Antiviral Antibody Responses Research Articles

Escalating Dose Immunization Regimen in Non-Human Primates to Improve Immunogen-Specific Responses

Abstract HIV-1 remains a major health threat, highlighting the need for a vaccine that induces broadly neutralizing antibodies. Epitope-based vaccine designs that focus humoral responses to vulnerable sites on the HIV-1 Env trimer protein are promising approaches, including those targeting the HIV-1 fusion peptide (FP). Escalating dose (ED) immunizations are a strategy to increase immunogen uptake into germinal centers and boost affinity maturation of the antiviral antibody response. In this study, we tested the impact of an ED immunization scheme on enhancing the FP-directed humoral response. Five groups of non-human primates were immunized: four received an ED immunization of either FP or a cocktail of FP+trimer, and one control group was dosed with a bolus FP+trimer cocktail. Two ED groups were adjuvanted with SMNP. The remaining groups used 3M052/alum. Fourteen weeks post-immunization, all ED groups had higher anti-FP IgG titers compared to the control, with the cocktail ED group adjuvanted with 3M052/alum characterized by 14.5-fold higher titers than the bolus control. While the ED cocktail and bolus groups had similar anti-trimer IgG titers, the ED groups had a higher non-base trimer response, shown by an 8.6-fold IgG increase between the 3M052/alum cocktail ED group and its bolus control. ED prime seems promising in raising anti-immunogen titers and lowering responses to the artificial trimer base, and further boosts will be administered to elicit serum neutralizing activity.

Minimal Determinants for Lifelong Antiviral Antibody Responses in Mice from a Single Exposure to Virus-like Immunogens at Low Doses.

The durability of an antibody (Ab) response is highly important for antiviral vaccines. However, due to the complex compositions of natural virions, the molecular determinants of Ab durability from viral infection or inactivated viral vaccines have been incompletely understood. Here we used a reductionist system of liposome-based virus-like structures to examine the durability of Abs from primary immune responses in mice. This system allowed us to independently vary fundamental viral attributes and to do so without additional adjuvants to model natural viruses. We show that a single injection of protein antigens (Ags) orderly displayed on a virion-sized liposome is sufficient to induce a long-lived neutralizing Ab (nAb) response. The introduction of internal nucleic acids dramatically modulates the magnitude of Ab responses without an alteration of the long-term kinetic trends. These Abs are characterized by very slow off-rates of ~0.0005 s-1, which emerged as early as day 5 after injection and these off-rates are comparable to that of affinity-matured monoclonal Abs. A single injection of these structures at doses as low as 100 ng led to lifelong nAb production in mice. Thus, a minimal virus-like immunogen can give rise to potent and long-lasting antiviral Abs in a primary response in mice without live infection. This has important implications for understanding both live viral infection and for optimizing vaccine design.

Studying the Humoral Response against SARS‐CoV‐2 in Cuban COVID‐19 Recovered Patients

Understanding the immune response generated by SARS‐CoV‐2 is critical for assessing efficient therapeutic protocols and gaining insights into the durability of protective immunity. The current work was aimed at studying the specific humoral responses against SARS‐CoV‐2 in Cuban COVID‐19 convalescents. We developed suitable tools and methods based on ELISA methodology, for supporting this evaluation. Here, we describe the development of an ELISA for the quantification of anti‐RBD IgG titers in a large number of samples and a similar test in the presence of NH4SCN as chaotropic agent for estimating the RBD specific antibody avidity. Additionally, a simple and rapid ELISA based on antibody‐mediated blockage of the binding RBD‐ACE2 was implemented for detecting, as a surrogate of conventional test, the levels of anti‐RBD inhibitory antibodies in convalescent sera. In a cohort of 273 unvaccinated convalescents, we identified higher anti‐RBD IgG titer (1 : 1,330, p < 0.0001) and higher levels of inhibitory antibodies blocking RBD‐ACE2 binding (1 : 216, p < 0.05) among those who had recovered from severe illness. Our results suggest that disease severity, and not demographic features such as age, sex, and skin color, is the main determinant of the magnitude and neutralizing ability of the anti‐RBD antibody response. An additional paired longitudinal assessment in 14 symptomatic convalescents revealed a decline in the antiviral antibody response and the persistence of neutralizing antibodies for at least 4 months after the onset of symptoms. Overall, SARS‐CoV‐2 infection elicits different levels of antibody response according to disease severity that declines over time and can be monitored using our homemade serological assays.

