The novel SARS-CoV-2 is a recently emerging virus causing a human pandemic. A great variety of symptoms associated with COVID-19 disease, ranging from mild to severe symptoms, eventually leading to ...death. Specific SARS-CoV-2 RT-PCR is the standard method to screen symptomatic people; however, asymptomatic subjects and subjects with undetectable viral load escape from the screening, contributing to viral spread. Currently, the lock down imposed by many governments is an important measure to contain the spread, as there is no specific antiviral therapy or a vaccine and the main treatments are supportive. Therefore, there is urgent need to characterize the virus and the viral-mediated responses, in order to develop specific diagnostic and therapeutic tools to prevent viral transmission and efficiently cure COVID-19 patients. Here, we review the current studies on two viral mediated-responses, specifically the cytokine storm occurring in a subset of patients and the antibody response triggered by the infection. Further studies are needed to explore both the dynamics and the mechanisms of the humoral immune response in COVID-19 patients, in order to guide future vaccine design and antibody-based therapies for the management of the disease.
Since its discovery 35 years ago, there have been no therapeutic interventions shown to enable full HIV-1 remission. Combined antiretroviral therapy (cART) has achieved the sustained control of HIV-1 ...replication, however, the life-long treatment does not eradicate long-lived latently infected reservoirs and can result in multiple side effects including the development of multidrug-resistant escape mutants. Antibody-based treatments have emerged as alternative approaches for a HIV-1 cure. Here, we will review clinical advances in coreceptor-targeting antibodies, with respect to anti-CCR5 antibodies in particular, which are currently being generated to target the early stages of infection. Among the Env-specific antibodies widely accepted as relevant in cure strategies, the potential role of those targeting CD4-induced (CD4i) epitopes of the CD4-binding site (CD4bs) in eliminating HIV-1 infected cells has gained increasing interest and will be presented. Together, with approaches targeting the HIV-1 replication cycle, we will discuss the strategies aimed at boosting and modulating specific HIV-1 immune responses, highlighting the harnessing of TLR agonists for their dual role as latency reverting agents (LRAs) and immune-modulatory compounds. The synergistic combinations of different approaches have shown promising results to ultimately enable a HIV-1 cure.
Currently, evaluation of the IgG antibodies specific for the SARS-CoV-2 Spike protein following vaccination is used worldwide to estimate vaccine response. Limited data are available on ...vaccine-elicited IgM antibodies and their potential implication in immunity to SARS-CoV-2.
We performed a longitudinal study to quantify anti-S SARS-CoV-2 IgG and IgM (IgG-S and IgM-S) in health care worker (HCW) recipients of the BNT162b2 vaccine. Samples were collected before administration (T0), at the second dose (T1) and three weeks after T1 (T2). The cohort included 1584 immunologically naïve to SARS-CoV-2 (IN) and 289 with history of previous infection (PI).
IN showed three patterns of responses: (a) IgG positive/IgM negative (36.1%), (b) coordinated IgM-S/IgG-S responses appearing at T1 (37.4%) and (c) IgM appearing after IgG (26.3%). Coordinated IgM-S/IgG-S responses were associated with higher IgG titres. In IgM-S positive PI, 64.5% were IgM-S positive before vaccination, whereas 32% and 3.5% developed IgM-S after the first and second vaccine dose, respectively. IgM-S positive sera had higher pseudovirus neutralization titres compared to the IgM-S negative.
Coordinated expression of IgG-S and IgM-S after vaccination was associated with a significantly more efficient response in both antibody levels and virus-neutralizing activity. The unconventional IgG-S positive/IgM-S negative responses may suggest a recruitment of cross coronaviruses immunity by vaccination, warranting further investigation.
Italian Ministry of Health under “Fondi Ricerca Corrente”- L1P5 and “Progetto Ricerca Finalizzata COVID-2020-12371675”; FUR 2020 Department of Excellence 2018-2022, MIUR, Italy; The Brain Research Foundation Verona.
COVID-19 vaccines have demonstrated effectiveness in reducing SARS-CoV-2 mild and severe outcomes. In vaccinated subjects with SARS-CoV-2 history, RBD-specific IgG and pseudovirus neutralization ...titers were rapidly recalled by a single BTN162b2 vaccine dose to higher levels than those in naïve recipients after the second dose, irrespective of waning immunity. In this study, we inspected the long-term kinetic and neutralizing responses of S-specific IgG induced by two administrations of BTN162b2 vaccine in infection-naïve subjects and in subjects previously infected with SARS-CoV-2.
Twenty-six naïve and 9 previously SARS-CoV-2 infected subjects during the second wave of the pandemic in Italy were enrolled for this study. The two groups had comparable demographic and clinical characteristics. By means of ELISA and pseudotyped-neutralization assays, we investigated the kinetics of developed IgG-RBD and their neutralizing activity against both the ancestral D614G and the SARS-CoV-2 variants of concern emerged later, respectively. The Wilcoxon matched pair signed rank test and the Kruskal-Wallis test with Dunn's correction for multiple comparison were applied when needed.
Although after 15 weeks from vaccination IgG-RBD dropped in all participants, naïve subjects experienced a more dramatic decline than those with previous SARS-CoV-2 infection. Neutralizing antibodies remained higher in subjects with SARS-CoV-2 history and conferred broad-spectrum protection.
