High Incidence of SARS-CoV-2 Variant of Concern Breakthrough Infections Despite Residual Humoral and Cellular Immunity Induced by BNT162b2 Vaccination in Healthcare Workers: A Long-Term Follow-Up Study in Belgium

IntroductionCOVID-19 vaccines are expected to provide effective protection. However, emerging strains can cause breakthrough infection in vaccinated individuals. The immune response of vaccinated individuals who have experienced breakthrough infection is still poorly understood.MethodsHere, we studied the humoral and cellular immune responses of fully vaccinated individuals who subsequently experienced breakthrough infection due to the Delta variant of SARS-CoV-2 and correlated them with the severity of the disease.ResultsIn this study, an effective humoral response alone was not sufficient to induce effective immune protection against severe breakthrough infection, which also required effective cell-mediated immunity to SARS-CoV-2. Patients who did not require oxygen had significantly higher specific (p=0.021) and nonspecific (p=0.004) cellular responses to SARS-CoV-2 at the onset of infection than those who progressed to a severe form.DiscussionKnowing both humoral and cellular immune response could allow to adapt preventive strategy, by better selecting patients who would benefit from additional vaccine boosters.Trial registration numbershttps://clinicaltrials.gov, identifier NCT04355351; https://clinicaltrials.gov, identifier NCT04429594.

Section: Discussionsupporting

confidence: 89%

Breakthrough infections due to SARS-CoV-2 Delta variant: relation to humoral and cellular vaccine responses

Buscot

Crémoni

Graça³

et al. 2023

“…Many studies have demonstrated the rapid decay of anti-spike antibodies elicited by vaccination (6)(7)(8)(9)(10)(11)(12)(13)(14)(15), as well as those from SARS-CoV-2 infection (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). This is likely a factor in the high frequency of "breakthrough" infections and re-infections among vaccinees (27-32) and COVID-19-recovered persons (33)(34)(35)(36)(37), although variation of the spike sequence (particularly the receptor binding domain that is the main target of neutralizing antibodies) is a major contributor (13,29,(38)(39)(40)(41)(42). Vaccine protection from severe illness has been more durable (43)(44)(45), which might be due at least in part to cellular immunity and epitope sequences being less affected by spike sequence variation than neutralizing antibodies (38,(46)(47)(48)(49)(50).…”

Section: Introductionmentioning

confidence: 99%

Persistent memory despite rapid contraction of circulating T Cell responses to SARS-CoV-2 mRNA vaccination

Taus

Hofmann²,

Ibarrondo³

et al. 2023

IntroductionWhile antibodies raised by SARS-CoV-2 mRNA vaccines have had compromised efficacy to prevent breakthrough infections due to both limited durability and spike sequence variation, the vaccines have remained highly protective against severe illness. This protection is mediated through cellular immunity, particularly CD8+ T cells, and lasts at least a few months. Although several studies have documented rapidly waning levels of vaccine-elicited antibodies, the kinetics of T cell responses have not been well defined.MethodsInterferon (IFN)-γ enzyme-linked immunosorbent spot (ELISpot) assay and intracellular cytokine staining (ICS) were utilized to assess cellular immune responses (in isolated CD8+ T cells or whole peripheral blood mononuclear cells, PBMCs) to pooled peptides spanning spike. ELISA was performed to quantitate serum antibodies against the spike receptor binding domain (RBD). ResultsIn two persons receiving primary vaccination, tightly serially evaluated frequencies of anti-spike CD8+ T cells using ELISpot assays revealed strikingly short-lived responses, peaking after about 10 days and becoming undetectable by about 20 days after each dose. This pattern was also observed in cross-sectional analyses of persons after the first and second doses during primary vaccination with mRNA vaccines. In contrast, cross-sectional analysis of COVID-19-recovered persons using the same assay showed persisting responses in most persons through 45 days after symptom onset. Cross-sectional analysis using IFN-γ ICS of PBMCs from persons 13 to 235 days after mRNA vaccination also demonstrated undetectable CD8+ T cells against spike soon after vaccination, and extended the observation to include CD4+ T cells. However, ICS analyses of the same PBMCs after culturing with the mRNA-1273 vaccine in vitro showed CD4+ and CD8+ T cell responses that were readily detectable in most persons out to 235 days after vaccination.DiscussionOverall, we find that detection of spike-targeted responses from mRNA vaccines using typical IFN-γ assays is remarkably transient, which may be a function of the mRNA vaccine platform and an intrinsic property of the spike protein as an immune target. However, robust memory, as demonstrated by capacity for rapid expansion of T cells responding to spike, is maintained at least several months after vaccination. This is consistent with the clinical observation of vaccine protection from severe illness lasting months. The level of such memory responsiveness required for clinical protection remains to be defined.

“…In this experiment, sPLS-DA revealed 45 discriminatory peptides, of which 44 were induced by vaccination/infection and of which 17 overlapped with experiment #3. For experiment 4, data on RBD-specific B lymphocytes was available ( 13 ). RBD-specific B lymphocytes evaluated 10 months after vaccination amounted to 0.30% and 0.25% of total living B lymphocytes in two individuals with a breakthrough infection and 0%, 0% and 0.02% in 3 individuals without a breakthrough infection, indicating that the breakthrough infection expanded RBD-specific memory B lymphocytes.…”

Section: Resultsmentioning

confidence: 99%

“…The study was approved by the ethics committee of the University Hospitals Leuven and AZ Groeninge Hospital Kortrijk and participants signed informed consent (S64152, S64089, S2021005 [AZG Kortrijk]). The individuals included in this study have been included in previous studies ( 12 , 13 ).…”

Section: Methodsmentioning

confidence: 99%

Complementarity determining regions in SARS-CoV-2 hybrid immunity

Frans

Dillaerts²,

Dehaemers³

et al. 2023

Self Cite

Pre-vaccination SARS-CoV-2 infection can boost protection elicited by COVID-19 vaccination and post-vaccination breakthrough SARS-CoV-2 infection can boost existing immunity conferred by COVID-19 vaccination. Such ‘hybrid immunity’ is effective against SARS-CoV-2 variants. In order to understand ‘hybrid immunity’ at the molecular level we studied the complementarity determining regions (CDR) of anti-RBD (receptor binding domain) antibodies isolated from individuals with ‘hybrid immunity’ as well as from ‘naive’ (not SARS-CoV-2 infected) vaccinated individuals. CDR analysis was done by liquid chromatography/mass spectrometry-mass spectrometry. Principal component analysis and partial least square differential analysis showed that COVID-19 vaccinated people share CDR profiles and that pre-vaccination SARS-CoV-2 infection or breakthrough infection further shape the CDR profile, with a CDR profile in hybrid immunity that clustered away from the CDR profile in vaccinated people without infection. Thus, our results show a CDR profile in hybrid immunity that is distinct from the vaccination-induced CDR profile.