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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.
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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.
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SARS-CoV-2 variants accumulating immune escape mutations provide a significant risk to vaccine-induced protection. The novel variant of concern (VoC) Omicron (B.1.1.529) has the largest number of amino acid alterations in its Spike protein to date. Thus, it may efficiently escape recognition by neutralizing antibodies, allowing breakthrough infections in convalescent and vaccinated individuals. We analyzed neutralization activity of sera from individuals after vaccination with all mRNA-, vector- or heterologous immunization schemes currently available in Europe by in vitro neutralization assay at peak response towards SARS-CoV-2 B.1, Omicron, Beta and Delta pseudotypes and also provide longitudinal follow-up data from BNT162b2 vaccinees. All vaccines apart from Ad26.CoV2.S showed high levels of responder rates (93-100%) towards SARS-CoV-2 wild-type, but some reductions in neutralizing Beta and Delta VoC pseudotypes. The novel Omicron variant had the biggest impact, both in terms of response rates and neutralization titers. Only mRNA-1273 showed a 100% response rate to Omicron and induced the highest level of neutralizing antibody titers, followed by heterologous prime-boost approaches. Homologous BNT162b2 vaccination or vector-based AZD1222 or Ad26.CoV2.S performed less well with peak responder rates of 33%, 50% and 9%, respectively. However, Omicron responder rates in BNT162b2 recipients were maintained in our six month longitudinal follow-up indicating that individuals with cross-protection against Omicron maintain it over time. Overall, our data strongly argues for urgent booster doses in individuals who were previously vaccinated with BNT162b2, or a vector-based immunization scheme.
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BackgroundWhile SARS-CoV-2 vaccinations were successful in decreasing COVID-19 caseloads, recent increases in SARS-CoV-2 infections have led to questions about duration and quality of the subsequent immune response. While numerous studies have been published on immune responses triggered by vaccination, these often focused on the initial peak response generated in specific population subgroups (e.g. healthcare workers or immunocompromised individuals) and have often only examined the effects of one or two different immunisation schemes. Methods and FindingsWe analysed serum samples from participants of a large German seroprevalence study (MuSPAD) who had received all available vaccines and dose schedules (mRNA-1273, BNT162b2, AZD1222, Ad26.CoV2S.2 or a combination of AZD1222 plus either mRNA-1273 or BNT162b2). Antibody titers against various SARS-CoV-2 antigens and ACE2 binding inhibition against SARS-CoV-2 wild-type and the Alpha, Beta, Gamma and Delta variants of concern were analysed using a previously published multiplex immunoassay MULTICOV-AB and an ACE2-RBD competition assay. Among the different vaccines and their dosing regimens, homologous mRNA-based or heterologous prime-boost vaccination produced significantly higher antibody responses than vector-based homologous vaccination. Ad26.CoV2S.2 performance was significantly reduced, even compared to AZD1222, with 91.67% of samples being considered non-responsive forACE2 binding inhibition. mRNA-based vaccination induced a higher ratio of RBD- and S1-targeting antibodies than vector-based vaccination, which resulted in an increased proportion of S2-targeting antibodies. Previously infected individuals had a robust immune response once vaccinated, regardless of which vaccine they received. When examining antibody kinetics post-vaccination after homologous immunisation regimens, both titers and ACE2 binding inhibition peaked approximately 28 days post-vaccination and then decreased as time increased. ConclusionsAs one of the first and largest population-based studies to examine vaccine responses for all currently available immunisation schemes in Germany, we found that homologous mRNA or heterologous vaccination elicited the highest immune responses. The high percentage of non-responders for Ad26.CoV2.S requires further investigation and suggests that a booster dose with an mRNA-based vaccine may be necessary. The high responses seen in recovered and vaccinated individuals could aid future dose allocation, should shortages arise for certain manufacturers. Given the role of RBD- and S1-specific antibodies in neutralising SARS-CoV-2, their relative over-representation after mRNA vaccination may explain why mRNA vaccines have an increased efficacy compared to vector-based formulations. Further investigation on these differences will be of particular interest for vaccine development and efficacy, especially for the next-generation of vector-based vaccines.
