EMA and ECDC recommendations on heterologous vaccination courses against COVID-19
‘Mix-and-match’ approach can be used for both initial courses and boosters
The EU is currently experiencing a rising number of infections in the ongoing COVID-19 pandemic, as well as an increase in hospitalisation rates. Vaccines are continuing to prevent many millions of EU citizens from becoming very ill or dying and figures show that numbers of hospitalisations and deaths remain lowest in those Member States with the highest vaccination rates. The European Medicines Agency (EMA) and the European Centre for Disease Prevention and Control (ECDC) therefore continue to urge all EU citizens to get fully vaccinated and to adhere to recent recommendations on booster vaccination.
In line with measures already taken by many Member States, an increasing number of clinical studies, supported by real world evidence, have now looked at the possibility of using two different COVID-19 vaccines, either for the first and second doses of a primary (initial) course, which is known as heterologous primary vaccination, or using a third dose of a different COVID-19 vaccine as a booster 3 to 6 months after a primary vaccination course (heterologous boosting).
In order to provide scientific grounds and further provide flexibility to vaccination schemes EMA and ECDC, in collaboration with EU experts in EMA’s COVID-ETF group, have reviewed the available evidence, and provided technical recommendations and advice on heterologous vaccination against COVID-19, either in the primary course or as a booster.
Evidence from studies on heterologous vaccination suggests that the combination of viral vector vaccines and mRNA vaccines produces good levels of antibodies against the COVID-19 virus (SARS-CoV-2) and a higher T-cell response than using the same vaccine (homologous vaccination) whether in a primary or booster regimen. The heterologous regimens were generally well tolerated.
The use of a viral vector vaccine as a second dose in primary vaccination schemes, or use of two different mRNA vaccines, is less well studied.
While research is ongoing to provide more evidence on long-term safety, duration of immunity and effectiveness, the use of heterologous schedules may offer flexibility in terms of vaccination options, particularly to reduce the impact on the vaccine rollout should a vaccine not be available for any reason.
EMA’s and ECDC’s expert considerations, the outcome of which are detailed below, are intended to help decision makers for national vaccination campaigns ensure that the maximum number of EU citizens are vaccinated and protected as quickly as possible.
Marketing authorisation holders are also being encouraged to submit variations to add details about such use to the product information. Although the review did not look at other vaccines not yet licensed in the EU, research into heterologous combinations of these will be taken into account in future if these are licensed and more evidence becomes available.
 Four vaccines are currently authorised in the EU, the two mRNA vaccines Comirnaty and Spikevax, and the adenoviral vector vaccines Vaxzevria and COVID-19 Vaccine Janssen; the first 3 require a two-dose course, the latter is currently authorised as a single dose.
Technical recommendations and advice on heterologous primary and booster COVID-19 vaccination
Following the analysis of the available evidence, EMA and ECDC are issuing the following technical recommendations and advice. A detailed review of the literature supporting the advice will be published by EMA and ECDC in the near future.
Considerations for heterologous primary vaccination
Considerations for heterologous booster vaccination
Other protective measures
Even with vaccination, other measures such as physical distancing, ensuring adequate ventilation in closed spaces, the maintenance of hand and respiratory hygiene measures, appropriate use of face masks, and staying home when ill remain a major pillar of our response to COVID-19, particularly as variants like Delta continue to spread and new variants such as Omicron continue to arise.
While vaccines are hugely important in preventing hospitalisation and death, and have offered protection against all variants so far, they cannot prevent illness in every case. To avoid a resurgence of cases with a possible increase in hospitalisations and deaths, EMA and ECDC urge citizens to follow advice at national and European level to protect themselves, and the wider community.
Working together for public health
EMA and ECDC re-emphasise the need to ensure that as many people as possible are fully vaccinated against COVID-19. There is an urgent need to close immunity gaps in the adult population and ensure effective and equitable coverage across countries and regions in Europe.
Both agencies will continue to work closely together with other EU bodies and national agencies to share the best scientific data and help the Member States come to informed public health decisions in the light of their national as well as the European situation.
EMA and ECDC will continue to follow the scientific evidence and communicate their recommendations and decisions with the maximum possible transparency.