SARS-CoV-2 Seroprevalence Trends in the Netherlands in the Variant of Concern Era: Input for Future Response.

BACKGROUND: To inform future response planning we aimed to assess SARS-CoV-2 trends in infection- and/or vaccine-induced immunity, including breakthrough infections, among (sub)groups, professions and regions in the Dutch population during the Variant of Concern (VOC)-era. METHODS: In this prospective population-based cohort, randomly selected participants (n = 9985) aged 1-92 years (recruited early-2020) donated home-collected fingerstick-blood samples at six timepoints in 2021/2022, covering waves dominated by Alpha, Delta, and multiple Omicron (sub-)variants. IgG antibody assessment against Spike-S1 and Nucleoprotein was combined with vaccination- and testing data to estimate infection-induced (inf) and total (infection- and vaccination-induced) seroprevalence. RESULTS: Nationwide inf-seroprevalence rose modestly from 12% (95% CI 11-13) since Alpha to 26% (95% CI 24-28) amidst Delta, while total seroprevalence increased rapidly to 87% (95% CI 85-88), particularly in elderly and those with comorbidities (i.e., vulnerable groups). Interestingly, highest infection rates were noticeable among low/middle educated elderly, non-Western, those in contact professions, adolescents and young adults, and in low-vaccination coverage regions. Following Omicron emergence, inf-seroprevalence elevated sharply to 62% (95% CI 59-65) and further to 86% (95% CI 83-90) in late-2022, with frequent breakthrough infections and decreasing seroprevalence dissimilarities between most groups. Whereas > 90% of < 60-year-olds had been infected at least once, 30% of vaccinated vulnerable individuals had still not acquired hybrid immunity. CONCLUSIONS: Groups identified to have been infected disproportionally during the acute phase of the pandemic require specific attention in evaluation of control measures and future response planning worldwide. Furthermore, ongoing tailored vaccination efforts and (sero-)monitoring of vulnerable groups may remain important.

Determinants of Systemic SARS-CoV-2-Specific Antibody Responses to Infection and to Vaccination: A Secondary Analysis of Randomised Controlled Trial Data.

SARS-CoV-2 infections elicit antibodies against the viral spike (S) and nucleocapsid (N) proteins; COVID-19 vaccines against the S-protein only. The BCG-Corona trial, initiated in March 2020 in SARS-CoV-2-naïve Dutch healthcare workers, captured several epidemic peaks and the introduction of COVID-19 vaccines during the one-year follow-up. We assessed determinants of systemic anti-S1 and anti-N immunoglobulin type G (IgG) responses using trial data. Participants were randomised to BCG or placebo vaccination, reported daily symptoms, SARS-CoV-2 test results, and COVID-19 vaccinations, and donated blood for SARS-CoV-2 serology at two time points. In the 970 participants, anti-S1 geometric mean antibody concentrations (GMCs) were much higher than anti-N GMCs. Anti-S1 GMCs significantly increased with increasing number of immune events (SARS-CoV-2 infection or COVID-19 vaccination): 104.7 international units (IU)/mL, 955.0 IU/mL, and 2290.9 IU/mL for one, two, and three immune events, respectively (p < 0.001). In adjusted multivariable linear regression models, anti-S1 and anti-N log10 concentrations were significantly associated with infection severity, and anti-S1 log10 concentration with COVID-19 vaccine type/dose. In univariable models, anti-N log10 concentration was also significantly associated with acute infection duration, and severity and duration of individual symptoms. Antibody concentrations were not associated with long COVID or long-term loss of smell/taste.

The Impact of Infant Bacille Calmette-Guérin Vaccination on the Immunogenicity of Other Vaccines: A Randomized Exploratory Study.

The effect of the Bacille Calmette-Guérin (BCG) vaccine on the immunogenicity of separately administered serogroup C meningococcal vaccine and other vaccinations was examined in 28 infants randomized to receive BCG at age ≤7 days, at 3 months or after study completion. Immunogenicity of the serogroup C meningococcal vaccine and other routine vaccines might be improved when BCG is administered in early infancy.

Multiplex Bead Assay for the Serological Surveillance of Measles and Rubella.