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As global vaccination campaigns against SARS-CoV-2 proceed, there is particular interest in the longevity of immune protection, especially with regard to increasingly infectious virus variants. Neutralizing antibodies (Nabs) targeting the receptor binding domain (RBD) of SARS-CoV-2 are promising correlates of protective immunity and have been successfully used for prevention and therapy. As SARS-CoV-2 variants of concern (VOCs) are known to affect binding to the ACE2 receptor and by extension neutralizing activity, we developed a bead-based multiplex ACE2-RBD inhibition assay (RBDCoV-ACE2) as a highly scalable, time-, cost-, and material-saving alternative to infectious live-virus neutralization tests. By mimicking the interaction between ACE2 and the RBD, this serological multiplex assay allows the simultaneous analysis of ACE2 binding inhibition to the RBDs of all SARS-CoV-2 VOCs and variants of interest (VOIs) in a single well. Following validation against a classical virus neutralization test and comparison of performance against a commercially available assay, we analyzed 266 serum samples from 168 COVID-19 patients of varying severity. ACE2 binding inhibition was reduced for ten out of eleven variants examined compared to wild-type, especially for those displaying the E484K mutation such as VOCs beta and gamma. ACE2 binding inhibition, while highly individualistic, positively correlated with IgG levels. ACE2 binding inhibition also correlated with disease severity up to WHO grade 7, after which it reduced.
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Patients undergoing chronic hemodialysis were among the first to receive SARS-CoV-2 vaccinations due to their increased risk for severe COVID-19 disease and high case fatality rates. To date, there have been minimal longitudinal studies in hemodialysis patients to ascertain whether protection offered by vaccination is long-lasting. To assess how surrogates for protection changed over time, we examined both the humoral and cellular response in a previously reported cohort of at-risk hemodialysis patients and healthy donors, four months after their second dose of Pfizer BNT162b2. Compared to three weeks post-second vaccination, both cellular and humoral responses against the original SARS-CoV-2 isolate as well as variants of concern were significantly reduced, with some dialyzed individuals having no B- or T-cell response. Our data strongly support the need for a third booster in hemodialysis patients and potentially other at-risk individuals.
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BackgroundLong-term persistence of antibodies against SARS-CoV-2, particularly the SARS-CoV-2 Spike Trimer, determines individual protection against infection and potentially viral spread. The quality of childrens natural humoral immune response following SARS-CoV-2 infection is yet incompletely understood but crucial to guide pediatric SARS-CoV-2 vaccination programs. MethodsIn this prospective observational multi-center cohort study, we followed 328 households, consisting of 548 children and 717 adults, with at least one member with a previous laboratory-confirmed SARS-CoV-2 infection. The serological response was assessed at 3-4 months and 11-12 months after infection using a bead-based multiplex immunoassay for 23 human coronavirus antigens including SARS-CoV-2 and its Variants of Concern (VOC) and endemic human coronaviruses (HCoVs), and additionally by three commercial SARS-CoV-2 antibody assays. ResultsOverall, 33.76% of SARS-CoV-2 exposed children and 57.88% adults were seropositive. Children were five times more likely to have seroconverted without symptoms compared to adults. Despite the frequently asymptomatic course of infection, children had higher specific antibody levels, and their antibodies persisted longer than in adults (96.22% versus 82.89% still seropositive 11-12 months post infection). Of note, symptomatic and asymptomatic infections induced similar humoral responses in all age groups. In symptomatic children, only dysgeusia was found as diagnostic indicator of COVID-19. SARS-CoV-2 infections occurred independent of HCoV serostatus. Antibody binding responses to VOCs were similar in children and adults, with reduced binding for the Beta variant in both groups. ConclusionsThe long-term humoral immune response to SARS-CoV-2 infection in children is robust and may provide long-term protection even after asymptomatic infection. (Study ID at German Clinical Trials Register: 00021521)
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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.
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The SARS-CoV-2 pandemic virus is consistently evolving with mutations within the receptor binding domain (RBD)1 being of particular concern2-4. To date, there is little research into protection offered following vaccination or infection against RBD mutants in emerging variants of concern (UK3, South African5, Mink6 and Southern California7). To investigate this, serum and saliva samples were obtained from groups of vaccinated (Pfizer BNT-162b28), infected and uninfected individuals. Antibody responses among groups, including salivary antibody response and antibody binding to RBD mutant strains were examined. The neutralization capacity of the antibody response against a patient-isolated South African variant was tested by viral neutralization tests and further verified by an ACE2 competition assay. We found that humoral responses in vaccinated individuals showed a robust response after the second dose. Interestingly, IgG antibodies were detected in large titers in the saliva of vaccinated subjects. Antibody responses showed considerable differences in binding to RBD mutants in emerging variants of concern. A substantial reduction in RBD binding and neutralization was detected for the South African variant. Taken together our data reinforces the importance of administering the second dose of Pfizer BNT-162b2 to acquire high levels of neutralizing antibodies. High antibody titers in saliva suggest that vaccinated individuals may have reduced transmission potential. Substantially reduced neutralization for the South African variant highlights importance of surveillance strategies to detect new variants and targeting these in future vaccines.