Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID (LC) are clinical conditions classified within the broader category of post-acute infection syndrome. No previous studies have explored the IgG isotype profile against the SARS-CoV-2 Spike-1 antigen in these populations induced by vaccination. This exploratory study aimed to analyze IgG isotyping in European patients with ME/CFS and LC who have received multiple doses of mRNA- and adenovirus-based vaccines, investigating the association between IgG isotypes and illness severity. Ninety-two convalescent COVID-19 patients, comprising 75 patients with ME/CFS, 10 patients with LC, and 7 healthy controls, were included. Serum levels of specific IgG isotypes of the anti-Spike-1-RBD antibody were measured using a previously optimized ELISA. Among the participants, 55.4% had received three or more doses of mRNA vaccines, 18.5% received two doses, and 4.3% received a single dose of mRNA vaccine. Additionally, 15.2% had received several doses of adenovirus-based vaccines combined with a booster of an mRNA vaccine, while 6.5% only received adenovirus-based vaccinations. We found that IgG4 was identified as the predominant antibody isotype in all seropositive individuals from the study participants, followed by IgG1 and IgG2 isotypes. No statistically significant differences were observed in the levels of IgG1, IgG2, or IgG4 in the participants. In the seropositive ME/CFS group, IgG4 was present in individuals who had received two or more doses of mRNA vaccines and sustained high levels during a median of 60 months post-vaccination, unaffected by subsequent breakthrough infections. Nonetheless, 37 ME/CFS subjects remained seronegative, regardless of the number of mRNA doses received. In contrast, 70% of LC subjects and 100% of controls showed prolonged persistence for IgG4 levels over time. Notably, subjects who received only adenovirus-based vaccines or those combined with a single mRNA booster tested negative for IgG4. This investigation suggests an immune dysregulation underlying an ineffective response to persistent antigenic stimuli, emphasizing the potential immune exhaustion in this population.