Vaccines against AMR

Speaker: Padmini Srikantiah, United States

Overview: Vaccines as a Strategy Against AMR

Dr. Srikantiah highlighted the enormous burden of antimicrobial resistance (AMR), particularly among children under five in low- and middle-income countries (LMICs). The core message: preventing infections through vaccines—both bacterial and viral—is a critical strategy to reduce AMR-related deaths and antibiotic use.

Global Burden of AMR:

• In 2021:
  • 1 million deaths were directly attributable to AMR
  • 7 million deaths were associated with AMR
• Bacterial infections are the main drivers of AMR mortality.
• Children under 5:
  • Represent 7–8% of global population
  • Account for ~18% of AMR-associated deaths (840,000 deaths in 2021)

Geographical Burden:

• Highest burden of AMR-associated deaths in children <5 was seen in:
  • Western Sub-Saharan Africa
  • Other LMICs with high infectious disease burdens

Top 10 Pathogens Causing AMR-Associated Deaths in Children <5:

• Among children under five, ten bacterial pathogens are responsible for the majority of AMR-associated deaths.
• Leading the list is Streptococcus pneumoniae, followed by Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Pseudomonas spp., and Acinetobacter baumannii. Other significant contributors include Group B Streptococcus, Serratia, Salmonella typhi, and Shigella spp.
• Notably, vaccines are currently available for only two of these pathogens—S. pneumoniae and S. typhi—highlighting a major gap and opportunity in vaccine development to address AMR in this highly vulnerable age group.

How Vaccines Help Address AMR:

Vaccines can:

• Prevent infections from both susceptible and resistant pathogens
• Reduce need for antibiotics and hospitalizations
• Lower complications and bacterial transmission
• Suppress the emergence of resistance
• Even vaccines against viruses (e.g., rotavirus, RSV) reduce inappropriate antibiotic use

Evidence from Existing Vaccines

1. Pneumococcal Conjugate Vaccine (PCV)
   1. South Africa data post-PCV introduction:
      1. 82% ↓ in penicillin-resistant invasive pneumococcal disease
      2. 85% ↓ in ceftriaxone-resistant pneumococcus
      3. Associated with ↓ in overall antibiotic use

1. Modelling projection (WHO): 90% PCV coverage could avert:
   1. 27,000 AMR deaths
   2. 1.3 million DALYs
   3. Significant healthcare cost savings

2. Typhoid Conjugate Vaccine (TCV) – Pakistan Example
   1. Introduced during XDR Salmonella typhi outbreaks in Sindh
   2. Outcomes:
      1. 95% efficacy against XDR strains
      2. Marked decline in typhoid incidence after campaign
      3. Proportion of XDR strains remained >50% post-intervention

3. Rotavirus Vaccine
   1. Estimated 50 million antibiotic-treated diarrheal episodes due to rotavirus (pre-vaccine)
   2. With 2018 coverage: 13 million episodes averted
   3. With universal coverage: Additional 18.3 million cases could be prevented
   4. Shows that viral vaccines also reduce AMR by lowering inappropriate antibiotic use
4. RSV Prevention (Nirsevimab Monoclonal Antibody)
   1. 23% reduction in any antibiotic prescription in first 6 months of life
   2. Likely due to:
      1. Prevented RSV-related illness
      2. Avoidance of secondary bacterial infections
      3. Effective in lowering unnecessary antibiotic exposure in infants

Future Vaccines for AMR Priority Pathogens:

• Klebsiella pneumoniae: A High-Priority Target
  • ~120,000 neonatal deaths/year due to Klebsiella
    • ~80,000 AMR-associated
    • ~34,000 AMR-attributable
  • Maternal conjugate vaccine strategy being explored
  • Preclinical development underway for:
    • 10+ valent conjugate vaccine
    • Aiming for 70% strain coverage and 70% efficacy
  • Modelling impact: Such a vaccine could avert up to 80,000 neonatal deaths/year

Key Takeaways:

1. AMR in LMICs is driven by high infectious disease burden, not just antibiotic overuse.
2. Vaccines are a critical AMR strategy:
   1. Bacterial: PCV, TCV
   2. Viral: Rotavirus, RSV
3. Scaling existing vaccine coverage can save hundreds of thousands of lives
4. R&D efforts for vaccines targeting AMR-priority pathogens (e.g., Klebsiella pneumoniae) are urgently needed

Panel of Experts: Can We Forsee the Future of AMR?

Panellists: Keith Klugman (United States of America), Ursula Theuretzbacher (Austria), Ramanan Laxminarayan (United States of America), Peter Beyer (Switzerland), Padmini Srikantiah (United States of America), Valeria Gigante (Switzerland)

Pediatric Antibiotic Pipeline & Regulatory Challenges:

• Current Gap: Only 9 of 17 authorized antibiotics have pediatric development plans; toxicity, formulation issues, and lack of pediatric-specific indications pose barriers.
• WHO & GAP-f Initiatives:
  • Development of target product profiles (TPPs) for key antibiotics (e.g., nitrofurantoin, enisamium).
  • Regulatory inefficiencies between regions increase burden for SMEs (Small and Medium-sized Enterprises) developing pediatric antibiotics.
  • Pediatric trials are delayed due to ethical, financial, and developmental complexities.

Improving Access, Regulation, and Data:

WHO aims to issue guidance on pediatric data generation to support regulatory submission and inform clinical practice by next year. Emphasis on integrating real-world evidence, registries, and post-marketing data with pre-marketing safety assumptions.

Neonatal Sepsis Trials & Practical Barriers:

• The NEOSEP trial, a multi-country, personalized RCT, evaluates optimized regimens (e.g., fosfomycin + flomoxef + amikacin).
• Challenges: Regulatory approvals, trial design innovation, financial constraints.
• Cost cited: ~$50 million for 2 large neonatal studies – considered efficient given the scale.

Integrated Clinical Strategies:

1. Infection Prevention & Control (IPC): Needs system-wide infrastructure and training.
2. Antimicrobial Stewardship (AMS): Must balance access and conservation, especially in LMICs where diagnostics and drug availability are limited.
3. Vaccines: Crucial advocacy needed to ensure implementation and address hesitancy.
4. Diagnostics: Essential for stewardship but limited by cost and healthcare infrastructure

Policy Advocacy & Innovation Needs:

Politicians are overwhelmed by competing global health crises. Effective messaging should focus on:

• Clear, actionable solutions (e.g., vaccines, IPC, affordable diagnostics).
• Demonstrating cost-effective impact rather than alarmist statistics.
• AI and digital tools were recognized as future enablers of smarter, localized antibiotic use and stewardship.

Rethinking AMR Strategies in LMICs:

Stewardship in LMICs must focus on access without over-reliance on diagnostics, given capacity and infrastructure challenges. Examples from India show widespread empirical use of carbapenems without diagnostics, reflecting an urgent need for context-sensitive approaches.

Non-Antibiotic Innovations:

Interest in alternatives like anti-adhesion agents, anti-quorum sensing molecules, antiseptics, and anti-toxin strategies. These approaches must be scalable, low-cost, and effective in broader populations to make global impact.

Conclusion:

The discussion emphasized a holistic and context-sensitive approach to AMR in children, combining vaccine implementation, smarter trial design, pediatric-specific formulations, regulatory reform, IPC, and non-antibiotic innovations. Sustained political will, system integration, and global collaboration remain critical.

ESPID 2025, 26-30 May, Bucharest