Recommendations of the WHO Strategic Advisory Group of Experts on Immunization on heterologous schedules


On 16 December 2021, WHO published interim recommendations of the Strategic Advisory Expert Group on

Immunization (SAGE) regarding heterologous COVID-19 vaccine schedules, for vaccines included in the WHO

Emergency Use Listing (EUL) (Ad26.COV2.S, BBV152, BNT162b2,  ChAdOx1-S [recombinant], mRNA-1273, Sinopharm-BIBP, and Sinovac CoronaVac).  

These recommendations note that, due to the multiplicity of possible heterologous vaccine combinations, the limited direct evidence on the benefits of specific heterologous combinations against the primary outcome of interest (i.e., the level of protection conferred against severe COVID-19), and the lack of an established immune-correlate of protection against COVID-19, the available body of evidence was deemed not to lend itself to formal GRADEing of evidence (Grading of Recommendations, Assessment, Development and Evaluation). Nevertheless, SAGE considered these indirect data from multiple sources as sufficient to proceed with issuing this good practice statement, which is summarized below.  

  • Homologous schedules are considered standard practice based on substantial safety, immunogenicity, and efficacy data available for each WHO EUL COVID-19 vaccine. However, WHO supports a flexible approach to vaccination schedules, and considers that two heterologous doses of any WHO EUL COVID-19 vaccine constitute a complete primary series.
  • Heterologous vaccination should only be implemented with careful consideration of current vaccine supply, vaccine supply projections, and other access considerations, alongside the potential benefits and risks of the specific products being used.
  • Rapidly achieving high vaccination coverage with a primary vaccination series in priority-use groups, as defined in the WHO Prioritization Roadmap, should continue to be the focus while vaccine supply remains constrained.
    Either homologous or heterologous immunization schedules should be utilized. This process should not be delayed over considerations regarding the potential benefits of heterologous schedules.
  • For countries considering heterologous schedules, WHO makes the following recommendations on the basis of equivalent or favorable immunogenicity or effectiveness for heterologous versus homologous schedules:
  • Recommendations on the relative risks and benefits of homologous versus heterologous primary and booster doses will be reviewed as additional data become available.
  • WHO emphasizes the need for key gaps in the evidence to be addressed, including:
    • Effectiveness and duration of protection of heterologous versus homologous schedules for specific WHO EUL product combinations, especially for heterologous schedules involving inactivated vaccines, given the relative lack of data available for these.
    • Long-term safety of heterologous schedules for specific WHO EUL product combinations, including surveillance for rare adverse events.
    • Influence of the order of products and platforms on the safety, immunogenicity, and effectiveness of heterologous vaccination.
    • Effectiveness of heterologous vaccination in relation to the time interval between the first and second doses, and between the primary series and booster dose.
    • Correlates of initial protection or duration of protection for homologous and heterologous schedules. o Safety, immunogenicity, and effectiveness of fractional doses in the context of heterologous vaccination. o Relative immunogenicity and effectiveness of heterologous versus homologous vaccination schedules against variants of concern, including the Omicron variant.

For more information on these recommendations and the evidence considered by SAGE/WHO, please refer to the full document available at:

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