Longitudinal analysis of antibody responses to the Pfizer BNT162b2 vaccine in Patients Undergoing Maintenance Hemodialysis

BackgroundHemodialyzed patients are at higher risk for COVID-19 and were prioritized in the Portuguese vaccination campaign MethodsWe performed a prospective, longitudinal, cohort analysis of 143 patients on hemodialysis and 143 age-matched controls along BTN162b2 vaccination. ELISA quantified anti-full-length Spike IgG, IgM and IgA levels prior to the first vaccine dose (t0); 3 weeks later (second dose, t1); and 3 weeks later (t2); 127 patients were re-evaluated140 (t3) and 180 days (t4) after the first dose. ResultsSeroconversion at t1 was remarkably low in patients, with positivity for anti-spike IgG, IgM and IgA antibodies of 29.4%, 12% and 41%, respectively, increasing to 90.9% (IgG) and 83.9% (IgA) in t2, (IgM remained unchanged). Below 70 years of age anti-spike IgG levels at t1 were significantly lower compared to age-matched controls and showed a profile similar to older individuals. Immunosuppression was associated with lower antibody responses (p=0.005 at t1; p=0.008 at t2). Previous unresponsiveness to hepatitis B vaccination (75/129, 58% of patients negative for anti-HBs antibodies) did not correlate with humoral unresponsiveness to BTN162b2. Anti-spike IgG, IgM and IgA positivity and antibody levels significantly decay at t3, with IgG levels showing further waning at t4. ConclusionsThe large majority of hemodialyzed patients showed IgG seroconversion upon BNT162b2 mRNA vaccination, albeit a sizable proportion of patients presented poor responses. Follow-up of antibody responses 180 days post vaccination unveiled significant decay of anti-spike antibodies and warrant close monitoring of COVID-19 infection and further studies on reinforced vaccination schedules in patients undergoing maintenance hemodialysis.

Amino acids 484 and 494 of SARS-CoV-2 spike are hotspots of immune evasion affecting antibody but not ACE2 binding

Understanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemics. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 (ACE2) recognition, a function of the viral protein spike. Mutations in spike impacting antibody and/or ACE2 binding are appearing worldwide, with the effect of mutation synergy still incompletely understood. We engineered 25 spike-pseudotyped lentiviruses containing individual and combined mutations, and confirmed that E484K evades antibody neutralization elicited by infection or vaccination, a capacity augmented when complemented by K417N and N501Y mutations. In silico analysis provided an explanation for E484K immune evasion. E484 frequently engages in interactions with antibodies but not with ACE2. Importantly, we identified a novel amino acid of concern, S494, which shares a similar pattern. Using the already circulating mutation S494P, we found that it reduces antibody neutralization of convalescent and post-immunization sera, particularly when combined with E484K and N501Y. Our analysis of synergic mutations provides a landscape for hotspots for immune evasion and for targets for therapies, vaccines and diagnostics. One-Sentence SummaryAmino acids in SARS-CoV-2 spike protein implicated in immune evasion are biased for binding to neutralizing antibodies but dispensable for binding the host receptor angiotensin-converting enzyme

Population homogeneity for the antibody response to COVID-19 Comirnaty vaccine is only reached after the second dose

While mRNA vaccines authorized for emergency use are administrated worldwide in an effort to contain the COVID19 crisis, little is known about the heterogeneity of the immune response they induce. Here, we report the first 6 weeks of a longitudinal study that quantifies the humoral immune response to BNT162b2 mRNA COVID-19 (Pfizer/BioNTech, Comirnaty) in 1245 health care providers, the Lx1000HCW-PZF cohort. We reveal a striking inter-individual variation 3 weeks after the 1st dose administration that only in part related to age and sex. While population homogeneity in robust IgG responses was reached upon 2nd dose administration, IgM and IgA levels remain low and heterogenous. Our findings of isotypic and heterogenous antibody responses to Comirnaty highlight the need for evaluating the efficacy of COVID-19 mRNA vaccine in preventing infection aside disease, and - contrary to what has been proposed - advocate for the interval between the two doses not to be extended.

