kind of rational pairing of an innate immune agonist with a delivery vehicle, as in the licensed system AS04, which couples the TLR4 agonist MPL to aluminum salt. The logic is mechanistic complementarity. A naive B cell requires not only antigen recognition but costimulatory instruction, delivered largely by activated dendritic cells; alum excels at shaping how antigen is presented and retained, while CpG 1018 excels at converting antigen-presenting cells into potent, interferon-secreting teachers and at directly co-stimulating B cells through TLR9. Together, the two can simultaneously increase the quantity of antigen available, the quality of its presentation and the intensity of the danger signal — a combination that, in principle, should deepen germinal-center reactions, expand populations of T follicular helper cells and sharpen antibody affinity maturation. What remained uncertain was whether such a partnership, delivered by conventional intramuscular injection, could reach beyond the bloodstream into the mucosal immune compartment that injected vaccines so rarely engage.
That uncertainty is what makes the findings striking. According to the paper, when the N2 neuraminidase vaccine was formulated with CpG 1018 and alum together, the responses it generated outperformed what either adjuvant achieved alone — the hallmark of true synergy rather than simple addition. The combined formulation drove markedly stronger serum antibody responses against the neuraminidase antigen, and, crucially, those antibodies were functional, showing enhanced activity in neuraminidase-inhibition assays — the laboratory readouts, classically performed as enzyme-linked lectin assays, that measure how effectively antibodies jam the enzyme’s catalytic head and that have repeatedly correlated with clinical protection in human studies. The systemic arm of immunity — the circulating IgG that travels through blood and tissue fluid and intercepts virus in the earliest hours of infection — was thus fortified on both quantitative and qualitative fronts. For a field in which neuraminidase-based vaccines have often struggled to produce antibody levels competitive with hemagglutinin-focused formulations, that result alone carries real weight.
The more consequential surprise lies in the mucosal compartment. Conventional injected vaccines are largely blind to the mucosa: they generate abundant serum antibodies but little of the secretory immunoglobulin A that bathes the lining of the nose, throat and bronchial tree, even though the respiratory tract is precisely where influenza makes first contact. Secretory IgA is a dimeric, highly specialized antibody ferried across the epithelial barrier by the polymeric immunoglobulin receptor, where it sits directly in the path of incoming virions, capable of neutralizing them before a single cell is infected. Yet the study reports that the CpG 1018–alum combination achieved what alum alone typically cannot: a substantive boost to mucosal as well as systemic defenses against the N2 antigen. The finding fits accumulating evidence that innate immune signals can instruct circulating B cells to acquire mucosal-homing properties, prompting them to seed respiratory tissues rather than remain sequestered in the systemic compartment. In effect, the adjuvant pairing appears to re-educate a needle-delivered vaccine so that its benefits arrive at the very doorway where infection begins.
Why should two chemically dissimilar molecules cooperate so effectively? The study’s results point to a division of labor that covers the principal bottlenecks of antigen-specific immunity. Alum constrains and presents the antigen, creating the particulate, phagocyte-friendly substrate from which antibody responses are built. CpG 1018 detonates the innate alarm: through TLR9 it drives interferon and co-stimulatory signals that transform antigen-presenting cells into far more persuasive instructors of naive lymphocytes. Where either input alone leaves gaps — alum’s weak Th1 tone, CpG’s limited capacity to retain and present antigen — the other fills them, producing the synergistic outcome the authors describe. Synergy in the immunological sense is a demanding standard: the combined response must exceed what would be predicted by simply adding each adjuvant’s individual contribution, which requires the components to engage complementary, mutually reinforcing pathways rather than duplicating one another. There is also a sober practical dividend. Neuraminidase is historically a difficult antigen to manufacture at high yield, and NA-based vaccines often require substantial antigen doses to elicit competitive titers. An adjuvant pairing that extracts more immunity per microgram of protein translates directly into dose-sparing capacity — an asset of enormous consequence in a pandemic, when manufacturing capacity and antigen supply become the binding constraints on global vaccine availability.
The strategic implications reach well beyond a single subtype. H2N2 vanished from human circulation in 1968, meaning most people alive today have never encountered either its hemagglutinin or its neuraminidase — a population-scale immune naivety that places H2 viruses high on the lists of potential pandemic threats maintained by global health authorities. Vaccines built around N2 neuraminidase and supercharged by an adjuvant pairing already embedded in licensed products could form part of the preparedness arsenal for such an emergence. For seasonal influenza, meanwhile, the findings feed a long-running argument that vaccines should incorporate neuraminidase alongside hemagglutinin to broaden coverage, blunt transmission and preserve protection against severe disease even in years when the hemagglutinin component is mismatched to circulating strains. And because both adjuvants are inexpensive, chemically simple, thermally robust and thoroughly woven into regulatory experience worldwide, the approach does not depend on the cold-chain fragility or manufacturing complexity that constrains newer platforms. It is, in a sense, a retrofit: established immune-stimulating chemistry applied to a second antigen the field has long undervalued.
None of this guarantees a swift path to the clinic. As with any early-stage vaccine study, the findings will need to survive human evaluation, where the performance seen in experimental models does not always predict outcomes in diverse, previously exposed populations — not least because the biology of Toll-like receptor 9 itself differs between species. Key questions remain open: how durable the mucosal responses prove to be, how well the strategy generalizes to other neuraminidase subtypes, what the optimal balance of CpG 1018 to alum might be, and how tolerable the intensified innate stimulation will feel in practice, since stronger danger signals can bring stronger reactogenicity. Standardizing neuraminidase-inhibition titers as a regulatory correlate of protection remains a work in progress. Even so, the study lands at a moment of gathering momentum, as funders and manufacturers begin to take the “second antigen” of influenza seriously. It suggests that the tools needed to build better flu defenses may already be sitting on the shelf — waiting, much like neuraminidase itself, for their full value to be recognized.
Subject of Research: Adjuvant synergy of CpG 1018 and alum in enhancing systemic and mucosal immune responses to an N2 neuraminidase influenza vaccine
Subject of Research: Medicine
Article Title: CpG 1018 and alum synergistically enhance systemic and mucosal immunity to an N2 neuraminidase vaccine
Article References: Hoxie, I., Vasilev, K., Clark, J., Hoelzl, R., Puente-Massaguer, E., Bhavsar, D., Alzua, G. P., Campbell, J. D., & Krammer, F. (2026). CpG 1018 and alum synergistically enhance systemic and mucosal immunity to an N2 neuraminidase vaccine. npj Viruses. https://doi.org/10.1038/s44298-026-00225-1
Image Credits: AI Generated
DOI: 10.1038/s44298-026-00225-1
Keywords: influenza vaccine, neuraminidase, N2 neuraminidase, CpG 1018, alum adjuvant, adjuvant synergy, mucosal immunity, secretory IgA, systemic immunity, neuraminidase inhibition, Toll-like receptor 9, pandemic preparedness
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Cedric L. (August 29, 2026). Adjuvant duo CpG 1018 and alum supercharges N2 flu vaccine immunity. Scienmag. https://scienmag.com/adjuvant-duo-cpg-1018-and-alum-supercharges-n2-flu-vaccine-immunity/
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