Reply to "Caution Regarding Conclusions about COVID-19 Vaccine and Encephalitis".

We appreciate the comments by Dr Wiznitzer and consider it a cautionary note, consistent with his testimony as an expert witness for the US Department of Health and Human Services in the Vaccine Injury Compensation Program. We agree (and also emphasized in our publication ) that causality between the ChAdOx1 nCoV‐19 vaccination and encephalitis has not yet been established. In the reported cases, the temporal correlation and the detailed exclusion of other causes drew our attention to the possibility that the encephalitis might be a vaccination side effect.

Dr Wiznitzer expresses skepticism about the postvaccinal clinical time course in our patients as compared to established antibody responses. The clinical course was characterized by initial systemic symptoms and subsequent definite central neurological symptoms. This is specified in more detail in the Table 1, showing that the onset of symptoms was within the first 2 weeks (days 8–11) after vaccination. This is consistent with the data we cited, which provided a large database of postvaccinal encephalitis in which 50.7% of cases occurred within the first 2 weeks.

TABLE 1

Overview of the Time Course of Systemic and Definite CNS Symptoms after ChAdOx1 nCoV‐19 Vaccination

Patient #	Vaccination	Systemic Symptoms	Definite CNS Symptoms
1	First vaccination with ChAdOx1 nCoV‐19, day 0	Day 1: fever and malaise Day 5: headache progressive disturbances of attention and concentration (possible but not definite CNS symptoms) Day 10: repulsive behavior	Day 10: confusion Day 11: evidence of pleocytosis in CSF
2	First vaccination with ChAdOx1 nCoV‐19, day 0	Day 2: deep vein thrombosis of left leg Day 6: gait deterioration, vigilance disorder	Day 8: OMS Day 12: evidence of pleocytosis in CSF
3	First vaccination with ChAdOx1 nCoV‐19, day 0	Day 8: fever	Day 8: aphasia Day 11: evidence of pleocytosis in CSF

All patients received the first vaccination with ChAdOx1 nCoV‐19. This overview suggests that systemic symptoms occurred first, followed by definite CNS symptoms. Definite CNS symptoms occurred between days 8 and 11, which in our opinion is consistent with a possible postvaccinal reaction.

CNS = central nervous system; CSF = cerebrospinal fluid; OMS = opsoclonus–myoclonus syndrome.

Recently, in a case series of patients with adverse events associated with various COVID‐19 vaccinations, immune‐mediated neurologic disorders including encephalitis were reported to occur with a median of 11 days following vaccination. In the meantime, a case comparable to ours has been reported and attributed similarly. Observations of other autoimmune central nervous system diseases such as acute disseminated encephalomyelitis (ADEM) after ChAdOx1 nCoV‐19 vaccination are also consistent with our data. , Furthermore, these findings are supported by a review of the literature focusing on case reports of ADEM after vaccinations against various pathogens, , in which the average time between exposure to vaccines and the onset of symptoms ranged between 1 and 14 days.

We are aware that the immunological mechanism of postvaccination encephalitis is not fully understood. In the study by Ewer et al, an unbiased approach was used to measure gross phenotypic and cellular changes at days 7, 14, and 28 after vaccination. Measurements before or shortly after day 7 were not performed. A multiplex cytokine analysis at day 7 after vaccination revealed increased secretion of interferon‐γ and interleukin‐2, indicating Th1 cytokine secretion in response to stimulation with SARS‐CoV‐2 spike peptides in subjects receiving the ChAdOx1 nCoV‐19 vaccine. The cellular immune response showed discrete populations of T cells, natural killer cells, and B cells as early as 7 days after ChAdOx1 nCoV‐19 vaccination. At all time points after vaccination, B cells, particularly the immunoglobulin G+ B‐cell population, exhibited increased levels of Ki‐67, a marker of increased cell proliferation, which in turn can be interpreted as an early immune response after vaccination.

Importantly, Dr Wiznitzer refers to an mRNA vaccine. However, our case series exclusively focused an adenovirus‐vectored vaccine, which may impact the side effect potential as well as the immunological mechanisms postvaccination.

Regardless of established causalities, we believe that we are obliged as clinical neurologists to report potential complications of ChAdOx1 nCoV‐19 vaccination, thus enabling an open discussion and timely diagnosis as well as treatment of similar cases. Despite established or presumed complications, we emphasize that the benefits of vaccination clearly outweigh its risks.

Potential Conflicts of interest

Nothing to report.