A needle-free vaccine: what if it were possible to vaccinate by massaging the skin?

The prospect of vaccinating without using a needle primarily addresses a well-documented barrier: the fear of injections.

In some people, this anxiety is enough to postpone or even avoid a recommended vaccination. However, this phenomenon is not anecdotal: it reduces vaccine uptake, creates disparities in access and complicates large-scale campaigns, particularly among children, hypersensitive individuals and adults anxious about medical care. A needle-free vaccination technology could therefore overcome a major psychological barrier, transforming an anxiety-inducing procedure into a simple, painless one.

The appeal of an injection‐free vaccine also lies in a context where aluminium salts, commonly used as adjuvants, continue to fuel debate. Indeed, aluminium hydroxide and aluminium phosphate have been employed for over 90 years to optimise the immune response. They serve to retain antigens at the injection site and to attract immune cells locally, thereby prolonging antigenic stimulation. However, many fear that aluminium may accumulate in the body and cause allergic reactions, or prove toxic to the brain.

However, the efficacy and safety of aluminium in vaccines have been assessed in several dozen publications, which concluded that it primarily causes transient local reactions : pain, redness, swelling, occasionally a small nodule. No robust link has been established with lasting effects, autoimmune diseases or an increased risk of allergies according to available data. The aluminium present in vaccines is eliminated via the same pathways as that contained in food, where daily exposure is substantially higher: an adult ingests 7 to 9 mg per day, whereas a vaccine dose contains between 0.125 and 0.85 mg. Infants receive approximately 4.5 mg via their vaccination schedule, compared with 7 to 117 mg via their diet depending on whether they are breastfed, formula-fed or on soy-based milk. Despite this consensus, doubts persist in part of the population and fuel mistrust of vaccines.

Thus, the concept of a needle-free vaccine administered by massage could reduce two obstacles: the fear and pain associated with injections, and the perceived risk associated with injected adjuvants such as aluminium.

Recent research conducted by Élodie SEGURA’s team has revealed the possibility of vaccinating through skin massage, showing that mechanical stimuli had an impact on immunity. The researchers employed a device capable of applying a controlled stretch to the skin, equivalent to that of a therapeutic massage or the vigorous application of a cream. For twenty minutes, the skin of mice and human volunteers was subjected to this mechanical constraint without causing any visible injury. Observations showed that this stretch immediately altered the activity of epidermal cells, particularly keratinocytes, which respond to mechanical changes by releasing pro-inflammatory cytokines, such as TNF-α, and recruiting neutrophils and monocytes, immune cells. This response indicates that the skin interprets the massage not as a simple physical stimulation, but as a potential danger signal capable of mobilising local immunity.

It is, however, the effect of massage on the skin’s microarchitecture that constitutes the most remarkable discovery of the study. The researchers observed that stretching induces a transient opening of hair follicles, measured both by imaging and by the ability of fluorescent macromolecules to penetrate the skin (in this case dextran, a glucose polymer). Under normal conditions, follicles are relatively closed structures, limiting the entry of bulky compounds. However, under the influence of massage, their opening increases sufficiently to allow molecules of considerable size, far larger than those that generally cross the skin barrier (< 500 Da) to enter the follicular canal. Human skin, like that of the mouse, thereby becomes temporarily permeable to antigens applied at the surface. It should be noted that this increased permeability is temporary, with researchers observing that both mouse and human skin returned to their initial structure after several tens of minutes.

The study also revealed that this follicular opening not only permits the passage of exogenous antigens: it also facilitates the penetration of compounds derived from the cutaneous microbiota, thereby activating dermal dendritic cells. This notion was supported by the upregulation of genes associated with their pathogen-induced maturation, such as Cd86, Cxcl9, Cxcl10, and Myd88. In germ-free mice, that is, those without a microbiota, stretching did indeed increase neutrophil infiltration, demonstrating that this response is independent of the microbiota. However, stretching did not recruit monocytes or monocyte-derived macrophages, nor did it accelerate the migration of dendritic cells to the lymph nodes. In normal mice lacking hair follicles, stretching then elicited infiltration of neutrophils, monocytes and macrophages, but without increasing dendritic cell migration.

These results show that stretching alone is sufficient to recruit neutrophils and monocytes, but that the full activation of dendritic cells, and notably their migration to the lymph nodes, requires the penetration, via hair follicles, of molecules derived from the microbiota.

Vaccination by massage or injection does not rely on the same mechanisms. Intramuscular injection introduces the antigen into tissue that is sparsely populated with immune cells, which explains why injected vaccines often have to be combined with adjuvants, such as aluminium salts, to attract and activate local dendritic cells. The immune response then arises as follows: the injection causes a micro-lesion, the adjuvant creates an inflammatory focus, and together they generate a sufficient signal to trigger the maturation of dendritic cells and their migration to the lymph nodes.