There is increasing interest in evaluating antibody responses to multiple antigen targets in a single assay. Immunity to measles and rubella are often evaluated together because immunity is provided through combined vaccines and because routine immunization efforts and surveillance for measles and rubella pathogens are combined in many countries. The multiplex bead assay (MBA) also known as the multiplex immunoassay (MIA) described here combines the measurement of measles- and rubella-specific IgG antibodies in serum quantitatively according to international serum standards and has been successfully utilized in integrated serological surveillance.

High-resolution African HLA resource uncovers HLA-DRB1 expression effects underlying vaccine response.

How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.

IgG1 glycosylation highlights premature aging in Down syndrome.

Down syndrome (DS) is characterized by lowered immune competence and premature aging. We previously showed decreased antibody response following SARS-CoV-2 vaccination in adults with DS. IgG1 Fc glycosylation patterns are known to affect the effector function of IgG and are associated with aging. Here, we compare total and anti-spike (S) IgG1 glycosylation patterns following SARS-CoV-2 vaccination in DS and healthy controls (HC). Total and anti-Spike IgG1 Fc N-glycan glycoprofiles were measured in non-exposed adults with DS and controls before and after SARS-CoV-2 vaccination by liquid chromatography-mass spectrometry (LC-MS) of Fc glycopeptides. We recruited N = 44 patients and N = 40 controls. We confirmed IgG glycosylation patterns associated with aging in HC and showed premature aging in DS. In DS, we found decreased galactosylation (50.2% vs. 59.0%) and sialylation (6.7% vs. 8.5%) as well as increased fucosylation (97.0% vs. 94.6%) of total IgG. Both cohorts showed similar bisecting GlcNAc of total and anti-S IgG1 with age. In contrast, anti-S IgG1 of DS and HC showed highly comparable glycosylation profiles 28 days post vaccination. The IgG1 glycoprofile in DS exhibits strong premature aging. The combination of an early decrease in IgG1 Fc galactosylation and sialylation and increase in fucosylation is predicted to reduce complement activity and decrease FcγRIII binding and subsequent activation, respectively. The altered glycosylation patterns, combined with decreased antibody concentrations, help us understand the susceptibility to severe infections in DS. The effect of premature aging highlights the need for individuals with DS to receive tailored vaccines and/or vaccination schedules.

Protective mucosal SARS-CoV-2 antibodies in the majority of the general population in the Netherlands.

Antibodies to SARS-CoV-2 on the mucosal surfaces of the respiratory tract are understood to contribute to protection against SARS-CoV-2 infection. We aimed to describe the prevalence, levels, and functionality of mucosal antibodies in the general Dutch population. Nasal samples were collected from 778 randomly selected participants, 1-90 years of age, nested within the nationwide prospective SARS-CoV-2 PIENTER corona serosurvey in the Netherlands. Spike-specific immunoglobulin (Ig)G was detected in the nasal samples of 94.6% (in case of the wild-type S1 variant) and 94.9% (Omicron BA.1) of the individuals, whereas 44.2% and 62.7% of the individuals were positive for wild-type and Omicron BA.1 S1 IgA, respectively. The lowest prevalence of mucosal antibodies was observed in children under 12 years of age. The prevalence and levels of IgA and IgG were higher in individuals with a history of SARS-CoV-2 infection. Mucosal antibodies inhibited the binding of Wuhan, Delta, and Omicron BA.1 receptor binding domain to human angiotensin-converting enzyme 2 in 94.4%, 95.4%, and 92.6% of the participants, respectively. Higher levels of mucosal antibodies were associated with a lower risk of future infection.

Young infants display heterogeneous serological responses and extensive but reversible transcriptional changes following initial immunizations.

Infants necessitate vaccinations to prevent life-threatening infections. Our understanding of the infant immune responses to routine vaccines remains limited. We analyzed two cohorts of 2-month-old infants before vaccination, one week, and one-month post-vaccination. We report remarkable heterogeneity but limited antibody responses to the different antigens. Whole-blood transcriptome analysis in an initial cohort showed marked overexpression of interferon-stimulated genes (ISGs) and to a lesser extent of inflammation-genes at day 7, which normalized one month post-vaccination. Single-cell RNA sequencing in peripheral blood mononuclear cells from a second cohort identified at baseline a predominantly naive immune landscape including ISGhi cells. On day 7, increased expression of interferon-, inflammation-, and cytotoxicity-related genes were observed in most immune cells, that reverted one month post-vaccination, when a CD8+ ISGhi and cytotoxic cluster and B cells expanded. Antibody responses were associated with baseline frequencies of plasma cells, B-cells, and monocytes, and induction of ISGs at day 7.

