Preliminary recommendations of the WHO Strategic Advisory Group of Experts on heterologous immunization schemes, fractional doses, and booster doses of COVID-19 vaccines


On 10 August 2021, the World Health Organization published preliminary recommendations, issued by the Strategic Advisory Group of Experts on Immunization (SAGE), and the Working Group on COVID-19 Vaccines, regarding the use of heterologous vaccination schedules, fractional dosing, and booster doses. The following is a summary of the SAGE report.

Heterologous vaccination schedules, also known as mix-and-match schedules, consist of administering the second dose with a vaccine different from that used for the first dose, for which SAGE provides the following recommendations: 

  • For COVID-19 vaccines listed for emergency use by WHO with a 2-dose primary series schedule, WHO recommends that the same vaccine product be used for both doses.
  • If different COVID-19 vaccine products are inadvertently administered in the two doses, no additional doses of either vaccine are recommended.
  • At present, mix-and-match schedules constitute off-label use of the vaccines, and as such should only be used if the benefits outweigh the risks, such as in situations of interrupted vaccine supply.
  • The first results on short-term vaccine effectiveness (VE) against infection following a heterologous schedule are now available from Denmark. They show an effectiveness of 88% (95% CI 83-92%) when combining the ChAdOx1-based vaccine with an mRNA vaccine, similar to the VE achieved using two doses of an mRNA vaccine. However, this study was performed when the Alpha variant was dominant.
  • Currently, a large number of trials of various combinations and immunization schedules are being conducted, and these recommendations will be updated as data become available. 

Dose fractionation: In the face of a limited global supply of COVID-19 vaccines, SAGE is reviewing available information related to dose fractionation from clinical trials conducted in the development of COVID-19 vaccines, and indicates the following:

  • SAGE recommendations for COVID-19 vaccines on the WHO emergency use listing are based on evidence from phase 3 clinical trials, which used full doses. Additional trials would therefore be needed in order to make recommendations related to the use of different doses.
  • There are some preliminary data for fractional doses derived from the phase 3 clinical trial of the ChAdOx-1 S (recombinant) vaccine, and from a phase 2 trial of the mRNA-1273 vaccine.
  • There are no known studies using reduced doses for inactivated virus vaccines, such as Sinovac's CoronaVac, and the COVID-19 vaccine BIBP, nor for the BNT162b2 or Ad26.COV2.S vaccines.
  • SAGE recognizes the potential public health benefits of dose fractionation strategies to increase vaccine supply and accelerate vaccination coverage, as well as to reduce reactogenicity. However, the group believes that there is currently insufficient evidence to recommend the use of fractional doses.

Booster doses of COVID-19 vaccines: 

  • The introduction of booster doses should be based on evidence showing that they are necessary. The duration of vaccine-induced protection depends on many variables, such as type of vaccine, primary vaccination schedule, age, underlying medical conditions of the individual, risk of exposure, and circulation of specific variants.
  • The decision to recommend a booster dose should take into account national strategic and programmatic aspects, in addition to clinical and epidemiological data.
  • In the context of current global vaccine supply constraints, the ongoing priority is to increase global vaccination coverage with the primary series of vaccinations (i.e., for current EUL vaccines, one or two doses).
  • The introduction of booster doses should be based on firm evidence, and should be targeted to the population groups most in need.
  • To date, the evidence remains limited and inconclusive regarding any widespread need for booster doses following a primary series of vaccinations. 


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