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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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Reports suggest that COVID-19 vaccine effectiveness is decreasing, either due to waning immune protection, emergence of new variants of concern, or both. Heterologous prime/boost vaccination with a vector-based approach (ChAdOx-1nCov-19, ChAd) followed by an mRNA vaccine (e.g. BNT162b2, BNT) appeared to be superior in inducing protective immunity, and large scale second booster vaccination is ongoing. However, data comparing declining immunity after homologous and heterologous vaccination as well as effects of a third vaccine application after heterologous ChAd/BNT vaccination are lacking. We longitudinally monitored immunity in ChAd/ChAd (n=41) and ChAd/BNT (n=88) vaccinated individuals and assessed the impact of a second booster with BNT in both groups. The second booster greatly augmented waning anti-spike IgG but only moderately increased spike-specific CD4+ and CD8+ T cells in both groups to cell frequencies already present after the boost. More importantly, the second booster efficiently restored neutralizing antibody responses against Alpha, Beta, Gamma, and Delta, but neutralizing activity against B.1.1.529 (Omicron) stayed severely impaired. Our data suggest that inferior SARS-CoV-2 specific immune responses after homologous ChAd/ChAd vaccination can be cured by a heterologous BNT vaccination. However, prior heterologous ChAd/BNT vaccination provides no additional benefit for spike-specific T cell immunity or neutralizing Omicron after the second boost.
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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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Cerebral venous thrombosis was reported as a rare but serious adverse event in young and middle-aged vaccinees following immunization with AstraZenecas ChAdOx1-nCov-19 vaccine. As a consequence, several European governments recommended using this vaccine only in individuals older than 60 years leaving millions of ChAd primed individuals with the decision to either receive a second shot of ChAd or a heterologous boost with mRNA-based vaccines. However, such combinations have not been tested so far. We used Hannover Medical Schools COVID-19 Contact (CoCo) Study cohort of health care professionals (HCP) to monitor ChAd primed immune responses before and three weeks after booster with ChAd or BioNTech/Pfizers BNT162b2. Whilst both vaccines boosted prime-induced immunity, BNT induced significantly higher frequencies of Spike-specific CD4 and CD8 T cells and, in particular, high titers of neutralizing antibodies against the B.1.1.7, B.1.351 and the P.1 variants of concern of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2).
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Vaccine-induced neutralizing antibodies are key in combating the COVID-19 pandemic. However, delays of boost immunization due to limited availability of vaccines may leave individuals vulnerable to infection and disease for prolonged periods. The emergence of SARS-CoV-2 variants of concern (VOC), B.1.1.7 (United Kingdom), B.1.351 (South Africa) and P.1 (Brazil), may reinforce this issue with the latter two being able to evade control by antibodies. We assessed humoral and T cell responses against SARS-CoV-2 WT and VOC and endemic human coronaviruses (hCoV) that were induced after single and double vaccination with BNT162b2. Despite readily detectable IgG against the receptor-binding domain (RBD) of the SARS-CoV-2 S protein at day 14 after a single vaccination, inhibition of SARS-CoV-2 S-driven host cell entry was weak and particularly low for the B.1.351 variant. Frequencies of SARS-CoV-2 specific T cells were low in many vaccinees after application of a single dose and influenced by immunity against endemic hCoV. The second vaccination significantly boosted T cell frequencies reactive for WT, B.1.1.7 and B.1.351 variants. These results call into question whether neutralizing antibodies significantly contribute to protection against COVID-19 upon single vaccination and suggest that cellular immunity is central for the early defenses against COVID-19.