Exploring viral aetiology in upper respiratory tract infections: insights from metagenomic next-generation sequencing in Swiss outpatients before and during the SARS-CoV-2 pandemic.

AIMS OF THE STUDY: Upper respiratory tract infections are among the most common reasons for primary care consultations. They are diagnosed predominantly based on clinical assessment. Here, we investigated the benefit of viral metagenomic next-generation sequencing (mNGS) in an outpatient setting. METHODS: This prospective cross-sectional study included immunocompetent patients with acute upper respiratory tract infections. General practitioners collected pharyngeal swabs and demographic and clinical data. Specimens were analysed using viral mNGS and conventional tests. RESULTS: Two hundred seventy-seven patients were recruited by 21 general practitioners between 10/2019 and 12/2020, of which 91% had a suspected viral aetiology. For 138 patients (49.8%), mNGS identified one or more respiratory viruses. The mNGS showed a high overall agreement with conventional routine diagnostic tests. Rhinoviruses were the most frequently detected respiratory viruses (20.2% of patients). Viral mNGS reflected the influenza wave in early 2020 and the SARS-CoV-2 pandemic outbreak in Switzerland in March 2020. Notably, rhinoviruses continued to circulate despite non-pharmaceutical hygiene measures. CONCLUSIONS: Viral mNGS allowed the initial diagnosis to be retrospectively re-evaluated. Assuming reduced turnaround times, mNGS has the potential to directly guide the treatment of upper respiratory tract infections. On an epidemiological level, our study highlights the utility of mNGS in respiratory infection surveillance, allowing early detection of epidemics and providing information crucial for prevention.

How much should we sequence? An analysis of the Swiss SARS-CoV-2 surveillance effort.

During the SARS-CoV-2 pandemic, many countries directed substantial resources toward genomic surveillance to detect and track viral variants. There is a debate over how much sequencing effort is necessary in national surveillance programs for SARS-CoV-2 and future pandemic threats. We aimed to investigate the effect of reduced sequencing on surveillance outcomes in a large genomic data set from Switzerland, comprising more than 143k sequences. We employed a uniform downsampling strategy using 100 iterations each to investigate the effects of fewer available sequences on the surveillance outcomes: (i) first detection of variants of concern (VOCs), (ii) speed of introduction of VOCs, (iii) diversity of lineages, (iv) first cluster detection of VOCs, (v) density of active clusters, and (vi) geographic spread of clusters. The impact of downsampling on VOC detection is disparate for the three VOC lineages, but many outcomes including introduction and cluster detection could be recapitulated even with only 35% of the original sequencing effort. The effect on the observed speed of introduction and first detection of clusters was more sensitive to reduced sequencing effort for some VOCs, in particular Omicron and Delta, respectively. A genomic surveillance program needs a balance between societal benefits and costs. While the overall national dynamics of the pandemic could be recapitulated by a reduced sequencing effort, the effect is strongly lineage-dependent-something that is unknown at the time of sequencing-and comes at the cost of accuracy, in particular for tracking the emergence of potential VOCs.IMPORTANCESwitzerland had one of the most comprehensive genomic surveillance systems during the COVID-19 pandemic. Such programs need to strike a balance between societal benefits and program costs. Our study aims to answer the question: How would surveillance outcomes have changed had we sequenced less? We find that some outcomes but also certain viral lineages are more affected than others by sequencing less. However, sequencing to around a third of the original effort still captured many important outcomes for the variants of concern such as their first detection but affected more strongly other measures like the detection of first transmission clusters for some lineages. Our work highlights the importance of setting predefined targets for a national genomic surveillance program based on which sequencing effort should be determined. Additionally, the use of a centralized surveillance platform facilitates aggregating data on a national level for rapid public health responses as well as post-analyses.

Cross-protective HCoV immunity reduces symptom development during SARS-CoV-2 infection.