Immunosuppressants in dermatology on vaccine immunogenicity: a prospective cohort study of pemphigus patients in the pandemic.

Both cellular and humoral responses are important for vaccine protection, but recommendations on immunosuppressants in dermatology are largely based on pre-pandemic experiences. This study aimed to investigate the impacts of immunosuppressants on humoral and cellular immunogenicity to COVID-19 vaccinations in pemphigus patients. SARS-CoV-2-naïve pemphigus patients and age-, and sex-matched healthy controls were recruited from multiple tertiary medical centers during 2021-2023. Anti-spike protein-related T-cell responses, antibody titers, and high-parameter cell analysis of the peripheral blood were utilized to investigate the inhibitory effects of immunosuppressants, including rituximab and azathioprine. A total of 32 patients and 120 healthy controls were enrolled. COVID-19 vaccinations spaced at least six months after the last rituximab infusion did not cause a significant difference in anti-viral T-cell or antibody responses between rituximab-naïve and rituximab-treated patients. All pemphigus patients demonstrated improved antibody responses after the third vaccination and none of them suffered from severe COVID-19 illness. Intriguingly, we found that daily dosages of 100 mg or more of azathioprine were linked to significantly decreased anti-viral T-cell responses induced by the vaccination (mean of fold change [SD]; higher azathioprine dosage = 0.70 [0.61] folds vs. lower azathioprine dosage = 2.11 [1.03] folds; p = 0.044). Except for a subset of patients with unrecovered B-cell deficiency, rituximab infusion with proper scheduling of vaccination preserved better anti-viral T-cell responses and did not lead to hindered antibody responses in pemphigus patients. All pemphigus patients benefited from receiving the third booster regardless of B-cell status.

Transient Anti-Interferon Auto Antibodies in the Airway Are Associated with Recovery in Mild COVID-19

Pre-existing blood anti-interferon autoantibodies have been associated with susceptibility to severe COVID-19. However, nothing is known about the autoantibody response in the airway mucosa of mild to severe COVID-19 patients. We profiled longitudinal samples collected from the airway and matching blood of more than 100 donors over >18 months, spanning from mild COVID-19 to hospitalized patients in the ICU. We found that transiently induced anti-type I interferon autoantibodies in the nasal mucosa are a common feature and are associated with recovery from mild and moderate COVID-19. To quantify the breadth of antibody response in blood and the airway site of infection, we developed flowBEAT, a novel flow cytometry-based assay capable of simultaneously measuring all 8 human antibody isotypes against 22 SARS-CoV-2 structural and non-structural antigens, including autoantigens. We identified the induction of nasal anti-type I interferon autoantibodies within the first two weeks of infection, waning with disease recovery. Notably, there was an inverse association between nasal and blood anti-interferon responses, while nasal anti-interferon was linked to recovery in cases of mild/moderate disease. In contrast, near-ubiquitous anti-interferon in the endotracheal aspirates of critical cases correlated with heightened airway hyper-inflammation. In both blood and mucosa, anti-interferon positively correlated with a broad anti-viral antibody response, including non-structural proteins. While nasal anti-interferon was universally transient, we identified a group of donors sustaining long-term blood anti-interferon autoantibodies who may be at risk for a more severe subsequent viral infection. Within our longitudinal cohort, we assessed 500 infected-recovered and vaccinated samples and showed that nasal anti-SARS-CoV-2 antibodies are sustained over 18 months by repeated vaccination and boosting. We identified isotype signatures associated with disease severity and an autoantibody signature predictive of vaccine non-response. Thus, our findings emphasize the importance of continued vaccination/boosting to sustain nasal immunity and help prevent ongoing community spread. More importantly, our studies reveal predictive blood markers of protective nasal immunity and highlight a protective role for nasal anti-interferon autoantibodies in the immunopathology of COVID-19.

