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Published: 30 July 2021
by MDPI
Viruses, Volume 13; doi:10.3390/v13081508

Abstract:
The development of rapid serological detection methods re urgently needed for determination of neutralizing antibodies in sera. In this study, four rapid methods (ACE2-RBD inhibition assay, S1-IgG detection, RBD-IgG detection, and N-IgG detection) were established and evaluated based on chemiluminescence technology. For the first time, a broadly neutralizing antibody with high affinity was used as a standard for the quantitative detection of SARS-CoV-2 specific neutralizing antibodies in human sera. Sera from COVID-19 convalescent patients (N = 119), vaccinated donors (N = 86), and healthy donors (N = 299) confirmed by microneutralization test (MNT) were used to evaluate the above methods. The result showed that the ACE2-RBD inhibition assay calculated with either ACE2-RBD binding inhibition percentage rate or ACE2-RBD inhibiting antibody concentration were strongly correlated with MNT (r ≥ 0.78, p< 0.0001) and also highly consistent with MNT (Kappa Value ≥ 0.94, p< 0.01). There was also a strong correlation between the two evaluation indices (r ≥ 0.99, p< 0.0001). Meanwhile, S1-IgG and RBD-IgG quantitative detection were also significantly correlated with MNT (r ≥ 0.73, p< 0.0001), and both methods were highly correlated with each other (r ≥ 0.95, p< 0.0001). However, the concentration of N-IgG antibodies showed a lower correlation with the MNT results (r < 0.49, p< 0.0001). The diagnostic assays presented here could be used for the evaluation of SARS-CoV-2 vaccine immunization effect and serological diagnosis of COVID-19 patients, and could also have guiding significance for establishing other rapid serological methods to surrogate neutralization tests for SARS-CoV-2.
Alice Cho, Frauke Muecksch, Dennis Schaefer-Babajew, Zijun Wang, Shlomo Finkin, Christian Gaebler, Victor Ramos, Melissa Cipolla, Marianna Agudelo, Eva Bednarski, et al.
Published: 29 July 2021
Abstract:
Summary Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection produces B-cell responses that continue to evolve for at least one year. During that time, memory B cells express increasingly broad and potent antibodies that are resistant to mutations found in variants of concern1. As a result, vaccination of coronavirus disease 2019 (COVID-19) convalescent individuals with currently available mRNA vaccines produces high levels of plasma neutralizing activity against all variants tested1, 2. Here, we examine memory B cell evolution 5 months after vaccination with either Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) mRNA vaccines in a cohort of SARS-CoV-2 naïve individuals. Between prime and boost, memory B cells produce antibodies that evolve increased neutralizing activity, but there is no further increase in potency or breadth thereafter. Instead, memory B cells that emerge 5 months after vaccination of naïve individuals express antibodies that are equivalent to those that dominate the initial response. We conclude that memory antibodies selected over time by natural infection have greater potency and breadth than antibodies elicited by vaccination. These results suggest that boosting vaccinated individuals with currently available mRNA vaccines would produce a quantitative increase in plasma neutralizing activity but not the qualitative advantage against variants obtained by vaccinating convalescent individuals.
Ali Hamady, Jinju Lee,
Published: 29 July 2021
Infection pp 1-15; doi:10.1007/s15010-021-01664-z

