After receiving mRNA Covid-19 vaccines, two HCW who had recently been vaccinated with BCG as a part of the BCG-DENMARK-COVID trial experienced reactivation at the site of the trial BCG vaccines administered 6 to 8 months earlier. There was no reactivation in childhood BCG scars. The participant who reacted most strongly after receiving BCG vaccination both as a child and when entering the BCG-DENMARK-COVID trial experienced symptoms from the trial BCG scar site already after the first Covid-19 vaccination, whereas the participant who had only had moderate symptoms following the BCG inoculation 6 months earlier only noted reactivation after the second injection.
Reactivation of BCG scars has previously been reported following influenza vaccination [7, 8], but the participant who received an influenza vaccination 2 months before the Covid-19 vaccination did not experience any such reactions.
Two recent case reports described similar reactions in scars after neonatal BCG vaccines in four health care workers aged between 28- and 45-years following mRNA Covid-19 vaccines [9, 10]. Reactivation of BCG scars has also been described during viral infections in children, e.g., measles and human herpes virus type 6 [11,12,13]. However, reactivation of BCG scars has mainly been associated with Kawasaki disease (KD), and local reactions such as erythema and induration at the BCG scar site have even been suggested as a diagnostic tool in diagnosing KD [14]. A study from Singapore, where BCG is given to all new-born infants, reported that 43% of patients with KD developed reactivation at the BCG scar site, most frequently the youngest children [13]. The study indicated that the higher prevalence in the youngest children was due to the shorter duration between BCG inoculation and onset of KD, rather than age per se [13]. This could explain why we only observed reactivation in the most recent BCG scars.
Interestingly, a new pediatric disease associated with Covid-19, called multisystem inflammatory syndrome in children (MIS-C) has been identified, with pathogenesis and clinical presentation similar to KD [15]. The fact that COVID-19 can cause MIS-C, that MIS-C resembles KD, and KD is associated with BCG reactivation points to some degree of shared etiology. The pathophysiology of MIS-C is still unknown [15]. MIS-C has mostly been diagnosed in high-income countries where BCG is not widely used, and to our knowledge, no reactivations of BCG scars have been reported in children suffering from MIS-C. However, this is likely due to the rarity of MIS-C, and the low epidemiological chance that this would happen in a child vaccinated with BCG. On the other hand, based on the available evidence, BCG scar reactivation in children with MIS-C could be anticipated in countries where BCG is used routinely.
Live BCG organisms have been shown to remain in BCG-vaccinated mice for up to 5 months [16], and have been cultured from children born to HIV positive mothers 9 years after receiving BCG at birth [17]. It is, however, improbable that the changes seen in the two cases are due to live BCG bacteria. It is thus more likely that the local reaction was induced by cross-reactivity between BCG microbial components persisting at the site of vaccination and SARS-CoV-2 vaccines. An in silico analysis suggested that BCG vaccine has the potential to generate cross-reactive T cells against SARS-CoV-2 [18]. Corroborating this finding, eight BCG-derived peptides with significant sequence homology to either SARS-CoV-2 nonstructural protein 3 (NSP3) or nonstructural protein 13 (NSP13) derived peptides were recently identified [19]. Interestingly, human CD4+ and CD8+ T cells primed with a BCG-derived peptide developed enhanced reactivity to its corresponding SARS-CoV-2 derived peptide, supporting the hypothesis that BCG vaccination induces cross-reactive SARS-CoV-2 specific T cell responses [19]. Furthermore, a high homology of the SARS-CoV-2 envelope protein with the consensus protein LytR C unique to Mycobacteria indicates that BCG vaccination induces a specific immunity against SARS CoV-2 that targets the viral envelope protein that is essential for infectivity [20]. The reactivation of the BCG scar experienced by two HCW after receiving mRNA vaccines might therefore have been caused by an immunological reaction due to the cross reactivity between BCG and SARS-CoV-2.
In the BCG-DENMARK-COVID trial, 614 HCW participants were randomized to receive BCG. Two participants reported BCG scar reactivation following Covid-19-vaccination. In both cases, the symptoms were irritating, but self-limiting, and they left no sequelae. Both participants were glad to have contributed to the trial and would be happy to participate in similar trials in the future. Our case one participant felt that her general health had improved compared to before the trial, whereas the participant from case two felt her general health to be unchanged.
A limitation of the cases reported is that no testing was done to elucidate the pathogenesis causing the symptoms. However, the two participants experienced the symptoms to the degree that they spontaneously reported them, why it is important for clinicians to know about the possibility of seeing similar reactions and it also seems worthwhile to alert physicians to the fact that BCG scar reactivation might be an indicator of MIS-C. Still, there is no reason to avoid vaccination with either of the mRNA Covid-19 vaccines.