Numerous clinical parameters link to severe coronavirus disease 2019, but factors that prevent symptomatic disease remain unknown. We investigated the impact of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and endemic human coronavirus (HCoV) antibody responses on symptoms in a longitudinal children cohort (n = 2,917) and a cross-sectional cohort including children and adults (n = 882), all first exposed to SARS-CoV-2 (March 2020 to March 2021) in Switzerland. Saliva (n = 4,993) and plasma (n = 7,486) antibody reactivity to the four HCoVs (subunit S1 [S1]) and SARS-CoV-2 (S1, receptor binding domain, subunit S2 [S2], nucleocapsid protein) was determined along with neutralizing activity against SARS-CoV-2 Wuhan, Alpha, Delta, and Omicron (BA.2) in a subset of individuals. Inferred recent SARS-CoV-2 infection was associated with a strong correlation between mucosal and systemic SARS-CoV-2 anti-spike responses. Individuals with pre-existing HCoV-S1 reactivity exhibited significantly higher antibody responses to SARS-CoV-2 in both plasma (IgG regression coefficients = 0.20, 95% CI = [0.09, 0.32], P < 0.001) and saliva (IgG regression coefficient = 0.60, 95% CI = [0.088, 1.11], P = 0.025). Saliva neutralization activity was modest but surprisingly broad, retaining activity against Wuhan (median NT50 = 32.0, 1Q-3Q = [16.4, 50.2]), Alpha (median NT50 = 34.9, 1Q-3Q = [26.0, 46.6]), and Delta (median NT50 = 28.0, 1Q-3Q = [19.9, 41.7]). In line with a rapid mucosal defense triggered by cross-reactive HCoV immunity, asymptomatic individuals presented with higher pre-existing HCoV-S1 activity in plasma (IgG HKU1, odds ratio [OR] = 0.53, 95% CI = [0.29,0.97], P = 0.038) and saliva (total HCoV, OR = 0.55, 95% CI = [0.33, 0.91], P = 0.019) and higher SARS-CoV-2 reactivity in saliva (IgG S2 fold change = 1.26, 95% CI = [1.03, 1.54], P = 0.030). By investigating the systemic and mucosal immune responses to SARS-CoV-2 and HCoVs in a population without prior exposure to SARS-CoV-2 or vaccination, we identified specific antibody reactivities associated with lack of symptom development.IMPORTANCEKnowledge of the interplay between human coronavirus (HCoV) immunity and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection is critical to understanding the coexistence of current endemic coronaviruses and to building knowledge potential future zoonotic coronavirus transmissions. This study, which retrospectively analyzed a large cohort of individuals first exposed to SARS-CoV-2 in Switzerland in 2020-2021, revealed several key findings. Pre-existing HCoV immunity, particularly mucosal antibody responses, played a significant role in improving SARS-CoV-2 immune response upon infection and reducing symptoms development. Mucosal neutralizing activity against SARS-CoV-2, although low in magnitude, retained activity against SARS-CoV-2 variants underlining the importance of maintaining local mucosal immunity to SARS-CoV-2. While the cross-protective effect of HCoV immunity was not sufficient to block infection by SARS-CoV-2, the present study revealed a remarkable impact on limiting symptomatic disease. These findings support the feasibility of generating pan-protective coronavirus vaccines by inducing potent mucosal immune responses.

Deciphering factors linked with reduced SARS-CoV-2 susceptibility in the Swiss HIV Cohort Study.

BACKGROUND: Factors influencing susceptibility to SARS-CoV-2 remain to be resolved. Using data of the Swiss HIV Cohort Study (SHCS) on 6,270 people with HIV (PWH) and serologic assessment for SARS-CoV-2 and circulating-human-coronavirus (HCoV) antibodies, we investigated the association of HIV-related and general parameters with SARS-CoV-2 infection. METHODS: We analyzed SARS-CoV-2 PCR-tests, COVID-19 related hospitalizations, and deaths reported to the SHCS between January 1, 2020 and December 31, 2021. Antibodies to SARS-CoV-2 and HCoVs were determined in pre-pandemic (2019) and pandemic (2020) bio-banked plasma and compared to HIV-negative individuals. We applied logistic regression, conditional logistic regression, and Bayesian multivariate regression to identify determinants of SARS-CoV-2 infection and Ab responses to SARS-CoV-2 in PWH. RESULTS: No HIV-1-related factors were associated with SARS-CoV-2 acquisition. High pre-pandemic HCoV antibodies were associated with a lower risk of subsequent SARS-CoV-2 infection and with higher SARS-CoV-2 antibody responses upon infection. We observed a robust protective effect of smoking on SARS-CoV-2-infection risk (aOR= 0.46 [0.38,0.56], p=2.6*10-14), which occurred even in previous smokers, and was highest for heavy smokers. CONCLUSIONS: Our findings of two independent protective factors, smoking and HCoV antibodies, both affecting the respiratory environment, underscore the importance of the local immune milieu in regulating susceptibility to SARS-CoV-2.