Assessment of hybrid population immunity to SARS-CoV-2 following breakthrough infections of distinct SARS-CoV-2 variants by the detection of antibodies to nucleoprotein.

Immunity induced by vaccination and infection, referred to as hybrid immunity, provides better protection against SARS-CoV-2 infections compared to immunity induced by vaccinations alone. To assess the development of hybrid immunity we investigated the induction of Nucleoprotein-specific antibodies in PCR-confirmed infections by Delta or Omicron in vaccinated individuals (n = 520). Eighty-two percent of the participants with a breakthrough infection reached N-seropositivity. N-seropositivity was accompanied by Spike S1 antibody boosting, and independent of vaccination status or virus variant. Following the infection relatively more antibodies to the infecting virus variant were detected. In conclusion, these data show that hybrid immunity through breakthrough infections is hallmarked by Nucleoprotein antibodies and broadening of the Spike antibody repertoire. Exposure to future SARS-CoV-2 variants may therefore continue to maintain and broaden vaccine-induced population immunity.

Targeting hepatitis B vaccine escape using immunogenetics in Bangladeshi infants.

Hepatitis B virus (HBV) vaccine escape mutants (VEM) are increasingly described, threatening progress in control of this virus worldwide. Here we studied the relationship between host genetic variation, vaccine immunogenicity and viral sequences implicating VEM emergence. In a cohort of 1,096 Bangladeshi children, we identified human leukocyte antigen (HLA) variants associated with response vaccine antigens. Using an HLA imputation panel with 9,448 south Asian individuals DPB1*04:01 was associated with higher HBV antibody responses (p=4.5×10-30). The underlying mechanism is a result of higher affinity binding of HBV surface antigen epitopes to DPB1*04:01 dimers. This is likely a result of evolutionary pressure at the HBV surface antigen 'a-determinant' segment incurring VEM specific to HBV. Prioritizing pre-S isoform HBV vaccines may tackle the rise of HBV vaccine evasion.

Fourth mRNA COVID-19 vaccination in immunocompromised patients with haematological malignancies (COBRA KAI): a cohort study.

Background: Patients with haematological malignancies have impaired antibody responses to SARS-CoV-2 vaccination. We aimed to investigate whether a fourth mRNA COVID-19 vaccination improved antibody quantity and quality. Methods: In this cohort study, conducted at 5 sites in the Netherlands, we compared antibody concentrations 28 days after 4 mRNA vaccinations (3-dose primary series plus 1 booster vaccination) in SARS-CoV-2 naive, immunocompromised patients with haematological malignancies to those obtained by age-matched, healthy individuals who had received the standard primary 2-dose mRNA vaccination schedule followed by a first booster mRNA vaccination. Prior to and 4 weeks after each vaccination, peripheral blood samples and data on demographic parameters and medical history were collected. Concentrations of antibodies that bind spike 1 (S1) and nucleocapsid (N) protein of SARS-CoV-2 were quantified in binding antibody units (BAU) per mL according to the WHO International Standard for COVID-19 serological tests. Seroconversion was defined as an S1 IgG concentration >10 BAU/mL and a previous SARS-CoV-2 infection as N IgG >14.3 BAU/mL. Antibody neutralising activity was tested using lentiviral-based pseudoviruses expressing spike protein of SARS-CoV-2 wild-type (D614G), Omicron BA.1, and Omicron BA.4/5 variants. This study is registered with EudraCT, number 2021-001072-41. Findings: Between March 24, 2021 and May 4, 2021, 723 patients with haematological diseases were enrolled, of which 414 fulfilled the inclusion criteria for the current analysis. Although S1 IgG concentrations in patients significantly improved after the fourth dose, they remained significantly lower compared to those obtained by 58 age-matched healthy individuals after their first booster (third) vaccination. The rise in neutralising antibody concentration was most prominent in patients with a recovering B cell compartment, although potent responses were also observed in patients with persistent immunodeficiencies. 19% of patients never seroconverted, despite 4 vaccinations. Patients who received their first 2 vaccinations when they were B cell depleted and the third and fourth vaccination during B cell recovery demonstrated similar antibody induction dynamics as patients with normal B cell numbers during the first 2 vaccinations. However, the neutralising capacity of these antibodies was significantly better than that of patients with normal B cell numbers after two vaccinations. Interpretation: A fourth mRNA COVID-19 vaccination improved S1 IgG concentrations in the majority of patients with a haematological malignancy. Vaccination during B cell depletion may pave the way for better quality of antibody responses after B cell reconstitution. Funding: The Netherlands Organisation for Health Research and Development and Amsterdam UMC.