Abstract:
Objectives The coronavirus disease 2019 (COVID-19), caused by the novel betacoronavirus severe acute respiratory syndrome 2 (SARS-CoV-2), was declared a pandemic in March 2020. Due to the continuing surge in incidence and mortality globally, determining whether protective, long-term immunity develops after initial infection or vaccination has become critical. Methods/Results In this narrative review, we evaluate the latest understanding of antibody-mediated immunity to SARS-CoV-2 and to other coronaviruses (SARS-CoV, Middle East respiratory syndrome coronavirus and the four endemic human coronaviruses) in order to predict the consequences of antibody waning on long-term immunity against SARS-CoV-2. We summarise their antibody dynamics, including the potential effects of cross-reactivity and antibody waning on vaccination and other public health strategies. At present, based on our comparison with other coronaviruses we estimate that natural antibody-mediated protection for SARS-CoV-2 is likely to last for 1–2 years and therefore, if vaccine-induced antibodies follow a similar course, booster doses may be required. However, other factors such as memory B- and T-cells and new viral strains will also affect the duration of both natural and vaccine-mediated immunity. Conclusion Overall, antibody titres required for protection are yet to be established and inaccuracies of serological methods may be affecting this. We expect that with standardisation of serological testing and studies with longer follow-up, the implications of antibody waning will become clearer.
Kevin J. Kramer, , Kelsey Voss, , , Nagarajan Raju, , Naveenchandra Suryadevara, Lauren Walker, Steven C. Wall, et al.
Published: 28 July 2021
Abstract:
SUMMARY RNA-based vaccines against SARS-CoV-2 are critical to limiting COVID-19 severity and spread. Cellular mechanisms driving antigen-specific responses to these vaccines, however, remain uncertain. We used single-cell technologies to identify and characterized antigen-specific cells and antibody responses to the RNA vaccine BNT162b2 in longitudinal samples from a cohort of healthy donors. Mass cytometry and machine learning pinpointed a novel expanding, population of antigen-specific non-canonical memory CD4+ and CD8+ T cells. B cell sequencing suggested progression from IgM, with apparent cross-reactivity to endemic coronaviruses, to SARS-CoV-2-specific IgA and IgG memory B cells and plasmablasts. Responding lymphocyte populations correlated with eventual SARS-CoV-2 IgG and a donor lacking these cell populations failed to sustain SARS-CoV-2-specific antibodies and experienced breakthrough infection. These integrated proteomic and genomic platforms reveal an antigen-specific cellular basis of RNA vaccine-based immunity. ONE SENTENCE SUMMARY Single-cell profiling reveals the cellular basis of the antigen-specific response to the BNT162b2 SARS-CoV-2 RNA vaccine.
, Margaretha L.M. Prins, , , Vincent P. Kuiper, Corine Prins, Jacqueline J. Janse, Annelieke C. Kruithof, , Marjan Kuijer, et al.
Published: 28 July 2021
Abstract:
Background There is an urgent need for fair and equitable access to safe and effective vaccines to end the COVID-19 pandemic. Shortages in reagents and vaccines are a major challenge, as well as limited knowledge on dose response relationship with mRNA COVID-19 vaccines. We explored intradermal fractional dose administration of a mRNA SARS-CoV-2/COVID-19 vaccine as a potential dose-sparing strategy. Methods We conducted a proof-of-concept, dose-escalation, open-label, randomised-controlled vaccine trial (IDSCOVA) in healthy adults aged 18-30 years. To test initial safety, ten participants received 10 µg mRNA-1273 vaccine through intradermal injection at day 1 and 29. Following a favourable safety review, thirty participants were 1:1 randomised to receive 20 µg mRNA-1273 either intradermally or intramuscularly. The primary endpoint was tolerability and safety. The secondary endpoint was seroconversion and specific IgG concentration against SARS-CoV-2 spike S1 and Receptor Binding Domain (RBD) after the second dose at day 43. We compared results to two historical cohorts of non-hospitalised COVID-19 patients and vaccinated individuals. Findings Thirty-eight of forty included participants (median age 25 years) completed the study. There were no serious adverse events. Self-reported local adverse reactions after intradermal delivery were mild, both in the 10 µg and the 20 µg group. In the higher dose group, systemic adverse reactions were more common, but still well tolerated. All 38 participants mounted substantially higher IgG-anti-S1 and IgG-anti-RBD concentrations at day 43 than COVID-19 controls. At day 43, anti-S1 (95% CI) was 1,696 (1,309-2,198) BAU/mL for the 10 µg intradermal group, 1,406 (953·5-2,074) BAU/mL for the 20 µg intramuscular group and 2,057 (1,421-2,975) BAU/mL for the 20 µg intradermal group. Anti-S1 was 107·2 (63-182·2) BAU/mL for the convalescent plasma control group and 1,558 (547·8-4,433) BAU/mL for the individuals vaccinated with 100 µg mRNA-1273. Interpretation Intradermal administration of 10 µg and 20 µg mRNA-1273 vaccine was well tolerated and safe, and resulted in a robust antibody response. Intradermal vaccination has the potential to be deployed for vaccine dose-sparing. Funding The trial was supported by crowdfunding (Wake Up to Corona).
Thuy P. Nguyen, Quyet Do, Lan T. Phan, Duc V. Dinh, , Luong V. Hoang, Thuong V. Nguyen, Hung N. Pham, Men V. Chu, Toan T. Nguyen, et al.
Published: 25 July 2021
Abstract:
Background Nanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminum hydroxide adjuvant. Methods We conducted a dose-escalation, open label trial (phase 1) and a randomized, double-blind, placebo-controlled trial (phase 2) to evaluate the safety and immunogenicity of the Nanocovax vaccine (in 25 microgram (mcg), 50 mcg, and 75 mcg doses, aluminum hydroxide adjuvanted). In phase 1, 60 participants received two intramuscular injection of the vaccine following dose-escalation procedure. The primary outcomes were reactogenicity and laboratory tests to evaluate the vaccine safety. In phase 2 which involved in 560 healthy adults, the primary outcomes are vaccine safety; and anti-S IgG antibody response. Secondary outcomes were surrogate virus neutralization, wild-type SARS-CoV-2 neutralization, and T-cell responses by intracellular staining (ICS) for interferon gamma (IFNg). We performed primary analyses at day 35 and day 42. Results For phase 1 study, no serious adverse events (SAE) were observed for all 60 participants. Most adverse events (AE) were grade 1 and disappeared shortly after injection. For phase 2 study, after randomization, 480 participants were assigned to receive the vaccine with adjuvant, and 80 participants were assigned to receive placebo. Reactogenicity was absent or mild in the majority of participants and of short duration (mean, ≤3 days). Unsolicited adverse events were mild in most participants. There were no serious adverse events related to Nanocovax. Regarding the immunogenicity, Nanocovax induced robust anti-S antibody responses. There was no statistical difference in antibody responses among dose strengths on Day 42, in terms of anti S-IgG level and neutralizing antibody titer. Conclusions Up to 42 days, Nanocovax vaccine was safe, well tolerated and induced robust immune responses. We propose using Nanocovax 25 mcg for Phase 3 to evaluate the vaccine efficacy. (Research funded by Nanogen Pharmaceutical Biotechnology JSC., and the Ministry of Science and Technology of Vietnam; ClinicalTrials.gov number, NCT04683484.)
Juan Manuel Carreño, Hala Alshammary, Gagandeep Singh, Ariel Raskin, Fatima Amanat, Angela Amoako, Ana Silvia Gonzalez-Reiche, Adriana van de Guchte, Mahmoud Awawda, Radhika Banu, et al.
Published: 23 July 2021
Abstract:
Highly efficacious vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed.1 However, the emergence of viral variants that are more infectious than the earlier SARS-CoV-2 strains is concerning.2 Several of these viral variants have the potential to partially escape neutralizing antibody responses warranting continued immune-monitoring. Here, we tested a number of currently circulating viral variants of concern/interest, including B.1.526 (Iota), B.1.1.7+E484K (Alpha), B.1.351 (Beta), B.1.617.2 (Delta) and C.37 (Lambda) in neutralization assays using a panel of post-mRNA vaccination sera. The assays were performed with authentic SARS-CoV-2 clinical isolates in an assay that mimics physiological conditions. We found only small decreases in neutralization against B.1.526 and an intermediate phenotype for B.617.2. The reduction was stronger against a sub-variant of C.37, followed by B.1.351 and B.1.1.7+E484K. C.37 is currently circulating in parts of Latin America3 and was detected in Germany, the US and Israel. Of note, reduction in a binding assay that also included P.1, B.1.617.1 (Kappa) and A.23.1 was negligible. Taken together, these findings suggest that mRNA SARS-CoV-2 vaccines may remain effective against these viral variants of concern/interest and that spike binding antibody tests likely retain specificity in the face of evolving SARS-CoV-2 diversity.