Vaccinating people living with HIV: a fast track to preventive and therapeutic HIV vaccines.

Globally, the number of new HIV infections remains unacceptably high, and urgent new approaches are needed to advance HIV vaccine science. However, the development of a preventive HIV vaccine has proven to be an intractable scientific challenge. Recent advances in HIV immunogen design have taken the field a step closer to triggering the rare precursors of broadly neutralising antibodies, which are widely assumed to be necessary for a vaccine. Nonetheless, these same studies and previous studies in people living with HIV have also highlighted the major hurdles that must be overcome to boost the cross-reactivity and potency of these responses to sufficient levels. Here, we describe an opportunity for fast-tracking the evaluation of candidate preventive and therapeutic vaccines by immunising people with HIV who are antiretroviral therapy suppressed. We argue that such studies, unlike traditional studies of vaccines in participants not infected with HIV, will be faster and more informative and will allow the vaccine field to bypass multiple hurdles. This approach will accelerate the process of defining the capacity of immunogens to trigger relevant antibodies, currently an extremely slow and expensive pathway, and provide a quick path to creating an HIV vaccine.

Bridging the gap: identifying factors impacting mRNA severe acute respiratory syndrome coronavirus 2 vaccine booster response in people with HIV-1.

OBJECTIVES: This study aimed to investigate the association of demographic and clinical characteristics, including HIV-specific parameters with the antibody response to a third dose of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine in people with HIV-1 (PWH). DESIGN: Post hoc analysis of data collected during the observational extension of the COrona VaccinE tRiAL pLatform trial (COVERALL-2) nested into the Swiss HIV Cohort Study (SHCS). METHODS: Serological measurements were conducted on a total of 439 PWH who had received a third dose of either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) SARS-CoV-2 vaccine. Antibody reactivity was assessed using the multifactorial ABCORA immunoassay that defines SARS-CoV-2 seroconversion and predicts neutralization activity. The association between log transformed antibody reactivity and various baseline factors, including vaccine type, demographics, immune and viral status, smoking status, comorbidities, infection history, and co-medication with chemotherapy and immunosuppressive drugs, was investigated using a multivariable linear regression model. RESULTS: Antibody response to third SARS-CoV-2 vaccination was significantly lower among PWH with CD4 + cell count less than 350 cells/µl [ratio of means 0.79; 95% confidence interval (CI) 0.65-0.95]. Having a detectable HIV-1 viral load at least 50 copies/ml and being on concurrent chemotherapy was associated with an overall lower humoral immune response (ratio of means 0.75; 95% CI 0.57-1.00 and 0.34; 95% CI 0.22-0.52, respectively). CONCLUSION: The study highlights the importance of optimal antiretroviral treatment for PWH, emphasizing the need for timely intervention to enhance the vaccine immunogenicity in this population. Moreover, it underscores the significance of sequential mRNA vaccination and provides important evidence for informing vaccine guidelines.

Antibody Response After the Third SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients and People Living With HIV (COVERALL-2).

Background: After basic immunization with 2 mRNA SARS-CoV-2 vaccine doses, only a small proportion of patients who are severely immunocompromised generate a sufficient antibody response. Hence, we assessed the additional benefit of a third SARS-CoV-2 vaccine in patients with different levels of immunosuppression. Methods: In this observational extension of the COVERALL trial (Corona Vaccine Trial Platform), we recruited patients from the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study (ie, lung and kidney transplant recipients). We collected blood samples before and 8 weeks after the third SARS-CoV-2 vaccination with either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech). The primary outcome was the proportion of participants showing an antibody response (Elecsys Anti-SARS-CoV-2 S test; threshold ≥100 U/mL) 8 weeks after the third SARS-CoV-2 vaccination. We also compared the proportion of patients who reached the primary outcome from basic immunization (the first and second vaccines) to the third vaccination. Results: Nearly all participants (97.2% [95% CI, 95.9%-98.6%], 564/580) had an antibody response. This response was comparable between mRNA-1273 (96.1% [95% CI, 93.7%-98.6%], 245/255) and BNT162b2 (98.2% [95% CI, 96.7%-99.6%], 319/325). Stratification by cohort showed that 99.8% (502/503) of people living with HIV and 80.5% (62/77) of recipients of solid organ transplants achieved the primary endpoint. The proportion of patients with an antibody response in solid organ transplant recipients improved from the second vaccination (22.7%, 15/66) to the third (80.5%, 62/77). Conclusions: People living with HIV had a high antibody response. The third vaccine increased the proportion of solid organ transplant recipients with an antibody response. Clinical Trials Registration. NCT04805125 (ClinicalTrials.gov).