Individual variation in susceptibility or exposure to SARS-CoV-2 lowers the herd immunity threshold

Individual variation in susceptibility and exposure is subject to selection by natural infection, accelerating the acquisition of immunity, and reducing herd immunity thresholds and epidemic final sizes. This is a manifestation of a wider population phenomenon known as "frailty variation". Despite theoretical understanding, public health policies continue to be guided by mathematical models that leave out considerable variation and as a result inflate projected disease burdens and overestimate the impact of interventions. Here we focus on trajectories of the coronavirus disease (COVID-19) pandemic in England and Scotland until November 2021. We fit models to series of daily deaths and infer relevant epidemiological parameters, including coefficients of variation and effects of non-pharmaceutical interventions which we find in agreement with independent empirical estimates based on contact surveys. Our estimates are robust to whether the analysed data series encompass one or two pandemic waves and enable projections compatible with subsequent dynamics. We conclude that vaccination programmes may have contributed modestly to the acquisition of herd immunity in populations with high levels of pre-existing naturally acquired immunity, while being critical to protect vulnerable individuals from severe outcomes as the virus becomes endemic. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/20081893v5_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@aeb87forg.highwire.dtl.DTLVardef@d2c441org.highwire.dtl.DTLVardef@152aeceorg.highwire.dtl.DTLVardef@1526779_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIVariation in susceptibility/exposure responds to selection by natural infection C_LIO_LISelection on susceptibility/exposure flattens epidemic curves C_LIO_LIModels with incomplete heterogeneity overestimate intervention impacts C_LIO_LIIndividual variation lowered the natural herd immunity threshold for SARS-CoV-2 C_LI

Entre Nós: Instituto Gulbenkian de Ciência

Uma conversa com Carlos Penha Gonçalves, investigador do Laboratório de Genética de Doenças no Instituto Gulbenkian de Ciência, em Oeiras. Referência Vídeográfica: Universidade Aberta - Entre Nós [Em linha] : Instituto Gulbenkian de Ciência. Realização de Vanda Caxeiro; Tecnóloga Helena Leão. Lisboa : Universidade Aberta, [2004]. 1 prog. vídeo (25 min., 12 seg.)

Association of BANK1 and cytokine gene polymorphisms with type 1 diabetes in Tunisia.

Type 1 diabetes (T1D) is an autoimmune disease (AID) with both genetic and environmental components. We aimed to investigate the genetic association of polymorphisms in genes previously linked with other AIDs, namely BANK1, IL15 and IL2/IL21 region. A total of 76 T1D patients and 162 controls from Southern Tunisia were recruited for a case-control association study investigating the relationship between sixteen SNPs of the BANK1, IL15 and IL2/IL21 gene region and T1D. In the BANK1 gene, G allele and GG genotype of rs3733197 were significantly increased in the group of T1D patients compared to controls. In addition, in the IL15 gene, the minor allele A of rs10519613 polymorphism was significantly higher in patients than in controls. No significant association was found for SNPS in IL2/IL21 gene region. The analysis of the haplotype structure revealed the G-C-A-C-T haplotype of the IL15 gene as associated with a reduction in the risk of developing T1D, while A-T-A-C-T haplotype increased the risk of developing the disease. Furthermore, in the IL2/IL21 region, only one haplotype consisting of eight SNPs was markedly associated with T1D susceptibility. Moreover, G-C combination of the BANK1/IL15 was significantly increased in T1D patients, compared to controls. Our results establish BANK1 and IL15 as new T1D genetic susceptibility factors and replicate the association of the 4q27 region with T1D. Our data agree with the effect previously observed for other autoimmune conditions and delineate a shared underlying mechanism.

Mapping of quantitative trait loci using the skew-normal distribution / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

In standard interval mapping (IM) of quantitative trait loci (QTL), the QTL effect is described by a normal mixture model. When this assumption of normality is violated, the most commonly adopted strategy is to use the previous model after data transformation. However, an appropriate transformation may not exist or may be difficult to find. Also this approach can raise interpretation issues. An interesting alternative is to consider a skew-normal mixture model in standard IM, and the resulting method is here denoted as skew-normal IM. This flexible model that includes the usual symmetric normal distribution as a special case is important, allowing continuous variation from normality to non-normality. In this paper we briefly introduce the main peculiarities of the skew-normal distribution. The maximum likelihood estimates of parameters of the skew-normal distribution are obtained by the expectation-maximization (EM) algorithm. The proposed model is illustrated with real data from an intercross experiment that shows a significant departure from the normality assumption. The performance of the skew-normal IM is assessed via stochastic simulation. The results indicate that the skew-normal IM has higher power for QTL detection and better precision of QTL location as compared to standard IM and nonparametric IM.