Hanna Renk, Alex Dulovic, , Dorit Fabricius, Maria Zernickel, Daniel Junker, Alina Seidel, Rüdiger Groß, Alexander Hilger, Sebastian Bode, et al.
Published: 22 July 2021
Abstract:
Background Long-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 children’s natural humoral immune response following SARS-CoV-2 infection is yet incompletely understood but crucial to guide pediatric SARS-CoV-2 vaccination programs. Methods In 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. Results Overall, 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. Conclusions The 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)
Vivek Naranbhai, Wilfredo F. Garcia-Beltran, Cristhian Berrios Mairena, Julia C. Thierauf, Christina C. Chang, Grace Kirkpatrick, Maristela L. Onozato, Ju Cheng, Kerri J. St. Denis, Evan C. Lam, et al.
Published: 22 July 2021
Abstract:
Background Understanding variation in immunogenicity may help rationalize use of existing SARS-CoV-2 vaccines. Methods We compared immune responses in ambulatory adults vaccinated with mRNA-1273, BNT-162b2 or Ad26.COV2.S in Massachusetts, USA between February and May 2021. Control groups were pre-pandemic controls (n=1220) and individuals without (n=112) or with prior SARS-CoV-2 infection (n=130) sampled in mid-2020. We measured total anti-spike IgG/M/A antibodies (Roche Elecsys Anti-SARS-COV-2 S assay), anti-receptor-binding-domain (RBD) antibodies; neutralization of SARS-CoV-2 pseudovirus; and T-cell responses. Findings In individuals with prior infection, all vaccines were associated with higher antibody concentrations and neutralization than those in convalescent individuals, even after a single dose. In individuals without prior infection, a single dose of either mRNA vaccine yielded comparable concentrations and neutralization to convalescent unvaccinated individuals, and Ad26.COV2.S yielded lower antibody concentrations and neutralization titers. The second dose of either mRNA vaccine boosted responses. At a median of 24 days after vaccination, two of 21 (9.5%) Ad26.COV2.S recipients had a neutralization titer higher than pre-pandemic controls; repeat sampling at a median 66 days after vaccination found most (11/15 (73%) remained negative. Antibody concentrations and neutralization titers increased similarly after the first dose of either vaccine, and even further in recipients of a second dose of vaccine. T-cell responses were higher in mRNA1273 and BNT162b2 than Ad26.COV2.S recipients. Interpretation SARS-CoV-2 vaccines vary significantly in immunogenicity in individuals without prior infection. If confirmed in effectiveness studies, public health policy may need to be tailored to each vaccine, or even individual responses.
, Barbara Seitz-Polski, Michel Carles, Vesna Brglez, Daisy Graça, Sylvia Benzaken, Stéphane Liguori, Khaled Zahreddine, Margaux Delforge, Benjamin Verrière, et al.
Published: 22 July 2021
Abstract:
BACKGROUND Immunocompromised patients such as patients with hematological malignancies have impaired immune response to two doses of BNT162b2 (Pfizer / BioNtech) vaccine against SARS-CoV-2. Evaluation of a repeated immune stimulation with a third vaccine dose is needed. METHODS a vaccine monitoring observatory was conducted in outpatients who were treated for lymphoid malignancies (LM) to monitor both immune and cellular response measured the day of administration of the dose 3 of the mRNA vaccine BNT162b2 and again three to four weeks. Elecsys ® Anti-SARS-CoV-2 immunoassay was used to asses to the level of SARS-CoV-2 anti-Spike (S) antibodies (Abs) titer and SARS-CoV-2-specific T-cell responses were assessed by a whole blood Interferon-Gamma Release Immuno Assay (IGRA) (QuantiFERON Human IFN-gamma SARS-CoV-2, Qiagen®). RESULTS Among the 43 assessable patients (suffering from chronic lymphocytic leukemia (CLL) (n=15), indolent and aggressive B cell non-Hodgkin lymphoma (NHL) (n=14), and multiple myeloma (MM) (n=16)), 18 (41,8%) had no anti-S Abs before the dose 3 of BNT162b2 vaccine (n=9 CLL, n=8 NHL, n=1 MM), and they all 18 remained negative after the dose 3. Amongst the 25 patients with positive anti-S titers before dose 3, all patients remained positive and 23 patients increased their anti-S titer after dose 3. Patients with CLL and/or with previous anti-CD20 therapy treated within 12 months of administration of dose 3 had no significant increase of the humoral response. Among 22 available patients, dose 3 of BNT162b2 vaccine significantly increased the median IFN-gamma secretion. On eight (36.4%) patients who were double-negative for both immune and cellular response, five (22.7%) patients remained double-negative after dose 3. CONCLUSIONS Dose 3 of BNT162b2 vaccine stimulated humoral immune response among patients with LM, in particular patients with MM (who had higher anti-S baseline titer after dose 2) and those with no anti-CD20 treatment history within a year. T-cell response was increased among patients in particular with no active chemotherapy regimen. Our data support the use of an early third vaccine dose among immunocompromised patients followed for LM though some of them will still have vaccine failure.
, Hector Rincon-Arevalo, , Kirsten Karberg, Franziska Szelinski, Jacob Ritter, Bernd Jahrsdörfer, , Carolin Ludwig, , et al.
Published: 22 July 2021
Abstract:
Objectives Patients with autoimmune inflammatory rheumatic diseases receiving rituximab (RTX) therapy show substantially impaired anti-SARS-CoV-2 vaccine humoral but partly inducible cellular immune responses. However, the complex relationship between antigen-specific B and T cells and the level of B cell repopulation necessary to achieve anti-vaccine responses remain largely unknown. Methods Antibody responses to SARS-CoV-2 vaccines and induction of antigen-specific B and CD4/CD8 T cell subsets were studied in 19 rheumatoid arthritis (RA) and ANCA-associated vasculitis (AAV) patients receiving RTX, 12 RA patients on other therapies and 30 healthy controls after SARS-CoV-2 vaccination with either mRNA or vector based vaccines. Results A minimum of 10 B cells/µL in the peripheral circulation was necessary in RTX patients to mount seroconversion to anti-S1 IgG upon SARS-CoV-2 vaccination. RTX patients lacking IgG seroconversion showed reduced antigen-specific B cells, lower frequency of TfH-like cells as well as less activated CD4 and CD8 T cells compared to IgG seroconverted RTX patients. Functionally relevant B cell depletion resulted in impaired IFNγ secretion by spike-specific CD4 T cells. In contrast, antigen-specific CD8 T cells were reduced in patients independently of IgG formation. Conclusions Patients receiving rituximab with B cell numbers above 10 B cells/µl were able to mount humoral and more robust cellular responses after SARS-CoV-2 vaccination that may permit optimization of vaccination in these patients. Mechanistically, the data emphasize the crucial role of co-stimulatory B cell functions for the proper induction of CD4 responses propagating vaccine-specific B and plasma cell differentiation.
Yu-An Kung, Chung-Guei Huang, Sheng-Yu Huang, Kuan-Ting Liu, Peng-Nien Huang, Kar-Yee Yu, Shu-Li Yang, Chia-Pei Chen, Ching-Yun Cheng, Yueh-Te Lin, et al.
Published: 22 July 2021
Abstract:
The World Health Organization (WHO) has highlighted the importance of an international standard (IS) for SARS-CoV-2 neutralizing antibody titer detection, with the aim of calibrating different diagnostic techniques. In this study, IS was applied to calibrate neutralizing antibody titers (IU/mL) and binding antibody titers (BAU/mL) in response to SARS-CoV-2 vaccines. Serum samples were collected from participants receiving the Moderna (n = 20) and Pfizer (n = 20) vaccines at three time points: pre-vaccination, after one dose, and after two doses. We obtained geometric mean titers of 1404.16 and 928.75 IU/mL for neutralizing antibodies after two doses of the Moderna and Pfizer vaccines, respectively. These values provide an important baseline for vaccine development and the implementation of non-inferiority trials. We also compared three commercially available kits from Roche, Abbott, and MeDiPro for the detection of COVID-19 antibodies based on binding affinity to S1 and/or RBD. Our results demonstrated that antibody titers measured by commercial assays are highly correlated with neutralizing antibody titers calibrated by IS.
Jia Wei, , Philippa C. Matthews, Daniel Ayoubkhani, Ruth Studley, Iain Bell, John I. Bell, John N. Newton, Jeremy Farrar, Ian Diamond, et al.
Nature Microbiology pp 1-10; doi:10.1038/s41564-021-00947-3