Assessing immunogenicity barriers of the HIV-1 envelope trimer.

Understanding the balance between epitope shielding and accessibility on HIV-1 envelope (Env) trimers is essential to guide immunogen selection for broadly neutralizing antibody (bnAb) based vaccines. To investigate the antigenic space of Env immunogens, we created a strategy based on synthetic, high diversity, Designed Ankyrin Repeat Protein (DARPin) libraries. We show that DARPin Antigenicity Analysis (DANA), a purely in vitro screening tool, has the capability to extrapolate relevant information of antigenic properties of Env immunogens. DANA screens of stabilized, soluble Env trimers revealed that stronger trimer stabilization led to the selection of highly mutated DARPins with length variations and framework mutations mirroring observations made for bnAbs. By mimicking heterotypic prime-boost immunization regimens, DANA may be used to select immunogen combinations that favor the selection of trimer-reactive binders. This positions DANA as a versatile strategy for distilling fundamental antigenic features of immunogens, complementary to preclinical immunogenicity testing.

Trapping the HIV-1 V3 loop in a helical conformation enables broad neutralization.

The third variable (V3) loop on the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein trimer is indispensable for virus cell entry. Conformational masking of V3 within the trimer allows efficient neutralization via V3 only by rare, broadly neutralizing glycan-dependent antibodies targeting the closed prefusion trimer but not by abundant antibodies that access the V3 crown on open trimers after CD4 attachment. Here, we report on a distinct category of V3-specific inhibitors based on designed ankyrin repeat protein (DARPin) technology that reinstitute the CD4-bound state as a key neutralization target with up to >90% breadth. Broadly neutralizing DARPins (bnDs) bound V3 solely on open envelope and recognized a four-turn amphipathic α-helix in the carboxy-terminal half of V3 (amino acids 314-324), which we termed 'αV3C'. The bnD contact surface on αV3C was as conserved as the CD4 binding site. Molecular dynamics and escape mutation analyses underscored the functional relevance of αV3C, highlighting the potential of αV3C-based inhibitors and, more generally, of postattachment inhibition of HIV-1.

Rapid and sensitive single-sample viral metagenomics using Nanopore Flongle sequencing.

The ability of viral metagenomic Next-Generation Sequencing (mNGS) to unbiasedly detect nucleic acids in a clinical sample is a powerful tool for advanced diagnosis of viral infections. When clinical symptoms do not provide a clear differential diagnosis, extensive laboratory testing with virus-specific PCR and serology can be replaced by a single viral mNGS analysis. However, widespread diagnostic use of viral mNGS is thus far limited by long sample-to-result times, as most protocols rely on Illumina sequencing, which provides high and accurate sequencing output but is time-consuming and expensive. Here, we describe the development of an mNGS protocol based on the more cost-effective Nanopore Flongle sequencing with decreased turnaround time and lower, yet sufficient sequencing output to provide sensitive virus detection. Sample preparation (6 h) and sequencing (2 h) times are substantially reduced compared to Illumina mNGS and allow detection of DNA/RNA viruses at low input (up to 33-38 cycle threshold of specific qPCR). Although Flongles yield lower sequencing output, direct comparison with Illumina mNGS on diverse clinical samples showed similar results. Collectively, the novel Nanopore mNGS approach is specifically tailored for use in clinical diagnostics and provides a rapid and cost-effective mNGS strategy for individual testing of severe cases.

Mechanisms and clinical relevance of the bidirectional relationship of viral infections with metabolic diseases.

Viruses have been present during all evolutionary steps on earth and have had a major effect on human history. Viral infections are still among the leading causes of death. Another public health concern is the increase of non-communicable metabolic diseases in the last four decades. In this Review, we revisit the scientific evidence supporting the presence of a strong bidirectional feedback loop between several viral infections and metabolic diseases. We discuss how viruses might lead to the development or progression of metabolic diseases and conversely, how metabolic diseases might increase the severity of a viral infection. Furthermore, we discuss the clinical relevance of the current evidence on the relationship between viral infections and metabolic disease and the present and future challenges that should be addressed by the scientific community and health authorities.

