Discussion
As mentioned above, this case report documents a strong reactivation of a pulmonary pathology beginning some hours after the administration of a first dose of a mRNA vaccine in a patient having presented a symptomatic pulmonary form of covid-19 one month before. It confirms previous reports of stronger adverse effects of mRNA vaccine in patients previously infected and sero-positive for SARS-CoV-2 (1-3). However, the clinical history, by contrast with the previous reports, highlights an unexpected renewal of the same severe pulmonary symptomatology in the post vaccination episode as during the initial covid-19 infection.
The main information brought by this clinical observation is the need to delay much more the first inoculation of anti-covid-19 mRNA vaccine in patients having suffered from a symptomatic pulmonary form of covid-19. In order to avoid such unpleasant and painful episode in vaccinated subjects, it would be wise to postpone to some months the first dose of mRNA vaccine to apply in these patients. In such cases, 3 months should be a minimum delay, as already recommended by the health authorities in USA and France for SARS-CoV-2-seropositive individuals.
Otherwise, this case report raises the question of the need to apply or not a second dose of vaccine, since the first one seems plainly wake up the immunological memory of the previous infection with SARS-CoV-2. Indeed, it was shown that: i) stable levels of neutralizing antibodies and T-cells responses are observed until at least 6 months after mild or severe COVID-19 episodes (5, 6), and, ii) the immune responses to a first vaccine dose in patients having previously suffered covid-19 are strongly stimulated and much more important (up to 10 to 45 times) than in previously uninfected subjects having received 2 vaccine doses (up to 3 times) (1, 3, 7-9). Changing the policy to give to these individuals only one dose of vaccine would not negatively impact on their antibody titers, spare them from unnecessary pain and free up many urgently needed vaccine doses.
Another speculative question concerns why this vaccine injection induced symptoms mimicking the severe pulmonary covid-19 clinical form appeared one month before? A potential role of an antibody dependent enhancement (ADE) of SARS-CoV-2 infection (10) with the newly synthesized antibodies in response to vaccine is unlikely, since: i) circulating antibodies are already present following the past natural infection; ii) the timing of symptoms appearance after vaccine inoculation is too short for allowing a significant antibody synthesis. Nevertheless, the presence of living circulating viruses necessary to the ADE of infection in the observed patient remains questionable since the performed SARS-Cov-2 antigen positive test is not sufficient enough to confirm their presence and a PCR test was not performed after vaccination. A reinfection with another SARS-CoV-2 variant at the vaccination time can not be excluded, but remains unlikely since no other cases were observed in the area. The short time occurring between the vaccine inoculation and the symptoms onset is compatible with a strong non-specific inflammatory reaction to the mRNA vaccine. Although reactivity to mRNA vaccines is known to be higher than for more classical protein-based vaccines (11), generally they lead to mild local (at the inoculation site) or systemic symptoms. Such a non-specific inflammatory reaction can hardly explain why the vaccinated patient felt symptoms and presented pulmonary signs mimicking those occurring during its running covid-19 infection one month before. So, we raise the working hypothesis of an initial release in blood flow of the SARS-Cov-2 S protein antigen synthetized at the vaccine IM inoculation site. Indeed, the initiation of protein synthesis and its running production needs few hours in cells (12, 13). Such circulating antigen might be recognized and captured by still activated specific T-cells, which, with dendritic cells and monocytes/macrophages, are particularly present and concentrated at the pulmonary bases, where lung lesions were objectified in chest CT during the covid-19 episode. This specific recognizing by T-cell receptors might induce again an important release of inflammatory cytokines reinitiating the lung pathology of the first clinical episode, through a viral antigen-specific mechanism not needing the presence of viruses. Another non-exclusive possibility, besides the specific recognition of components of the S protein, relates to the concept of “trained immunity”, by which cells of the innate immune system, such as macrophages, monocytes and natural killer cells, show enhanced responsiveness and some capacity to remember (driven by epigenetic changes) when they reencounter pathogen elements (14). Such considerations deserve further investigations.
In conclusion, the case report presented herein confirms the occurrence of strong adverse effects of anti-covid-19 mRNA vaccine in patients having suffering previously a pulmonary form of covid-19, and the need to delay for some months the first inoculation of such vaccine in these patients. Among different possible mechanisms, it puts forward a prospective antigen-specific inducible inflammatory mechanism needing further investigations.