Abstract:
We report that in a cohort of 45,965 adults, who were receiving either the ChAdOx1 or the BNT162b2 SARS-CoV-2 vaccines, in those who had no prior infection with SARS-CoV-2, seroconversion rates and quantitative antibody levels after a single dose were lower in older individuals, especially in those aged >60 years. Two vaccine doses achieved high responses across all ages. Antibody levels increased more slowly and to lower levels with a single dose of ChAdOx1 compared with a single dose of BNT162b2, but waned following a single dose of BNT162b2 in older individuals. In descriptive latent class models, we identified four responder subgroups, including a ‘low responder’ group that more commonly consisted of people aged >75 years, males and individuals with long-term health conditions. Given our findings, we propose that available vaccines should be prioritized for those not previously infected and that second doses should be prioritized for individuals aged >60 years. Further data are needed to better understand the extent to which quantitative antibody responses are associated with vaccine-mediated protection.
Takuya Tada, Hao Zhou, Marie I. Samanovic, Belinda M. Dcosta, Amber Cornelius, Mark J. Mulligan,
Published: 19 July 2021
Abstract:
The increasing prevalence of SARS-CoV-2 variants has raised concerns regarding possible decreases in vaccine efficacy. Here, neutralizing antibody titers elicited by mRNA-based and an adenoviral vector-based vaccine against variant pseudotyped viruses were compared. BNT162b2 and mRNA-1273-elicited antibodies showed modest neutralization resistance against Beta, Delta, Delta plus and Lambda variants whereas Ad26.COV2.S-elicited antibodies from a significant fraction of vaccinated individuals were of low neutralizing titer (IC50 <50). The data underscore the importance of surveillance for breakthrough infections that result in severe COVID-19 and suggest the benefit of a second immunization following Ad26.COV2.S to increase protection against the variants.
Sam Afkhami, Michael R. D’Agostino, Ali Zhang, Hannah D. Stacey, Art Marzok, Alisha Kang, RamanDeep Singh, Jegarubee Bavananthasivam, Gluke Ye, Xiangqian Luo, et al.
Published: 19 July 2021
Abstract:
Summary The emerging SARS-CoV-2 variants of concern (VOC) increasingly threaten the effectiveness of current first-generation COVID-19 vaccines that are administered intramuscularly and are designed to only target the spike protein. There is thus a pressing need to develop next-generation vaccine strategies to provide more broad and long-lasting protection. By using adenoviral vectors (Ad) of human and chimpanzee origin, we developed Ad-vectored trivalent COVID-19 vaccines expressing Spike-1, Nucleocapsid and RdRp antigens and evaluated them following single-dose intramuscular or intranasal immunization in murine models. We show that respiratory mucosal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the three-arm immunity, consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells, and mucosal trained innate immunity. We further show that single-dose intranasal immunization provides robust protection against not only the ancestral strain of SARS-CoV-2, but also two emerging VOC, B.1.1.7 and B.1.351. Our findings indicate that single-dose respiratory mucosal delivery of an Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy against current and future VOC. This strategy has great potential to be used not only to boost first-generation vaccine-induced immunity but also to expand the breadth of protective T cell immunity at the respiratory mucosa.
, Matt Whitaker, Sonja N Tang, , , , , , , Wendy S Barclay, et al.
Published: 18 July 2021
Abstract:
Background The programme to vaccinate adults in England has been rapidly implemented since it began in December 2020. The community prevalence of SARS-CoV-2 anti-spike protein antibodies provides an estimate of total cumulative response to natural infection and vaccination. We describe the distribution of SARS-CoV-2 IgG antibodies in adults in England in May 2021 at a time when approximately 7 in 10 adults had received at least one dose of vaccine. Methods Sixth round of REACT-2 (REal-time Assessment of Community Transmission-2), a cross-sectional random community survey of adults in England, from 12 to 25 May 2021; 207,337 participants completed questionnaires and self-administered a lateral flow immunoassay test producing a positive or negative result. Results Vaccine coverage with one or more doses, weighted to the adult population in England, was 72.9% (95% confidence interval 72.7-73.0), varying by age from 25.1% (24.5-25.6) of those aged 18 to 24 years, to 99.2% (99.1-99.3) of those 75 years and older. In adjusted models, odds of vaccination were lower in men (odds ratio [OR] 0.89 [0.85-0.94]) than women, and in people of Black (0.41 [0.34-0.49]) compared to white ethnicity. There was higher vaccine coverage in the least deprived and highest income households. People who reported a history of COVID-19 were less likely to be vaccinated (OR 0.61 [0.55-0.67]). There was high coverage among health workers (OR 9.84 [8.79-11.02] and care workers (OR 4.17 [3.20-5.43]) compared to non-key workers, but lower in hospitality and retail workers (OR 0.73 [0.64-0.82] and 0.77 [0.70-0.85] respectively) after adjusting for age and key covariates. The prevalence of antibodies (weighted to the adult population of England and adjusted for test characteristics) was 61.1% (95% CI 60.9-61.4), up from 6.6% (5.4-5.7) in round 4 (27 October to 10 November 2020) and 13.9% (13.7-14.1) in round 5 (26 January to 8 February 2021). Prevalence (adjusted and weighted) increased with age, from 35.8% (35.1-36.5) in those aged 18 to 24 years, to 95.3% (94.6-95.9) in people 75 and over. Antibodies were 30% less likely to be detected in men than women (adjusted OR 0.69, 0.68-0.70), and were higher in people of Asian (OR 1.67 [1.58-1.77]), Black (1.55 [1.41-1.69]), mixed 1.17 [1.06-1.29] and other (1.37 [1.23-1.51]) ethnicities compared with white ethnicity. Workers in hospitality (OR 0.69 [0.63-0.74]) and retail (0.71 [0.67-0.75]) were less likely to have antibodies. Following two doses of Pfizer-BioNTech vaccine, antibody positivity (adjusted for test performance) was 100% (100-100) at all ages except 80 years and older when it was 97.8% (95.9-99.6). For AstraZeneca positivity was over 90% up to age 69, and then 89.2% (88.5-89.9) in 70-79 year olds and 83.6% (78.5-88.3) in those aged 80 and over. Following a single dose of Pfizer-BioNTech positivity ranged from 100.0% (91.1-100.0) in those aged 18-29 to 32.2% (18.2-51.1) in those aged 70-79 years. For AstraZeneca this was 72.2% (68.5-75.9) in the youngest and 46.2% (40.0-52.7) in the oldest age group. Discussion The successful roll out of the vaccination programme in England has led to a high proportion of individuals having detectable antibodies, particularly in older age groups and those who have had two doses of vaccine. This is likely to be associated with high levels of protection from severe disease, and possibly from infection. Nonetheless, there remain some key groups with a lower prevalence of antibody, notably unvaccinated younger people, certain minority ethnic groups, those living in deprived areas and workers in some public facing employment. Obtaining improved rates of vaccination in these groups is essential to achieving high levels of protection against the virus through population immunity. Funding Department of Health and Social Care in England.
Xin Zhao, Anqi Zheng, Dedong Li, Rong Zhang, Huan Sun, Qihui Wang, George F. Gao, , Lianpan Dai
Published: 16 July 2021
Abstract:
SARS-CoV-2 variants brought new waves of infection worldwide. In particular, Delta variant (B.1.617.2 lineage) has become predominant in many countries. These variants raised the concern for their potential immune escape to the currently approved vaccines. ZF2001 is a subunit vaccine received emergency use authorization (EUA) in both China and Uzbekistan, with more than 100-million doses administrated with a three-dose regimen. The tandem-repeat dimer of SARS-CoV-2 spike protein receptor binding domain (RBD) was used as the antigen. In this work, we evaluated the neutralization of ZF2001-elicited antisera to SARS-CoV-2 variants including all four variants of concern (Alpha, Beta, Gamma and Delta) and other three variants of interest (Epsilon, Eta and Kappa) by pseudovirus-based assay. We found antisera preserved majority of the neutralizing activity against these variants. E484K/Q substitution is the key mutation to reduce the RBD-elicited sera neutralization. Moreover, ZF2001-elicited sera with a prolonged intervals between the second and third dose enhanced the neutralizing titers and resilience to SARS-CoV-2 variants.
, Candice Clarke, Jonathan Brown, Tina Thomson, Maria Prendecki, Maya Moshe, Anjna Badhan, , Ara Darzi, Steven Riley, et al.
Published: 16 July 2021
Abstract:
Background Lateral flow immunoassays (LFIAs) have the potential to deliver affordable, large scale antibody testing and provide rapid results without the support of central laboratories. As part of the development of the REACT programme extensive evaluation of LFIA performance was undertaken with individuals following natural infection. Here we assess the performance of the selected LFIA to detect antibody responses in individuals who have received at least one dose of SARS-CoV-2 vaccine. Methods This is a prospective diagnostic accuracy study. Setting Sampling was carried out at renal outpatient clinic and healthcare worker testing sites at Imperial College London NHS Trust. Laboratory analyses were performed across Imperial College London sites and university facilities. Participants Two cohorts of patients were recruited; the first was a cohort of 108 renal transplant patients attending clinic following SARS-CoV-2 vaccine booster, the second cohort comprised 40 healthcare workers attending for first SARS-CoV-2 vaccination, and 21 day follow up. A total of 186 paired samples were collected. Interventions During the participants visit, capillary blood samples were analysed on LFIA device, while paired venous sampling was sent for serological assessment of antibodies to the spike protein (anti-S) antibodies. Anti-S IgG were detected using the Abbott Architect SARS-CoV-2 IgG Quant II CMIA. Main outcome measures The accuracy of Fortress LFIA in detecting IgG antibodies to SARS-CoV-2 compared to anti-spike protein detection on Abbott Assay. Results Using the threshold value for positivity on serological testing of ≥7.10 BAU/ml, the overall performance of the test produces an estimate of sensitivity of 91.94% (95% CI 85.67% to 96.06%) and specificity of 93.55% (95% CI 84.30% to 98.21%) using the Abbott assay as reference standard. Conclusions Fortress LFIA performs well in the detection of antibody responses for intended purpose of population level surveys, but does not meet criteria for individual testing.
, , Anna Solastie, Camilla Virta, Pamela Österlund, Elina Isosaari, Hanna Nohynek, Arto A. Palmu, Merit Melin
Published: 16 July 2021
Abstract:
Understanding for how long antibodies persist following Severe acute respiratory coronavirus 2 (SARS-CoV-2) infection provides important insight into estimating the duration of immunity induced by infection. We assessed the persistence of serum antibodies following wild-type SARS-CoV-2 infection six and twelve months after diagnosis in 367 individuals of whom 13% had severe disease requiring hospitalization. We determined the SARS-CoV-2 spike (S-IgG) and nucleoprotein IgG concentrations and the proportion of subjects with neutralizing antibodies (NAb). We also measured the NAb titers among a smaller subset of participants (n=78) against a wild-type virus (B.1) and three variants of concern (VOCs): Alpha (B.1.1.7), Beta (B.1.351) and Delta (B.1.617.2). We found that NAb against the wild-type virus and S-IgG persisted in 89% and 97% of subjects for at least twelve months after infection, respectively. IgG and NAb levels were higher after severe infection. NAb titers were significantly lower against variants compared to the wild-type virus.
Victoria Sa. Momyer, Samantha Dixon, Q. John Liu, Brian Wee, Tiffany Y. Chen, Anna Petropoulos,
Published: 14 July 2021
Abstract:
Given the ongoing transmission and emergence of SARS-Cov-2 variants globally, it is critical to have a timely assessment on individuals’ immune responses as well as population immunity. Important questions such as the durability of COVID-19 immunity or the efficacy of vaccines require large datasets to generate meaningful insights. However, due to the complexity and relatively high-cost of many immunity assays and the needs for blood-drawing specialists, these assays were mostly limited to small-scale clinical studies. Our work demonstrated the potential of a non-invasive, inexpensive and data-driven solution for large-scale immunity surveillance and for predictive modeling of vaccine efficacy. Combining a proprietary saliva processing method and an ultra-sensitive digital detection technology, we were able to rapidly gather information regarding personalized immune response following infection or vaccination, monitor temporal evolution, and optimize predictive models for variant protection.
Vimvara Vacharathit, , Suwimon Manopwisedjaroen, Chanya Srisaowakarn, Thanida Laopanupong, Natali Ludowyke, , Chavachol Setthaudom, Supanuch Ekronarongchai, Sirawat Srichatrapimuk, et al.
Published: 14 July 2021
Abstract:
Recent surges in SARS-CoV-2 variants of concern (VOCs) call for the need to evaluate levels of vaccine-and infection-induced SARS-CoV-2 neutralizing antibodies (NAbs). CoronaVac (Sinovac Biotech, Beijing, China) is currently being used for mass vaccination in Thailand as well as other low-income countries. Three VOCs currently circulating within Thailand include the B.1.1.7 (Alpha), B.1.351 (Beta), and B.1.617.2 (Delta) strains. We assessed NAb potency against the prototypic strain containing the original spike sequence (WT) compared to that against the 3 VOCs using sera derived from a cohort of healthcare workers who received a full 2-dose regimen of CoronaVac. Sera from two other cohorts consisting of COVID-19 patients who had been hospitalized in 2020 and 2021 were evaluated for comparison. We found that, despite equally robust production of S1-RBD-binding IgG and 100% seropositivity, sera from both CoronaVac vaccinees and naturally infected individuals had significantly reduced neutralizing capacity against all 3 VOCs compared to WT. Strikingly, NAb titers against Alpha and Beta were comparable, but Delta appears to be significantly more refractory to NAbs in all groups. Our results may help inform on CoronaVac NAb-inducing capacity, which is a proxy for vaccine efficacy, in the context of the WT strain and 3 VOCs. Our results also have critical implications for public health decision-makers who may need to maintain efficient mitigation strategies amid a potentially high risk for infection with VOCs even in those who have been previously infected.
Nguyen Van Vinh Chau, Lam Anh Nguyet, Nguyen Thanh Truong, Le Mau Toan, Nguyen Thanh Dung, Le Manh Hung, Mai Thanh Nhan, Dinh Nguyen Huy Man, Nghiem My Ngoc, Huynh Phuong Thao, et al.
Published: 10 July 2021
Abstract:
We studied the immunogenicity of Oxford-AstraZeneca vaccine in Vietnamese healthcare workers. We collected blood samples before each dose, at 14 days after each dose, and month 1 and 3 after dose 1 from each participant alongside demographics data. We measured neutralizing antibodies using a surrogate virus neutralization assay. The 554 study participants (136 males and 418 females) were aged between 22-71 years (median: 36 years). 104 and 94 out of 144 selected participants were successfully followed up at 14 days after dose 2 and 3 months after dose 1, respectively. Neutralizing antibodies increased after each dose, with the sero-conversion rate reaching 98.1% (102/104) at 14 days after dose 2. At month 3 after dose 1, neutralizing antibody levels decreased, while 94.7% (89/94) of the study participants remained seropositive. Oxford-AstraZeneca COVID-19 vaccine is immunogenic in Vietnamese healthcare workers. The requirement for a third dose warrants further research.
Published: 9 July 2021
Current Medical Science pp 1-15; doi:10.1007/s11596-021-2395-1

