Table 2.

Preferred Product Characteristics for Group A Streptococcus Vaccines

Parameter	Preferred Characteristics
Indication	Prevention of GAS-related pharyngitis, superficial skin infections, cellulitis, toxin-mediated disease, invasive infections and associated antibiotic use, secondary rheumatic fever, rheumatic heart disease, and poststreptococcal glomerulonephritis
	Notes: Prevention of pharyngitis and skin infections would constitute relevant and feasible early vaccine development targets. See Efficacy section for further considerations on efficacy evaluation.
Target population for primary immunization	Primary schedule: infants and/or young children.
	Notes: Further evidence is needed to define the optimal vaccination age according to epidemiological setting, and whether GAS vaccination would be most appropriately introduced in early infancy, or require later, early childhood doses, and late booster doses. Research should determine the role of primary immunization in the following special circumstances: • Secondary prevention in subjects at increased risk of RHD • Immunization of adults at increased risk of cellulitis or severe invasive disease such as the elderly and individuals with diabetes, obesity, or other immunosuppressive conditions • Women, including pregnant women, for prevention of puerperal and neonatal sepsis • Immunization campaigns for interruption of outbreaks of GAS-related disease
Schedule of primary immunization and boosting	No more than 3 doses required for primary immunization.
	Notes: Research should determine the required number of doses and schedule for primary immunization and the requirements for booster doses. Boosting around school age, young adulthood and/or pregnancy, and old age could be proposed. Considering the age distribution of the disease burden, several booster doses may be required and acceptable.
Efficacy targets	Preferences for target efficacy differ according to the severity of the target disease syndrome: • 80% protection against nonsevere, noninvasive, confirmed GAS disease • 70% protection against confirmed GAS cellulitis and other invasive infections • 50% protection against long-term immune-mediated sequelae
	Notes: Lower limits of acceptable vaccine efficacy are not defined here. Long-term protection is required given the age distribution of the disease risk. The preferred minimum follow-up time for efficacy evaluation is 2 years. Appropriate efficacy endpoint case definitions and ascertainment methodologies for vaccine trials should be defined. The preferred efficacy thresholds for more severe outcomes are lower than those for less severe outcomes because of the public and individual value assessment. A strategy including predefined stage-gate criteria should be developed with the aim to minimize risk and accelerate vaccine development and to promote responsible research investment: • The availability of a clinically relevant human experimental infection model may be valuable. • Early proof of concept focusing on more frequent, less severe endpoints (with pharyngitis and skin infection as a priority) should establish the potential protective profile. • Vaccine efficacy against cellulitis and other invasive infections will require larger sample size. • The impact on longer-term, less frequent, severe complications may need to be evaluated in pilot implementation or postlicensure studies. The vaccine impact on carriage and transmission should be characterized.
Strain and serotype coverage	Efficacy targets are set irrespective of strain/serotype considerations. The vaccine composition should ensure that a vast majority (preference for at least 90%) of the current disease-causing isolates from the region targeted for use are prevented.
	Notes: The role of variation over time and potential for bacterial population replacement should be characterized. Further research is needed to determine role of immunoassays to infer strain/serotype specificity of protection.
Safety	Safety and reactogenicity profile at least as favorable as current WHO-recommended routine vaccines.
	Notes: As a minimum, a standard safety monitoring plan should be implemented as part of clinical development efforts. The appropriate use of additional safety monitoring tools including human antigen immune reactivity testing and echocardiography should be predefined, considering the risk of unspecific, coincidental findings, especially if multiple comparisons are planned. The intensity of safety investigations should be tailored to the amount of accrued evidence about the safety profile. Safety endpoints of interest should be protocol defined and supported by sample size analyses.
Adjuvant requirement	Evidence should be generated to justify adjuvant inclusion in the formulation.
	Notes: Adjuvants with established, favorable safety profiles are preferred over new adjuvants.
Immunogenicity	Established correlate/surrogate of protection based on a validated assay measuring immune effector levels/functionality.
	Notes: The longevity of the immune response should be characterized, and the relationship to duration of protection should be investigated. Collaborative efforts toward the generation of relevant nonclinical assays, using open source reference reagents (including immune sera) with international standards of quality may greatly contribute to comparability assessments, generation of a regulatory acceptable correlate of protection, ultimately supporting immune bridging steps and clinical development plan simplification, and accelerating the pathway to licensure. The role of reference laboratories is acknowledged.
Noninterference	Demonstration of favorable safety and immunologic noninterference upon coadministration with recommended other vaccines if used in the same target population.
Route of administration	Injectable (IM or SC) using standard volumes for injection as specified in programmatic suitability for PQ or needle-free delivery.
	Notes: The role of pain-free mucosal delivery via the pharynx or nasopharynx, and dermal delivery, should be considered. Preference for IM or SC over ID.
Registration, prequalification, and programmatic suitability	The vaccine should be prequalified according to the process outlined in Procedures for assessing the acceptability, in principle, of vaccines for purchase by United Nations agencies. WHO-defined criteria for programmatic suitability of vaccines should be met.
Value proposition	Dosage, regimen, and cost of goods amenable to affordable supply. The vaccine should be cost-effective and price should not be a barrier to access including in LMICs.
	Notes: Reduction of antibiotic use in routine practice would be of high added value. The vaccine impact on health systems, economic impact, and other aspects of implementation science should be evaluated in large trials, pre- or postapproval, as practicable.

Abbreviations: GAS, group A Streptococcus; ID, intradermal; IM, intramuscular; LMICs, low- and middle-income countries; PQ, prequalification; RHD, rheumatic heart disease; SC, subcutaneous; WHO, World Health Organization.