The situation is different for vaccination by massage. The skin is naturally rich in dendritic cells and lymphocytes, which facilitates the immune response. When the antigen is applied to the skin and then "pushed" into the follicles by massage, follicular dendritic cells can immediately capture and process the antigen. Unlike muscle, the skin does not need to be "awakened" by an adjuvant, since mechanical stress and the penetration of microbial fragments act as immune-activation signals.

The researchers then confirmed that the transient opening of hair follicles and the migration of dendritic cells induced by skin stretching could be harnessed to administer a vaccine in mice. To this end, they combined an H1N1 antigen (influenza vaccine) with the QS-21 adjuvant encapsulated in nanoliposomes, then used a fluorescent tracer to demonstrate that a single stretch of skin enabled efficient, non-invasive penetration of the vaccine into the epidermis and dermis.

The nanoliposomes penetrated the skin, then gradually released their contents into the bloodstream. The HA antigen also reached the draining lymph nodes, indicating active transport by dermal dendritic cells. The researchers then compared administration via skin stretching with an intramuscular injection containing the same antigen dose. They observed that the stretching method led to greater antigen accumulation in the lymph nodes and a higher anti-HA IgG response.

These results suggest that massage enables effective, needle-free and non-invasive vaccination in mice.

Although this study provides compelling evidence that stretching the skin can favour the penetration of macromolecules and activate certain immune cells through the transient opening of hair follicles, several questions remain unanswered.

One might first question the tolerance of this procedure in sensitive skin, which might respond poorly to 20 minutes of vigorous massage. Furthermore, one could ask whether a mechanical alternative such as microneedling – allowing a controlled disruption of the skin barrier without 20 minutes of massage – might represent a simpler strategy to implement.

Furthermore, the transcriptomic analyses conducted have not precisely identified which cell populations respond to this stimulation: it is still unknown whether keratinocytes, dermal fibroblasts or other stromal cells detect the stretch, nor which mechanoreceptors are involved. The exact role of the skin microbiota in this response also remains to be clarified, notably the microbe-derived molecules capable of triggering inflammation and activating immune cells. This issue is all the more important because the microbiota varies greatly from one individual to another, and people with skin diseases (atopic dermatitis, psoriasis, rosacea…) often exhibit dysbiosis that could alter the immune response induced by massage.

Moreover, the researchers observed a rapid influx of innate immune cells within 24 hours following the stretch, but their fate and their contribution to dendritic cell activation were not tracked over time. This lack of long-term immune monitoring therefore prevents an assessment of the durability of protection and the identification of any delayed adverse effects.

The toxicological implications highlighted by the study also pose a significant challenge. Demonstrating that massage transiently opens follicles and increases the penetration of macromolecules suggests that this route could also facilitate the entry of unwanted substances, such as atmospheric pollutants or allergens. If this technique were performed incorrectly, it could trigger undesired immune responses. Moreover, it remains to be determined whether this mode of administration would induce systemic side effects similar to those sometimes observed after conventional vaccination, such as fever or muscle aches.

Furthermore, one could question the types of vaccines compatible with this approach. In the study, the example used was an inactivated virus vaccine (H1N1), whose viral particles can penetrate the skin via the open hair follicles and be captured by local immune cells. However, it is unclear whether this method is suitable for live-attenuated vaccines, whose viral particles might be ineffective if the skin environment does not allow their replication. Similarly, messenger RNA vaccines, which are highly sensitive to stability conditions and require precise intracellular delivery, may not be compatible with topical application.

Furthermore, the question of the absorbed antigen dose The study demonstrates that, in mice, massage facilitates a qualitative immune response following application of an H1N1 vaccine. However, the exact amount of antigen actually taken up by cutaneous dendritic cells has not been precisely measured, and vaccine efficacy often relies on strict quantitative thresholds. Indeed, an insufficient dose could elicit a weak or heterogeneous response. This limitation is particularly significant given that the study does not measure the functional intensity of the response (antibodies, viral neutralisation, immunological memory...).

Finally, if the study confirms that stretching increases the penetration of macromolecules into human skin, other experimental components carried out in mice cannot be directly replicated in humans. Given the significant differences between human and murine skin, further research will be required to determine whether the immune activation induced by stretching and its vaccination potential can genuinely be translated to humans.

• BOS J. D. & al. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Experimental Dermatology (2000).

• EXLEY C. & al. Insight into the cellular fate and toxicity of aluminium adjuvants used in clinically approved human vaccinations. Scientific Reports (2016).

• ROGERS M. A. M. & al. The fear of needles: A systematic review and meta-analysis. Leading Global Nursing Research (2018).

• ANDERSSON N. W. & al. Aluminum-adsorbed vaccines and chronic diseases in childhood: A nationwide cohort study. Annals of Internal Medicine (2025).

• SEGURA E. & al. Transient skin stretching stimulates immune surveillance and promotes vaccine delivery via hair follicles. Cell Reports (2025).