Designing Anti-Viral Vaccines that Harness Intrastructural Help from Prior BCG Vaccination.

Vaccines are among the most effective tools for combatting the impact and spread of infectious diseases. However, the effectiveness of a vaccine can be diminished by vaccine inequality, particularly during severe outbreaks of infectious diseases in resource-poor areas. As seen in many developing countries that lack adequate healthcare infrastructure and economic resources, the acquisition and distribution of potentially life-saving vaccines may be limited, leading to prolonged suffering and increased deaths. To improve vaccine equity, vaccine design must take into consideration the logistics needed to implement a successful vaccination drive, particularly among the most vulnerable populations. In the manuscript titled "Exploiting Pre-Existing CD4+ T Cell Help from Bacille Calmette-Guérin Vaccination to Improve Antiviral Antibody Responses" published in the Journal of Immunology, the authors designed a recombinant subunit vaccine against the Ebola virus (EBOV) glycoprotein that can harness the pre-existing T helper cells from prior BCG vaccination. As a recombinant subunit vaccine adjuvanted with alum, this approach has many features that make it well suited for the design of vaccines for developing nations, such as relative ease of production, scalability, and distribution. In addition, the high prevalence of BCG immunization and natural immunity to mycobacteria in many regions of the world endow such vaccines with features that should increase potency and efficacy among populations residing in such regions. As a result of using the helper activity of pre-existing BCG-specific Th cells to drive antibody responses, a lower vaccine dose is needed, which is a major advantage for vaccine manufacture. Furthermore, the BCG-specific Th cells also stimulate immunoglobulin class switching to IgG isotypes that have strong affinities for activating Fc-gamma receptors (FcγRs). Taken together, we propose that the design of subunit vaccines with intrastructural help from BCG-specific Th cells can improve protection against viral infection and represents a vaccine design that can be generally adapted to other emerging viral pathogens for the control and prevention of infection in many developing countries.

Viral co-infection, autoimmunity, and CSF HIV antibody profiles in HIV central nervous system escape

Antiretroviral therapy (ART) suppresses plasma and cerebrospinal fluid (CSF) HIV replication. Neurosymptomatic (NS) CSF escape is a rare exception in which CNS HIV replication occurs in the setting of neurologic impairment. The origins of NS escape are not fully understood. We performed a case-control study of asymptomatic (AS) escape and NS escape subjects with HIV-negative subjects as controls in which we investigated differential immunoreactivity to self-antigens in the CSF of NS escape by employing neuroanatomic CSF immunostaining and massively multiplexed self-antigen serology (PhIP-Seq). Additionally, we utilized pan-viral serology (VirScan) to deeply profile the CSF anti-viral antibody response and metagenomic next-generation sequencing (mNGS) for pathogen detection. We detected Epstein-Barr virus (EBV) DNA more frequently in the CSF of NS escape subjects than in AS escape subjects. Based on immunostaining and PhIP-Seq, there was evidence for increased immunoreactivity against self-antigens in NS escape CSF. Finally, VirScan revealed several immunodominant epitopes that map to the HIV envelope and gag proteins in the CSF of AS and NS escape subjects. Whether these additional inflammatory markers are byproducts of an HIV-driven process or whether they independently contribute to the neuropathogenesis of NS escape will require further study.

Antibody Responses Against Emerging SARS-CoV-2 Omicron Lineages After the Fourth Dose of mRNA Vaccine in Kidney Transplant Recipients.

Antibody Responses Against Emerging SARS-CoV-2 Omicron Lineages After the Fourth Dose of mRNA Vaccine in Kidney Transplant Recipients.