Seroprofiling of Antibodies Against Endemic Human Coronaviruses and Severe Acute Respiratory Syndrome Coronavirus 2 in a Human Immunodeficiency Virus Cohort in Lesotho: Correlates of Antibody Response and Seropositivity.

BACKGROUND: Serological data on endemic human coronaviruses (HCoVs) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in southern Africa are scarce. Here, we report on (1) endemic HCoV seasonality, (2) SARS-CoV-2 seroprevalence, and (3) correlates of SARS-CoV-2 seropositivity and strength of SARS-CoV-2 and endemic HCoV serological responses among adults living with human immunodeficiency virus (HIV). METHODS: Plasma samples were collected from February 2020 to July 2021 within an HIV cohort in Lesotho. We used the AntiBody CORonavirus Assay (ABCORA) multiplex immunoassay to measure antibody responses to endemic HCoV (OC43, HKU1, NL63, and 229E) and SARS-CoV-2 antigens. RESULTS: Results for 3173 samples from 1403 adults were included. Serological responses against endemic HCoVs increased over time and peaked in winter and spring. SARS-CoV-2 seropositivity reached >35% among samples collected in early 2021 and was associated with female sex, obesity, working outside the home, and recent tiredness or fever. Positive correlations were observed between the strength of response to endemic HCoVs and to SARS-CoV-2 and between older age or obesity and the immunoglobulin G response to SARS-CoV-2. CONCLUSIONS: These results add to our understanding of the impact of biological, clinical, and social/behavioral factors on serological responses to coronaviruses in southern Africa.

Antibody Response After Third Vaccination With mRNA-1273 or BNT162b2: Extension of a Randomized Controlled SARS-CoV-2 Noninferiority Vaccine Trial in Patients With Different Levels of Immunosuppression (COVERALL-2).

Extension of the COVERALL (COrona VaccinE tRiAL pLatform) randomized trial showed noninferiority in antibody response of the third dose of Moderna mRNA-1273 vaccine (95.3% [95% confidence interval {CI}, 91.9%-98.7%]) compared to Pfizer-BioNTech BNT162b2 vaccine (98.1% [95% CI, 95.9%-100.0%]) in individuals with different levels of immunosuppression (difference, -2.8% [95% CI, -6.8% to 1.3%]).

Antibody response to a third SARS-CoV-2 vaccine dose in recipients of an allogeneic haematopoietic cell transplantation.

Allogeneic haematopoietic cell transplantation (allo-HCT) recipients show impaired antibody (Ab) response to a standard two-dose vaccination against severe acute respiratory syndrome coronavirus-2 and currently a third dose is recommended as part of the primary vaccination regimen. By assessing Ab titres 1 month after a third mRNA vaccine dose in 74 allo-HCT recipients we show sufficient neutralisation activity in 77% of the patients. Discontinuation of immunosuppression before the third vaccine led to serological responses in 50% of low responders to two vaccinations. Identifying factors that might contribute to better vaccine responses in allo-HCT recipients is critical to optimise current vaccination strategies.

Swiss public health measures associated with reduced SARS-CoV-2 transmission using genome data.

Genome sequences from evolving infectious pathogens allow quantification of case introductions and local transmission dynamics. We sequenced 11,357 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from Switzerland in 2020-the sixth largest effort globally. Using a representative subset of these data, we estimated viral introductions to Switzerland and their persistence over the course of 2020. We contrasted these estimates with simple null models representing the absence of certain public health measures. We show that Switzerland's border closures decoupled case introductions from incidence in neighboring countries. Under a simple model, we estimate an 86 to 98% reduction in introductions during Switzerland's strictest border closures. Furthermore, the Swiss 2020 partial lockdown roughly halved the time for sampled introductions to die out. Last, we quantified local transmission dynamics once introductions into Switzerland occurred using a phylodynamic model. We found that transmission slowed 35 to 63% upon outbreak detection in summer 2020 but not in fall. This finding may indicate successful contact tracing over summer before overburdening in fall. The study highlights the added value of genome sequencing data for understanding transmission dynamics.

Alpha Variant Coronavirus Outbreak in a Nursing Home Despite High Vaccination Coverage: Molecular, Epidemiological, and Immunological Studies.