Immune Response following BNT162b2 mRNA COVID-19 Vaccination in Pediatric Cancer Patients.

COVID-19 vaccinations are recommended for children with cancer but data on their vaccination response is scarce. This study assesses the antibody and T-cell response following a 2- or 3-dose vaccination with BNT162b2 mRNA COVID-19 vaccine in children (5-17 years) with cancer. For the antibody response, participants with a serum concentration of anti-SARS-CoV-2 spike 1 antibodies of >300 binding antibody units per milliliter were classified as good responders. For the T-cell response, categorization was based on spike S1 specific interferon-gamma release with good responders having >200 milli-international units per milliliter. The patients were categorized as being treated with chemo/immunotherapy for less than 6 weeks (Tx < 6 weeks) or more than 6 weeks (Tx > 6 weeks) before the first immunization event. In 46 patients given a 2-dose vaccination series, the percentage of good antibody and good T-cell responders was 39.3% and 73.7% in patients with Tx < 6 weeks and 94.4% and 100% in patients with Tx > 6 weeks, respectively. An additional 3rd vaccination in 16 patients with Tx < 6 weeks, increased the percentage of good antibody responders to 70% with no change in T-cell response. A 3-dose vaccination series effectively boosted antibody levels and is of value for patients undergoing active cancer treatment.

BCG Vaccination of Health Care Workers Does Not Reduce SARS-CoV-2 Infections nor Infection Severity or Duration: a Randomized Placebo-Controlled Trial.

Bacillus Calmette-Guerin (BCG) vaccination has been hypothesized to reduce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, severity, and/or duration via trained immunity induction. Health care workers (HCWs) in nine Dutch hospitals were randomized to BCG or placebo vaccination (1:1) in March and April 2020 and followed for 1 year. They reported daily symptoms, SARS-CoV-2 test results, and health care-seeking behavior via a smartphone application, and they donated blood for SARS-CoV-2 serology at two time points. A total of 1,511 HCWs were randomized and 1,309 analyzed (665 BCG and 644 placebo). Of the 298 infections detected during the trial, 74 were detected by serology only. The SARS-CoV-2 incidence rates were 0.25 and 0.26 per person-year in the BCG and placebo groups, respectively (incidence rate ratio, 0.95; 95% confidence interval, 0.76 to 1.21; P = 0.732). Only three participants required hospitalization for SARS-CoV-2. The proportions of participants with asymptomatic, mild, or moderate infections and the mean infection durations did not differ between randomization groups. In addition, unadjusted and adjusted logistic regression and Cox proportional hazards models showed no differences between BCG and placebo vaccination for any of these outcomes. The percentage of participants with seroconversion (7.8% versus 2.8%; P = 0.006) and mean SARS-CoV-2 anti-S1 antibody concentration (13.1 versus 4.3 IU/mL; P = 0.023) were higher in the BCG than placebo group at 3 months but not at 6 or 12 months postvaccination. BCG vaccination of HCWs did not reduce SARS-CoV-2 infections nor infection duration or severity (ranging from asymptomatic to moderate). In the first 3 months after vaccination, BCG vaccination may enhance SARS-CoV-2 antibody production during SARS-CoV-2 infection. IMPORTANCE While several BCG trials in adults were conducted during the 2019 coronavirus disease epidemic, our data set is the most comprehensive to date, because we included serologically confirmed infections in addition to self-reported positive SARS-CoV-2 test results. We also collected data on symptoms for every day during the 1-year follow-up period, which enabled us to characterize infections in detail. We found that BCG vaccination did not reduce SARS-CoV-2 infections nor infection duration or severity but may have enhanced SARS-CoV-2 antibody production during SARS-CoV-2 infection in the first 3 months after vaccination. These results are in agreement with other BCG trials that reported negative results (but did not use serological endpoints), except for two trials in Greece and India that reported positive results but had few endpoints and included endpoints that were not laboratory confirmed. The enhanced antibody production is in agreement with prior mechanistic studies but did not translate into protection from SARS-CoV-2 infection.