Abstract:
Summary Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of the coronavirus disease 2019 (COVID-19), has caused more than 179 million infections and 3.8 million deaths worldwide. Throughout the past year, multiple vaccines have already been developed and used, while some others are in the process of being developed. However, the emergence of new mutant strains of SARS-CoV-2 that have demonstrated immune-evading characteristics and an increase in infective capabilities leads to potential ineffectiveness of the vaccines against these variants. The purpose of this review article is to highlight the current understanding of the immunological mechanisms of the virus and vaccines, as well as to investigate some key variants and mutations of the virus driving the current pandemic and their impacts on current management guidelines. We also discussed new technologies being developed for the prevention, treatment, and detection of SARS-CoV-2. In this paper, we thoroughly reviewed and provided crucial information on SARS-CoV-2 virology, vaccines and drugs being used and developed for its prevention and treatment, as well as important variant strains. Our review paper will be beneficial to health care professionals and researchers so they can have a better understanding of the basic sciences, prevention, and clinical treatment of COVID-19 during the pandemic. This paper consists of the most updated information that has been available as of June 21, 2021.
Published: 8 July 2021
Nature Medicine pp 1-2; doi:10.1038/s41591-021-01432-4

Abstract:
Recent studies suggest that neutralizing antibodies could serve as a correlate of protection for vaccines against SARS-CoV-2 in humans.
Quentin Moyon, Delphine Sterlin, Makoto Miyara, François Anna, Alexis Mathian, Raphael Lhote, Pascale Ghillani-Dalbin, Paul Breillat, Sasi Mudumba, Sophia de Alba, et al.
Published: 8 July 2021
Abstract:
Objectives Our aims were to evaluate Systemic Lupus Erythematosus (SLE) disease activity and SARS-CoV-2 specific immune responses after BNT162b2 vaccination. Methods In this prospective study, disease activity and clinical assessments were recorded from the first dose of vaccine, until day 15 after the second dose in 126 SLE patients. SARS-CoV-2 antibody responses were measured against wild-type spike antigen while serum-neutralizing activity was assessed against the SARS-CoV-2 historical strain and variants of concerns (VOCs). Vaccine-specific T-cell responses were quantified by Interferon (IFN)-γ release assay after the second dose. Results BNT162b2 was well tolerated and no statistically significant variations of BILAG and SLEDAI scores were observed throughout the study in SLE patients with active and inactive disease at baseline. Mycophenolate Mofetil (MMF) and Methotrexate (MTX) treatments were associated with drastically reduced BNT162b2 antibody-response (β=-78; p=0.007, β=-122; p<0.001, respectively). Anti-spike antibody response was positively associated with baseline total IgG serum levels, naïve B cell frequencies (β=2; p=0.018, β=2.5; p=0.003) and SARS-CoV-2-specific T cell response (r=0.462; p=0.003). In responders, serum neutralization activity decreased against VOCs bearing the E484K mutation but remained detectable in a majority of patients. Conclusion MMF, MTX and poor baseline humoral immune status, particularly: low naïve B cell frequencies, are independently associated with impaired BNT162b2 mRNA antibody response, delineating SLE patients who might need adapted vaccine regimens and follow-up. KEY MESSAGES What is already known about this subject? BNT162b2 efficacy and safety has been described in studies mixing different RMDs What does this study add? No serious adverse effects, nor SLE flares have been documented after BNT162b2 in SLE patients. Not only MMF and MTX, but also a poor humoral immune status at baseline impair vaccine antibody response Albeit decreased, serum neutralizing activity against VOCs is conferred to vaccine-responders. How might this impact on clinical practice or future developments? These parameters could be helpful for physicians to delineate which patients should have antibody measurement after full BNT162b2 vaccination and should be proposed a third injection of BNT162b2 vaccine.
Dung Nguyen, Peter Simmonds, Maurice Steenhuis, Elise Wouters, Daniel Desmecht, Mutien Garigliany, Marta Romano, Cyril Barbezange, Piet Maes, Bram Van Holm, et al.
Eurosurveillance, Volume 26; doi:10.2807/1560-7917.es.2021.26.27.2100568

Abstract:
We compared the performance of SARS-CoV-2 neutralising antibody testing between 12 European laboratories involved in convalescent plasma trials. Raw titres differed almost 100-fold differences between laboratories when blind-testing 15 plasma samples. Calibration of titres in relation to the reference reagent and standard curve obtained by testing a dilution series reduced the inter-laboratory variability ca 10-fold. The harmonisation of neutralising antibody quantification is a vital step towards determining the protective and therapeutic levels of neutralising antibodies.
, Jean-Louis Bayart, François Mullier, Marc Elsen, Christine Eucher, Sandrine Van Eeckhoudt, Tatiana Roy, Gregoire Wieers, Christine Laurent, Jean-Michel Dogné, et al.
Emerging Microbes & Infections pp 1-8; doi:10.1080/22221751.2021.1953403