BACKGROUND: Vaccination may control the coronavirus disease 2019 (COVID-19) pandemic, including in nursing homes where many high-risk people live. We conducted extensive outbreak investigations. METHODS: We studied an outbreak at a nursing home in Switzerland, where the uptake of messenger RNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was 82% among residents as of 21 January 2021. After diagnosis of COVID-19 in a vaccinated symptomatic healthcare worker (HCW) on 22 February, we performed outbreak investigations in house A (47 residents; 37 HCWs), using SARS-CoV-2-specific polymerase chain reaction testing of nasopharyngeal swab samples. We performed whole-genome sequencing of SARS-CoV-2 and serological analyses. RESULTS: We identified 17 individuals with positive polymerase chain reaction results, 10 residents (5 vaccinated) and 7 HCWs (3 vaccinated). The median age (interquartile range) was 86 (70-90) years among residents and 49 (29-59) years among HCWs. Of the 5 vaccinated residents, 3 had mild disease and 2 had no symptoms, whereas all 5 unvaccinated residents had mild to severe disease, and 2 died. Vaccine effectiveness for the prevention of infection among residents was 73.0% (95% confidence interval, 24.7%-90.1%). The 12 available genomes were all alpha variants. Neutralizing titers were significantly higher in vaccinated individuals on reexposure (>1 week after diagnosis) than in vaccinated, unexposed HCWs (P = .01). Transmission networks indicated 4 likely or possible transmissions from vaccinated to other individuals and 12 transmission events from unvaccinated individuals. CONCLUSIONS: COVID-19 outbreaks can occur in nursing homes, including transmission from vaccinated persons to others. Outbreaks might occur silently, underlining the need for continued testing and basic infection control measures in these high-risk settings.

Long-term course of neutralising antibodies against SARS-CoV-2 in vaccinated and unvaccinated staff and residents in a Swiss nursing home: a cohort study 2021-2022.

BACKGROUND: Given their high-risk resident population, nursing homes were critical institutions in the COVID-19 pandemic, calling for continued monitoring and vaccine administration to healthcare workers and residents. Here, we studied long-term severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity in vaccinated and unvaccinated healthcare workers and residents of a nursing home in Switzerland between February 2021 and June 2022. METHODS: Our study comprised 45 participants, of which 39 were healthcare workers and six were residents. All participants were offered a maximum of three mRNA vaccine doses (Pfizer/BioNTech, BNT162b2) in December 2020, January 2021, and November/December 2021. Thirty-five participants received three vaccinations, seven either one or two, and three remained unvaccinated. We collected four blood samples: one in March 2021 and three during follow-ups in November 2021, February 2022, and June 2022. We performed a multifactorial serological SARS-CoV-2 assay (ABCORA) for immunoglobulin G, A, and M responses to spike (receptor-binding domain, S1, and S2) and nucleocapsid (N) proteins. Furthermore, we assessed predicted neutralisation activity based on signal over cutoff in ABCORA. We collected epidemiological data from participants via a standardised questionnaire. RESULTS: Thirty-two (71%) of the 45 participants showed hybrid immunity from combined vaccination and previous infection; 10 (22%) had only vaccine-induced immunity; and three (7%) had only post-infection immunity. Participants with hybrid immunity showed the highest predicted neutralisation activity at the end of the study period (median Sum S1 = 273), and unvaccinated participants showed the lowest (median Sum S1 = 41). Amongst participants who reported a SARS-CoV-2 infection, median Sum S1 levels increased with the number of vaccinations (p = 0.077). The healthcare worker group showed a significant time-dependent decrease in median Sum S1 after base immunisation (93% decrease, p = 0.0005) and the booster dose (26% decrease, p = 0.010). Predicted neutralisation activity was lower amongst residents (adjusted ratio of means [AM] = 0.7, 95% confidence interval [CI] = 0.3-1.0) and amongst smokers (AM = 0.5, 95% CI 0.3-0.8). Activity increased with the number of vaccinations (booster: AM = 3.6, 95% CI 1.5-8.8; no booster: AM = 2.3, 95% CI 0.9-2.5). Positive SARS-CoV-2 infection status tended to confer higher predicted neutralisation levels (AM = 1.5, 95% CI 0.9-2.5). CONCLUSIONS: Our study of the long-term serological course of SARS-CoV-2 in a nursing home showed that the first SARS-CoV-2 booster vaccine was essential for maintaining antiviral antibody levels. Hybrid immunity sustained SARS-CoV-2 immunity at the highest level. In critical settings such as nursing homes, monitoring the SARS-CoV-2 immune status may guide booster vaccinations.

