Third dose COVID-19 vaccination elicits immune memory in patients with inborn errors of immunity even in absence of neutralizing antibodies

BackgroundImmunocompromised people, including those with Inborn Errors of Immunity (IEI), are at increased risk of severe disease from viral infections. Therefore, regular booster vaccinations are recommended for SARS-CoV-2 and influenza, but it is unclear if these elicit protective immunity. ObjectiveComprehensive evaluation of adaptive immune responses, including SARS-COV-2 specific antibodies, memory B-(Bmem) and memory T-cells (Tmem), to COVID-19 vaccination in IEI patients. MethodsBlood samples were collected at 1-month post doses 2 and 3 of the ancestral COVID-19 vaccine, SARS-CoV-2 neutralizing antibodies (NAb) and Spike receptor binding domain (RBD) specific IgG were determined in 25 IEI patients and 29 controls. Ancestral Spike specific Tmem, and ancestral and Omicron subvariant RBD-specific Bmem were evaluated with flow cytometry. ResultsAfter dose 2, IEI patients had significantly lower Nab, RBD-specific IgG and Bmem against ancestral and Omicron subvariants. Third dose vaccination boosted NAb, IgG and Bmem levels, but these remained lower than healthy controls. Especially IgG1+ Bmem were lower in the IEI patients, while they carried higher frequencies of CD71+ ancestral RBD-specific Bmem. IEI patients and controls had similar numbers of Spike-specific CD4+ and CD8+ Tmem after both doses. However, patients Tmem had lower CD69 expression and reduced cytokine co-expression. While 9/25 IEI patients did not have NAb after dose 3, all had detectable SARS-CoV-2 specific IgG, Bmem- and/or Tmem. ConclusionPatients with IEI form lower levels of antibodies and immune memory cells to COVID-19 vaccination than controls. Still, all patients displayed formation of adaptive immune memory. This suggests a beneficial effect of vaccination, and supports the strategy for offering regular booster vaccinations to limit severe COVID-19 in this at-risk population. KEY MESSAGESO_LIWhilst antibody-deficient patients fail to generate NAb, all evaluated IEI patients could form spike-specific Tmem after COVID-19 vaccination. C_LIO_LIA 3-dose regimen boosted humoral and/or cellular responses in 60% of IEI patients, reinforcing the importance of prioritizing this population for early and repeated vaccination. C_LIO_LIComprehensive analysis of Bmem and Tmem responses revealed COVID-19 vaccination elicited adaptive immunity, underscoring the need for monitoring of immune cells in addition to serology in immunodeficient populations. C_LI CAPSULE SUMMARYFollowing 3-dose COVID-19 vaccination, all adult patients with inborn errors of immunity formed memory B- and/or memory T cells regardless of whether neutralizing antibodies are elicited. Therefore, IEI patients generate adaptive immunity to COVID-19 vaccination.