Antiviral and autoimmune antibody levels for two years post SAR-CoV-2 infection show uniquely durable vaccination responses and partial waning of self-reactive IgG

Abstract As temporal distance from the start of the COVID-19 pandemic increases, there is mounting concern of the long-term immunological consequences of SARS-CoV-2 infection(s). Abnormally high levels of a panoply of autoantibodies are found during acute COVID-19, and to date it is still unclear if these antibodies are sustained for a year or longer post-infection. Additionally, if there is improved longevity of vaccine-induced antibodies when administered against the immune backdrop of previous SARS-CoV-2 infection remains to be elucidated. To address these questions, we measured a series of anti-viral and autoimmune antibodies from samples taken at intervals from seven subjects infected with SARS-CoV-2 in the spring of 2020 (five outpatient and two hospitalized). Blood draws were performed beginning at acute disease and for an additional 10–25 months. Plasma IgG and IgA antibodies reactive with SARS-CoV-2 spike, RBD, and nucleocapsid, as well as CMV Mosaic, EBV GP 350, and Flu H1 were measured using the BU ELISA protocol, autoantibodies to self-antigens associated with connective tissue disease were measured using a commercial kit. Anti-viral antibody responses induced by vaccination were sustained for more than one year post SARS-CoV-2 infection in multiple subjects. Autoantibody trajectories varied, with many positive ‘hits’ falling below baseline after 1 year, and others remaining high for all time points measured. Future work will include increasing subject numbers to a larger cohort with differing clinical presentations and outcomes to define connections between serological signatures, protection from re-infection, and PASC. Supported by grants from CTSI Pilot grant (NIH/NCATS 5UL1TR001430-05), BU Internal Funding, MassCPR PASC Subaward #FP-0034311, and NIH R01 AG065050-01A1

BBIBP-CorV vaccination accelerates anti-viral antibody responses in heterologous Omicron infection: A retrospective observation study in Shanghai.

To investigate how BBIBP-CorV vaccination affecting antibody responses upon heterologous Omicron infection. 440 Omicron-infected patients were recruited in this study. Antibodies targeting SARS-CoV-2 spike protein receptor binding domain (RBD) and nucleoprotein of both wild-type (WT) and Omicron were detected by ELISA. The clinical relevance was further analyzed. BBIBP-CorV vaccinated patients exhibited higher anti-RBD IgG levels targeting both WT and Omicron than non-vaccinated patients at different stages. By using a 3-day moving average analysis, we found that BBIBP-CorV vaccinated patients exhibited the increases in both anti-WT and Omicron RBD IgG from the onset and reached the plateau at Day 8 whereas those in non-vaccinated patients remained low during the disease. Significant increase in anti-WT RBD IgA was observed only in vaccinated patients. anti-Omicron RBD IgA levels remained low in both vaccinated and non-vaccinated patients. Clinically, severe COVID-19 only occurred in non-vaccinated group. anti-RBD IgG and IgA targeting both WT and Omicron were negatively correlated with virus load, hospitalization days and virus elimination in vaccinated patients. BBIBP-CorV vaccination effectively reduces the severity of Omicron infected patients. The existence of humoral memory responses established through BBIBP-CorV vaccination facilitates to induce rapid recall antibody responses when encountering SARS-CoV-2 variant infection.

Accentuating the detection of immunological signatures as a diagnostic tool for monkeypox virus.