Reduced Antibody Acquisition with Increasing Age following Vaccination with BNT162b2: Results from Two Longitudinal Cohort Studies in The Netherlands.

Vaccine-induced protection against severe COVID-19, hospitalization, and death is of the utmost importance, especially in the elderly. However, limited data are available on humoral immune responses following COVID-19 vaccination in the general population across a broad age range. We performed an integrated analysis of the effect of age, sex, and prior SARS-CoV-2 infection on Spike S1-specific (S1) IgG concentrations up to three months post-BNT162b2 (Pfizer/BioNTech; Comirnaty) vaccination. In total, 1735 persons, eligible for COVID-19 vaccination through the national program, were recruited from the general population (12 to 92 years old). Sixty percent were female, and the median vaccination interval was 35 days (interquartile range, IQR: 35−35). All participants had seroconverted to S1 one month after two vaccine doses. S1 IgG was higher in participants with a history of SARS-CoV-2 infection (median: 4535 BAU/mL, IQR: 2341−7205) compared to infection-naive persons (1842 BAU/mL, 1019−3116), p < 0.001. In infection-naive persons, linear mixed effects regression showed a strong negative association between age and S1 IgG (p < 0.001) across the entire age range. Females had higher S1 IgG than males (p < 0.001). In persons with an infection history, age nor sex was associated with S1 IgG concentrations. The lower magnitude of S1 antibodies in older persons following COVID-19 vaccination will affect long-term protection.

Antibody Response in Immunocompromised Patients With Hematologic Cancers Who Received a 3-Dose mRNA-1273 Vaccination Schedule for COVID-19.

Importance: It has become common practice to offer immunocompromised patients with hematologic cancers a third COVID-19 vaccination dose, but data substantiating this are scarce. Objective: To assess whether a third mRNA-1273 vaccination is associated with increased neutralizing antibody concentrations in immunocompromised patients with hematologic cancers comparable to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. Design, Setting, and Participants: This prospective observational cohort study was conducted at 4 university hospitals in the Netherlands and included 584 evaluable patients spanning the spectrum of hematologic cancers and 44 randomly selected age-matched adults without malignant or immunodeficient comorbidities. Exposures: One additional mRNA-1273 vaccination 5 months after completion of the standard 2-dose mRNA-1273 vaccination schedule. Main Outcomes and Measures: Serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens prior to and 4 weeks after a third mRNA-1273 vaccination, and antibody neutralization capacity of wild-type, Delta, and Omicron variants in a subgroup of patients. Results: In this cohort of 584 immunocompromised patients with hematologic cancers (mean [SD] age, 60 [11.2] years; 216 [37.0%] women), a third mRNA-1273 vaccination was associated with median S1-IgG concentrations comparable to concentrations obtained by healthy individuals after the 2-dose mRNA-1273 schedule. The rise in S1-IgG concentration after the third vaccination was most pronounced in patients with a recovering immune system, but potent responses were also observed in patients with persistent immunodeficiencies. Specifically, patients with myeloid cancers or multiple myeloma and recipients of autologous or allogeneic hematopoietic cell transplantation (HCT) reached median S1-IgG concentrations similar to those obtained by healthy individuals after a 2-dose schedule. Patients receiving or shortly after completing anti-CD20 therapy, CD19-directed chimeric antigen receptor T-cell therapy recipients, and patients with chronic lymphocytic leukemia receiving ibrutinib were less responsive or unresponsive to the third vaccination. In the 27 patients who received cell therapy between the second and third vaccination, S1 antibodies were preserved, but a third mRNA-1273 vaccination was not associated with significantly enhanced S1-IgG concentrations except for patients with multiple myeloma receiving autologous HCT. A third vaccination was associated with significantly improved neutralization capacity per antibody. Conclusions and Relevance: Results of this cohort study support that the primary schedule for immunocompromised patients with hematologic cancers should be supplemented with a delayed third vaccination. Patients with B-cell lymphoma and allogeneic HCT recipients need to be revaccinated after treatment or transplantation. Trial Registration: EudraCT Identifier: 2021-001072-41.

