Covid-19 vaccines – can we mix and match yet?

8th August 2021, Dr Chee L Khoo


We know that the incidence of thrombocytopaenic thrombosis syndrome (TTS) can occur with the AstraZeneca (AZ) Covid-19 vaccines although it is pretty uncommon. What do you do with patients who had TTS with the first jab and it’s now ready for the next jab? Obviously, they can’t have the second jab with AZ. They will have to have Pfizer Comirnaty vaccine as their next jab. We don’t know whether this mix and match vaccination schedule, so-called heterologous vaccination schedule, is safe or efficacious in developing immunity against Covid-19. A recent Phase 2 randomised controlled trial was conducted looking into those issues.

You wouldn’t think that the 80-100 cases of confirmed TTS related to AZ vaccines in Australia is a big deal. The need for supporting data regarding the safety and efficacy of heterologous vaccination is more urgent than you think. The emergence of TTS relating to the AZ vaccine threw the vaccination plans of many countries (including Australia) into chaos. Many millions of people were already vaccinated with the AstraZeneca ChAdOx1-S vaccine when the issue of TTS emerged in April 2021. Many European countries and Canada had to dramatically modify their immunisation strategies and switched to heterologous vaccination using Pfizer’s Comirnaty (BNT162b2) as second dose. This was all done without supporting data about the immunogenicity and reactogenicity of that approach. There was an urgent call for outcome trials on this issue.

CombiVacS is a phase 2, multicentre, open-label, randomised, controlled trial done at five university hospitals in Spain. Participants were healthy, or clinically stable, adults (aged 18–60 years) who had received a prime AstraZeneca ChAdOx1-S vaccination between 8 weeks and 12 weeks (50–84 days) before the screening visit. 663 participants were randomly assigned (2:1) to receive one intramuscular injection of Pfizer Comirnaty BNT162b2 (intervention group) or maintain observation (control group). Follow-up visits on days 7 and 14 were scheduled to measure vital signs, review any adverse events, update medical and medication records, and collect blood samples.

The primary outcome was the assessment of the humoral immune response to vaccination as per antibodies against SARS-CoV-2 spike protein titres measured by immunoassay 14 days after the BNT162b2 dose. A secondary immunogenicity outcome measure was neutralising antibody titres measured by virus neutralisation assay at day 14. The exploratory outcomes were the relationship between neutralising antibodies and antibodies against SARS-CoV-2 spike protein measured by immunoassay, and cellular response to vaccination (defined as inflammatory IFN-γ cytokine production against SARS-CoV-2 spike peptide pools at day 14).


Demographics and baseline characteristics were balanced between groups. No race or ethnicity data were collected. The mean age of both groups was 43·98 years (SD 8·85). Time elapsed since AstraZeneca ChAdOx1-S administration was between 8 weeks and 9 weeks for 411 (61%) participants and between 10 weeks and 12 weeks for 263 (39%) participants.

There were marked increases in antibody responses seen at Day 7 and these were continued into Day 14. When measured at days 7 and 14, there were marked increases in antibody to spike protein, neutralising antibodies and IFN-γ compared with control as well as compared with Day 0 (see Table 1). Neutralising antibody responses had a strong positive correlation with RBD antibody titres.

Reactogenicity analysis was based on solicited adverse events in 448 individuals from the intervention group, with headache (n=199 [44%]), myalgia (n=194 [43%]), and malaise (n=187 [42%]), the most commonly reported systemic reactions. Other systemic adverse reactions, including fever (n=11 [2%]), were less common (appendix 3 p 17). Injection site pain (n=395 [88%]), induration (n=159 [35%]), and erythema (n=139 [31%]) were the most commonly reported local reactions. Of 1771 solicited adverse events reported in the 7 days after vaccination in the intervention group, most were mild (n=1210 [68%]) or moderate (n=530 [30%]), and self-limited. In 31 participants, the most frequent severe adverse events were malaise (n=7 [23%]), myalgia (n=6 [19%]), and headache (n=5 [16%]). All these participants were contacted and subsequently evaluated by investigators, who did not report any serious adverse events. The severity of solicited local and systemic reactions was highest on day 2 after vaccination.

Thus, Pfizer Comirnaty vaccine given as a second dose in individuals prime vaccinated with AstraZeneca ChAdOx1-S induced a robust immune response, with an acceptable and manageable reactogenicity profile. We don’t know yet whether these responses would be similar had the second dose been AstraZeneca ChAdOx1-S as there were no control receiving AstraZeneca ChAdOx1-S. The trial was conducted in Spain where the use of AstraZeneca ChAdOx1-S was suspended at the time of the trial. The trial is ongoing. The results of this and future studies comparing homologous and heterologous vaccination schedules will allow direct comparisons and substantiate COVID-19 vaccination decision making.

By the way, women who receive the AstraZeneca ChAdOx1-S as the first dose prior to being pregnant can be assured that receiving Pfizer Comirnaty vaccine as a second dose is both safe and efficacious.


Borobia AM, Carcas AJ, Pérez-Olmeda M, et al. CombiVacS Study Group. Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet. 2021 Jul 10;398(10295):121-130. doi: 10.1016/S0140-6736(21)01420-3. Epub 2021 Jun 25. PMID: 34181880; PMCID: PMC8233007.