These data suggest that hybrid immunity to SARS-CoV-2 has a relevant impact on the development of IgG-RBD upon vaccination. However, the rapid decay of vaccination-elicited antibodies highlights that the administration of a third dose is expected to boost the response and acquire high levels of cross-neutralizing antibodies.
Recent studies showed that immunological tolerance may restrict the development of Env-specific autoreactive broadly neutralizing antibodies. This evidence is consistent with the finding that Env ...immunization of a systemic lupus erythematosus (SLE) murine model produced antibodies that neutralize tier 2 HIV-1 strains. In this study, we address the possibility of eliciting neutralizing anti-Env antibodies in other autoimmune diseases such as multiple sclerosis (MS). While, as reported for SLE, we showed for the first time that a small number of HIV-1 negative, relapsing remitting MS patients exhibited antibodies with neutralizing properties, our attempts at inducing those antibodies in a EAE mouse model of MS failed. The success in eliciting Env-specific neutralizing antibodies might be related to the specific characteristics of the autoimmune disease, or it might rely in improving the vaccination design. Studies using mouse models are useful to gain insight in how HIV-specific neutralizing antibody responses are regulated in order to develop a protective HIV-1 vaccine.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is primarily diagnosed through viral RNA positivity in nasopharyngeal swabs, and it is associated with the early detection of ...specific immunoglobulins to SARS-CoV-2 proteins. We describe two moderate coronavirus disease 2019 (COVID-19) patients with WHO score 4/5 at the time of hospitalization, pneumonia, and oxygen saturation <94% and with a strong discrepancy between viral RNA and antibodies to SARS-CoV-2. One patient was positive for viral RNA but completely negative for binding and neutralizing antibodies, whereas the second patient was negative for viral RNA but with high levels of both neutralizing and binding antibodies. This observation is relevant to better understand the pathogenesis of this novel infection.
The vasodilator neuropeptide calcitonin gene-related peptide (CGRP) plays both detrimental and protective roles in different pathologies. CGRP is also an essential component of the neuro-immune ...dialogue between nociceptors and mucosal immune cells. We previously discovered that CGRP is endowed with anti-viral activity and strongly inhibits human immunodeficiency virus type 1 (HIV-1) infection, by suppressing Langerhans cells (LCs)-mediated HIV-1 trans-infection
and mucosal HIV-1 transmission
. This inhibition is mediated
activation of the CGRP receptor non-canonical NFκB/STAT4 signaling pathway that induces a variety of cooperative mechanisms. These include CGRP-mediated increase in the expression of the LC-specific pathogen recognition C-type lectin langerin and decrease in LC-T-cell conjugates formation. The clinical utility of CGRP and modalities of CGRP receptor activation, for inhibition of mucosal HIV-1 transmission, remain elusive.
We tested the capacity of CGRP to inhibit HIV-1 infection
in humanized mice. We further compared the anti-HIV-1 activities of full-length native CGRP, its metabolically stable analogue SAX, and several CGRP peptide fragments containing its binding C-terminal and activating N-terminal regions. These agonists were evaluated for their capacity to inhibit LCs-mediated HIV-1 trans-infection
and mucosal HIV-1 transmission in human mucosal tissues
.
A single CGRP intravaginal topical treatment of humanized mice, followed by HIV-1 vaginal challenge, transiently restricts the increase in HIV-1 plasma viral loads but maintains long-lasting higher CD4+ T-cell counts. Similarly to CGRP, SAX inhibits LCs-mediated HIV-1 trans-infection
, but with lower potency. This inhibition is mediated
CGRP receptor activation, leading to increased expression of both langerin and STAT4 in LCs. In contrast, several N-terminal and N+C-terminal bivalent CGRP peptide fragments fail to increase langerin and STAT4, and accordingly lack anti-HIV-1 activities. Finally, like CGRP, treatment of human inner foreskin tissue explants with SAX, followed by polarized inoculation with cell-associated HIV-1, completely blocks formation of LC-T-cell conjugates and HIV-1 infection of T-cells.
Our results show that CGRP receptor activation by full-length CGRP or SAX is required for efficient inhibition of LCs-mediated mucosal HIV-1 transmission. These findings suggest that formulations containing CGRP, SAX and/or their optimized agonists/analogues could be harnessed for HIV-1 prevention.
This contribution explores in a new statistical perspective the antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 141 coronavirus disease 2019 (COVID-19) patients ...exhibiting a broad range of clinical manifestations. This cohort accurately reflects the characteristics of the first wave of the SARS-CoV-2 pandemic in Italy. We determined the IgM, IgA, and IgG levels towards SARS-CoV-2 S1, S2, and NP antigens, evaluating their neutralizing activity and relationship with clinical signatures. Moreover, we longitudinally followed 72 patients up to 9 months postsymptoms onset to study the persistence of the levels of antibodies. Our results showed that the majority of COVID-19 patients developed an early virus-specific antibody response. The magnitude and the neutralizing properties of the response were heterogeneous regardless of the severity of the disease. Antibody levels dropped over time, even though spike reactive IgG and IgA were still detectable up to 9 months. Early baseline antibody levels were key drivers of the subsequent antibody production and the long-lasting protection against SARS-CoV-2. Importantly, we identified anti-S1 IgA as a good surrogate marker to predict the clinical course of COVID-19. Characterizing the antibody response after SARS-CoV-2 infection is relevant for the early clinical management of patients as soon as they are diagnosed and for implementing the current vaccination strategies.
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