Mixing COVID-19 Vaccines Increases Side Effects, Preliminary Data Suggests

In February 2021, a clinical trial was launched in the UK that aimed to test the effects of using two different authorized COVID-19 vaccines for dose one and two of the immunization schedule. The study, named "Comparing COVID-19 Vaccine Schedule Combinations", or "Com-COV", is being run by the University of Oxford's Vaccine Group. Com-COV received "Urgent Public Health Study" classification by the National Institutes for Health and Research (NIHR).

The rationale behind the research is that if different vaccines can be safely and efficaciously combined it would offer greater flexibility and resilience for the vaccine rollout program should there be any issues with supply. “If we do show that these vaccines can be used interchangeably in the same schedule this will greatly increase the flexibility of vaccine delivery, and could provide clues as to how to increase the breadth of protection against new virus strains," Matthew Snape, associate professor in pediatrics and vaccinology at the University of Oxford and chief investigator of the trial, said in a press release.

The research study was divided into eight arms, each exploring the following vaccine combinations:

• Pfizer/BioNTech followed by Pfizer/BioNTech - 28 days apart
  
  
• Pfizer/BioNTech followed by Pfizer/BioNTech - 12 weeks apart – (control group)
  
  
• Oxford/AstraZeneca followed by Oxford/AstraZeneca - 28 days apart
  
  
• Oxford/AstraZeneca followed by Oxford/AstraZeneca - 12 weeks apart – (control group)
  
  
• Oxford/AstraZeneca followed by Pfizer/BioNTech - 28 days apart
  
  
• Oxford/AstraZeneca followed by Pfizer/BioNTech - 12 weeks apart
  
  
• Pfizer/BioNTech followed by Oxford/AstraZeneca - 28 days apart
  
  
• Pfizer/BioNTech followed by Oxford/AstraZeneca - 12 weeks apart

In a peer-reviewed Research Letter published today in the Lancet, the study leaders share preliminary findings that suggest combining the different vaccines increases the reactogenicity (side effect profile) associated with vaccination.

Side effects are common after receiving COVID-19 vaccines, with more than one in ten individuals reporting tenderness, pain, warmth, itching or bruising at the injection site, and tiredness, chills, joint pain and nausea.

When administered at a four-week interval, the "mixed" schedules (Pfizer-BioNTech followed by Oxford-AstraZeneca, and Oxford-AstraZeneca followed by Pfizer-BioNTech) were found to result in more frequent mild-moderate systemic reactions – such as headaches, chills and fatigue – one week after the second dose when compared to non-mixed schedules. It is important to note that these adverse side effects were temporary and there were no additional safety concerns.

The symptom data was collected via self-report diaries completed by the participants. "It is worth emphasizing that [the trial] is a single blind study, so the participants do not know which vaccine they have received," Snape said in a briefing. Thus far, the data has not been broken down into categories that distinguish between co-morbidities and gender, Snape clarified.

The study investigators emphasized that this finding is a secondary part of what the study aims to explore. However, they felt it was pertinent to share the data at this time due to some European countries looking to adopt heterologous COVID-19 vaccination methods. Snape said, "The results from this study suggest that mixed dose schedules could result in an increase in work absences the day after immunization, and this is important to consider when planning immunization of health care workers," Snape commented. 

It is important to note that the participants of the Com-COV study are all aged 50-years-old and above. "We have [in general] seen higher rate of reactions in younger age groups, and I think this could be relevant here. Reactions might be higher still in younger age groups," Snape said. He informed Technology Networks that there are no plans to conduct a further study regarding mixing vaccines in younger populations.  

No evidence for a change in the body's immune response

The preliminary data on side effect profiles does not prove that there will be a change in the body's immune response as a result of mixing vaccines, however the investigators hope to explore and report on this in the near future.

The team are taking advantage of these findings while the study is ongoing and exploring whether therapeutics can ease the symptoms observed in the mixed doses: "We have adapted the ongoing study to assess whether early and regular use of paracetamol reduces the frequency of these reactions," said Snape.

Snape stated that the preliminary information has been presented to National Immunization Technical Advisory Groups (NITAGs) in Scandinavia and Canada. "We present it to the policy makers there and leave them to draw their own conclusions," he explained.

A second trial – Com-COV2 – will extend the study to incorporate further COVID-19 vaccines that have been authorized, Moderna (mRNA-1273) and Novavax (NVX-CoV2373).

To learn more about COVID-19 vaccines, visit the Technology Networks hub page. 

Reference: Shaw RH, Stuart A, Greenland M, Liu X, Van-Tam JSN, Snape MD. Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data. The Lancet. doi:10.1016/S0140-6736(21)01115-6.