Dear Editor, The WHO declared the recent monkeypox surge as a Public Health Emergency of International Concern on 23 July 2022. Rapid measures are being taken in terms of diagnosis, immunization, treatment and management of the disease to prevent another catastrophe. Although monkeypox disease is not proven to be fatal for majority of the people, early diagnosis and appropriate therapeutic regiment has to be followed to curb the transmission of virus. Currently, the predominant diagnostic test performed is the Centers for Disease Control and Prevention (CDC)’s Nonvariola-Orthopox Virus PCR test using samples of skin lesions1. Such invasive methods pose the risk of infection, contamination and reluctant behaviour from patients and healthcare staff while obtaining the sample. This raises the need for a simple, feasible yet accurate mode of detection such as blood or other body fluid investigations. But there is lack of evidence on the use of blood, saliva or other body secretions for detection and confirmation of virus. This article explores the available literature on the detection of immunological signatures in blood as a probable testing method for diagnosing monkeypox virus. The altered kinetics in antiviral antibody response is evident among the confirmed cases of monkeypox disease indicating a significant association between onset of rashes and pattern of rise of immunoglobulins (Igs) in patients’ sera. The viral culture results and PCR finding were found to be were consistent with the seroconversion of Igs. IgM enzyme-linked immunosorbent assay and IgG enzyme-linked immunosorbent assay were thus efficient as diagnostic indicators and phase-of-illness indicators of monkeypox infection2. In addition to this, comparing the serum signatures between monkeypox infected monkey and human cell lines, a characteristic elevation of cluster of differentiation (CD) 40, plasmin and histamine was seen in monkey cell lines, while interferons macrophages and neutrophil-related signalling pathways were predominant in human cell lines3. However, these findings have not been studied in a larger cohort and hence require more intense clinical research to establish these biological constituents as immunological signatures of monkeypox disease. Monkeypox disease has also been strongly associated with early T-cell response and increased inflammatory mediators. An early elevation of CD8+ T cells and reduction in CD4+ T cells is seen in patients with monkeypox virus. This is combined with high expression of CD38 activation marker. This elevated T-cell pattern was found to be normalized within 12–20 days from the onset of symptoms. Inflammatory markers such as interleukins, particularly IL-6, IL-8, IL-16 and tumour necrosis factor are also found to be elevated in these patients. A specific characteristic finding was the detection of Th-1 biased pox-specific T cells in the serum. This antigen specific finding was almost predominant in all of the patients diagnosed with monkeypox virus4,5. Although these studies have provided information about the use of immune markers in detection of monkeypox, the laboratory method of using these immunological signatures for diagnosing monkeypox and disease progression is still at its nascent stage. The detection of immune markers in patient’s serum to identify monkeypox disease will improve the quality and efficacy of testing when compared with conventional skin lesion sampling. Thus, we emphasize on conducting more clinical trials and evidence-based studies to make such immune signatures reliable and accurate for disease detection. Ethical approval Not applicable. Sources of funding None. Authors’ contribution V.P.V.: conceptualization, data curation, writing – original draft preparation. L.P., S.P., J.N.B., U.M.: data curation, writing – original draft preparation. K.M.S.: conceptualization, study design, data curation, writing – original draft preparation, reviewing and editing, visualization and supervision. Conflicts of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number (UIN) Not applicable. Guarantor Krishna Mohan Surapaneni.

Durable spike-specific T cell responses after different COVID-19 vaccination regimens are not further enhanced by booster vaccination.

Several COVID-19 vaccines are approved to prevent severe disease outcome after SARS-CoV-2 infection. Whereas induction and functionality of antiviral antibody response are largely studied, the induction of T cells upon vaccination with the different approved COVID-19 vaccines is less studied. Here, we report on T cell immunity 4 weeks and 6 months after different vaccination regimens and 4 weeks after an additional booster vaccination in comparison with SARS-CoV-2T cell responses in convalescents and prepandemic donors using interferon-gamma ELISpot assays and flow cytometry. Increased T cell responses and cross-recognition of B.1.1.529 Omicron variant-specific mutations were observed ex vivo in mRNA- and heterologous-vaccinated donors compared with vector-vaccinated donors. Nevertheless, potent expandability of T cells targeting the spike protein was observed for all vaccination regimens, with frequency, diversity, and the ability to produce several cytokines of vaccine-induced T cell responses comparable with those in convalescent donors. T cell responses for all vaccinated donors significantly exceeded preexisting cross-reactive T cell responses in prepandemic donors. Booster vaccination led to a significant increase in anti-spike IgG responses, which showed a marked decline 6months after complete vaccination. In contrast, T cell responses remained stable over time after complete vaccination with no significant effect of booster vaccination on T cell responses and cross-recognition of Omicron BA.1 and BA.2 mutations. This suggested that booster vaccination is of particular relevance for the amelioration of antibody response. Together, our work shows that different vaccination regimens induce broad and long-lasting spike-specific CD4+ and CD8+ T cell immunity to SARS-CoV-2.

