Here we report an extensive inflammatory skin reaction that occurred at the site of vaccination in a 67-year-old Caucasian woman following a single dose of PCV13 (Fig. 1). Prior to PCV vaccination she underwent a detailed immunological work-up at our immunodeficiency clinic because of recurrent lower respiratory tract infections. Over the past 6 years, she experienced three CAP, once with sepsis. Bacterial blood cultures and search of urinary pneumococcal and legionella antigens were performed after initiation of antibiotic therapy. No causative agent could be isolated for any of the three episodes. Patient history was remarkable for two episodes of diverticulitis, recurrent herpes labialis ("cold sore"; reactivation rate <1/year and not for several months preceding PCV administration), obesity (BMI 39 kg/m2), and non-insulin-dependent diabetes mellitus. No opportunistic infections were documented. She was not taking any immunosuppressive drugs. She had been vaccinated according to the Swiss vaccination guidelines. The last tetanus/diphtheria booster dose had been administered 17 years ago. She had never received any pneumococcal vaccine. The physical examination and CT scan imaging were normal, with no evidence for chronic pulmonary disease or lympho proliferation. Body pletysmography was normal, excluding asthma or chronic obstructive lung disease. Immunologic analysis in the clinical routine showed normal total serum IgG, IgM, IgA, and IgG1-4 subclass levels. Lymphocyte (T vs. B vs. NK cell) and B cell subset distribution (naive vs. memory vs. marginal zone-like B cells) were normal (Table 1). Functional complement screening revealed normal classical and alternative pathways (Table 1). In summary, there was no evidence of an underlying immunodeficiency that would have predisposed to the recurrent infections. Diabetes and obesity were potential risk factors.
Given the history of recurrent lower respiratory tract infections, the patient was vaccinated with PCV13 (Prevenar13, Pfizer). Three days later, she developed a progressive, extensive, and painful swelling and erythema of about 10 x 20 cm (4 x 8 inches), affecting almost all of her upper arm around the site of injection (Fig. 1a). Given the strong pain and extensive local inflammatory reaction, she received glucocorticosteroid (20 mg prednisone daily) and an antihistaminic for 4 days, with a favorable evolution. A skin biopsy obtained on day 4 following vaccination, and 46 h following the first dose of prednisone/antihistamine, showed a dense dermal and subdermal perivascular-intensified infiltration dominated by CD4+ T cells and CD68+ macrophages. This pathology is classical of a type IV delayed hypersensitivity reaction:as seen with a positive Mantoux tuberculosis skin test (Fig. 1b). CD8+ T cells were very sparse and B cells were almost completely absent (Fig. 1b). Pre-vaccine and 4 weeks post-vaccine anti-pneumococcal IgG levels were determined in a multiplexed serotype-specific assay testing a total of 14 serotypes: 7 that are included in PCV13, and 7 that are not (Fig. 1c). Seroresponses were very vigorous against all tested PCV13 serotypes plus serotypes 9N and 20, not included in PCV13. Strikingly, a very high pre-vaccination IgG titer was observed against the non-PCV13 serotype 8, suggesting prior infection with this serotype (Fig. 1c). There was a humoral response against the diphtheria carrier protein CRM197, as anti-diphtheria titers increased following PCV13 vaccination, which was not observed for an irrelevant control protein (tetanus) (Fig. 1d). Notably, this anti-diphteria titer increase was recorded before the subsequent DiTe booster dose that was given 4 weeks after the PCV vaccination.
In vitro B cell activation 2 months after PCV13 vaccination showed a strong PCV13-induced B cell proliferation and plasmablast induction, and also a high spontaneous B cell proliferation rate in the absence of exogenous antigen (Supplementary Fig. S1). In vitro T cell responses (2 months post PCV13 vaccination and 1 month post DiTe booster vaccination), as measured by directly ex vivo ELISpot and T cell proliferation assay following in vitro stimulation with DiTe and PCV vaccines were measurable, but not different from control individuals (Supplementary Fig. S2).