Postvaccination anti-S IgG levels predict anti-SARS-CoV-2 neutralising activity over 24 weeks in patients with RA.

OBJECTIVES: To correlate immune responses following a two-dose regimen of mRNA anti-SARS-CoV-2 vaccines in patients with rheumatoid arthritis (RA) to the development of a potent neutralising antiviral activity. METHODS: The RECOVER study was a prospective, monocentric study including patients with RA and healthy controls (HCs). Assessments were performed before, and 3, 6, 12 and 24 weeks, after the first vaccine dose, respectively, and included IgG, IgA and IgM responses (against receptor binding domain, S1, S2, N), IFN-γ ELISpots as well as neutralisation assays. RESULTS: In patients with RA, IgG responses developed slower with lower peak titres compared with HC. Potent neutralising activity assessed by a SARS-CoV-2 pseudovirus neutralisation assay after 12 weeks was observed in all 21 HCs, and in 60.3% of 73 patients with RA. A significant correlation between peak anti-S IgG levels 2 weeks after the second vaccine dose and potent neutralising activity against SARS-CoV-2 was observed at weeks 12 and 24. The analysis of IgG, IgA and IgM isotype responses to different viral proteins demonstrated a delay in IgG but not in IgA and IgM responses. T cell responses were comparable in HC and patients with RA but declined earlier in patients with RA. CONCLUSION: In patients with RA, vaccine-induced IgG antibody levels were diminished, while IgA and IgM responses persisted, indicating a delayed isotype switch. Anti-S IgG levels 2 weeks after the second vaccine dose correlate with the development of a potent neutralising activity after 12 and 24 weeks and may allow to identify patients who might benefit from additional vaccine doses or prophylactic regimen.

Determinants of antibody response to severe acute respiratory syndrome coronavirus 2 mRNA vaccines in people with HIV.

We identified determinants of SARS-CoV-2 mRNA vaccine antibody response in people with HIV (PWH). Antibody response was higher among PWH less than 60 years, with CD4+ cell count superior to 350 cells/µl and vaccinated with mRNA-1273 by Moderna compared with BNT162b2 by Pfizer-BioNTech. Preinfection with SARS-CoV-2 boosted the antibody response and smokers had an overall lower antibody response. Elderly PWH and those with low CD4+ cell count should be prioritized for booster vaccinations.

Antibodies from convalescent plasma promote SARS-CoV-2 clearance in individuals with and without endogenous antibody response.

BACKGROUNDNeutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines. The manner in which human infections respond to therapeutic SARS-CoV-2 antibodies, including convalescent plasma therapy, remains to be fully elucidated.METHODSWe conducted a proof-of-principle study of convalescent plasma therapy based on a phase I trial in 30 hospitalized COVID-19 patients with a median interval between onset of symptoms and first transfusion of 9 days (IQR, 7-11.8 days). Comprehensive longitudinal monitoring of the virological, serological, and disease status of recipients allowed deciphering of parameters on which plasma therapy efficacy depends.RESULTSIn this trial, convalescent plasma therapy was safe as evidenced by the absence of transfusion-related adverse events and low mortality (3.3%). Treatment with highly neutralizing plasma was significantly associated with faster virus clearance, as demonstrated by Kaplan-Meier analysis (P = 0.034) and confirmed in a parametric survival model including viral load and comorbidity (adjusted hazard ratio, 3.0; 95% CI, 1.1-8.1; P = 0.026). The onset of endogenous neutralization affected viral clearance, but even after adjustment for their pretransfusion endogenous neutralization status, recipients benefitted from plasma therapy with high neutralizing antibodies (hazard ratio, 3.5; 95% CI, 1.1-11; P = 0.034).CONCLUSIONOur data demonstrate a clear impact of exogenous antibody therapy on the rapid clearance of viremia before and after onset of the endogenous neutralizing response, and point beyond antibody-based interventions to critical laboratory parameters for improved evaluation of current and future SARS-CoV-2 therapies.TRIAL REGISTRATIONClinicalTrials.gov NCT04869072.FUNDINGThis study was funded via an Innovation Pool project by the University Hospital Zurich; the Swiss Red Cross Glückskette Corona Funding; Pandemiefonds of the UZH Foundation; and the Clinical Research Priority Program "Comprehensive Genomic Pathogen Detection" of the University of Zurich.