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Fact check: How does the immune system respond to spike protein in the long term?
Executive Summary
Long-term immune responses to the SARS-CoV-2 spike protein include durable memory B and T cell populations and waning circulating antibodies, while traceable spike protein or fragments have been detected in some tissues or blood without consistent links to ongoing symptoms. Evidence from multiple studies through 2025 shows robust cellular memory that can be boosted by vaccination or reinfection, whereas antibody durability varies widely by exposure history and boosting [1] [2] [3].
1. Why antibodies fall but immunity often lasts: the antibody decay story that matters
Studies consistently show that neutralizing antibodies decline over months after vaccination or infection, with estimated half-lives ranging from ~60 days after a primary two-dose mRNA series to much longer durations after boosters or hybrid immunity. A late‑2025 analysis estimated anti-spike IgG half-lives of about 59.8 days after two doses and 99.7 days after a booster, while individuals with hybrid immunity showed a markedly prolonged half-life of 241.8 days and sustained antibody levels above correlates of protection for many months [2]. This pattern explains why circulating antibody levels fall yet does not imply loss of immune protection, because memory B cells and rapidly inducible neutralizing responses persist and can be reactivated by antigen re‑exposure, maintaining functional protection against severe disease [1] [3].
2. T cells stay put — durable cellular memory and what it means for long COVID and protection
Longitudinal studies reveal that SARS-CoV-2-specific CD4+ and CD8+ T cell populations can be maintained for years, with preserved effector phenotypes and T cell receptor signatures detectable two years after infection. These durable T cell responses are similar between people with and without long COVID and can be boosted by vaccination, suggesting that cellular immunity remains a stable pillar of long-term defense and is less affected by spike antigenic drift than antibodies [4]. Additional findings indicate long-persisting spike-specific CD4+ T cells correlate with milder disease and increased cytotoxic potential post-infection, supporting a protective role rather than a pathogenic one [5]. Together these studies underscore that T cell memory reduces the risk of severe outcomes even as viral variants evolve [1].
3. Detectable spike protein: persistence in tissues or blood and the contested link to symptoms
Several investigations have reported detectable spike protein or fragments in tissues (including the skull‑meninges‑brain axis) or in serum months after infection, raising hypotheses about antigen persistence driving post‑acute sequelae. A December 2024 study reported spike persistence in the skull‑meninges‑brain axis of deceased COVID-19 patients, suggesting a potential contribution to neurological sequelae [6]. Conversely, a November 2024 preprint found persistent serum spike in a subset of convalescent patients but no association with post-COVID syndrome or disease severity, indicating detection alone does not prove causation of symptoms [7]. These findings present competing interpretations: antigen persistence could be mechanistically relevant in certain contexts, but current population-level evidence does not uniformly link circulating spike to long COVID symptoms [7] [6].
4. How vaccination changes the long‑term picture: boosters, hybrid immunity, and T cell boosts
Vaccination with mRNA vaccines produces strong anti-spike IgG and neutralizing responses that wane but are substantially reinforced by boosters; boosting increases antibody durability and functional titers, and hybrid immunity (infection plus vaccination/boost) yields the longest-lasting antibody half-lives and prolonged protection intervals [3] [2]. Vaccination also amplifies spike‑specific T cell populations in both long COVID and non‑long COVID individuals, enhancing cellular readiness without evidence that vaccine‑induced spike causes persistent pathogenic immune activation in the general population [4]. Therefore, the collective data indicate that vaccination and boosting optimize both humoral and cellular long-term immunity, reducing risk of severe illness even as antibody titers decline.
5. Synthesis and remaining open questions researchers still need to answer
The evidence paints a coherent picture: durable T cell and memory B cell responses provide long-term protection, while circulating antibodies wane at rates modulated by boosters and hybrid exposures; occasional persistent spike detection in tissues or serum is documented but its causal role in long COVID remains unresolved [1] [2] [7] [6]. Key unanswered questions include the frequency and clinical significance of tissue‑restricted antigen persistence, mechanisms by which it might drive local inflammation or symptoms, and patient-level predictors of persistence versus clearance. Future work must combine longitudinal immune profiling with precise tissue assays and clinical phenotyping to determine when antigen persistence is incidental or causative [6] [7] [4].