Effect of early two-dose measles vaccination on childhood mortality and modification by maternal measles antibody in Guinea-Bissau, West Africa: A single-centre open-label randomised controlled trial.

Background: Early 2-dose measles vaccine (MV) at 4 and 9 months of age vs. the WHO strategy of MV at 9 months of age reduced all-cause child mortality in a previous trial. We aimed to test two hypotheses: 1) a 2-dose strategy reduces child mortality between 4 and 60 months of age by 30%; 2) receiving early MV at 4 months in the presence versus absence of maternal measles antibodies (MatAb) reduces child mortality by 35%. Methods: Single-centre open-label community-based randomised controlled trial in Guinea-Bissau, with 2:1 block-randomisation by sex to a 2-dose (4 + 9 months) vs. 1-dose (9 months) MV strategy. Healthy children were eligible 4 weeks after the 3rd diphtheria-tetanus-pertussis-containing vaccine. Before randomisation a blood sample was collected to determine MatAb level. The primary outcome was all-cause mortality. Hazard ratios (HR) were derived from Cox regression in the per protocol population. We tested for interactions with national campaigns with oral polio vaccine (C-OPV). Trial registration: NCT01486355. Findings: Between August 2011-April 17th 2015, 6,636 children were enroled, 6,598[n2-dose=4,397; n1-dose=2,201] were included in the analysis of the primary outcome, The HR(2-dose/1-dose) between 4 and 60 months was 1.38 (95%CI: 0.92-2.06) [deaths: n2-dose=90; n1-dose=33]. Before the 9-month MV and the HR(1-dose/no dose) was 0.94 (0.45-1.96) [deaths: n2-dose=21; n1-dose=11]. The HR(2-dose/1-dose) was 0.81 (0.29-2.22) for children, who received no C-OPV [deaths/children: n2-dose=10/2,801; n1-dose=6/1,365], and 4.73 (1.44-15.6) for children, who received C-OPV before and after enrolment (p for interaction=0.027) [deaths/children: n2-dose=27/1,602; n1-dose=3/837]. In the 2-dose group receiving early MV at 4 months, mortality was 50% (20-68%) lower for those vaccinated in the presence of MatAb vs. the absence of MatAb [deaths/children: nMatAb=51/3,132; nnoMatAb=31/1,028]. Interpretation: The main result contrasts with previous findings but may, though based on a small number of events, be explained by frequent OPV campaigns that reduced the mortality rate, but apparently interacted negatively with early MV. The beneficial non-specific effects of MV in the presence of MatAb should be investigated further. Funding: ERC, Danish National Research Foundation, the Danish Council for Development Research, Ministry of Foreign Affairs, Novo Nordisk Foundation, European Union and the Lundbeck Foundation.

SARS-CoV-2 Spike S1-specific IgG kinetic profiles following mRNA or vector-based vaccination in the general Dutch population show distinct kinetics.

mRNA- and vector-based vaccines are used at a large scale to prevent COVID-19. We compared Spike S1-specific (S1) IgG antibodies after vaccination with mRNA-based (Comirnaty, Spikevax) or vector-based (Janssen, Vaxzevria) vaccines, using samples from a Dutch nationwide cohort. In adults 18-64 years old (n = 2412), the median vaccination interval between the two doses was 77 days for Vaxzevria (interquartile range, IQR: 69-77), 35 days (28-35) for Comirnaty and 33 days (28-35) for Spikevax. mRNA vaccines induced faster inclines and higher S1 antibodies compared to vector-based vaccines. For all vaccines, one dose resulted in boosting of S1 antibodies in adults with a history of SARS-CoV-2 infection. For Comirnaty, two to four months following the second dose (n = 196), S1 antibodies in adults aged 18-64 years old (436 BAU/mL, IQR: 328-891) were less variable and median concentrations higher compared to those in persons ≥ 80 years old (366, 177-743), but differences were not statistically significant (p > 0.100). Nearly all participants seroconverted following COVID-19 vaccination, including the aging population. These data confirm results from controlled vaccine trials in a general population, including vulnerable groups.

