Five doses of the mRNA vaccination potentially suppress ancestral-strain stimulated SARS-CoV2-specific cellular immunity: a cohort study from the Fukushima vaccination community survey, Japan

Abstract

The bivalent mRNA vaccine is recommended to address coronavirus disease variants, with additional doses suggested for high-risk groups. However, the effectiveness, optimal frequency, and number of doses remain uncertain. In this study, we examined the long-term cellular and humoral immune responses following the fifth administration of the mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in patients undergoing hemodialysis. To our knowledge, this is the first study to monitor long-term data on humoral and cellular immunity dynamics in high-risk populations after five doses of mRNA vaccination, including the bivalent mRNA vaccine. Whereas most patients maintained humoral immunity throughout the observation period, we observed reduced cellular immune reactivity as measured by the ancestral-strain-stimulated ELISpot assay in a subset of patients. Half of the individuals (50%; 14/28) maintained cellular immunity three months after the fifth dose, despite acquiring humoral immunity. The absence of a relationship between positive controls and T-Spot reactivity suggests that these immune alterations were specific to SARS-CoV-2. In multivariable analysis, participants aged ≥70 years showed a marginally significant lower likelihood of having reactive results. Notably, among the 14 individuals who received heterologous vaccines, 13 successfully acquired cellular immunity, supporting the effectiveness of this administration strategy. These findings provide valuable insights for future vaccination strategies in vulnerable populations. However, further research is needed to evaluate the involvement of immune tolerance and exhaustion through repeated vaccination to optimize immunization strategies.

Keywords: SARS-CoV2; cellular immunity; dialysis patient; immune imprinting; vaccination; vulnerable population.

Figure 1

The dynamics of humoral and cellular immunity. (A) The timing of vaccinations and blood collections, (B) The dynamics of T-SPOT.COVID COV(A) results, (C) IgG(S) levels, (D) NAb titers, and (E) IgG against the nucleocapsid protein (IgG(N)) levels. In (B), spots ≥50 are scored as 50. Spots ≤4, 5–7, and ≥8 were considered nonreactive, borderline, and reactive, respectively. Blue and red lines indicate the limit of detection as four spots and the limit of sensitivity as eight spots, respectively.

Figure 2

The dynamics of humoral and cellular immunity: comparison of the reactive and the nonreactive and borderline groups. We divided the cohort into two groups: the reactive group (n = 11) and the nonreactive and borderline group (n = 14), and illustrated the dynamics of humoral and cellular immunity. (A) The dynamics of T-SPOT.COVID COV(A) results, (B) IgG(S) levels, and (C) NAb titers. In (A), spots ≥50 are scored as 50. Spots ≤4, 5–7, and ≥8 were considered nonreactive, borderline, and reactive, respectively. Blue and red lines indicate the limit of detection as four spots and the limit of sensitivity as eight spots, respectively.