Lymphatic coagulation and neutrophil extracellular traps in lung-draining lymph nodes of COVID-19 decedents

AbstractClinical manifestations of severe COVID-19 include coagulopathies that are exacerbated by the formation of neutrophil extracellular traps (NETs). Here, we report that pulmonary lymphatic vessels, which traffic neutrophils and other immune cells to the lung-draining lymph node (LDLN), can also be blocked by fibrin clots in severe COVID-19. Immunostained tissue sections from COVID-19 decedents revealed widespread lymphatic clotting not only in the lung but also in the LDLN, where the extent of clotting correlated with the presence of abnormal, regressed, or missing germinal centers (GCs). It strongly correlated with the presence of intralymphatic NETs. In mice, tumor necrosis factor α induced intralymphatic fibrin clots; this could be inhibited by DNase I, which degrades NETs. In vitro, TNF-α induced lymphatic endothelial cell upregulation of ICAM-1 and CXCL8, among other neutrophil-recruiting factors, as well as thrombomodulin downregulation; in decedents, lymphatic clotting in LDLNs. In a separate cohort of hospitalized patients, serum levels of Myeloperoxidase-DNA (MPO-DNA, a NET marker) inversely correlated with antiviral antibody titers, but D-dimer levels, indicative of blood thrombosis, did not correlate with either. Patients with high MPO-DNA but low D-dimer levels generated poor antiviral antibody titers. This study introduces lymphatic coagulation in lungs and LDLNs as a clinical manifestation of severe COVID-19 and suggests the involvement of NETosis of lymphatic-trafficking neutrophils. It further suggests that lymphatic clotting may correlate with impaired formation or maintenance of GCs necessary for robust antiviral antibody responses, although further studies are needed to determine whether and how lymphatic coagulation affects adaptive immune responses.

Serological profiling of Crohn's disease and ulcerative colitis patients reveals anti-microbial antibody signatures.

BACKGROUNDThe healthcare burden of inflammatory bowel disease (IBD) is rising globally and there are limited non-invasive biomarkers for accurate and early diagnosis. AIMTo understand the important role that intestinal microbiota play in IBD pathogenesis and identify anti-microbial antibody signatures that benefit clinical management of IBD patients.METHODSWe performed serological profiling of 100 Crohn’s disease (CD) patients, 100 ulcerative colitis (UC) patients and 100 healthy controls against 1173 bacterial and 397 viral proteins from 50 bacteria and 33 viruses on protein microarrays. The study subjects were randomly divided into discovery (n = 150) and validation (n = 150) sets. Statistical analysis was performed using R packages. RESULTSAnti-bacterial antibody responses showed greater differential prevalence among the three subject groups than anti-viral antibody responses. We identified novel antibodies against the antigens of Bacteroidetes vulgatus (BVU_0562) and Streptococcus pneumoniae (SP_1992) showing higher prevalence in CD patients relative to healthy controls. We also identified antibodies against the antigen of Streptococcus pyogenes (SPy_2009) showing higher prevalence in healthy controls relative to UC patients. Using these novel antibodies, we built biomarker panels with area under the curve (AUC) of 0.81, 0.87, and 0.82 distinguishing CD vs control, UC vs control, and CD vs UC, respectively. Subgroup analysis revealed that penetrating CD behavior, colonic CD location, CD patients with a history of surgery, and extensive UC exhibited highest antibody prevalence among all patients. We demonstrated that autoantibodies and anti-microbial antibodies in CD patients had minimal correlation.CONCLUSIONWe have identified antibody signatures for CD and UC using a comprehensive analysis of anti-microbial antibody response in IBD. These antibodies and the source microorganisms of their target antigens improve our understanding of the role of specific microorganisms in IBD pathogenesis and, after future validation, should aid early and accurate diagnosis of IBD.

A bivalent CMV vaccine formulated with human compatible TLR9 agonist CpG1018 elicits potent cellular and humoral immunity in HLA expressing mice.