Abstract:
Several studies reported on the humoral response in subjects having received the BNT162b2 mRNA COVID-19 vaccine. However, data on the kinetics of antibodies 3 months post-vaccination are currently lacking and are important to drive the future vaccination strategy. The CRO-VAX HCP study is an ongoing multicenter, prospective and interventional study designed to assess the antibody response in a population of healthcare professionals who had received two doses of the BNT162b2 mRNA COVID-19 vaccine. Two-hundred individuals underwent a blood drawn within 2 days before the first vaccine dose. One-hundred and forty-two persons (71%) were categorized as seronegative at baseline while 58 (29%) were seropositive. Samples were then collected after 14, 28, 42, 56, and 90 days. Antibodies against the SARS-CoV-2 nucleocapsid and the receptor binding domain of the S1 subunit of the spike protein were measured in all individuals at different time points. Using a one-compartment kinetics model, the time to maximum concentration was estimated at 36 ± 3 days after the first dose and the estimated half-life of antibodies was 55 days (95% CI: 37-107 days) in seronegative participants. In seropositive participants, the time to maximum concentration was estimated at 24 ± 4 days and the estimated half-life was 80 days (95% CI: 46-303 days). The antibody response was higher in seropositive compared to seronegative participants. In both seropositive and seronegative subjects, a significant antibody decline was observed at 3 months compared to the peak response. Nevertheless, the humoral response remained robust in all participants.
Matthias Tenbusch, Sofie Schumacher, Emanuel Vogel, Alina Priller, Jürgen Held, Philipp Steininger, Stephanie Beileke, Pascal Irrgang, Ronja Brockhoff, Jon Salmanton-García, et al.
Published: 6 July 2021
Abstract:
Administration of a first dose of the COVID-19 vaccine ChAdOx1 nCoV-19 (Vaxzevria®, AstraZeneca) is associated with a certain risk for vaccine-induced immune thrombotic thrombocytopenia. Therefore, several countries have recommended replacing the second dose of ChAdOx1 nCoV-19 with an mRNA-based vaccine as a precautionary measure, although data on safety and efficacy of such heterologous prime-boost regimen are sparse. Therefore, vaccinees, who had received a heterologous vaccination using ChAdOx1 nCoV-19 as prime and BNT162b2 (Comirnaty®, BioNTech-Pfizer) mRNA as boost vaccination were offered SARS-CoV-2 antibody testing to quantify their vaccine-induced neutralizing antibody response5. The results were compared to cohorts of healthcare workers or volunteers, who received homologous BNT162b2 or homologous ChAdOx1 nCoV-19 vaccination regimens, respectively. A striking increase of vaccine-induced SARS-CoV-2 neutralizing antibody activity was observed in 229 vaccinees that received a BNT162b2 boost 9 to 12 weeks after ChAdOx1 nCoV-19 prime. In our cohort comprising over 480 individuals, the heterologous vaccination scheme induced significantly higher neutralizing antibody titers than homologous ChAdOx1 nCoV-19 and even than homologous BNT162b2 vaccination. This proves that a single dose of a COVID-19 mRNA vaccine after ChAdOx1 nCoV-19 prime vaccination is sufficient to achieve high neutralizing antibody levels predicting immune protection from SARS-CoV-2 infection, and may even increase vaccine efficacy offering an alternative in a setting of vaccine shortage.
Jia Wei, , , Thomas Maddox, Luke Lorenzi, Ruth Studley, John I Bell, John N Newton, Jeremy Farrar, Ian Diamond, et al.
Published: 5 July 2021
Abstract:
We estimated the duration and determinants of antibody response after SARS-CoV-2 infection in the general population using representative data from 7,256 United Kingdom COVID-19 infection survey participants who had positive swab SARS-CoV-2 PCR tests from 26-April-2020 to 14-June-2021. A latent class model classified 24% of participants as ‘non-responders’ not developing anti-spike antibodies. These seronegative non-responders were older, had higher SARS-CoV-2 cycle threshold values during infection (i.e. lower viral burden), and less frequently reported any symptoms. Among those who seroconverted, using Bayesian linear mixed models, the estimated anti-spike IgG peak level was 7.3-fold higher than the level previously associated with 50% protection against reinfection, with higher peak levels in older participants and those of non-white ethnicity. The estimated anti-spike IgG half-life was 184 days, being longer in females and those of white ethnicity. We estimated antibody levels associated with protection against reinfection likely last 1.5-2 years on average, with levels associated with protection from severe infection present for several years. These estimates could inform planning for vaccination booster strategies.
, , Zeli Zhang, Carolyn Rydyznski Moderbacher, Marshall Lammers, Benjamin Goodwin, , ,
Published: 5 July 2021
Abstract:
Understanding human immune responses to SARS-CoV-2 RNA vaccines is of interest for a panoply of reasons. Here we examined vaccine-specific CD4+ T cell, CD8+ T cell, binding antibody, and neutralizing antibody responses to the 25 μg Moderna mRNA-1273 vaccine over 7 months post-immunization, including multiple age groups, with a particular interest in assessing whether pre-existing crossreactive T cell memory impacts vaccine-generated immunity. Low dose (25 μg) mRNA-1273 elicited durable Spike binding antibodies comparable to that of convalescent COVID-19 cases. Vaccine-generated Spike memory CD4+ T cells 6 months post-boost were comparable in quantity and quality to COVID-19 cases, including the presence of TFH cells and IFNγ-expressing cells. Spike CD8+ T cells were generated in 88% of subjects, with equivalent percentages of CD8+ T cell memory responders at 6 months post-boost compared to COVID-19 cases. Lastly, subjects with pre-existing crossreactive CD4+ T cell memory had increased CD4+ T cell and antibody responses to the vaccine, demonstrating a biological relevance of SARS-CoV-2 crossreactive CD4+ T cells. One-Sentence Summary The mRNA-1273 vaccine induces a durable and functional T cell and antibody response comparable to natural infection.
Wey Wen Lim, Loretta Mak, Gabriel M Leung, , Malik Peiris
Published: 1 July 2021
The Lancet Microbe; doi:10.1016/s2666-5247(21)00177-4

Abstract:
We report here comparative data on SARS-CoV-2 vaccine immunogenicity in health-care workers in Hong Kong who received either the BNT162b2 vaccine (Comirnaty; Fosun–BioNTech) or the inactivated virus (vero cell) vaccine (Coronavac; Sinovac). We collected blood samples before vaccination, before the second dose, and 21–35 days after the second dose. We tested the samples for antibodies to SARS-CoV-2 using an ELISA to detect antibodies that bind to the receptor binding domain of the spike protein, testing ELISA-positive samples for neutralising antibodies with a surrogate virus neutralisation (sVNT) assay, and then a plaque reduction neutralisation test (PRNT) with live SARS-CoV-2 virus.1Perera RA Mok CK Tsang OT et al.Serological assays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), March 2020.Euro Surveill. 2020; 252000421Crossref Scopus (109) Google Scholar, 2Perera RAPM Ko R Tsang OTY et al.Evaluation of a SARS-CoV-2 surrogate virus neutralization test for detection of antibody in human, canine, cat, and hamster sera.J Clin Microbiol. 2021; 59: e02504-e02520Crossref PubMed Scopus (10) Google Scholar
Published: 1 July 2021
Cell Host & Microbe, Volume 29, pp 1111-1123; doi:10.1016/j.chom.2021.06.016

Abstract:
Summary The rapid and remarkably successful development, manufacture, and deployment of several effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines is now tempered by three key challenges. First, reducing virus transmission will require prevention of asymptomatic and mild infections in addition to severe symptomatic infections. Second, the emergence of variants of concern with mutations in the S protein's receptor binding domain increases the likelihood that vaccines will have to be updated because some of these mutations render variants less optimally targeted by current vaccines. This will require coordinated global SARS-CoV-2 surveillance to link genotypes to phenotypes, potentially using the WHO's global influenza surveillance program as a guide. Third, concerns about the longevity of vaccine-induced immunity highlight the potential need for re-vaccination, depending on the extent to which the virus has been controlled and whether re-vaccination can target those at greatest risk of severe illness. Fortunately, as I discuss in this review, these challenges can be addressed.
International Journal of Infectious Diseases, Volume 108, pp 483-486; doi:10.1016/j.ijid.2021.05.080

Abstract:
Introduction A large number of COVID-19 patients are in recovery, and millions of people are vaccinated for COVID-19 globally. This calls for a rapid screening strategy of SARS-CoV-2 protective antibodies, generated in rehabilitated and vaccinated populations. Methods Serum samples collected over a follow-up period of six months from 306 COVID-19 cases discharged from Wuhan Tongji Hospital were analyzed. Anti-S Abs were detected by colloidal gold immunochromatographic assay (GICA), and neutralizing antibodies (nAbs) were detected by chemiluminescent microparticle immunoassay (CMIA). Results Most COVID-19 survivors tested positive for anti-S Abs (83.7%) and nAbs (98.0%) 6 months after being discharged from the hospital, and the levels of anti-S Abs in the blood were highly positively correlated with nAbs (r = 0.652, P < 0.0001). The positivity rate of nAbs for patients with anti-S Abs positive was 100%. Conclusions There is a good agreement between anti-S Abs detected by GICA and nAbs detected by CMIA. It indicates that anti-S Abs detected by GICA may be used as a cheaper screening strategy for detectable SARS-CoV-2 nAbs in COVID-19 convalescent individuals.
Arturo Blazquez-Navarro, Lema Safi, Toni L. Meister, Constantin J. Thieme, Sviatlana Kaliszczyk, Krystallenia Paniskaki, Mara Stockhausen, Jan Hörstrup, Okan Cinkilic, Linus Flitsch-Kiefner, et al.
Published: 1 July 2021
Kidney International; doi:10.1016/j.kint.2021.07.006

Abstract:
Patients undergoing maintenance dialysis (DP) have a high risk of fatal coronavirus disease 2019 (COVID-19).1ERA-EDTA Council, ERACODA Working GroupChronic kidney disease is a key risk factor for severe COVID-19: a call to action by the ERA-EDTA.Nephrol Dial Transplant. 2021; 36: 87-94Google Scholar Recent epidemiological data raise apprehension with respect to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) for DP.2Kumar V. Iyengar K. Garg R. Vaishya R. Elucidating reasons of COVID-19 re-infection and its management strategies.Diabetes Metab Syndr. 2021; 15: 1001-1006Google Scholar,3Geers D. Immunol S. Geers D. et al.SARS-CoV-2 variants of concern partially escape humoral but not T-cell responses in COVID-19 convalescent donors and vaccinees.Sci Immunol. 2021; 6eab1750Google Scholar Therefore, ensuring cellular and humoral immunity directed to SARS-CoV-2 including VOC isolates is essential for this population. There are no data on vaccine-induced nor on natural SARS-CoV-2 infection–induced long-term immunity and its responsiveness to VOC isolates in DP.
Emma C Wall, Mary Wu, Ruth Harvey, Gavin Kelly, Scott Warchal, Chelsea Sawyer, Rodney Daniels, Lorin Adams, Philip Hobson, Emine Hatipoglu, et al.
Published: 1 July 2021
The Lancet, Volume 398, pp 207-209; doi:10.1016/s0140-6736(21)01462-8