Seropositivity to Nucleoprotein to detect mild and asymptomatic SARS-CoV-2 infections: A complementary tool to detect breakthrough infections after COVID-19 vaccination?

BACKGROUND: With COVID-19 vaccine roll-out ongoing in many countries globally, monitoring of breakthrough infections is of great importance. Antibodies persist in the blood after a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Since COVID-19 vaccines induce immune response to the Spike protein of the virus, which is the main serosurveillance target to date, alternative targets should be explored to distinguish infection from vaccination. METHODS: Multiplex immunoassay data from 1,513 SARS-CoV-2 RT-qPCR-tested individuals (352 positive and 1,161 negative) without COVID-19 vaccination history were used to determine the accuracy of Nucleoprotein-specific immunoglobulin G (IgG) in detecting past SARS-CoV-2 infection. We also described Spike S1 and Nucleoprotein-specific IgG responses in 230 COVID-19 vaccinated individuals (Pfizer/BioNTech). RESULTS: The sensitivity of Nucleoprotein seropositivity was 85% (95% confidence interval: 80-90%) for mild COVID-19 in the first two months following symptom onset. Sensitivity was lower in asymptomatic individuals (67%, 50-81%). Participants who had experienced a SARS-CoV-2 infection up to 11 months preceding vaccination, as assessed by Spike S1 seropositivity or RT-qPCR, produced 2.7-fold higher median levels of IgG to Spike S1 ≥ 14 days after the first dose as compared to those unexposed to SARS-CoV-2 at ≥ 7 days after the second dose (p = 0.011). Nucleoprotein-specific IgG concentrations were not affected by vaccination in infection-naïve participants. CONCLUSIONS: Serological responses to Nucleoprotein may prove helpful in identifying SARS-CoV-2 infections after vaccination. Furthermore, it can help interpret IgG to Spike S1 after COVID-19 vaccination as particularly high responses shortly after vaccination could be explained by prior exposure history.

Quantitative analysis of mRNA-1273 COVID-19 vaccination response in immunocompromised adult hematology patients.

Vaccination guidelines for patients treated for hematological diseases are typically conservative. Given their high risk for severe COVID-19, it is important to identify those patients that benefit from vaccination. We prospectively quantified serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens during and after 2-dose mRNA-1273 (Spikevax/Moderna) vaccination in hematology patients. Obtaining S1 IgG ≥ 300 binding antibody units (BAUs)/mL was considered adequate as it represents the lower level of S1 IgG concentration obtained in healthy individuals, and it correlates with potent virus neutralization. Selected patients (n = 723) were severely immunocompromised owing to their disease or treatment thereof. Nevertheless, >50% of patients obtained S1 IgG ≥ 300 BAUs/mL after 2-dose mRNA-1273. All patients with sickle cell disease or chronic myeloid leukemia obtained adequate antibody concentrations. Around 70% of patients with chronic graft-versus-host disease (cGVHD), multiple myeloma, or untreated chronic lymphocytic leukemia (CLL) obtained S1 IgG ≥ 300 BAUs/mL. Ruxolitinib or hypomethylating therapy but not high-dose chemotherapy blunted responses in myeloid malignancies. Responses in patients with lymphoma, patients with CLL on ibrutinib, and chimeric antigen receptor T-cell recipients were low. The minimal time interval after autologous hematopoietic cell transplantation (HCT) to reach adequate concentrations was <2 months for multiple myeloma, 8 months for lymphoma, and 4 to 6 months after allogeneic HCT. Serum IgG4, absolute B- and natural killer-cell number, and number of immunosuppressants predicted S1 IgG ≥ 300 BAUs/mL. Hematology patients on chemotherapy, shortly after HCT, or with cGVHD should not be precluded from vaccination. This trial was registered at Netherlands Trial Register as #NL9553.