Speaker: Mary Hamel, United States

Malaria Control Landscape and Challenges:

Despite decades of progress, malaria remains a major global health threat. Current interventions—vector control (notably insecticide-treated nets), chemoprevention, diagnostics, and treatment—are only partially effective. With rapid disease progression (fever to death in 24–48 hours), timely prevention is essential.

Malaria Vaccine Implementation Programme (MVIP):

The WHO-coordinated MVIP (2019–2023) evaluated the RTS,S malaria vaccine across Ghana, Kenya, and Malawi. Vaccination schedules were adapted per country, though uptake of the fourth dose proved challenging due to misalignment with routine visits. Adjustments—like Ghana moving the fourth dose to 18 months—boosted coverage.

Key outcomes:

1. Safety: RTS,S was confirmed safe; prior concerns from phase 3 trials were not substantiated.
2. Impact: Among vaccinated children, there was a 13% reduction in all-cause mortality and a 22% decrease in severe malaria hospitalizations.
3. Coverage: Over 2 million children received 6 million+ doses.
4. Equity: The program extended the reach of preventive tools without negatively affecting care-seeking or uptake of other vaccines.

Optimizing Vaccine Impact Through Seasonal Delivery:

In areas with intense seasonal transmission (e.g., Mali and Burkina Faso), delivering RTS,S just before peak malaria months yielded:

• 72% reduction in clinical malaria in the first year
• 67% fewer severe malaria hospitalizations
• 45% lower all-cause mortality over five years

WHO now recommends age-based, seasonal, or hybrid (age + seasonal) schedules to maximize impact, as implemented in countries like Mali.

Introduction of a Second Vaccine: R21/Matrix-M:

In 2023, WHO recommended the R21 vaccine, similar in construct to RTS,S but with:

• Comparable efficacy: 66% with age-based and 73% with seasonal dosing
• Lower cost and higher manufacturing capacity, enabling wider access
• Cost-effectiveness comparable to other malaria interventions

Rollout and Future Prospects:

• 20 countries have introduced malaria vaccines; most start sub-nationally and scale up gradually.
• Ghana and DRC (Democratic Republic of Congo) have achieved national scale-up.
• Over 5 million children are targeted annually; 25 countries approved for Gavi support.
• Funding constraints currently limit support to 85% of required volume for high-transmission areas.

Conclusion:

Malaria vaccines represent a historic advance in child health. With proper integration into national strategies and funding alignment, these tools can significantly reduce malaria burden—especially when combined with nets and chemoprevention. Continued scale-up and innovation are essential to maximize their life-saving potential.

Efficacy and Safety of Clesrovimab, an Investigational RSV Antibody, in Healthy Preterm and Full-Term Infants: Subgroup Analyses of a Phase 2b/3 Trial (CLEVER) 

Speaker: Andrea Guerra, United Kingdom

Background on RSV and Clesrovimab:

RSV is a major cause of serious respiratory illness and hospitalization in infants, especially in the first months of life. Clesrovimab is an extended half-life, RSV-neutralizing monoclonal antibody that binds to the prefusion RSV F protein (IFN D2 site 4). Engineered with YDE substitutions for improved recycling and mucosal distribution, it was evaluated in the CLEVR Phase IIb/III trial.

Objective of the CLEVER study was to evaluate:

• Efficacy of a single intramuscular 105 mg dose of clesrovimab in preventing RSV-associated medically attended lower respiratory tract infection (MALRTI) through 150 days post-dose in healthy preterm and full-term infants.
• Safety of clesrovimab through 365 days post-dose, across subgroups defined by:
  1. Body weight (<5 kg & >5 kg)
  2. Gestational age (>29 to <35 weeks & >35 weeks)
  3. Chronological age at randomization (<2 weeks, <6 months, >6 months)

Study Design (CLEVER Trial):

1. Participants: ~3,600 healthy infants (≥29 weeks gestational age), entering their first RSV season.
2. Design: Randomized, double-blind, placebo-controlled (2:1 ratio of clesrovimab 105 mg IM vs. placebo).
3. Stratification: By gestational age, hemisphere, and chronological age.
4. Follow-up: All infants followed for 365 days; efficacy and safety assessed through day 150 and day 365, respectively.
5. Endpoints:
   1. Primary endpoint: RSV-associated medically attended lower respiratory tract infection (MALRTI) through day 150.
   2. Key secondary endpoint: RSV-associated hospitalization through day 150.
   3. Other outcomes: A range of RSV-associated disease severities from mild to severe were assessed.

Baseline Characteristics:

Subgroup Efficacy Analysis:

1. Primary Endpoint: RSV-associated medically attended lower respiratory tract infection (MA-LRTI) through 150 days post-dose
2. Key Secondary Endpoint: RSV-associated hospitalization through 150 days post-dose
3. Other Efficacy Observations:
   1. Efficacy increased with disease severity, remaining consistently high for more severe outcomes.
   2. Efficacy across body weight subgroups (<5 kg and ≥5 kg) was consistent with overall population results.
   3. Gestational age subgroups (<35 weeks and ≥35 weeks): Efficacy was comparable between groups, with overlapping 95% confidence intervals for both endpoints.
   4. Chronological age subgroups (<6 months and ≥6 months): Higher efficacy was noted in infants <6 months, as expected due to the higher RSV burden in younger infants. Efficacy for less severe RSV outcomes (e.g., acute respiratory tract infection) remained consistent even in older infants.

Subgroup Safety Analysis:

• Safety was evaluated across the same subgroups:
• Adverse events (AEs), serious AEs, and drug-related AEs were similar between clesrovimab and placebo across all groups.
• No safety signals emerged in any subgroup.
• All deaths reported were assessed as unrelated to the study drug.

Conclusion:

A single 105 mg IM dose of clesrovimab was well tolerated and efficacious in healthy infants across all body weight, gestational age, and chronological age subgroups. Protection was especially strong against severe RSV disease, with a safety profile comparable to placebo. These findings support broad preventive use of clesrovimab in infants during the RSV season.

ESPID 2025, 26-30 May, Bucharest