Abstract:
The SARS-CoV-2 B.1.617.2 Delta variant of concern (VOC) continues to drive a sharp increase in COVID-19 cases in the UK, with a current doubling time of 3·5–16 days,1Public Health EnglandSARS-CoV-2 variants of concern and variants under investigation in England. Technical briefing 16.https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/994839/Variants_of_Concern_VOC_Technical_Briefing_16.pdfDate: June 18, 2021Date accessed: June 24, 2021Google Scholar consistent with previous pandemic waves during 2020–21, and a sustained increase in the reproduction number (R) to 1·2–1·4.2Department of Health and Social Care and Scientific Advisory Group for EmergenciesThe R value and growth rate.https://www.gov.uk/guidance/the-r-value-and-growth-rateDate: June 18, 2021Date accessed: June 24, 2021Google Scholar Daily hospital admissions and the number of patients requiring mechanical ventilation are now increasing in both England and Scotland, despite the ongoing roll-out of widespread vaccination in the UK.1Public Health EnglandSARS-CoV-2 variants of concern and variants under investigation in England. Technical briefing 16.https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/994839/Variants_of_Concern_VOC_Technical_Briefing_16.pdfDate: June 18, 2021Date accessed: June 24, 2021Google Scholar
Matthias Tenbusch, Sofie Schumacher, Emanuel Vogel, Alina Priller, Jürgen Held, Philipp Steininger, Stephanie Beileke, Pascal Irrgang, Ronja Brockhoff, Jon Salmanton-García, et al.
Published: 1 July 2021
The Lancet Infectious Diseases; doi:10.1016/s1473-3099(21)00420-5

Abstract:
The Oxford-AstraZeneca COVID-19 vaccine ChAdOx1 nCoV-19 is associated with a risk for vaccine-induced immune thrombosis with thrombocytopenia syndrome in the range of one to two cases per 100 000 vaccinations, with younger women showing the highest risk.1Greinacher A Thiele T Warkentin TE Weisser K Kyrle PA Eichinger S Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination.N Engl J Med. 2021; 384: 2092-2101Crossref PubMed Scopus (159) Google Scholar, 2Scully M Singh D Lown R et al.Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination.N Engl J Med. 2021; 384: 2202-2211Crossref PubMed Google Scholar Additional cases have been reported for the Johnson & Johnson adenoviral vector-based Ad26.CoV2.S COVID-19 vaccine.3MacNeil JR Su JR Broder KR et al.Updated recommendations from the Advisory Committee on Immunization Practices for use of the Janssen (Johnson & Johnson) COVID-19 vaccine after reports of thrombosis with thrombocytopenia syndrome among vaccine recipients—United States, April 2021.MMWR Morb Mortal Wkly Rep. 2021; 70: 651-656Crossref PubMed Scopus (0) Google Scholar Vaccine-induced antibodies against platelet factor 4 have been implicated in the pathogenesis.1Greinacher A Thiele T Warkentin TE Weisser K Kyrle PA Eichinger S Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination.N Engl J Med. 2021; 384: 2092-2101Crossref PubMed Scopus (159) Google Scholar, 2Scully M Singh D Lown R et al.Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination.N Engl J Med. 2021; 384: 2202-2211Crossref PubMed Google Scholar These antibodies might be amplified by booster vaccination with an adenoviral vector, which prompted recommendations to boost with an mRNA-based vaccine instead, although data on safety and efficacy of heterologous prime–boost regimens are sparse.4Borobia AM Carcas AJ Pérez-Olmeda M et al.Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial.Lancet. 2021; 398: 121-130Summary Full Text Full Text PDF PubMed Google Scholar
Dami A Collier, Isabella A T M Ferreira, Prasanti Kotagiri, Rawlings Datir, Eleanor Lim, Emma Touizer, Bo Meng, Adam Abdullahi, CITIID-NIHR BioResource COVID-19 Collaboration, Anne Elmer, et al.
Published: 30 June 2021
Nature pp 1-9; doi:10.1038/s41586-021-03739-1

Abstract:
Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating.
Published: 23 June 2021
by MDPI
Viruses, Volume 13; doi:10.3390/v13071211

Abstract:
We summarize here in vitro evidences of efficacy for convalescent plasma, currently approved vaccines and monoclonal antibodies against SARS-CoV-2 variants of concern (VOC: B.1.1.7, B.1.351, P.1, and B.1.617.2), variants of interest (VOI: B.1.427/B.1.429, P.2, B.1.525, P.3, B.1.526, and B.1.671.1), and other strains (B.1.1.298 and B.1.258delta). While waiting from real world clinical efficacy, these data provide guidance for the treating physician.
F. Javier Ibarrondo, Christian Hofmann, Jennifer A. Fulcher, David Goodman-Meza, William Mu, Mary Ann Hausner, Ayub Ali, Arumugam Balamurugan, Ellie Taus, Julie Elliott, et al.
Published: 23 June 2021
ACS Nano, Volume 15, pp 11180-11191; doi:10.1021/acsnano.1c03972

Abstract:
Studies of two SARS-CoV-2 mRNA vaccines suggested that they yield ∼95% protection from symptomatic infection at least short-term, but important clinical questions remain. It is unclear how vaccine-induced antibody levels quantitatively compare to the wide spectrum induced by natural SARS-CoV-2 infection. Vaccine response kinetics and magnitudes in persons with prior COVID-19 compared to virus-naı̈ve persons are not well-defined. The relative stability of vaccine-induced versus infection-induced antibody levels is unclear. We addressed these issues with longitudinal assessments of vaccinees with and without prior SARS-CoV-2 infection using quantitative enzyme-linked immunosorbent assay (ELISA) of anti-RBD antibodies. SARS-CoV-2-naı̈ve individuals achieved levels similar to mild natural infection after the first vaccination; a second dose generated levels approaching severe natural infection. In persons with prior COVID-19, one dose boosted levels to the high end of severe natural infection even in those who never had robust responses from infection, increasing no further after the second dose. Antiviral neutralizing assessments using a spike-pseudovirus assay revealed that virus-naı̈ve vaccinees did not develop physiologic neutralizing potency until the second dose, while previously infected persons exhibited maximal neutralization after one dose. Finally, antibodies from vaccination waned similarly to natural infection, resulting in an average of ∼90% loss within 90 days. In summary, our findings suggest that two doses are important for quantity and quality of humoral immunity in SARS-CoV-2-naı̈ve persons, while a single dose has maximal effects in those with past infection. Antibodies from vaccination wane with kinetics very similar to that seen after mild natural infection; booster vaccinations will likely be required.
Carolina Garrido, Alan D. Curtis, Maria Dennis, Sachi H. Pathak, Hongmei Gao, , Mark Tomai, , Pamela A. Kozlowski, Trevor Scobey, et al.
Science Immunology, Volume 6; doi:10.1126/sciimmunol.abj3684

Abstract:
The inclusion of infants in the SARS-CoV-2 vaccine rollout is important to prevent severe complications of pediatric SARS-CoV-2 infections and to limit transmission and could possibly be implemented via the global pediatric vaccine schedule. However, age-dependent differences in immune function require careful evaluation of novel vaccines in the pediatric population. Toward this goal, we assessed the safety and immunogenicity of two SARS-CoV-2 vaccines. Two groups of eight infant rhesus macaques (RMs) were immunized intramuscularly at weeks 0 and 4 with stabilized prefusion SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or the purified S protein mixed with 3M-052, a synthetic TLR7/8 agonist in a squalene emulsion (Protein+3M-052-SE). Neither vaccine induced adverse effects. Both vaccines elicited high-magnitude IgG binding to RBD, amino-terminal domain, S1 and S2, ACE2 blocking activity, and high neutralizing antibody titers, all peaking at week 6. S-specific memory B cells were detected by week 4, and S-specific T cell responses were dominated by the production of IL-17, IFN-γ, or TNF-α. Antibody and cellular responses were stable through week 22. The immune responses for the mRNA-LNP vaccine were of a similar magnitude to those elicited by the Moderna mRNA-1273 vaccine in adults. The S-2P mRNA-LNP and Protein−3M-052-SE vaccines were well tolerated and highly immunogenic in infant RMs, providing proof of concept for a pediatric SARS-CoV-2 vaccine with the potential for durable immunity that might decrease the transmission of SARS-CoV-2 and mitigate the ongoing health and socioeconomic impacts of COVID-19.
Talia Kustin, Noam Harel, Uriah Finkel, Shay Perchik, Sheri Harari, Maayan Tahor, Itamar Caspi, Rachel Levy, Michael Leshchinsky, Shifra Ken Dror, et al.
Published: 14 June 2021
Nature Medicine pp 1-6; doi:10.1038/s41591-021-01413-7