There is now convincing evidence that the successful development of an effective CMV vaccine will require improved formulation and adjuvant selection that is capable of inducing both humoral and cellular immune responses. Here, we have designed a novel bivalent subunit vaccine formulation based on CMV-encoded oligomeric glycoprotein B (gB) and polyepitope protein in combination with human compatible TLR9 agonist CpG1018. The polyepitope protein includes multiple minimal HLA class I-restricted CD8+ T cell epitopes from different antigens of CMV. This subunit vaccine generated durable anti-viral antibodies, CMV-specific CD4+ and CD8+ T cell responses in multiple HLA expressing mice. Antibody responses included broad TH1 isotypes (IgG2a, IgG2b and IgG3) and potently neutralized CMV infection in fibroblasts and epithelial cells. Furthermore, polyfunctional antigen-specific T cell immunity and antiviral antibody responses showed long-term memory maintenance. These observations argue that this novel vaccine strategy, if applied to humans, could facilitate the generation of robust humoral and cellular immune responses which may be more effective in preventing CMV-associated complications in various clinical settings.

COVID-19 in patients with hematologic malignancy

AbstractThe coronavirus infectious disease (COVID-19) shows a remarkable symptomatic heterogeneity. Several risk factors including advanced age, previous illnesses, and a compromised immune system contribute to an unfavorable outcome. In patients with hematologic malignancy, the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is significantly reduced explaining why the mortality rate of hematologic patients hospitalized for a SARS-CoV-2 infection is about 34%. Active immunization is an essential pillar to prevent SARS-CoV-2 infections in patients with hematologic malignancy. However, the immune response to SARS-CoV-2 vaccines may be significantly impaired, as only half of patients with hematologic malignancy develop a measurable antiviral antibody response. The subtype of hematologic malignancy and B cell–depleting treatment predict a poor immune response to vaccination. Recently, antiviral drugs and monoclonal antibodies for pre-exposure or postexposure prophylaxis and for early treatment of COVID-19 have become available. These therapies should be offered to patients at high risk for severe COVID-19 and vaccine nonresponders. Importantly, as the virus evolves, some therapies may lose their clinical efficacy against new variants. Therefore, the ongoing pandemic will remain a major challenge for patients with hematologic malignancy and their caregivers who need to constantly monitor the scientific progress in this area.

Sex differences in B cell frequencies and antibody responses following influenza vaccination in healthcare workers during the 2019–2020 season

Abstract Annual influenza vaccination for healthcare workers (HCWs) is required at Johns Hopkins to reduce influenza spread in healthcare facilities. We conducted a clinical study to evaluate sex differences in virus-specific antibody-producing B cells (i.e., plasmablasts) following receipt of the seasonal influenza vaccine in a highly vaccinated population of healthcare workers. To understand sex differences in immune responses to the influenza vaccine in the HCWs, 83 participants consented to blood draws at baseline and 75 participants returned for the 7- and 28-days post-vaccination survey and blood draw. Participants received their annual quadrivalent influenza vaccine (QIV). Influenza A specific plasmablasts were quantified at baseline and day 7 post-vaccination. Males had a significantly greater percentage of influenza-specific plasmablasts than females after vaccination (p<0.0003) Plasma collected at baseline and at day 28 post-vaccination was used to measure neutralizing antibody (nAb) titers against H1N1 and H3N2 vaccine viruses. Neutralizing antibody responses against either the H1N1 and H3N2 viruses increase after vaccination to the same degree in both males and females. The proportion of plasmablasts at day 7 was significantly associated with the vaccine-induced fold rise in nAb. This relationship differed by sex, whereby for a given proportion of plasmablasts, females tended to mount a greater fold-rise in nAb than males. These data suggest that despite having potentially fewer plasmablasts after vaccination, females mount an antiviral antibody response to the influenza vaccine viruses equivalent to males. Identification of transcriptional differences in plasmablasts from male and female HCWs is ongoing.

COVID-19: Omicron - the latest, the least virulent, but probably not the last variant of concern of SARS-CoV-2.

