Vaginal Seeding Partially Modifies Infant Microbiome in ACTIVATE, With Jose Clemente, PhD

Vaginal seeding in cesarean-delivered infants was associated with altered early gut microbiome patterns and differences in food sensitization at 12 months, according to late-breaking ACTIVATE trial data presented at the 2026 American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting in Philadelphia.1

The Journal of Allergy and Clinical Immunology had published a report on the link between delivery mode and allergy risk had been reported > 2 decades ago. However, as cesarean delivery rates continue to rise in the United States and globally, rising from 7% in 1990 to 21% in 2025, interest has intensified around how birth mode influences early immune development and allergy risk.2

At AAAAI, HCPLive spoke with Jose Clemente, PhD, associate professor of Genetics and Genomics and Immunology at the Icahn School of Medicine at Mount Sinai, who discussed the biologic rationale behind the trial and what the findings may mean for clinicians.

“A few years ago, we thought, okay… c-section is associated with different type of colonization with microbes. Maybe if we restore microbes in this c-section babies, we can hopefully modulate the risk for allergies,” Clemente said. “That's the whole idea behind…this particular trial.”

ACTIVATE is a double-blind, placebo-controlled, randomized clinical trial evaluating whether exposure to maternal vaginal microbiota at birth can influence food allergen sensitization in cesarean-delivered infants at high risk for allergic disease.1 The study enrolled 39 vaginally delivered infants, 37 cesarean-delivered infants who received placebo seeding, and 37 cesarean-delivered infants who underwent vaginal seeding, along with their mothers.

Vaginal seeding in ACTIVATE involved placing sterile gauze in the maternal vagina approximately 1 hour prior to cesarean delivery. Immediately after birth, the gauze was used to swab the infant’s mouth, face, and body in an effort to approximate microbial exposure during vaginal birth.

Shotgun metagenomic sequencing confirmed microbial transfer. Lactobacillus, abundant in maternal vaginal samples, was enriched in the stool of infants who received vaginal microbial transfer compared with placebo immediately after birth (P = 0.002).

At 3 months, the stool microbiome of infants who underwent vaginal seeding more closely resembled that of vaginally delivered infants than infants who underwent placebo seeding (similarity indices 0.876 ± 0.07 vs 0.9 ± 0.06; P =.169), though the effect was partial and diminished over time. By 12 months, global microbiome composition differences between groups were no longer apparent.

Clemente emphasized that this partial modification is biologically meaningful. Vaginal seeding does not replicate the full microbial exposure of vaginal delivery, but even limited early colonization may act as a developmental primer, influencing downstream microbial succession and immune programming.

“When you're born, you're essentially born with no microbes,” Clemente said. “We think that this first exposure is important because it sets the baby on the correct developmental pathway. It sets the baby to acquire microbes then are going to lead to a transition to other microbes that might also be eventually beneficial, in terms of risk against risk of allergies.”

Maternal vaginal microbiome composition itself was not associated with food sensitization at 12 months (P =.86). Instead, specific infant gut microbes identified at 12 months were associated with allergen sensitization, including Rothia mucilaginosa with egg (unadjusted P =.036), Bifidobacterium breve with milk (unadjusted P =.028), and Ruminococcus gnavus with egg, milk, and peanut (unadjusted P = 0.013, 0.032, and 0.006, respectively). Infants with vagina seeding exhibited lower levels of R. gnavus, a microbe previously implicated in inflammatory pathways.

The investigators demonstrated that among infants who underwent vaginal seeding and in whom microbial transfer was effective, rates of sensitization were lower compared with placebo-seeded counterparts, although Clemente characterized the trial as exploratory and not yet practice-changing.

“It's important to remember that the activate trial is a pilot trial,” Clemente said. “One of the ideas behind the trial is to determine whether the procedure is safe, and that is the case, the procedure is not associated with increased adverse events. Two, whether we see a measurable benefit, and that's what we have shown that there is a measurable benefit, but it's not quite yet ready to be developing in clinic.”

Clemente has no relevant disclosures.

References

1. Clemente J, Bu K, Cantor A, et al. Microbiome Associations with Food Sensitization in the ACTIVATE Trial: Exposure to Vaginal Microbiome in C-section Infants at High-risk for Allergies. Journal of Allergy and Clinical Immunology. 2026;157(2):AB422. doi:https://doi.org/10.1016/j.jaci.2025.12.935

2. McKeever TM, Lewis SA, Smith C, Hubbard R. Mode of delivery and risk of developing allergic disease. Journal of Allergy and Clinical Immunology. 2002;109(5):800-802. doi:https://doi.org/10.1067/mai.2002.124046