Abstract:
The BNT162b2 mRNA vaccine is highly effective against SARS-CoV-2. However, apprehension exists that variants of concern (VOCs) may evade vaccine protection, due to evidence of reduced neutralization of the VOCs B.1.1.7 and B.1.351 by vaccine sera in laboratory assays. We performed a matched cohort study to examine the distribution of VOCs in infections of BNT162b2 mRNA vaccinees from Clalit Health Services (Israel) using viral genomic sequencing, and hypothesized that if vaccine effectiveness against a VOC is reduced, its proportion among breakthrough cases would be higher than in unvaccinated controls. Analyzing 813 viral genome sequences from nasopharyngeal swabs, we showed that vaccinees who tested positive at least 7 days after the second dose were disproportionally infected with B.1.351, compared with controls. Those who tested positive between 2 weeks after the first dose and 6 days after the second dose were disproportionally infected by B.1.1.7. These findings suggest reduced vaccine effectiveness against both VOCs within particular time windows. Our results emphasize the importance of rigorously tracking viral variants, and of increasing vaccination to prevent the spread of VOCs.
Published: 8 June 2021
by MDPI
Vaccines, Volume 9; doi:10.3390/vaccines9060615

Abstract:
Vaccination against SARS-CoV-2 is considered the most effective method of prevention to contain the pandemic. While highly effective SARS-CoV-2 vaccines are being applied on a large-scale, whether and to what extent the strength of the vaccine-induced immune response could be further potentiated is still an object of debate. Several reports studied the effect of different vaccines on the susceptibility and mortality of COVID-19, with conflicting results. We aimed to evaluate whether previous influenza and/or pneumococcal vaccination had an impact on the specific immune response to the SARS-CoV-2 BNT162b2 mRNA vaccine. The study population consists of 710 workers from our Institute who completed the BNT162b2 schedule and have been tested at least once after the second dose, from 27 December 2020 up to 15 April 2021. Of these, 152 (21.4%) had received an influenza and 215 (30.3%) a concomitant influenza and pneumococcal vaccination, a median of 102 days before the second dose of BNT162b2. Overall, 100% of workers were tested for anti-Spike receptor-binding domain (anti-S/RBD) antibodies, 224 workers for neutralization titer (Micro-neutralization assay, MNA), and 155 workers for a spike-specific T cell interferon-γ response (IFN-γ). The levels of anti-S/RBD, MNA and IFN-γ were evaluated and compared according to sex, age, involvement in direct care of COVID-19 patients, and previous influenza/pneumococcal vaccination. At the univariate analysis, no statistically significant association was observed with regard to a previous influenza and pneumococcal vaccination. A significant lower anti-S/RBD response was observed according to an older age and male sex, while MNA titers were significantly associated to sex but not to age. At the multivariable analysis, workers receiving a concomitant influenza and pneumococcal vaccination or only influenza showed a 58% (p 0.01) and 42% (p 0.07) increase in MNA titers, respectively, compared to those who did not receive an influenza/pneumococcal vaccination. Female workers showed an 81% MNA and a 44% anti-S/RBD increase compared to male workers (p< 0.001). Compared to workers aged 21 to 49 years, those aged 50 or older were associated with a reduction in the anti-S/RBD (16%; p 0.005), MNA (31%; p 0.019), and IFN.g (32%) immune response. Maintaining the influenza and pneumococcal immunization program for the coming season, in which COVID-19 could still be spreading, remains strongly recommended to protect those who are more vulnerable and to limit the potential burden of these infections on the healthcare system.
Heidi Ledford
Published: 4 June 2021
Nature, Volume 594, pp 164-167; doi:10.1038/d41586-021-01505-x

Abstract:
At a pivotal moment in the pandemic, Nature explores key questions about the vaccines that countries are racing to deliver while viral variants spread around the globe. At a pivotal moment in the pandemic, Nature explores key questions about the vaccines that countries are racing to deliver while viral variants spread around the globe.
, Kevin John Selva, Samantha K. Davis, Bruce D. Wines, Arnold Reynaldi, Robyn Esterbauer, Hannah G. Kelly, Ebene R. Haycroft, Hyon-Xhi Tan, , et al.
Published: 1 June 2021
Cell Reports Medicine, Volume 2; doi:10.1016/j.xcrm.2021.100296

Abstract:
The capacity of antibodies to engage with immune cells via the Fc region is important in preventing and controlling many infectious diseases. The evolution of such antibodies during convalescence from COVID-19 is largely unknown. We develop assays to measure Fc-dependent antibody functions against SARS-CoV-2 spike (S)-expressing cells in serial samples from subjects primarily with mild-moderate COVID-19, up to 149 days post-infection. We find that S-specific antibodies capable of engaging Fcγ receptors decay over time, with S-specific antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent phagocytosis (ADP) activity within plasma declining accordingly. Although there is significant decay in ADCC and ADP activity, they remain readily detectable in almost all subjects at the last timepoint studied (94%) in contrast with neutralisation activity (70%). While it remains unclear the degree to which Fc effector functions contribute to protection against SARS-CoV-2 re-infection, our results indicate that antibodies with Fc effector functions persist longer than neutralising antibodies.
Rüdiger Groß, Michelle Zanoni, Alina Seidel, Carina Conzelmann, Andrea Gilg, Daniela Krnavek, Sümeyye Erdemci-Evin, Benjamin Mayer, Markus Hoffmann, Stefan Pöhlmann, et al.
Published: 1 June 2021
Abstract:
Background Heterologous prime-boost schedules with vector- and mRNA-based COVID-19 vaccines are already administered, but immunological responses and elicited protection have not been reported. Methods We here analyzed a cohort of 26 individuals aged 25-46 (median 30.5) years that received a ChAdOx1 nCoV-19 prime followed by a BNT162b2 boost after an 8-week interval for reactogenicity, antibody responses and T cell reactivity. Results Self-reported solicited symptoms after ChAdOx1 nCoV-19 prime were in line with previous reports and less severe after the BNT162b2 boost. Antibody titers increased significantly over time resulting in strong neutralization titers 2 weeks after the BNT162b2 boost. Neutralizing activity against the prevalent strain B.1.1.7 was 3.9-fold higher than in individuals receiving homologous BNT162b2 vaccination, only 2-fold reduced for variant of concern B.1.351, and similar for variant B.1.617. In addition, CD4+ and CD8+ T cells reacted to SARS-CoV-2 spike peptide stimulus 2 weeks after the full vaccination. Conclusions The heterologous ChAdOx1 nCoV-19 / BNT162b2 prime-boost vaccination regimen is not associated with serious adverse events and results in a potent humoral immune response and elicits T cell reactivity. Variants of concern B.1.1.7, B.1.351 and B.1.617 are potently neutralized by sera of all participants. These results suggest that this heterologous vaccination regimen is at least as immunogenic and protective as homologous vaccinations.
, Robyn M. Stuart, Rafael C. Núñez, Bradley Wagner, Stewart Chang, Katherine Rosenfeld, Cliff C. Kerr, Michael Famulare, Daniel J. Klein
Published: 1 June 2021
Abstract:
Early waves of the SARS-CoV-2 pandemic were driven by importation events and subsequent policy responses. However, epidemic dynamics in 2021 are largely driven by the spread of more transmissible and/or immune-evading variants, which in turn are countered by vaccination programs. Here we describe updates to the methodology of Covasim (COVID-19 Agent-based Simulator) to account for immune trajectories over time, correlates of protection, co-circulation of different variants and the roll-out of multiple vaccines. We have extended recent work on neutralizing antibodies (NAbs) as a correlate of protection to account for protection against infection, symptomatic COVID-19, and severe disease using a joint estimation approach. We find that NAbs are strongly correlated with infection blocking and that natural infection provides stronger protection than vaccination for the same level of NAbs, though vaccines typically produce higher NAbs. We find only relatively weak correlations between NAbs and the probability of developing symptoms given a breakthrough infection, or the probability of severe disease given symptoms. A more refined understanding of breakthrough infections in individuals with natural and vaccine-derived immunity will have implications for timing of booster vaccines, the impact of emerging variants of concern on critical vaccination thresholds, and the need for ongoing non-pharmaceutical interventions.
International Journal of Infectious Diseases; doi:10.1016/j.ijid.2021.06.040

Abstract:
The world is currently engaged in a race of vaccination vs. infection in an effort to control the Covid-19 pandemic. Some countries have already achieved high vaccination rates, offering a glimpse into the so-called "post-vaccination" world. We describe here a striking comparison between the similarly-sized and neighboring countries of Bahrain and Qatar. While both countries have achieved impressive vaccination rates, cases increased to unprecedented levels in one country, while decreasing steadily in the other. Although this could be attributed to a number of factors, we argue here that the heavy reliance on alum-adjuvanted inactivated virus vaccines may have contributed to these discrepant outcomes. We then expand the analysis to compare the top 10 vaccinated countries, and compare their outcomes based on their reliance on inactivated virus vaccines. The results remarkably align with the initial findings seen in Bahrain and Qatar. Countries that did not use inactivated virus vaccines achieved steady declines in daily Covid-19 deaths, while other countries did not. This work highlights the urgent need to further study the effectiveness of alum-adjuvanted inactivated virus vaccines for Covid-19 before expanding their use.
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