ABSTRACT
BackgroundHaemodialysis patients are at-risk for severe COVID-19 and were among the first to receive a fourth COVID-19 vaccination. MethodsWe analysed humoral responses by multiplex-based IgG measurements against the receptor-binding domain (RBD) and ACE2-binding inhibition towards variants of concern including Omicron in haemodialysis patients and controls after triple BNT162b2 vaccination and in dialysis patients after a fourth full-dose of mRNA-1273. T-cell responses were assessed by interferon {gamma} release assay. FindingsAfter triple BNT162b2 vaccination, anti-RBD B.1 IgG and ACE2 binding inhibition reached peak levels in dialysis patients, but remained inferior compared to controls. Whilst we detected B.1-specific ACE2 binding inhibition in 84% of dialysis patients after three BNT162b2 doses, binding inhibition towards the Omicron variant was only 38% and declining to 16% before the fourth vaccination. By using mRNA-1273 as fourth dose, humoral immunity against all SARS-CoV-2 variants tested was strongly augmented with 80% of dialysis patients having Omicron-specific ACE2 binding inhibition. Modest declines in T-cell responses in dialysis patients and controls after the second vaccination were restored by the third BNT162b2 dose and significantly increased by the fourth vaccination. ConclusionsA fourth full-dose mRNA-1273 after triple BNT162b2 vaccination in haemodialysis patients leads to efficient humoral responses against Omicron. Our data support current national recommendation and suggest that other immune-impaired individuals may benefit from this mixed mRNA vaccination regimen. FundingInitiative and Networking Fund of the Helmholtz Association of German Research Centres, EU Horizon 2020 research and innovation program, State Ministry of Baden-Wurttemberg for Economic Affairs, Labour and Tourism, European Regional Development Fund Research in the contextO_ST_ABSEvidence before this studyC_ST_ABSInformation on how to best maintain immune protection after SARS-CoV-2 vaccination in at-risk individuals for severe COVID-19 such as haemodialysis patients is limited. We searched PubMed and medRxiv for keywords such as "haemodialysis", "SARS-CoV-2", "vaccine", "decay", "antibody kinetics", "cellular immunity", "longitudinal vaccination response", "immunisation scheme". To date, no peer-reviewed studies comprehensively assessed impact of both cellular and humoral immunogenicity after a triple BNT162b2 vaccination in combination with a fourth full-dose of mRNA-1273 and addressed the impact of currently dominating SARS-CoV-2 variants of concern on vaccine-induced immunity in this at-risk population. Added value of the studyWe provide to the best of our knowledge for the first time longitudinal vaccination response data over the course of the pandemic in dialysis patients. We studied not only systemic T- and B-cell but also mucosal responses in this at-risk group and determined levels of neutralizing antibodies towards Omicron BA.1 and Delta variants after a mixed mRNA vaccine schedule. Implications of all the available evidencePatients on haemodialysis show inferior response rates and thus a more rapid decline in humoral immune response after triple vaccination with BNT162b2. Our data strongly support the concept of administering a fourth full-dose of mRNA-1273 as part of a heterologous vaccination scheme to boost immunity and to prevent severe COVID-19 within this at-risk population. Strategic application of modified vaccine regimens may be an immediate response against SARS-CoV-2 variants with increased immune evasion potential.
ABSTRACT
The rapid emergence of the Omicron variant and its large number of mutations has led to its classification as a variant of concern (VOC) by the WHO(1). Initial studies on the neutralizing response towards this variant within convalescent and vaccinated individuals have identified substantial reductions(2-8). However many of these sample sets used in these studies were either small, uniform in nature, or were compared only to wild-type (WT) or, at most, a few other VOC. Here, we assessed IgG binding, (Angiotensin-Converting Enzyme 2) ACE2 binding inhibition, and antibody binding dynamics for the omicron variant compared to all other VOC and variants of interest (VOI)(9), in a large cohort of infected, vaccinated, and infected and then vaccinated individuals. While omicron was capable of binding to ACE2 efficiently, antibodies elicited by infection or immunization showed reduced IgG binding and ACE2 binding inhibition compared to WT and all VOC. Among vaccinated samples, antibody binding responses towards omicron were only improved following administration of a third dose. Overall, our results identify that omicron can still bind ACE2 while pre-existing antibodies can bind omicron. The extent of the mutations appear to inhibit the development of a neutralizing response, and as a result, omicron remains capable of evading immune control.
ABSTRACT
BackgroundPatients with chronic renal insufficiency on intermittent hemodialysis face an increased risk of COVID-19 induced mortality and impaired vaccine responses. To date, only few studies addressed SARS-CoV-2 vaccine elicited immunity in this immunocompromised population. MethodsWe assessed immunogenicity of the mRNA vaccine BNT162b2 in at risk dialysis patients and characterized systemic cellular and humoral immune responses in serum and saliva using interferon {gamma} release assay and multiplex-based cytokine and immunoglobulin measurements. We further compared binding capacity and neutralization efficacy of vaccination-induced immunoglobulins against emerging SARS-CoV-2 variants of concern B.1.1.7, B.1.351, B.1.429 and Cluster 5 by ACE2-RBD competition assay. FindingsPatients on intermittent hemodialysis exhibit detectable but variable cellular and humoral immune responses against SARS-CoV-2 and variants of concern after a two-dose regimen of BNT162b2. Although vaccination-induced immunoglobulins were detectable in saliva and plasma, both anti-SARS-CoV-2 IgG and neutralization efficacy was reduced compared to controls. Similarly, T-cell mediated interferon {gamma} release after stimulation with SARS-CoV-2 spike peptides was significantly diminished. InterpretationQuantifiable humoral and cellular immune responses after BNT162b2 vaccination in individuals on intermittent dialysis are encouraging, but urge for longitudinal follow-up to assess longevity of immunity. Diminished virus neutralization and interferon {gamma} responses in face of emerging variants of concern may favor this at risk population for re-vaccination using modified vaccines at the earliest opportunity. FundingInitiative and Networking Fund of the Helmholtz Association of German Research Centers, EU Horizon 2020 research and innovation program, State Ministry of Baden-Wurttemberg for Economic Affairs, Labor and Tourism. Research in the contextO_ST_ABSEvidence before this studyC_ST_ABSPatients on dialysis tend to have a reduced immune response to both infection and vaccination. We searched PubMed and MedRxiv for studies including search terms such as "COVID-19", "vaccine", and "dialysis" but no peer-reviewed studies to date assessed both SARS-CoV-2 specific B- and T-cell responses, mucosal immunoglobulins, and considered the impact of SARS-CoV-2 variants of concern in this at risk population. Added value of the studyWe provide a comprehensive functional characterization of both T- and B-cell responses following a two-dose regimen of BNT162b2 in at risk patients on maintenance hemodialysis. More importantly, to the best of our knowledge, we assess for the first time binding and neutralization capacity of vaccination-induced circulation and mucosal antibodies towards emerging SARS-CoV-2 variants of concern in an immunocompromised population. Implications of all the available evidencePatients on maintenance hemodialysis develop a substantial cellular and humoral immune response following the BNT162b2 vaccine. These findings should encourage patients on intermittent hemodialysis to receive the vaccine. However, we suggest continuing additional protection measures against variants of concern in this at risk population until longevity of the vaccine response is fully evaluated.
