Driven by the spread of the omicron variant of SARS-CoV-2, the CDC7 as well as the EMA6 have expanded the eligibility for a booster dose recently, and also recommended a mix-and-match approach for booster vaccinations in order to allow more flexibility in case of issues with vaccine acceptance, supply or availability. Hence, different COVID-19 vaccines can be used for a 3rd booster dose5 - regardless of the preceding vaccine that was applied for primary immunization. In more detail, booster doses are recommended with a preference for mRNA-based vaccines (Comirnaty or Spikevax) since boosting with a mRNA-vaccine after a vector primary series seems to be more immunogenic than the reverse. Noteworthy, data regarding safety issues of heterologous booster vaccinations with e.g. Comirnaty first followed by a Spikevax booster thereafter are scarce.
Currently, the German vaccine agency (STIKO) only recommends Comirnaty – but not Spikevax - for a 3rd booster vaccination in children and young adults aged < 30yrs since cases of peri-/myocarditis were more frequently observed after Spikevax vaccination compared to Comirnaty in this age group in some countries – including Germany8–10. In contrast to the German recommendations, the US CDC agency recommends Spikevax for booster vaccination in everyone ≥ 18yrs with successful primary immunization5. Hence, in the present case, the rather strict recommendations of the German vaccine agency (STIKO) regarding the use of Spikevax in young adults aged < 30yrs were – unfortunately – not in effect, since this was an already 31-year-old young man.
According to available data, a 3rd booster with Comirnaty seems to be associated with a lower risk of (autoimmune) myocarditis compared to the previous second dose of primary immunization in adolescents11. However, similar data are not available so far regarding a 3rd (heterologous) booster with Spikevax. It is unclear why vaccine-associated myocarditis seems to be less likely after a 3rd booster dose compared to the preceding second dose, but one may speculate that the activation of the immune system is more severe after the 2nd dose compared to 3rd booster dose due to the shorter time window between the 1st dose and the 2nd dose (only three weeks in case of Comirnaty) compared to the longer time window of 5–6 months between the 2nd dose and the 3rd booster dose. A potential over-activation may lead to edema and inflammation in the heart via complex pro-inflammatory cascades and may result in vaccine-associated myocarditis - as was already shown and discussed by our group in a previous publication3. Since neutralizing antibody levels gained by previous vaccines decrease with time, the vaccinated recipient has to start at a lower level of immunogenicity in case of the 3rd booster dose.
A challenging, however, highly important question needs to be asked in this context: Which combination of a 3rd booster dose should be preferred particularly in young adults who are prone to vaccine-associated myocarditis? Advantages and disadvantages of both options (homologous vs. heterologous) have been summarized in a recent review by Meng et al12. The observation that “heterologous” booster vaccination may induce more extensive protective immune responses seems to be true for both Comirnaty and Spikevax booster, but the essential question is whether we really need this “additional” protection of a “heterologous” approach compared to a “homologous” one, and what we will have to pay for this gain considering exuberant antibody and T cell reactions13 that may cause autoimmune damage, e.g. autoimmune myocarditis. In our present report, a heterologous combination of two primary series of Comirnaty followed by booster dose of Spikevax caused a massive inflammation in the patient’s myocardium - supposed to be due to over-activation of the immune system – that would not have been expected in case of a 3rd homologous booster dose with Comirnaty. As there are some reports of less damage caused by vaccine series of Comirnaty only14 including a booster dose, we need to ask whether a “heterologous” combination of a primary immunization with Comirnaty followed by a Spikevax booster dose is sufficiently studied yet and really necessary in young adults as long as safety data are scarce? Therefore, we suggest to act with caution when selecting the booster vaccine and to avoid a heterologous booster with Spikevax – if possible – particularly in young males – as long as respective safety data are missing.
Finally, it needs to be considered that the respective myocardial scars that will occur in the areas of myocardial inflammation observed in this patient by CMR will "persist” – even if this patient recovered quickly from a clinical point-of-view. And the future value of myocardial scars in a young adult cannot be foreseen at this point in time – even if this patient was absolutely asymptomatic after hospital discharge – since it is well known that (chronic) myocardial scars may be associated with ventricular arrhythmias in the future - at least in some patients.