Understanding Reactogenicity Patterns, Implications of Interim Findings

The Oxford-led Phase II Com-COV trial is investigating immune responses in patients who have been given heterologous prime-boost vaccine schedules using AstraZeneca’s Vaxzevria (ChAdOx1 nCov-19) and Pfizer’s Comirnaty (BNT162b2) COVID-19 vaccines.

The study includes two heterologous schedules: one for recipients of Vaxzevria to prime followed by Comirnaty to boost, and one for recipients of Comirnaty to prime followed by Vaxzevria to boost. Two additional groups were given homologous schedules, either two doses of Comirnaty or two of Vaxzevria, which served as control groups. The trial enrolled 830 participants ages 50 years and older, which may limit extrapolation of the final results to other age groups. Preliminary safety results indicate that mixing vaccines leads to higher reactogenicity and more frequent side effects. However, this analysis is based on self-reported descriptive symptoms. This may be correlated with stronger vaccination efficacy and broader protection, but will be difficult to determine from such a small sample size without a placebo control group. Com-COV was also not powered for reactogenicity, so it remains unclear if a true difference exists between the study groups.

Severe side effects such as thrombosis were not identified in previous large Phase III vaccine trials because they are extremely rare. Therefore, it is possible that other serious adverse events will not be observed until the mixed vaccine schedule is actually implemented in a real-world setting.

Com-COV investigators have indicated that the higher reactogenicity observed when mixing vaccines is especially important when planning immunization schedules of healthcare workers, as it may increase their need for time off work. Unfortunately, the majority of healthcare workers are under 50 years of age, and this study will not be able to capture the impact of heterologous vaccination in this population.

A similar Phase II study in Spain, Combivacs, recently announced positive preliminary data that slightly contradicts the Com-COV results, showing that the heterologous vaccine schedule is safe and effective. Participants receiving a Comirnaty boost showed a 150-fold increase in antibody titers, which remained evident seven days after they were dosed. Combivacs enrolled 670 participants ages 18–59 years who have already received one dose of Vaxzevria. The interim analysis consisted of 450 participants who were given Comirnaty as their second dose. Side effects such as headaches and muscle pain were reported in 1.7% of this group versus. 34% reported from the Com-COV arm receiving the same heterologous schedule. More data from larger trials is necessary to determine the reason for these differences and to confirm immune responses.

If further data for mixing vaccines indicates that there is higher reactogenicity, it is possible that heterologous schedules will also lead to more severe reactions in younger populations. More data will be required to assess how severe the reactions can be, and if greater reactogenicity could be coupled to broader or longer protection from contracting COVID-19.

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Given the rare adverse events associated with Oxford/AstraZeneca’s COVID-19 vaccine, countries including Germany, France, Sweden, Norway, and Denmark are advising individuals initially primed with this vaccine to receive an alternate vaccine as their second dose. Com-COV and Com-COV2 will likely uncover the effects of mixing vaccines in adults ages 50 years and older. However, data in younger populations is now crucial, as vaccine shortages continue to delay global pandemic recovery, and this age group seems to suffer most of the adverse reactions to all vaccines. If mixing vaccines is determined to be safe and effective, this strategy could greatly enhance vaccine rollouts in countries where there are concerns over safety or shortages of the priming vaccine, helping to ensure that these regions remain on a steady path toward herd immunity.