SummaryThe Omicron variant rapidly became the dominant SARS‐CoV‐2 strain in South Africa and elsewhere. This review explores whether this rise was due to an increased transmission of the variant or its escape from population immunity by an extensively mutated spike protein. The mutations affected the structure of the spike protein leading to the loss of neutralization by most, but not all, therapeutic monoclonal antibodies. Omicron also shows substantial immune escape from serum antibodies in convalescent patients and vaccinees. A booster immunization increased, however, the titre and breadth of antiviral antibody response. The cellular immune response against Omicron was largely preserved explaining a satisfying protection of boosted vaccinees against severe infections. Clinicians observed less severe infection with Omicron, but other scientists warned that this must not necessarily reflect less intrinsic virulence. However, in animal experiments with mice and hamsters, Omicron infections also displayed a lesser virulence than previous VOCs and lung functions were less compromised. Cell biologists demonstrated that Omicron differs from Delta by preferring the endocytic pathway for cell entry over fusion with the plasma membrane which might explain Omicron’s distinct replication along the respiratory tract compared with Delta. Omicron represents a distinct evolutionary lineage that deviated from the mainstream of evolving SARS‐CoV‐2 already in mid‐2020 raising questions about where it circulated before getting widespread in December 2021. The role of Omicron for the future trajectory of the COVID‐19 pandemic is discussed.

The COVID-19 Humoral Immunological Status Induced by CoronaVac and AstraZeneca Vaccines Significantly Benefits from a Booster Shot with the Pfizer Vaccine.

ABSTRACTA third vaccine dose against COVID-19 is already a reality in some countries around the world. In this study, we aimed to evaluate the effectiveness of the Brazilian immunization policy for COVID-19, which involves a booster shot. Participants (n = 210) provided serum samples, which were subjected to enzyme-linked immunosorbent assay (ELISA). Immunological profiles were defined as individuals with or without previous SARS-CoV-2 infection who received at least one vaccine dose in the immunization regimens of AstraZeneca, CoronaVac, or CoronaVac plus a booster shot with Pfizer. In addition, nonvaccinated/infected individuals were also included. As main results, we observed that the numbers of infected individuals were significantly reduced among those who were vaccinated, even with one dose. This result indicates that vaccines are highly protective against COVID-19. However, we observed a significant tendency of serum level decreases of specific antibodies over the time after the second dose. In contrast, the booster shot with the Pfizer vaccine after a CoronaVac immunization regimen showed a significant increase in the specific SARS-CoV-2 IgG serum levels. Moreover, we found that vaccination induced a significantly higher humoral immunological status than only the natural infection with SARS-CoV-2. Collectively, results presented here indicate that vaccines are necessary to induce a robust immunological status, which is maintained, restored, or even improved by booster shots.IMPORTANCE COVID-19 continues to spread around the world despite significant progress in vaccine distribution and population immunity. The dynamics of the antiviral antibody response postvaccination is critical to evaluate vaccine effectiveness across different vaccine platforms and over time. In this study, we evaluate the serum levels of antiviral antibodies in patients from Brazil that received either the CoronaVac or the AstraZeneca vaccine. We found that antibody levels wane over time, vaccines induce protective immunity, and humoral immunity is enhanced with a third vaccine dose. This study reveals that the COVID-19 humoral immunological status induced by vaccines significantly benefits from a booster shot.

High-affinity, neutralizing antibodies to SARS-CoV-2 can be made without T follicular helper cells.

T follicular helper (TFH) cells are the conventional drivers of protective, germinal center (GC)–based antiviral antibody responses. However, loss of TFH cells and GCs has been observed in patients with severe COVID-19. As T cell–B cell interactions and immunoglobulin class switching still occur in these patients, noncanonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both TFH-dependent and -independent antibodies were induced against SARS-CoV-2 infection, SARS-CoV-2 vaccination, and influenza A virus infection. Although TFH-independent antibodies to SARS-CoV-2 had evidence of reduced somatic hypermutation, they were still high affinity, durable, and reactive against diverse spike-derived epitopes and were capable of neutralizing both homologous SARS-CoV-2 and the B.1.351 (beta) variant of concern. We found by epitope mapping and B cell receptor sequencing that TFH cells focused the B cell response, and therefore, in the absence of TFH cells, a more diverse clonal repertoire was maintained. These data support an alternative pathway for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GC-derived antibodies that might compensate for GCs damaged by viral inflammation.