The Unmet Need for Completing RSV Protection: Disease Burden Beyond the First Season 

Speaker: Federico Martinon-Torres, Spain

Introduction:

RSV prevention has advanced significantly with the advent of immunoprophylaxis for infants. However, toddlers (1–5 years) continue to bear a significant but underappreciated burden of RSV disease. Dr. Martinon-Torres highlighted the need to recognize and address this gap to ensure complete and sustained RSV protection beyond the first season of life.

Burden of RSV in Toddlers:

RSV remains a leading cause of hospitalization, ER visits, and outpatient consultations in toddlers.

Though hospitalization rates are lower than in infants, the overall volume of cases in this age group is substantial.

Hospitalization and Disease Attribution by Age Group:

Age Group	% Community-Acquired Pneumonias due to RSV	Hospitalization Burden
<2 years	31%	High
2–4 years	26%	Moderate
1–5 years	~30% of all RSV-related hospitalizations	Non-negligible

Outpatient & ER Visit Burden:

1. For every 1 hospitalization, there are:
   1. 10–15 ER visits
   2. Up to 100 outpatient consultations
2. RSV is detected in ~33% of outpatient cases presenting with acute respiratory symptoms.
3. RSV testing is rare in outpatient settings (only ~2%), leading to significant underdiagnoses.

Transmission Dynamics:

Toddlers are the primary vectors (“RSV dealers”) within households and communities.

• Due to early day-care exposure and contact patterns, toddlers drive RSV epidemics.
• Household studies reveal:
  1. If an older sibling is infected, infants are highly likely to contract RSV.
  2. Children <5 years have a 3.5× higher risk of RSV infection in household outbreaks.

Clinical Phenotypes in Toddlers:

RSV manifests differently in toddlers compared to infants:

Symptom/Condition	Notes
Fever	Present in ~70% of toddlers with RSV
Acute Otitis Media	RSV is the most commonly detected virus; >70% cases in >1-year-olds
Recurrent Wheezing	Strongly associated with prior RSV infections
Use of Medications	Post-RSV, toddlers are 4–6× more likely to be prescribed antibiotics or anti-obstructive drugs

Long-Term Consequences of RSV Infection:

Reinfection with RSV is common, with nearly 60% of toddlers experiencing reinfection before the age of three. Beyond the initial acute illness, RSV is strongly associated with chronic respiratory conditions such as recurrent wheeze, bronchiolitis, and the development of asthma. This indicates that the burden of RSV extends well beyond immediate hospitalization or outpatient care, contributing to long-term respiratory morbidity. Notably, even non-medically attended RSV infections are not benign—studies show that 36% of such cases result in recurrent wheezing, highlighting the often-underestimated impact of mild or unrecognized infections in early childhood.

Emerging Research: Epigenetic Predictors:

Recent studies suggest that RSV infection can induce changes in DNA methylation patterns, particularly in genes like CD14, which play a role in immune regulation. These epigenetic modifications may help predict which children are likely to develop long-term respiratory complications such as wheeze or asthma, and which are more likely to recover fully. One such finding includes a 9-site methylation signature that has shown potential in distinguishing between future outcomes during the acute phase of infection. However, this research remains in the experimental stage, and such epigenetic markers are not yet applicable for bedside or clinical use.

Missed Opportunity and Unmet Need:

1. While infant RSV is now largely preventable, toddlers remain unprotected.
2. Current tools (maternal vaccination, nirsevimab) do not cover children >6 months.
3. RSV in toddlers results in:
   1. Frequent clinic visits
   2. Parental absenteeism
   3. Missed school/kindergarten
   4. High community transmission

Call for Toddler-Specific Vaccines:

Dr. Martinon-Torres' wish list for future RSV interventions includes:

1. Prevention of severe cases and non-severe phenotypes (e.g., otitis media)
2. Reduction in:
   1. Wheezing/asthma development
   2. Healthcare utilization
   3. Antibiotic and bronchodilator use
   4. Impact on RSV transmission dynamics to protect the wider community

Conclusion:

• “RSV is an immunization-preventable disease in infants—this is the moment to act globally.”
• Immunization strategies for infants and older adults are available and effective.
• The next frontier is clear: protecting toddlers, who remain vulnerable to both disease and reinfection, and who serve as amplifiers of transmission.
• An urgent public health focus is required to close this immunization gap and ensure comprehensive RSV protection.

Mucosal Immune Responses Against RSV Infection in Toddlers and Infants: The Role in Preventing RSV Infection in Toddlers and Infants 

Speaker: Ryan Thwaites, UK

Understanding Immune Outcomes After RSV Exposure:

Following RSV exposure, outcomes range from no infection, to asymptomatic infection, to symptomatic disease. The goal of prophylaxis should be to push the immune response toward non-infection or mild/asymptomatic infection.

Study Approach: Human Challenge Model:

1. Healthy adults (18–55 years) were experimentally inoculated with RSV (Intranasal 10⁴ pfu RSV-A)
2. Participants were kept in seclusion from D-1 to D+10
3. Nasal samples (fluid and tissue) were taken to study mucosal immune activity
4. Participants were categorized based on their response:
   1. Infected with symptoms
   2. Asymptomatic infection
   3. Uninfected

Key Findings: Early Immune Activity Determines Outcomes:

Group	Immune Activity
Infected (symptomatic)	Higher neutrophil-related gene expression at baseline
Uninfected	Lower neutrophilic activation

• 86 baseline genes were differentially expressed in those susceptible to infection.
• Cytokines and Chemokines
• In uninfected individuals, early and strong activation of T-cell–related chemokines (e.g., CXCL9, CXCL10) was observed.
• In infected individuals, neutrophilic inflammation was more dominant and associated with viral replication.

Role of the Microbiome:

Alterations in gut and airway microbiome composition (e.g., presence of Haemophilus influenzae) are associated with increased RSV susceptibility and severity in children. Disruption of microbial balance may prime the airways for inflammation, contributing to poorer immune responses.

Mucosal Immunity: Antibody Roles:

1. Secretory IgA
   1. IgA is the dominant antibody at mucosal surfaces (~90%).
   2. High baseline mucosal IgA titers were strongly associated with protection against infection.
   3. IgA was more predictive of protection than serum IgG.
2. IgG: Although long-lasting and multifunctional, serum IgG showed a weaker correlation with RSV protection in the airway.
3. Tissue-Resident T Cells
   1. CD8+ tissue-resident memory T cells exist in the airway but did not correlate with resistance to infection.
   2. They may influence disease severity, not susceptibility.

Conclusion:

• Innate mucosal defences, especially early epithelial and T-cell chemokine responses, are critical for preventing RSV.
• Neutrophilic inflammation may hinder protective responses, increasing susceptibility.
• Microbiome composition may modulate immune responses and disease risk.
• Mucosal IgA is key to preventing infection and limiting viral shedding—current injectable vaccines may not sufficiently induce this response.

ESPID 2025, 26-30 May, Bucharest