Interim statement on heterologous priming for COVID-19 vaccines

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10 August 2021 Statement

WHO with support of the Strategic Advisory Group of Experts (SAGE) on Immunization and its COVID-19 Vaccines Working Group is reviewing the emerging evidence on the use of heterologous priming schedules (also known as mix and match schedules). In a heterologous priming schedule, the second dose uses a different vaccine product than the first dose. By contrast, heterologous boosting refers to the administration of a vaccine from a different vaccine platform from the vaccine that was used to complete the primary vaccine series. The interim statement here pertains only to heterologous priming and not heterologous boosting.

The rationale for Heterologous Priming

The most common reason for considering a heterologous COVID-19 vaccine as the second priming dose is the lack of availability of the same vaccine in settings with limited vaccine supply or unpredictable supply. Interchangeability of vaccine products would therefore allow for added programmatic flexibility. There are other reasons to investigate the utility of heterologous priming such as reducing reactogenicity, increasing immunogenicity and enhancing vaccine effectiveness. Heterologous priming should only be instituted if supportive evidence is available.

The current state of knowledge

SAGE continuously reviews new data on heterologous priming vaccine schedules. Guidance is available in some of the product specific interim recommendations (to date, for mRNA vaccines, i.e. BNT162b2 or mRNA-1273, and ChAdOx1-S [recombinant] vaccines).

In general, for COVID-19 vaccines listed for emergency use by WHO with a 2-dose primary series schedule, WHO recommends that the same vaccine product should 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 respective vaccines and as such should only be used if benefits outweigh the risks such as in situations of interrupted vaccine supply.

Studies to date of immune responses after the first dose of ChAdOx1-S [recombinant] products followed by an mRNA vaccine (i.e., BNT162b2 or mRNA-1273) show higher neutralizing antibody levels and higher T cell-mediated immune responses in comparison with two doses of ChAdOx1-S [recombinant] products and similar levels to those of two mRNA vaccines (1). The sequence of the first dose being ChAdOx1-S [recombinant] followed by the mRNA vaccine as the second dose was more immunogenic than a first dose mRNA vaccine followed by ChAdOx1-S [recombinant] vaccine.

While these studies are encouraging, they require cautious interpretation given the limited sample sizes and lack of follow-up, especially related to safety data, and the uncertain relevance of immunological readouts in relation to clinical impact. The first results on short-term vaccine effectiveness (VE) against infection following a heterologous schedule have become available from Denmark showing the effectiveness of 88% (95% CI 83-92%) when combining the ChAdOx1 and an mRNA vaccine, similar to the VE of two doses of an mRNA vaccine, in a population-wide register-based study when the Alpha variant was dominant (2). More observational data on safety and effectiveness will be forthcoming.

While there is currently no data for heterologous priming with other vaccine products, a large number of clinical studies of various vaccine combinations and schedules are currently ongoing. SAGE will review these data as they become available and update the recommendations accordingly.